Foreword
We live in exciting times. Advances occur almost daily in the neurosciences, and their application to disorders of the neuromuscular apparatus is both challenging and rewarding. In recent years, the factors shaping the development of muscle and maintaining the function of its contractile apparatus have come to be better characterized. They reveal a level of complexity that is hard to imagine but exquisite in its detail, and provide a framework for understanding many of the disorders of muscle that are discussed in this volume of the Handbook of Clinical Neurology. Newly acquired knowledge of regulatory nuclear and mitochondrial genetic mechanisms, of the proteins involved in muscle function and their remarkable interactions, of the nature and function of ion channels and ionic activity, and of the complexity of inflammatory cascades has led to a wider appreciation of the nature of muscle diseases and suggested new approaches for their management. Many diseases, once considered to be distinct entities, are coming to be recognized as heterogeneous disorders that require different management strategies and have different prognostic implications depending on their underlying basis. Such is the pace of progress that it is difficult for clinicians and neuroscientists alike to keep abreast of developments in the field. Professors Frank Mastaglia and David Hilton-Jones, the editors of the present volume, are to be congratulated in bringing together a wide range of internationally acknowledged authorities to summarize these developments and their clinical implications. This ensures that this new volume will be an important and valuable resource for those interested in the fundamental aspects of muscle disease or involved in the care of patients with these disorders. A separate volume, however, is being devoted to the muscular dystrophies and is currently in preparation. We are grateful to the many authors who contributed their time and expertise to summarize developments in their field of interest and to Professors Mastaglia and Hilton-Jones for developing an outstanding volume that reflects the highest standards of scholarship and provides a critical appraisal and synthesis of current concepts concerning the acquired disorders of muscle. As series editors, we have each reviewed all of the chapters included in this volume and have been greatly impressed by their scope and implications. We are also proud that this new volume fully accords with our concept of the Handbook series in providing greater insight to the basic mechanisms of disease so that a greater appreciation is gained of the disorders encountered by clinicians. As always, we are also grateful to the team at Elsevier – and in particular to Ms Lynn Watt and Mr Michael Parkinson in Edinburgh – for their unfailing and expert assistance in the development and production of this volume. Michael J. Aminoff Francois Boller Dick F. Swaab
Preface
It has been 14 years since the first edition of this volume and during this time there have been many advances in the field of muscle diseases. These include the recognition and description of new clinical entities and improved classification of groups of disorders such as the distal myopathies, the discovery of disease-causing mutations for many of the muscular dystrophies and hereditary myopathies, and advances in our understanding of the molecular basis of these disorders. In addition, there have been improvements in the use of diagnostic techniques and new therapeutic directions have opened up, particularly in the treatment of the inflammatory myopathies as the underlying immunopathogenetic mechanisms have been elucidated. These new developments have brought with them an even greater level of sub-specialization in the field and have posed new challenges in terms of the availability of DNA testing for specific mutations and the organization of clinical and diagnostic services. The present volume brings together a group of international authorities in this field who have devoted their time and energy to producing comprehensive and up-to-date reviews of their topics. These cover the whole field of muscle diseases (with the exception of the muscular dystrophies which will be the subject of a separate volume) commencing with congenital muscle disorders in Chapter 1 and including a new chapter dealing with the biological changes and diseases associated with aging in Chapter 18. Other new chapters include those on mitochondrial myopathies and disorders of carbohydrate and lipid metabolism, hereditary inclusion body myopathies, lysosomal myopathies, malignant hyperthermia and muscle cramp syndromes. In addition, because of its importance as the foremost muscle disease associated with aging, a separate chapter has been devoted to sporadic inclusion body myositis, aspects of which are also dealt with in the chapters on inflammatory myopathies and ageing. We hope that this volume will provide a useful reference source for neurologists, myopathologists and other professionals dealing with this broad group of diseases and that it will provide them with guidance on the clinical investigation and management of such patients as well as the latest information on the pathological basis and molecular pathogenesis. As editors we have found this a challenging and rewarding project and we would like to express our gratitude to all of the contributing authors, to Ms Lynn Watt of Elsevier and to the Series Editors for their guidance and support in making it possible to bring this volume to fruition. Frank L. Mastaglia, MD David Hilton-Jones, MD
List of Contributors
O. Akman Department of Neurology, College of Physicians and Surgeons, New York, NY, USA
P.J. Halsall The Leeds MH Investigation Unit, St James’s University Hospital, Leeds, UK
Z. Argov Department of Neurology, Hadassah University Hospital, Jerusalem, Israel
M.G. Hanna Centre for Neuromuscular Disease, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust and Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK
L. Chimelli Department of Pathology, School of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil P.F. Chinnery Mitochondrial Research Group, School of Neurology, Neurobiology and Psychiatry, University of Newcastle upon Tyne, UK
A.P. Hays Department of Pathology, College of Physicians and Surgeons, New York, NY, USA
C. Angelini Department of Neurosciences, University of Padova, Padova, Italy
D. Hilton-Jones Muscular Dystrophy Campaign Muscle and Nerve Centre, Radcliffe Infirmary, Oxford, UK
M.C. Dalakas Neuromuscular Diseases Section, National Institutes of Health, Bethesda, MD, USA
K. Jurkatt-Rott Department of Applied Physiology, Ulm University, Ulm, Germany
M. de Visser Department of Neurology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
N.G. Laing Centre for Medical Research, University of Western Australia, West Australian Institute for Medical Research, Nedlands, Australia
S. DiMauro Department of Neurology, College of Physicians and Surgeons, New York, NY, USA D. Fialho Centre for Neuromuscular Disease, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust and Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK R.C. Griggs Department of Neurology, University of Rochester School of Medicine, Rochester, NY, USA
P. Lamont Neurogenetic Unit, Division of Neurosciences, Royal Perth Hospital, Perth, Australia F. Lehmann-Horn Department of Applied Physiology, Ulm University, Ulm, Germany F.L. Mastaglia Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Perth, Australia
xii
LIST OF CONTRIBUTORS
S. Mitrani-Rosenbaum Department of Neurology, Hadassah University Hospital, Jerusalem, Israel I. Nishino National Center of Neurology and Psychiatry, Tokyo, Japan A. Oldfors Sahlgrenska University Hospital, Go¨teborg, Sweden R.W. Orrell University Department of Neurosciences, Royal Free and University College Medical School, University College London, London, UK R.L. Robinson The Leeds MH Investigation Unit, St James’s University Hospital, Leeds, UK M.R. Rose King’s College Hospital and School of Medicine, King’s College, University of London, London, UK P. Serdaroglu Department of Neurology, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey
C.A. Sewry Centre for Inherited Neuromuscular Disorders, Department of Histopathology, Robert Jones and Agnes Hunt Orthopaedic and District Hospital NHS Trust, Oswestry, and Hammersmith Hospital, London, UK R.W. Taylor Mitochondrial Research Group, School of Neurology, Neurobiology and Psychiatry, University of Newcastle upon Tyne, UK P. D. Thompson Department of Neurology and University Department of Medicine, University of Adelaide, Royal Adelaide Hospital, Adelaide, Australia M. Tulinius Sahlgrenska University Hospital, Go¨teborg, Sweden D.M. Turnbull Mitochondrial Research Group, School of Neurology, Neurobiology and Psychiatry, University of Newcastle upon Tyne, UK B. Udd Vaasa Central Hospital, Vaasa, Finland
Contents
Foreword Preface List of contributors 1. Congenital myopathies Nigel G. Laing, Caroline A. Sewry and Phillipa Lamont (Nedlands and Perth, Australia and Oswestry, UK)
vii ix xi 1
2. Myopathies with early contractures Marianne de Visser (Amsterdam, The Netherlands)
35
3. Myotonic disorders Frank Lehmann-Horn and Karin Jurkat-Rott (Ulm, Germany)
61
4. Periodic paralysis Doreen Fialho and Michael G. Hanna (London, UK)
77
5. Malignant hyperthermia and associated conditions P. Jane Halsall and R.L. Robinson (Leeds, UK)
107
6. Mitochondrial encephalomyopathies .. Anders Oldfors and Ma´r Tulinius (Goteborg, Sweden)
125
7. Disorders of carbohydrate metabolism Salvatore DiMauro, Orhan Akman and Arthur P. Hays (New York, NY, USA)
167
8. Disorders of lipid metabolism Corrado Angelini (Padova, Italy)
183
9. Investigation of metabolic myopathies R.W. Taylor, P.F. Chinnery and D.M. Turnbull (Newcastle upon Tyne, UK)
193
10. Lysosomal myopathies Ichizo Nishino (Tokyo, Japan)
205
11. Distal myopathies Bjarne Udd (Vaasa, Finland)
215
12. Hereditary inclusion body myopathy and other rimmed vacuolar myopathies Zohar Argov and Stella Mitrani-Rosenbaum (Jerusalem, Israel)
243
13. Inclusion body myositis Michael R. Rose and Robert C. Griggs (London, UK and Rochester, NY, USA)
255
xiv
CONTENTS
14. Autoimmune inflammatory myopathies Marinos C. Dalakas (Bethesda, MD, USA)
273
15. Infective myopathies Leila Chimelli (Rio de Janeiro, Brazil)
303
16. Toxic and iatrogenic myopathies Frank L. Mastaglia and Zohar Argov (Perth, Australia and Jerusalem, Israel)
321
17. Endocrine myopathies Richard W. Orrell (London, UK)
343
18. Muscle diseases and aging Piraye Serdaroglu (Istanbul, Turkey)
357
19. Muscle cramp syndromes Philip D. Thompson (Adelaide, Australia)
389
20. Miscellaneous myopathies David Hilton-Jones (Oxford, UK)
397
Index
411
Color plate section
415
Handbook of Clinical Neurology, Vol. 86 (3rd series) Myopathies F. L. Mastaglia, D. Hilton-Jones, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 1
Congenital myopathies NIGEL G. LAING1*, CAROLINE A. SEWRY2, 3, AND PHILLIPA LAMONT4 1
Centre for Medical Research, University of Western Australia, West Australian Institute for Medical Research, Nedlands, Western Australia, Australia; 2Centre for Inherited Neuromuscular Disorders, Department of Histopathology, Robert Jones and Agnes Hunt Orthopaedic and District Hospital NHS Trust, Oswestry, UK; 3Dubowitz Neuromuscular Centre, Department of Paediatrics and Neonatal Medicine, Imperial College Faculty of Medicine, Hammersmith Hospital, London, UK and 4Neurogenetic Unit, Division of Neurosciences, Royal Perth Hospital, Perth, Western Australia, Australia
1.1. Introduction 1.1.1. Classification The congenital myopathies are a clinically, genetically and pathologically heterogeneous group of muscle disorders defined by muscle weakness usually present at birth and characteristic morphological features on muscle biopsy. The advent of histochemistry and electron microscopy in the 1960s led to the emergence of the congenital myopathies as a group, distinct from other causes of early-onset muscle weakness such as the congenital muscular dystrophies (CMD). Initially identified in this group were central core disease, nemaline myopathy, minicore–multicore disease, and myotubular myopathy. Although most of the congenital myopathies present at birth or in infancy, there are cases with similar histopathological findings presenting later, even as adults. Some entities such as the chromosome 15 rodcore myopathy (NEM6) may exclusively present in adulthood (Gommans et al., 2002, 2003). Other entities not classified as congenital myopathies, such as Laing distal myopathy, may present so early as to delay walking and therefore come into the differential diagnosis, but with a pronounced distal phenotype (Lamont et al., 2006). If the onset is typical, however, the patient is often described as a “floppy infant”. The muscular weakness may be slowly progressive, but is often relatively non-progressive, and rarely may even improve (Riggs et al., 1994). Weakness of the respiratory muscles may be disproportionately severe, when compared
to the skeletal muscles. The clinical features vary, but “typical” features of the early onset forms are hypotonia, generalized muscle weakness, poor muscle bulk, feeding difficulties, and skeletal abnormalities developing secondary to the muscle weakness, such as a high arched palate, pectus excavatum, kyphoscoliosis and hip dysplasia. Conversely, even early-onset cases can be extremely mild, presenting only with slight hypotonia. Serum creatine kinase levels are normal or only moderately elevated. The most significant advance in the congenital myopathies in the years since the chapter on Congenital Myopathies was last written for the Handbook of Clinical Neurology (Goebel and Lenard, 1992) has been the identification of many causative gene defects, which has led to an appreciation of the broad clinical spectra associated with them. When Hans Goebel and Hans Lenard wrote their chapter (1992), no genes had been identified for any of the congenital myopathies and localization of the genes by linkage analysis was only just beginning. Now in 2006, gene defects have been identified for all of the commoner congenital myopathies and for some of the rarer ones. This has radically changed the way in which the congenital myopathies can be viewed. Accurate DNA-based diagnosis is now possible, including prenatal diagnosis. Genotype/phenotype correlations can be made, and the pathobiology of the mutant proteins can be examined in vitro, in tissue culture and in animal models. Approaches to treatment can now be investigated based on knowledge of the defective genes and proteins.
*Correspondence to: Professor Nigel G. Laing, Centre for Medical Research, University of Western Australia, West Australian Institute for Medical Research, B Block, QEII Medical Centre, Nedlands, Western Australia 6009, Australia. E-mail:
[email protected], Tel: þ61-8-9346-4611, Fax: þ61-8-9346-1818.
2
N. G. LAING ET AL.
The advent of the genetic age in congenital myopathies might suggest that the traditional classification of the congenital myopathies based upon the histopathological abnormalities observed on muscle biopsy should be discarded and replaced by a classification based on the genes. However, the starting point for diagnosis remains clinical assessment. The clinical presentation of the congenital myopathies is nevertheless similar and somewhat non-specific, making them difficult to distinguish from each other. This leads to difficulty deciding which congenital myopathy the patient has, and therefore which gene/s to analyze on the basis of clinical features. An added layer of complexity is introduced by the fact that mutations in one gene may result in different diseases, or the same disease with highly variable severity. An example of this is central core disease and malignant hyperthermia, both caused by mutations of the ryanodine receptor gene (RYR1) (Quane et al., 1993). Another complicating factor is that some of the individual congenital myopathies are highly genetically heterogeneous, with several genes causing the same histopathological phenotype. The third factor making a primary genetic classification not particularly useful at this stage is the fact that some of the genes are large and difficult to screen routinely for mutations. The most notable examples of this are the nebulin gene (NEB) (Donner et al., 2004) and RYR1 (Phillips et al., 1996). Finally, a classification based solely on the abnormal protein will have drawbacks because the defective protein may demonstrate no morphological abnormalities. For example, a condition caused by a mutation in the ACTA1 skeletal actin gene might be called an “actinopathy”, but the only apparent abnormality morphologically may be a change in type I muscle fiber size (Laing et al., 2004). This means there is still a missing link between the routine investigation of the patient and the classification scheme. Therefore, in order to direct the molecular investigation of these cases, it is still necessary to rely on the clinical phenotype and the histopathology. There are also drawbacks to a classification based solely on histopathological features, as skeletal muscle has a limited repertoire of pathological alterations. However, advances have been made in the examination and interpretation of the histopathological changes, particularly with the availability of antibodies to the mutant proteins. The increasing use of magnetic resonance imaging (MRI) indicates that MRI can discriminate between congenital myopathies with mutations in different genes. Thus, at present, it is more useful and practical to employ the existing clinicopathological classification, supported by MRI and further refined by molecular genetic diagnosis.
However, in the future, a classification that takes into account histopathology, protein and gene will probably be the most useful. 1.1.2. Inheritance Congenital myopathies can be inherited as autosomal dominant (AD), autosomal recessive (AR) or X-linked disorders, or may arise through de novo mutations. At the time of the first European Neuromuscular Centre (ENMC) workshop on nemaline myopathy, it was stated that the incidence of new mutations was not known (Wallgren-Pettersson and Laing, 1996), although, at the workshop, Alan Emery recognized that there were too many singleton cases in the cohort collected for the disease to be recessive. We now know that the majority of mutations in the skeletal muscle a-actin gene associated with nemaline myopathy and other congenital myopathies are de novo dominant mutations (Sparrow et al., 2003) and de novo mutations are also common in the ryanodine receptor gene (RYR1) (Monnier et al., 2000, 2001; Davis et al., 2003). De novo mutations also occur in the slow skeletal/b cardiac myosin gene (MYH7) causing hyaline body myopathy (Tajsharghi et al., 2003) and in the tropomyosin genes (TPM2 and TPM3) causing nemaline myopathy (Donner et al., 2002; Durling et al., 2002). De novo mutation thus appears to be rather frequent in the congenital myopathies, which might logically be expected for severe, genetically lethal forms of the diseases. It has also been demonstrated that for a number of congenital myopathies, dominant and recessive inheritance may occur through different types of mutations in the one gene. This is well characterized for the actin gene, where the dominant and de novo dominant mutations tend to be missense mutations, while the recessive mutations tend to be genetic null mutations or missense mutations which result in functionally null actin protein (Sparrow et al., 2003; Costa et al., 2004). Dominant disease being caused by missense mutations and recessive disease being caused by null mutations also largely holds true for tropomyosin (Laing et al., 1995; Tan et al., 1999; Wattanasirichaigoon et al., 2002; Donner et al., 2002), troponin (Johnston et al., 2000), and myosin (Tajsharghi et al., 2003; Bohlega et al., 2004), though the missense, nonsense and splice site mutations in the nebulin gene are all recessive (Pelin et al., 1999). Missense mutations in the ryanodine receptor cause both dominant and recessive disease (Quane et al., 1993; Zhang et al., 1993; Jungbluth et al., 2002). Homozygous null mutations (i.e., a null mutation in the alleles inherited from both heterozygous unaffected parents), which should therefore result in complete absence of the protein, have been described for slow tropomyosin (Tan et al., 1999), actin
CONGENITAL MYOPATHIES (Sparrow et al., 2003) and slow troponin T in the Amish nemaline myopathy (Johnston et al., 2000). Homozygous and compound heterozygous null mutations have been described for the nebulin gene (Wallgren-Pettersson et al., 2004a), but the nebulin mutations, apparently through alternative splicing, do not result in total absence of nebulin protein. In many families there is variable disease severity even though all the affected individuals have the same mutation. The basis of this epigenetic modification is not fully understood, but at least some instances, where one or more children are more severely affected than the parent, result from somatic mosaicism for mutation for the disease-causing mutation in the mildly affected parent. This has been demonstrated both for the actin gene (Nowak et al., 1999; Nowak and Laing, 2002) and the ryanodine receptor gene (Quinlivan et al., 2003) (Fig. 1.1). Overall, the commonest congenital myopathies are nemaline myopathy and central core disease, with the genes most frequently implicated being nebulin (NEB) and skeletal muscle a-actin (ACTA1) for nemaline myopathy and the ryanodine receptor (RYR1) for central core disease. The other congenital myopathies and mutated genes are rarer. Our understanding of the molecular pathogenesis of the disorders, in other words, how the mutant proteins lead to the muscle weakness and specific histopathology, is still rudimentary for many of the congenital myopathies. However, it should increase rapidly in the next few years. The identification of gene defects for the congenital myopathies is allowing exploration of the molecular pathogenesis in multiple model systems. Despite the genetic advances in the congenital myopathies, as with the genetic advances in the muscular dystrophies, there are still no curative
M
1
2
3
treatments. Developing effective treatments must be a major research focus for the future. Advances in the supportive treatment of congenital myopathy patients have nevertheless been considerable, especially in the area of assisted ventilation.
1.2. Congenital myopathies for which genes have been identified Gene defects have now been identified in many of the congenital myopathies (Table 1.1; Quane et al., 1993; Zhang et al., 1993; Laing et al., 1995; Laporte et al., 1996; Pelin et al., 1999; Nowak et al., 1999; Donner et al., 2000; Johnston et al., 2000; Kerst et al., 2000; Monnier et al., 2000; Scacheri et al., 2000; Jungbluth et al., 2001; Ferreiro et al., 2002a, b; Jungbluth et al., 2002; Sparrow et al., 2003; Tajsharghi et al., 2003; Sung et al., 2003a, b; Agrawal et al., 2004; Bohlega et al., 2004; Kaindl et al., 2004; Laing et al., 2004; Veugelers et al., 2004; Bitoun et al., 2005; Laing et al., 2005; Schoser et al., 2005; Toydemir et al., 2006). The spectrum of diseases associated with each gene and the spectrum of genes associated with each disease illustrate the non-specific nature of the histopathological features and the considerable histopathological overlap between the various disorders. 1.2.1. Nemaline myopathy 1.2.1.1. Clinical aspects It is usually considered that the first description of nemaline myopathy was in 1963 (Conen et al., 1963;, Shy et al., 1963). However, in 1958 Dr Douglas Reye in Sydney, Australia, described a patient with “rod
3
4
B
Fig. 1.1. Somatic mosaicism for a ryanodine receptor (RYR1) mutation. Lane 1: normal control; lane 2: proband (A4940T mutation); lane 3: mother of proband; lane 4: normal control. Note the faint aberrant band in the mother’s sample (arrow). M: size standard; B: blank. Courtesy of Mark Davis.
4
Table 1.1 Congenital myopathies for which disease genes have been identified Disease
Gene
Symbol
Protein type
Inheritancea
Reference(s)
Nemaline myopathy
Slow a-tropomyosin b-tropomyosin Nebulin Actin: skeletal muscle a
TPM3 TPM2 NEB ACTA1
Sarcomeric Sarcomeric Sarcomeric Sarcomeric
protein protein protein protein
AD, AR AD AR AD, AR, de novo
Troponin T slow Actin: skeletal muscle a Actin: skeletal muscle a Actin: skeletal muscle a
TNNT1 ACTA1 ACTA1 ACTA1
Sarcomeric Sarcomeric Sarcomeric Sarcomeric
protein protein protein protein
AR De novo AD, de novo De novo
(Laing et al., 1995) (Donner et al., 2000) (Pelin et al., 1999) (Nowak et al., 1999), (Sparrow et al., 2003), (Agrawal et al., 2004) (Johnston et al., 2000) (Nowak et al., 1999) (Nowak et al., 1999) (Jungbluth et al., 2001)
Actin: skeletal muscle a Ryanodine receptor
ACTA1 RYR1
AD AD, AR, de novo
Multi-minicore disease
Selenoprotein-N1 Ryanodine receptor
SEPN1 RYR1
Core-rod disease
Ryanodine receptor
RYR1
Congenital fiber type disproportion
Actin: skeletal muscle a
ACTA1
Sarcomeric protein Sarcoplasmic reticulum calcium channel ? Sarcoplasmic reticulum calcium channel Sarcoplasmic reticulum calcium channel Sarcomeric protein
Hyaline body myopathy
Selenoprotein-N1 Slow: skeletal myosin
SEPN1 MYH7
? Sarcomeric protein
AR AD
Myotubular myopathy
Myotubularin
MTM1
X-linked
Centronuclear myopathy
Dynamin 2
DNM2
AD
(Bitoun et al., 2005)
Muscle regulatory factor 4/herculin Fast-twitch troponin I
MYF6 TNNI2
Protein tyrosine phosphatase GTPase involved in vesicle trafficking Muscle regulatory factor Sarcomeric protein
(Clarke et al., 2006) (Tajsharghi et al., 2003) (Bohlega et al., 2004) (Laing et al., 2005) (Laporte et al., 1996)
?AD AD
(Kerst et al., 2000) (Sung et al., 2003a)
b-tropomyosin Fast skeletal troponin T Perinatal myosin heavy chain Embryonic myosin heavy chain Tripartite motif-containing protein-32
TPM2 TNNT3 MYH8 MYH3 TRIM32
Sarcomeric protein Sarcomeric protein Sarcomeric protein Sarcomeric protein E3-ubiquitin ligase
AD AD AD AD AR
(Sung et al., 2003a) (Sung et al., 2003b) (Veugelers et al., 2004) (Toydemir et al., 2006) (Schoser et al., 2005)
Actin myopathy Intranuclear rod myopathy Nemaline myopathy with core-like areas Core-like disease Central core disease
Arthrogryposis multiplex congenita/distal arthrogryposis
Sarcotubular myopathy
AR AR AD probably de novo
(Kaindl et al., 2004) (Quane et al., 1993) (Zhang et al., 1993) (Jungbluth et al., 2002) (Ferreiro et al., 2002b) (Ferreiro et al., 2002a) (Monnier et al., 2000) (Scacheri et al., 2000) (Laing et al., 2004)
OMIM ¼ Online Mendelian Inheritance in Man, OMIM (TM). McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD), 2000. http://www.ncbi.nlm.nih.gov/omim/ a AD: autosomal dominant; AR: autosomal recessive; de novo: de novo dominant.
CONGENITAL MYOPATHIES myopathy” though at the time it was thought by others that the rod-like structures may have been an artefact (see Goebel and Lenard, 1992; Schnell et al., 2000). A mutation in the skeletal muscle a-actin gene has now been shown to have caused the disease in this patient (Schnell et al., 2000). Clinically, nemaline myopathy has a marked variability, with the disease spectrum forming a continuum from severe cases lethal at, or shortly after, birth, to mild adult cases. However, it is useful both from the clinical and pathogenetic points of view to establish a clinical classification. The European Neuromuscular Centre (ENMC) International Consortium on nemaline myopathy has classified nemaline myopathy into five clinical categories: 1. 2. 3. 4.
severe congenital nemaline myopathy intermediate congenital nemaline myopathy typical nemaline myopathy mild childhood- or juvenile-onset nemaline myopathy 5. adult forms of nemaline myopathy (WallgrenPettersson and Laing, 2000). In addition, there is a sixth category of “other forms of nemaline myopathy”, where there are associated features such as cardiomyopathy, ophthalmoplegia, an unusual distribution of weakness, or intranuclear nemaline bodies morphologically. Infants with the severe congenital form show no spontaneous movement or respiration at birth, with frequent occurrence of contractures or fractures. The prognosis is often, although not uniformly, poor. In the intermediate form, the onset is neonatal, but there are some breathing and limb movements. However, later the young child is unable to achieve independent respiration, sitting or walking. Also, contractures may develop, and a wheelchair is required by the end of the first decade of life. Prognosis in this group is guarded, although not as poor as in category 1. In one series, 8 out of 29 patients in category 2 died, all of respiratory-related problems, with the remaining 21 alive and aged between 8 months and 17 years (Ryan et al., 2001). There are often major swallowing and feeding difficulties, contributing to the poor prognosis. However, the clinical course cannot be estimated with any accuracy until 9–12 months of age because of overlap between categories 1, 2 and 3 and, as outlined below, because there can be considerable clinical improvement in category 3. Therefore, aggressive management of early pulmonary infections and feed intolerance is recommended for infants with nemaline myopathy. The typical form of nemaline myopathy (category 3) is thought to be the most common form, although there may be under-recognition of categories 1 and 5
5
(Wallgren-Pettersson and Laing, 2001). In the typical form of nemaline myopathy, the onset is in infancy, with the infant often being floppy at birth. The weakness is especially pronounced in the facial, bulbar and respiratory muscles, and in the neck flexors. Drooling is a common management problem. Weakness is usually more pronounced proximally than distally, although this may alter with time. In particular, the dorsiflexors of the feet can become severely affected (Wallgren-Pettersson et al., 1999). Extra-ocular muscles are spared. The facies is myopathic (Fig. 1.2), the palate high-arched, and the gag reflex typically absent. Build is usually slender (Fig. 1.2), and deep tendon reflexes reduced or absent. Gait is waddling, with a hyperlordotic spine. Scoliosis is common, coming on with rapid prepubertal growth. Gross motor milestones are delayed but are reached, whereas typically the fine motor milestones are normal. The disease course can be non-progressive, or slowly progressive. This can be difficult to assess sometimes, because as the child grows and there is increase in body mass, loss of abilities can be related simply to statically weak muscles being unable to cope with the increased load. Chest deformities are common, and contractures of the joints commonly develop over time. Intellect is normal. Affected children usually survive infancy if actively treated, but their respiratory function remains a major management concern. Swallowing difficulties and the risk of aspiration are interrelated. Childhood-/juvenile-onset patients (category 4) have no facial weakness and relatively mild limb weakness. However, despite the relatively mild limb weakness, respiratory function must still be monitored regularly, as life-threatening respiratory failure can present as late as the fourth decade of life (Jungbluth et al., 2001). Long-term follow-up of category 4 patients has reported that all surviving patients achieve independent ambulation and continue to walk during the time of follow-up (age range 8–62 years; Ryan et al., 2001). Adult onset nemaline myopathy is highly variable (Ryan et al., 2001). A proportion of adult onset nemaline myopathy patients have monoclonal gammopathy and these patients have a relatively poor prognosis compared to those who do not (Chahin et al., 2005; Keller et al., 2006). 1.2.1.2. Genotype–phenotype correlations As detailed below (2.1.4), mutations in five separate genes have been shown to cause nemaline myopathy. The muscle pathology associated with these mutations has been shown to correlate poorly with clinical course (Ryan et al., 2003). The question remains as to whether mutations in different genes cause different disease with respect to severity, phenotype, and natural history.
6
N. G. LAING ET AL.
Fig. 1.2. Seven-year-old twins with nemaline myopathy. The twin on the right has poor bulbar function and respiratory reserve, as evidenced by reduced body mass. There is obvious facial weakness in both girls.
A confounding factor in assessing this is the fact that even within one family, there can be substantial variability in disease severity, despite, presumably, the same mutation causing the disease in each family member (Fig. 1.2). In one series of 15 kindreds, substantial variation was seen in eight (Ryan et al., 2001) and similar variability has been seen in other cohorts (Agrawal et al., 2004). The genes appearing to cause the majority of cases of nemaline myopathy are the nebulin gene (NEB) and the skeletal muscle a-actin gene (ACTA1). In a series of 26 patients with NEB mutations, 23% had the severe phenotype, 12% intermediate, 46% typical and 19% mild (Wallgren-Pettersson et al., 2004a). In 34 cases with ACTA1 mutations, 53% had a severe phenotype, none were intermediate, 24% were typical and 9% were mild. Five cases (15%) were classified as “other nemaline myopathy”, i.e., having other associated features such as intranuclear rods (Wallgren-Pettersson et al., 2004a). Therefore, there appears to be more of a propensity for the severe phenotype with ACTA1 mutations, whereas NEB mutations are more likely to cause a typical phenotype. However, there is significant overlap as mutations in either gene may be associated with a wide range of severity. Mutations in the tropomyosin genes (TPM3 and TPM2) are rare, accounting for less than 3% of nemaline myopathy patients (Bruno and Minetti, 2004). TPM3 encodes the slow (type 1) fiber-specific isoform of skeletal muscle a-tropomysin. The clinical phenotype extends
from late-childhood onset (Laing et al., 1995), to a typical infantile case (Wattanasirichaigoon et al., 2002) to a severe infantile form (Tan et al., 1999). TPM2 codes for b-tropomysin and mutations in this gene have been associated with adult-onset and typical infantile onset (Donner et al., 2002). The final gene, troponin T 1 (TNNT1), is mutated in a specific disorder, Amish nemaline myopathy, only seen in the Older Order Amish (Johnston et al., 2000). The clinical picture is intermediate infantile nemaline myopathy, with hypotonia, tremors, mild contractures of the shoulders and hips, and death from respiratory insufficiency in the second year of life. The heart is seldom involved in nemaline myopathy. This is perhaps surprising for patients with mutations in ACTA1 when 20% of actin in the heart is a skeletal actin (Bergen et al., 2003), but not surprising for patients with mutations in NEB since nebulin is not expressed in the heart but nebulette is (Millevoi et al., 1998). 1.2.1.3. Histopathology The characteristic feature of nemaline myopathy is the presence of red staining structures, visible with the Gomori trichrome technique (Shy et al., 1963; Conen et al., 1963). These authors were uncertain if the structures were rod- or thread-like and Shy et al. (1963) suggested the name nemaline myopathy after the Greek word for thread—nema.
CONGENITAL MYOPATHIES The number of rods per fiber and per muscle is variable and there is no correlation between the number of rods and clinical severity (Ryan et al., 2003). They are often clustered at the periphery of the fiber near nuclei, but can also be present throughout the fiber (Fig. 1.3). In rare cases rods are solely intranuclear (Fig. 1.4; Weeks et al., 2003; Kaimaktchiev et al., 2006), in others they occur in both the cytoplasm and nucleus (Hutchinson et al., 2006). Accumulation of actin thin filaments may or may not accompany the presence of rods (Fig. 1.5). It has long been known that nemaline bodies may not necessarily be found in a muscle biopsy taken from a patient with nemaline myopathy, with sometimes a second biopsy being required to identify the nemaline bodies (Ryan et al., 2003). This has led to some centers taking biopsies from two different sites as standard practice. With electron microscopy “rods” are seen as electron-dense structures whose shape may be rod-like or sometimes more ovoid (Fig. 1.6). They are often parallel to the longitudinal axis of the sarcomeres, and the appearance of their shape is sometimes, but not always, dependent on the plane of section. Nemaline rods are considered to be derived from Z-lines as they show continuity with them, have a similar lattice structure (Luther and Squire, 2002), and contain similar proteins. The major constituent of both rods and Z-lines is a-actinin (Jockusch et al., 1980). Rods also contain tropomyosin (Yamaguchi et al., 1982), and other proteins anchored in the Z-line, such as actin (Ilkovski et al., 2001) and myotilin (Schroder et al., 2003) are associated with them. As with Z-lines, desmin occurs at the periphery of rods but not within them. Current data suggest that nuclear rods, like cytoplasmic rods, contain a-actinin and actin (Goebel, 2003).
7
Rod-like structures are not specific to the nemaline myopathies. They can also be found at normal myotendinous junctions, in normal ocular muscles (Martinez et al., 1976) and occasional examples may be seen in a variety of acquired and inherited neuromuscular disorders. In some patients with a mutation in the RYR1 gene they may be a particular feature (core–rod myopathy; section 1.2.4; Monnier et al., 2000; Scacheri et al., 2000). A diagnosis of nemaline myopathy is based on the number of rods present and the number of affected fibers, in association with a clinical phenotype consistent with a congenital myopathy. In common with other congenital myopathies, the normal checkerboard pattern of fiber types is often lost in nemaline myopathy, and there may be a predominance of type 1 fibers or uniformity of type with most fibers having a high oxidative (type 1) content, with a slow phenotype (Fig. 1.7). Fibrosis, internal nuclei, necrosis and fiber regeneration are not usual features of nemaline myopathies. Although regeneration is not a feature in mild cases, very small fibers expressing neonatal myosin may be visible and possibly represent attempts at regeneration. When fiber typing is visible, type 1 fibers may be atrophic and rods may be restricted to type 1 fibers. Disruption of myofibrils may also occur and be visible as core-like areas, devoid of mitochondria at the light and ultrastructural level (see Fig. 1.7; Jungbluth et al., 2001). Defects in five genes (see section 1.2.1.4) are known to be associated with nemaline myopathy. It is rarely possible to identify the causative gene from pathology alone. The exception is the presence of nuclear rods and accumulation of actin filaments which have only been seen in nemaline myopathies caused by mutations
Fig. 1.3. For full color figure, see plate section. Nemaline rods stained red with the Gomori trichrome technique in (A) a child aged 9 years in a case with a Met283Lys mutation in the ACTA1 gene and (B) a 2-month-old infant with a mutation in the nebulin gene.
8
N. G. LAING ET AL. in the actin gene. Nuclear rods have also been reported in cases with a deficiency in plectin (Banwell et al., 1999), but the phenotype of epidermolysis bullosa simplex with muscular dystrophy is distinct from cases with an ACTA1 abnormality. Research studies have suggested that mutations in the nebulin gene can be detected with antibodies to the C-terminal SH3 domain but there are no commercial antibodies available to verify this (Sewry et al., 2001; Wallgren-Pettersson et al., 2002). 1.2.1.4. Genetics To date, five genes have been identified for nemaline myopathy, more than any other of the congenital myopathies. All five of the genes code for protein components of the thin filament (Table 1.1). 1.2.1.4.1. Tropomyosin
Fig. 1.4. Intranuclear rod in the muscle biopsy of a patient with a Val163Met mutation in a-skeletal actin (ACTA1). Courtesy of Ana Domazetovska and Ross Boadle.
Genetic linkage for nemaline myopathy was first obtained in a large autosomal dominant Australian family (Laing et al., 1992) and the gene mutated at this locus was later shown to be the gene for slow a-tropomyosin (TPM3) (Laing et al., 1995), the a-tropomyosin expressed in slow skeletal muscle fibers. This was the first nemaline
Fig. 1.5. Electron micrograph showing actin accumulation and rod-like structures in a severely affected neonate with an Arg147Lys mutation in the ACTA1 gene. Inset shows a higher magnification of the actin filaments.
CONGENITAL MYOPATHIES
9
myopathy gene to be identified. Further mutations in TPM3 have been found to cause autosomal recessive nemaline myopathy (Tan et al., 1999; Wattanasirichaigoon et al., 2002) as well as dominant nemaline myopathy (Durling et al., 2002). However, mutations in TPM3 are now recognized to be only a rare cause of nemaline myopathy. The fact that TPM3 is expressed only in type 1 muscle fibers, explains the restriction of the pathology to type 1 fibers in patients with TPM3 mutations. Mutations in b-tropomyosin, which is expressed in all muscle fiber types (Donner et al., 2002), have been shown to cause rare cases of dominant nemaline myopathy (Donner et al., 2002) They also cause distal arthrogryposis without the presence of rods (Sung et al., 2003a; see below section 1.2.2.1).
Fig. 1.6. Electron micrograph of nemaline rods sectioned longitudinally and transversely. Note also the disruption of some Z-lines and that some rods show continuity with the Z-line.
Fig. 1.7. For full color figure, see plate section. Biopsy from a case of nemaline myopathy with a Met283Lys mutation in the ACTA1 gene. NADH-TR staining showing uniform fiber typing, core-like areas devoid of stain and disruption of the normal myofibrillar network. Some of the absence of stain probably relates to areas of rods that are not stained with techniques for oxidative enzymes.
1.2.1.4.2. Nebulin (NEB) The typical recessive form of nemaline myopathy was linked to a region of the long arm of chromosome 2 by analysis of only seven European sib-pair families (Wallgren-Pettersson et al., 1995) and the gene responsible was shown to be the gene for nebulin (Pelin et al., 1999). Nebulin is a giant protein ruler stretching the entire length of the thin filament and determining thin filament length (McElhinny et al., 2003). The coding region of nebulin is around 20 000 base pairs long, larger than many genes, and contains 183 exons (Donner et al., 2004). Though mutations in nebulin are the commonest cause of nemaline myopathy (Wallgren-Pettersson et al., 2004a), the nebulin gene, as well as being very large, is also highly repetitive, making it a nightmare gene in which to find mutations. The described mutations are nonsense, missense, frameshift and splicing mutations (Wallgren-Pettersson et al., 2004a). A specific deletion of exon 55 of nebulin causes recessive nemaline myopathy in Ashkenazi patients (Fig. 1.8; Anderson et al., 2004). The carrier frequency for the mutation in the Ashkenazi community is measured at 1:108 based on a sample of 4090 individuals (Anderson et al., 2004). 1.2.1.4.3. Skeletal muscle a-actin (ACTA1) Mutations in the skeletal muscle a-actin gene (ACTA1) are the second commonest cause of nemaline myopathy (Wallgren-Pettersson et al., 2004a). Actin mutations causing nemaline myopathy were first described in 1999 (Nowak et al., 1999). Now over 100 mutations are known (Nowak and Laing, 2002; Sparrow et al., 2003). Mutations in actin may cause dominant or recessive disease, but most commonly the mutations are de novo dominant mutations not present in the peripheral blood lymphocytes of either parent (Sparrow
10
N. G. LAING ET AL.
Fig. 1.8. The Ashkenazi nemaline myopathy mutation: deletion of exon 55 of the nebulin gene: lane 1: marker; lane 2: patient showing homozygous deletion of exon 55 of nebulin; lanes 3 and 4: heterozygous parents of the patient in lane 2; lane 5 and lane 13: blank; lanes 6–12: nemaline myopathy patients without the exon 55 deletion; lane 14: unaffected control; lane 15: heterozygous control; lane 16: homozygous deletion control. Courtesy of Cheryl Wise.
et al., 2003). In each of two families with mild disease in one parent and severe lethal disease in two children, the nemaline myopathy has been shown to result from an ACTA1 mutation, with somatic mosaicism in the affected parent (Nowak et al., 1999; N.G. Laing, unpublished observations). Five patients have been identified with homozygous null mutations of the skeletal muscle a-actin gene. The common phenotype for these patients is of a severe congenital myopathy requiring immediate ventilatory support at birth (Romero et al., 2003a; Laing et al., unpublished observations).
Molecular diagnosis is provided as a service for ACTA1, TNNT1, TPM2, and TPM3. The giant nebulin gene is currently only screened on a research basis. Mutations can be missed in the actin gene using the original protocol described by Nowak et al. (1999) because of intronic polymorphisms beneath and near the primers, and protocols have been published to overcome this difficulty (Ilkovski et al., 2001; Graziano et al., 2004). Graziano et al. attribute the high percentage of actin mutations they identified in their cohort of nemaline myopathy patients to overcoming the allele drop-out occurring with the original protocol.
1.2.1.4.4. Troponin T (TNNT1)
1.2.1.5. Actin myopathy (congenital myopathy with accumulation of actin filaments)
Homozygosity for a nonsense mutation, Glu180Ter in exon 11 of slow troponin T causes the unusual autosomal recessive nemaline myopathy identified in the Amish (Johnston et al., 2000). 1.2.1.4.5. Other nemaline myopathy genes At least one other nemaline myopathy gene exists since not all families can be accounted for by the known genes (Wallgren-Pettersson et al., 1999), though it is always hard to be certain that a mutation has not been missed in the known genes, especially nebulin, which is such a hard gene to screen for mutations. The genes that are candidate genes for nemaline myopathy are any and all proteins associated with the thin filament. To date screening such genes for mutations in nemaline myopathy patients has proved fruitless (N.G. Laing, unpublished observations). 1.2.1.4.6. Molecular diagnosis Molecular diagnosis for nemaline myopathy is easiest for the skeletal muscle a-actin gene, since the actin gene only has six coding exons and in any cohort of nemaline myopathy patients 20–29% will have mutations of ACTA1 (Nowak et al., 1999; Wallgren-Pettersson and Laing, 2001; Agrawal et al., 2004; Graziano et al., 2004).
In some patients accumulation of actin filaments is seen on muscle biopsy in the absence of nemaline bodies, although in some cases both actin accumulation and nemaline bodies occur. Those without rods cannot be labeled as nemaline myopathy. These patients do nevertheless have mutations in the skeletal muscle a-actin gene (ACTA1; see above) and so this myopathy is related to nemaline myopathy. 1.2.1.6. Intranuclear rod myopathy Similarly, some patients have only intranuclear rods (Weeks et al., 2003; Kaimaktchiev et al., 2006). A proportion of patients with intranuclear rods, but not all (Ilkovski et al., 2001), have mutations in the skeletal muscle a-actin gene (see above) and thus intranuclear rod myopathy may be considered a sub-set of nemaline myopathy. 1.2.1.7. Molecular pathogenesis How exactly nemaline bodies form is not known, but we do know that mutations in five thin filament proteins lead to their formation. Analysis of those mutations is beginning to provide insight into the molecular pathogenesis.
CONGENITAL MYOPATHIES
11
The slow a-tropomyosin mutation causing dominant childhood onset distal myopathy has been studied in a number of systems and a mouse model has been generated (Corbett et al., 2001). The mutation has been shown to: 1. alter the regulation of force production (Michele et al., 1999) 2. alter folding and reduce affinity for actin (Moraczewska et al., 2000) 3. alter dimer preference for a- and b-tropomyosin (Corbett et al., 2005). This indicates the multiple effects a single mutation may have on protein function. The homozygous truncating mutation of TPM3 seen in one patient leads to preferential severe atrophy of type 1 muscle fibers, while the type 2 fibers, which do not express TPM3, are remarkably unaltered, suggesting that man cannot live by type 2 fibers alone (Tan et al., 1999). The nebulin mutations causing nemaline myopathy include many null mutations, which however do not result in total absence of nebulin protein. Total absence of nebulin may well be embryonic lethal. The current hypothesis is that there is alternate splicing around the nonsense, frameshift or splice site mutations resulting in a shorter nebulin molecule retaining C-terminal ends (Pelin et al., 1999; Sewry et al., 2001; Wallgren-Pettersson et al., 2004a). Since nebulin acts as a ruler controlling the length of the thin filament (McElhinny et al., 2003), co-existence of nebulins of different lengths may lead to poorly functioning thin filaments (Wallgren-Pettersson et al., 2004a). The actin mutations causing actin myopathies have been studied theoretically and in a number of systems. Structural analysis suggests that there is at least some segregation of the mutations in actin associated with the different histopathological phenotypes. For example, it would appear that the mutations which cause accumulation of thin filaments are largely associated with the cleft binding the nucleotide (Sparrow et al., 2003), while the mutations causing congenital fiber type disproportion may interfere with tropomyosin–actin interaction (Laing et al., 2004). The mutations also tend to “breed true” in tissue culture models, with, for example, mutations associated with intranuclear rods in patients also causing intranuclear rods in culture (Fig. 1.9; Ilkovski et al., 2004). Most of the actin mutations are dominant negative mutations, creating poison proteins that interfere with the function of the normal actin from the wild-type allele on the other chromosome 1. Some of the ACTA1 mutations lead to abnormal folding and polymerization (Costa et al., 2004; Ilkovski et al., 2004). It is interesting that null actin mutations, which should lead to complete absence
Fig. 1.9. Tissue culture reproduction of intranuclear rods. C2C12 myoblasts were transfected with EGFP-tagged mutant actin construct V163M and examined for EGFP fluoresence 48 hours after transfection. Intranuclear rod-shaped aggregates were observed by EGFP staining. Courtesy of Biljana Ilkovski and Sandra Cooper.
of skeletal muscle a-actin, also generate nemaline bodies (Romero et al., 2003a; Laing et al., unpublished observations). In skeletal actin-null patients, there are no mutant proteins to accumulate. The nemaline bodies in these patients may arise through altered stoichiometry between the different protein components of the sarcomere. Skeletal actin null patients still demonstrate some normal sarcomeres, which presumably are formed based on cardiac actin, which is the isoform present in fetal muscle (Biben et al., 1996) and which is upregulated in at least some patients with recessive skeletal actin disease (Agrawal et al., 2004; Laing et al., unpublished observations) and the skeletal actin knockout mouse model (Crawford et al., 2002). The TNNT1 mutation of the Amish nemaline myopathy causes complete absence of slow troponin T in the patient’s muscle (Jin et al., 2003), which leads to a selective atrophy of type 1 muscle fibers, similar to the effect of the homozygous TPM3 null mutation described above. Experiments with the TPM3 mouse model of nemaline myopathy suggest that endurance exercise can reverse weakness and lead to resorption of the nemaline bodies (Joya et al., 2004; Nair-Shalliker et al., 2004). Array analysis in nemaline myopathy shows reduced glycolytic enzymes, suggesting decreased dependence on glucose metabolism and increased reliance on fatty acid metabolism as well as alterations in calcium
12
N. G. LAING ET AL.
homeostasis which should lead to increased intracellular calcium levels (Sanoudou et al., 2003). Nemaline myopathy patients showing uniform fiber typing have been shown by array analysis to exhibit a unique patttern of protein expression (Sanoudou et al., 2004). 1.2.1.8. Treatment of nemaline myopathy A single published report exists of a father and son with nemaline myopathy whose muscle strength improved with daily L-tyrosine (Kalita, 1989). Unpublished reports suggest that there may be an improvement in overall muscle strength and endurance. In particular it is said to reduce drooling. In a multicentre cohort of 143 patients, mortality was invariably due to respiratory insufficiency (Ryan et al., 2001). Thus the management of respiratory insufficiency is very important in nemaline myopathy. This is common to many of the congenital myopathies, and is dealt with in a separate section (see section 1.1.6). 1.2.2. Central core disease 1.2.2.1. Clinical aspects Central core disease (CCD) was the first congenital myopathy to be described (Magee and Shy, 1956), and the first congenital myopathy for which a gene was identified (Quane et al., 1994). Histologically, the first family described had muscle fibers that were devoid of oxidative enzyme activity in circumscribed areas, so-called “central cores”. Clinically, the patients were described as having a “congenital non-progressive myopathy”, manifesting with hypotonia, and delay in motor milestones in infancy. The weakness affected proximal muscles more than distal, and legs more than arms. Central core disease is one of the two most common congenital myopathies. Most cases have a typical phenotype, presenting with hypotonia at birth and developmental delay. Weakness is most noticeable in the hip girdle and axial musculature, and the muscles are often somewhat underdeveloped. The disease is typically non-progressive, or very slowly progressive. Facial involvement is usually mild, and inability to bury the eyelashes may be the only finding. Orthopedic complications are common, more so than in other congenital myopathies. Congenital dislocation of the hips is common and scoliosis later in childhood is seen. Tendo Achilles tightening is seen, but contractures elsewhere are rare. In fact, it is more common to have ligamentous laxity. Serum creatine kinase activity is usually normal or only mildly elevated. Most “typical” cases achieve independent ambulation, and stay ambulant throughout life. However, hip dislocation can complicate walking. As with other myopathies, there is a wide spectrum of severity. Asymptomatic family members with central
cores on muscle biopsy are well described (Quinlivan et al., 2003). Thirty-seven-year follow-up of a patient first described in 1961 (Engel et al., 1961) demonstrated that there had been only mild progression (Lamont et al., 1998). There are many anecdotal reports of patients presenting with nothing more than hypotonia and “clumsiness”, only to have central cores found on muscle biopsy (P. Walsh, personal communication). However, Romero and colleagues reported seven cases of fetal akinesia as the presentation of CCD (Romero et al., 2003b). Two fetuses died before birth, and five presented with severe hypotonia and arthrogryposis at birth. Among these five, three died early (8 days, 30 days, 10 months), and two are still alive. However, those two required a long period of intensive care and respiratory assistance. Therefore, although CCD can be a relatively benign disease, it can also be extremely severe. These two surviving patients illustrate the difficult choices faced in management of severely affected neonates as they both eventually showed considerable improvement and achieved unassisted ambulation (Muntoni and Sewry, 2003). Another potentially life-threatening clinical feature of CCD occurs because it is allelic with malignant hyperthermia (MH). Both are due to mutations within the RYR1 gene, and even clinically normal carriers of RYR1 mutations are susceptible to malignant hyperthermic reactions. Conversely, patients from large kindreds with the MH phenotype can have central cores seen in their muscle without any weakness on examination (Matthews, 2004). The association between CCD and MH is complex. Many CCD patients present early with orthopedic problems and these patients often need surgical procedures. Thus, appropriate precautions with respect to anaesthesia need to be taken. Cholesterol-lowering treatment in older CCD patients also needs to be approached with caution, with the report of a CCD patient whose susceptibility to MH was unmasked by increased creatine kinase levels during statin treatment (Krivosic-Horber et al., 2004). Central cores also occur in skeletal muscle in patients with hypertrophic cardiomyopathy (Smith et al., 1976; Caforio et al., 1989). This was later shown in at least some cases of hypertrophic cardiomyopathy to correlate with mutations in slow skeletal/b-cardiac myosin (Fananapazir et al., 1993). 1.2.2.2. Histopathology The muscle histopathology in cases of central core disease is now known to be very variable but is often mild (Fig. 1.10A; Sewry et al., 2002). The classical features are prominent areas devoid of oxidative enzyme activity extending down a considerable length of the fiber, and associated with type 1 uniformity or predominance.
CONGENITAL MYOPATHIES
13
Fig. 1.10. For full color figure, see plate section. Biopsy at three years of age from the quadriceps of a case of central core disease with a Tyr4864Cys mutation in the ryanodine receptor: (A) haematoxylin and eosin (H&E) and (B) cytochrome oxidase showing mild variation in fiber size, core areas devoid of enzyme activity and uniform fiber typing, with no differentiation into the normal two types. Some cores show pale staining with H&E. Note also the dark rim of some cores with COX because of aggregation of mitochondria and that cores may be central or peripheral.
These core areas may be central or peripheral; single or sometimes more than one per fiber and have a predilection for type 1 fibers when fiber typing is retained (Fig. 1.10B). However, as highlighted by Hans Goebel and Hans Lenard in the last edition of this chapter (Goebel and Lenard, 1992) members of families with CCD may not necessarily show classical central cores in a muscle biopsy. It is interesting now to look at the histopathology in genetically proven disease. It is possible to show that patients with ryanodine receptor (RYR1) mutations may display a large number of different histopathological phenotypes — including showing no cores at all, or only subtle unevenness of oxidative enzyme stain, or a ‘multi-minicore’ phenotype (see below, section 1.2.3; Sewry et al., 2002). Some of this variability may relate to age, with young cases showing minimal pathology, which then progresses with age to show the classical features. Some may also relate to the site of the muscle biopsy, as differential involvement of muscles is a particular feature of central core disease (see section 1.5 on MRI). In most cases of central core disease, the cores are the “structured” type and retain ATPase activity. The striated myofibrillar pattern is also retained, although the myofibrils of the core are often very contracted. In “unstructured cores”, seen in some cases, ATPase activity is lost and there is severe myofibrillar disruption with accumulation of smeared Z-line material and other material. The area devoid of mitochondria may be more extensive than the apparent ultrastructural myofibrillar disruption. Sarcoplasmic reticulum and T-tubules may also be reduced in cores but some tubular structures
may be apparent. Cores are often delineated by a rim of PAS stain and by desmin, while desmin and other proteins may accumulate within them. Other proteins that have been shown to accumulate in cores include B crystallin, g-filamin, small heat-shock proteins and myotilin (Sewry 2002; Sewry et al., 2002; Bonnemann et al., 2003; Schroder et al., 2003). Although cores are the characteristic feature of central core disease, core formation can also occur following tenotomy (Shafiq et al., 1969), or in neurogenic atrophy where they may be target-like (Engel, 1961) and in association with other gene defects such as ACTA1 (Jungbluth et al., 2001; Kaindl et al., 2004) and MYH7 mutations (Fananapazir et al., 1993). The coexistence of cores and rods can also occur in association with RYR1 mutations (Monnier et al., 2000; Scacheri et al., 2000). In some cases only a few fibers may show rods (Jungbluth et al., 2002). Central and internal nuclei are now also known to be a feature associated with RYR1 mutations. Similarly, although fibrosis is not usually a feature of “classical” cases it can occur, and some samples may show extensive deposition of adipose tissue (Fig. 1.11; Sewry et al., 2002). In these samples, the separation of fascicles of fibers by adipose tissue and fibrous tissue may cause diagnostic confusion with a congenital muscular dystrophy, particularly if classical large cores are absent and only subtle unevenness of oxidative enzyme stains is present (Sewry et al., 2002). The wide clinical and histopathological spectra associated with mutations in the RYR1 gene can cause diagnostic difficulties, especially in the absence of
14
N. G. LAING ET AL.
Fig. 1.11. Biopsy of the quadriceps from a case of central core disease aged 11 years with a Arg4861His mutation in the ryanodine receptor. Haematoxylin and eosin staining showing variation in fiber size, fibers with internal and central nuclei and an increase in connective tissue. Note also that several cores have a basophilic rim.
“classical” cores. Mutations in the RYR1 gene seem to be particularly common and the features that should alert pathologists are central nuclei, any unevenness in oxidative enzyme stain, be it marked or subtle, and type 1 uniformity or marked predominance. The coexistence of cores with any fibres with rods also suggests a RYR1 mutation. 1.2.2.3. Genetics Central core disease is generally autosomal dominant, though recessive cases do occur (Ferreiro et al., 2002a; Jungbluth et al., 2002). Central core disease was the first congenital myopathy for which a gene was identified. The principal gene for central core disease is the gene for the ryanodine receptor (RYR1) on chromosome 19. Linkage was established to chromosome 19 in a large Australian family (Haan et al., 1990) and smaller European families (Kausch et al., 1991). The authors searched for linkage on chromosome 19 because of the previously established linkage of the porcine stress syndrome, which is similar to human malignant hyperthermia, to glucose phosphate isomerase (GPI), which maps in humans to chromosome 19. Mutations were subsequently identified in RYR1 (Quane et al., 1993; Zhang et al., 1993) after the porcine stress syndrome had been shown to be caused by a mutation in RYR1 (Fujii et al., 1991). The RYR1 gene is a large gene consisting of 106 exons and having a cDNA of >15kb (Phillips et al., 1996). To begin with, the mutations found in RYR1 in central core disease were in the N-terminal and central regions of the protein. However, mutations were later found in the C-terminal transmembrane domain (Monnier
et al., 2001; Tilgen et al., 2001) and this was shown to be the major hotspot for central core disease mutations in RYR1, with two-thirds of patients having mutations in exons 95–105 (Davis et al., 2003). Additional phenotypes are also now known to be associated with RYR1 mutations, such as patients with ophthalmoplegia and minicores on biopsy (Monnier et al., 2003; Jungbluth et al., 2005a). Mutation of RYR1 has also been identified in cases of exercise-induced rhabdomyolysis (Davis et al., 2002) and malignant hyperthermia (Gillard et al., 1991), and since malignant hyperthermia with or without central core disease is associated with statin myopathy (Johi et al., 2003; Krivosic-Horber et al., 2004), probably also with statin myopathy. 1.2.2.4. Molecular pathogenesis It should be borne in mind that core formation is a secondary phenomenon and not in itself the reason for muscle weakness. Analysis of mutant ryanodine receptors in tissue culture models and after overexpression in frog oocytes indicates that the mutations that cause central core disease result in depletion of calcium stores by making the RYR1 channels leaky, or disrupt the coupling between excitation and release of calcium stores, while the mutations which cause malignant hyperthermia increase sensitivity to activation (Lyfenko et al., 2004). A RYR1 knockout mouse model has been created. These homozygous knockout RYR1 mice die perinatally, with gross abnormalities of skeletal muscle (Takeshima et al., 1994). This mouse model does not therefore model the dominant negative mutations of central core disease or malignant hyperthermia. The most similar disease would be the autosomal recessive fetal akinesia CCD patients described by Romero et al. (2003b). 1.2.3. Multi-minicore disease, and other selenoprotein-N-related myopathies: rigid spine muscular dystrophy, Mallory-body myopathy 1.2.3.1. Clinical aspects In all patients, onset is early and serum creatine kinase levels are normal or nearly normal. A large multicentre consortium in 2000 published a clinical classification of MmD that has subsequently allowed genetic progress to be made (Ferreiro et al., 2000). The consortium classified MmD into four groups. Group 1 is the classic form, seen in 30 of 38 patients in that series, with predominance of axial muscle weakness, high occurrence of often severe scoliosis, and major respiratory involvement. Marked limb contractures were not seen, and external eye movements were normal. It has now been shown that two-thirds of this group have mutations in the selenoprotein-N gene (SEPN1; Ferreiro et al., 2002b). Mutations in
CONGENITAL MYOPATHIES SEPN1 also cause congenital muscular dystrophy with rigid spine syndrome (RSMD) and a reevaluation of both phenotypes revealed that RSMD and the more severe forms of MmD are the same disease (Ferreiro et al., 2002b). Ferreiro and coworkers have also identified a SEPN1 mutation in a family initially described as having the “Mallory-body-like” form of desmin-related myopathy (Ferreiro et al., 2004). Reevaluation of that family’s phenotype was also consistent with group 1 MmD, and led the authors to name all three of these conditions “SEPN-related myopathies”. Group II MmD has varying degrees of external ophthalmoplegia in addition to the typical picture of axial muscle involvement. Group III is of moderate severity, and shows generalized muscle weakness, preferentially affecting the pelvic girdle, and weakness, amyotrophy, and hyperlaxity of the hands. Scoliosis and respiratory involvement is mild or absent in this group. Group IV is characterized by antenatal onset of hip-girdle weakness and arthrogryposis, plus the usual axial muscle group involvement. In two separate families, homozygous mutations in the RYR1 gene have been identified, one with a group II MmD phenotype (Jungbluth et al., 2002), and one with a group IV MmD phenotype (Ferreiro et al., 2002a). Further, independent, associations have been made between multi-minicores on biopsy and MH. Firstly, a large family shown biochemically to be MH susceptible were shown to have two heterozygous RYR1 mutations present on the same allele, and multi-minicores on muscle biopsy in 16 of 17 biopsied family members (Guis et al., 2004). A typical MmD phenotype was not described, although two family members complained of “paraspinal muscle weakness” and peripheral cramps. The second report described a patient who had been diagnosed previously with MmD, with congenital onset of hypotonia and weakness, and scoliosis starting in adolescence (Osada et al., 2004). She was shown to be MH susceptible by muscle biochemistry. Thus, precautions against triggering a MH reaction need to be taken in at least some patients with MmD. These patients/families highlight the overlapping pathology in disorders characterized by core-lesions and mutations in RYR1 (see section 1.2.3.2). 1.2.3.2. Histopathology The defining histopathological feature is multiple small areas devoid of oxidative enzymes which lack mitochondria and ultrastructurally show disruption of the sarcomeric pattern. These were described by Engel et al. in 1971 in a benign congenital non-progressive myopathy and the name “multicore disease” was suggested. Minicores are a non-specific feature that can occur in varying
15
degrees in a number of disorders, including muscular dystrophies and various congenital myopathies. Thus, the definition of “multi-minicore disease” is difficult. The phenotype most often referred to as “multiminicore disease” is that caused by mutations in the selenoprotein N1 (SEPN1; see section 1.2.3.3). This is allelic to congenital muscular dystrophy with rigid spine (RSMD1). In these cases the two-fiber-type pattern is usually preserved and the minicores occur in both fiber types (Fig. 1.12). There is usually also moderate variation in fiber size, some internal nuclei, and mild endomysial fibrosis and fat. Minicores are also associated with mutations in the RYR1 gene where they can be considered as part of the “central core” spectrum. They are also a feature of Ullrich congenital muscular dystrophy caused by mutations in collagen VI genes and may be associated with ACTA1 mutations (Monnier et al., 2000; Jungbluth et al., 2001, 2002). They also occur in association with additional structural defects such as rods or whorled fibers (Afifi et al., 1965; Seitz et al., 1984; Pourmand and Azzarelli, 1994; Pallagi et al., 1998). Many of the early cases reported with minicores are molecularly unresolved. 1.2.3.3. Genetics and pathobiology Classic multi-minicore disease is an autosomal recessive disease. A large proportion of the cases of the classical type of multi-minicore disease are caused by mutations in the selenoprotein N gene (SEPN1; Ferreiro et al., 2002b). The mutations are frameshift and missense mutations, dispersed throughout the gene. Not all patients with classical multi-minicore disease have mutations in the SEPN1 gene however, since some families with the classical phenotype do not link to the SEPN1 locus
Fig. 1.12. Biopsy from an 11-year-old child with a mutation in the SEPN1 gene: NADH-TR staining showing two populations of fiber types, and mini-core areas and unevenness of stain in both fiber types.
16
N. G. LAING ET AL.
(Ferreiro et al., 2002b). The SEPN1 gene had previously been shown to cause rigid spine muscular dystrophy (Moghadaszadeh et al., 2001) and some patients with MmD had exactly the same mutations as patients classified as having rigid spine muscular dystrophy. Thus rigid spine muscular dystrophy and multi-minicore disease are allelic. The SEPN1 gene is also responsible for patients described as having Mallory body myopathy (Ferreiro et al., 2004), who have clinical and pathological features in common with typical multi-minicore cases. The exact function of selenoprotein-N is not known, however it is known that it is a transmembrane glycoprotein located in the endoplasmic reticulum (Petit et al., 2003). It is also a selenoprotein, meaning that it has a cysteine residue converted to a selenocysteine. Selenoprotein-N is tightly associated with the endoplasmic reticulum, suggesting that it may be part of a protein complex. A calcium-binding motif may indicate a role in endoplasmic reticulum calcium homeostasis. It is expressed more in developing than adult tissues, which may imply a role in cell proliferation and regeneration (Petit et al., 2003). The moderate form of multi-minicore disease with hand involvement is caused by homozygous recessive mutation in the ryanodine receptor gene (Ferreiro et al., 2002a) and thus, this condition is allelic to central core disease. External ophthalmoplegia with minicores on muscle biopsy has also been shown to be caused by a homozygous RYR1 splicing defect in one affected patient. This patient had only about 10% of normal levels of RYR1 (Monnier et al., 2003). Mutations in the RYR1 gene in other cases with ophthalmoplegia have also been identified (Jungbluth et al., 2005a). Finally, there is the unique large dominant family segregating MH and multi-minicores and having two heterozygous mutations on the one allele of RYR1 (Guis et al., 2004). Why some RYR1 mutations produce a minicore phenotype is unclear. 1.2.4. Mixed myopathies Patients with congenital myopathy having multiple histopathologies in the one biopsy have been described since the earliest descriptions of congenital myopathies. The coexistence of rods and cores has been reported in multiple families (Afifi et al., 1965; Pallagi et al., 1998; Monnier et al., 2000; Scacheri et al., 2000; Gommans et al., 2002). Cores, minicores and rods have been described in the same biopsy (Bethlem et al., 1978; Seitz et al., 1984). The coexistence of nemaline and cytoplasmic bodies has also been reported (Itakura et al., 1998; Suwa et al., 2002). Two families with both cores and rods have had dominantly inherited mutations in the RYR1 gene identified, and both presented with mild generalized
weakness as infants, often delaying motor milestones (Monnier et al., 2000; Scacheri et al., 2000). The disease was relatively non-progressive, with family members in their eighth decade still ambulant. A sporadic case had onset of hypotonia in infancy, delay of motor milestones, hip joint contractures, scoliosis and lumber lordosis (Pallagi et al., 1998). Finally, a family was described with nemaline bodies and core-like areas where the inheritance was autosomal dominant, onset was not until adulthood, weakness was mainly proximal, and the disease was very slowly progressive (Gommans et al., 2002). Linkage to chromosome 15q has been demonstrated in this and another similar family (Gommans et al., 2003). 1.2.5. Congenital fiber type disproportion 1.2.5.1. Clinical aspects The term “congenital fiber type disproportion” (CFTD) was first used by Brooke to describe a group of infants with type 1 fibers at least 12% smaller than type 2 fibers (Brooke, 1973). The clinical phenotype was non-specific and common to many of the congenital myopathies, demonstrating hypotonia from birth, generalized weakness and poor muscle mass. Many had failure to thrive, multiple joint contractures, hip dislocation, scoliosis, myopathic facies, and high arched palate. On the whole, a relatively benign course was described, and many actually improved in muscle strength with time (Iannaccone et al., 1987). Difficulties have arisen with CFTD being a discrete diagnosis because the histological findings are shared by many myopathic and non-myopathic conditions. Also the clinical features have remained non-specific and extremely variable, without a great deal of data on the long-term outcome of these patients. This is well illustrated by the fact that in a cohort of 10 children with congenital myasthenic syndromes described by Gurnett et al. (2004), two of seven muscle biopsies had more than 12% difference in type 1 and type 2 fiber size, thus fulfilling criteria for CFTD. One series of 20 cases of CFTD were followed up over a minimum of 7 years (Glick et al., 1984). They had great variability in their outcomes. Two patients died of respiratory problems, and one 9-year-old patient had required continuous mechanical ventilation. At the other end of the spectrum, an infant requiring ventilation from birth for 2 months had achieved near normal muscle strength by 12 months of age. It is now recognized that up to 25% of patients with a morphological diagnosis of CFTD have severe weakness that does not improve, and a proportion die in infancy or childhood from respiratory failure (Clarke and North, 2003). The onset can be in late childhood with a mild nonprogressive proximal weakness (Eisler and Wilson, 1978), or even as an adult (Haltia et al., 1988).
CONGENITAL MYOPATHIES Two brothers with CFTD had clinical insulin resistance due to compound heterozygous insulin receptor mutations (Klein et al., 1999). This may be a chance association. However, the recent description of CFTD associated with SEPN1 mutations and insulin resistance (Clarke et al., 2006) suggests that the possible relationship between CFTD and insulin resistance warrants further investigation. 1.2.5.2. Histopathology Brooke (1973) noted that some biopsies only showed a disproportion in the size of type 1 fibers, in the absence of any other abnormality. The type 1 fibers are often quoted to be at least 12% smaller than type 2 fibers but the difference was acknowledged later to be at least 25% or more. Type 1 fiber predominance may also be present (Fig. 1.13). Type 1 hypotrophy and predominance are features of several disorders, including other congenital myopathies. 1.2.5.3. Genetics Congenital fiber type disproportion may show autosomal dominant, autosomal recessive and even X-linked inheritance (Clarke et al., 2005), or may result in sporadic cases from de novo mutation (Laing et al., 2004). To date mutations have been identified in CFTD in the a-skeletal actin gene (Laing et al., 2004) and SEPN1 (Clarke et al., 2006). The ACTA1 mutations associated with CFTD are heterozygous missense mutations like most of the ACTA1 mutations associated with other histopathological phenotypes (Sparrow et al., 2003). The SEPN1 mutation, pG315S, in patients with CFTD has previously been
Fig. 1.13. Congenital fiber type disproportion. Biopsy from a 9-year-old child stained for myosin ATPase with preincubation at pH 4.3 showing type 1 hypotrophy and a predominance of the darkly stained type 1 fibers.
17
associated with RSMD; Ferreiro et al., 2002b; Venance et al., 2005) and multi-minicore disease (Ferreiro et al., 2002b) and the CFTD patients have a phenotype similar to RSMD (Clarke et al., 2006). However, although we now know that rare cases of severe congenital fiber type disproportion are caused by mutations in skeletal muscle a-actin (6% in the one cohort in which actin mutations have been identified; Laing et al., 2004), the majority (94%) of CFTD is not caused by actin mutations, and the genes involved remain unknown. Insulin insensitivity (Vestergaard et al., 1995), associated with compound heterozygous insulin receptor mutations, has been described in patients with congenital muscle fiber type disproportion (Klein et al., 1999). The exact significance of these variations in the insulin receptor has yet to be clarified. 1.2.5.4. Molecular pathogenesis The three published actin mutations associated with CFTD all lie on one surface of the actin protein monomer, a surface swept by tropomyosin during contraction. This is the only known actin function that can be linked to all three mutations (Laing et al., 2004). This mechanism does not explain why only type 1 muscle fibers are small, since skeletal muscle a-actin is expressed in both type 1 and type 2 fibers and swept by tropomyosin in both. Similarly, the mechanisms which cause type 1 muscle fibers to be small with SEPN1 mutations and in other congenital myopathies are not known. 1.2.6. Myosin storage myopathy (also known as hyaline body myopathy) 1.2.6.1. Clinical aspects Myosin storage myopathy is rare, with only around 20 cases reported. In most cases the onset is in infancy or early childhood (Cancilla et al., 1971; Ceuterick et al., 1993; Barohn et al., 1994; Tajsharghi et al., 2003), although onset as an adult has been described (Masuzugawa et al., 1997; Bohlega et al., 2003). The clinical picture is variable, although the distribution of weakness tends to be proximal. One family was described as having a “scapuloperoneal syndrome”, although two members of this family had calf hypertrophy (Masuzugawa et al., 1997). Commonly described as “non-progressive”, it is probably described more accurately as slowly progressive, with only one report of some family members losing ambulation in the third decade (Bohlega et al., 2003). In more severe cases, there is poor muscle bulk, high arched palate, scoliosis, and the weakness can progress distally in the lower limbs and also affect neck flexion (Bohlega et al., 2003). With the progression of weakness, the resemblance to an allelic condition, Laing early-onset distal myopathy (Meredith et al., 2004; Lamont et al., 2006),
18
N. G. LAING ET AL. 3. destabilize the myosin protein (Bohlega et al., 2004) 4. prevent degradation of myosin (Laing et al. 2005).
becomes more evident. However, facial muscles are spared, and cardiac involvement has not been noted. In severe cases, there can be respiratory muscle weakness, leading to reduced respiratory reserve. Serum creatine kinase is usually normal or at most moderately elevated. 1.2.6.2. Histopathology Hyaline bodies are aggregates of disrupted myosin and are seen as clearly delineated areas with histological stains such as the Gomori trichrome and haematoxylin and eosin. They show myosin ATPase activity but not oxidative enzyme activity and label with antibodies to slow myosin heavy chains. Ultrastructurally, they have a granular appearance and contain disorganized filaments in continuity with the myosin filaments of the myofibrils. The granular areas contain few, or no, mitochondria or other organelles. 1.2.6.3. Genetics and molecular pathogenesis
Since hyaline body myopathy or myosin storage myopathy is characterized by the accumulation of at least myosin heads in slow muscle fibers, Anders Oldfors and his colleagues examined the slow myosin heavy chain gene MYH7 for mutations in two Swedish kindreds with hyaline body myopathy. One kindred consisted of three affected individuals over three generations, while the other contained only an isolated case. The same Arg1845Trp mutation was identified in both kindreds, and in the sporadic case as a de novo mutation (Tajsharghi et al., 2003). This Arg1845Trp has also been identified in two patients with sporadic hyaline body myopathy from Belgium (Laing et al., 2005) and two siblings from Australia (Shingde et al., 2006) for whom it was not possible to demonstrate whether or not the mutations were de novo or displaying reduced penetrance, indicating that this mutation is a common cause of myosin storage myopathy, at least amongst Caucasians. A large Saudi Arabian kindred with dominant hyaline body myopathy was shown to link to the region of the MYH7 gene on chromosome 14 (Bohlega et al., 2003), and subsequently a different mutation of the myosin tail, His1904Leu, was identified (Bohlega et al., 2004). Finally, it has been possible to identify a third myosin storage myopathy mutation Leu1793Pro (Dye et al., 2006) in the original myosin storage myopathy kindred described by Cancilla et al. (1971) as “familial myopathy with probable lysis of myofibres in type 1 fibers”. It has been suggested that the mutations that cause myosin storage myopathy: 1. disrupt the assembly of the myosin monomers into the thick filament (Tajsharghi et al., 2003; Bohlega et al., 2004) 2. increase breakdown of thick filaments (Tajsharghi et al., 2003)
1.2.7. X-linked myotubular myopathy 1.2.7.1. Clinical aspects The terms myotubular myopathy (MTM) and centronuclear myopathy were originally applied to all congenital myopathy patients in whom the muscle biopsy was characterized by central nuclei. With advances in molecular genetics and identification of gene defects the term “myotubular myopathy” is generally applied to the X-linked cases with a mutation in the gene encoding myotubularin, whilst “centronuclear myopathy” is used for the heterogenous autosomal conditions with central nuclei (Pierson et al., 2005). Consensus clinical criteria for myotubular myopathy put forth in 1994 include male gender, perinatal onset, and severe generalized muscle hypotonia associated with respiratory failure (Wallgren-Pettersson and Thomas, 1994). It is X-linked in inheritance, and caused by mutations in the gene for myotubularin (MTM1; Laporte et al., 1996). Typically affected males present in the neonatal period with profound hypotonia and an inability to establish spontaneous respiration. Death most often occurs in infancy or early childhood from respiratory failure (McEntagart et al., 2002). Problems can begin prenatally with weak fetal movements and polyhydramnios, and there is a high incidence of miscarriages and stillbirths in affected pregnancies. Facial weakness and ophthalmoplegia can occur. However, there are reports of milder phenotypes, such as one family with three affected males surviving into adulthood, with sufficient muscle strength to carry out “normal daily activities” (Yu et al., 2003). Improved neonatal intensive care, and the use of regular ventilatory support is also increasing the survival rate in these boys. In a survey of 116 affected males, the risk of death by respiratory failure before 18 months of age was 46% (McEntagart et al., 2002). However, 75% of the survivors received some level of ventilatory support, confirming that this is a severe congenital myopathy. Manifesting carriers of X-linked MTM are rare but reported (Heckmatt et al., 1985; Hammans et al., 2000; Sutton et al., 2001). There is evidence that they occur, at least in part, because of skewed X-inactivation (Kristiansen et al., 2003). In manifesting carriers, weakness and hypotonia can present as early as birth (Jungbluth et al., 2003), but ambulation at the age of 71 years is also reported (Kristiansen et al., 2003). Two families were recently reported as having both manifesting and non-manifesting carriers with the manifesting carriers demonstrating a novel phenotype with hemiatrophy and asymmetric weakness of one side of
CONGENITAL MYOPATHIES the body, as well as hemidiaphragm elevation (Grogan et al., 2005). An unusual feature of X-linked MTM is that many affected boys have accelerated linear growth and a bone age that is over one standard deviation above the normal for chronological age (Herman et al., 1999). This may relate to increased levels of insulin-related trophic factors (Bertini et al., 2004). A combination of X-linked MTM and intersex genitalia was reported in two boys who had a large deletion in the region Xq28, suggesting a contiguous gene syndrome (Hu et al., 1996). However, a Japanese case of X-linked MTM was reported who was carrying a 240 kb deletion in Xq28, without male hypogenitalism (Tsai et al., 2005). Therefore, the association in the first two cases may be incidental. 1.2.7.2. Histopathology The characteristic feature is centrally placed nuclei. The similarity in appearance to fetal myotubes led to the name ‘myotubular’. The muscle fibers are generally small in diameter and the central nuclei appear large and occur in both fiber types. In longitudinal section the central nuclei are regularly spaced down the fiber so the number seen in transverse section depends on the level of the section (Fig. 1.14). The central nuclei may not always be numerous, or be apparent at birth, and may vary between muscles (Sasaki et al., 1989; Helliwell et al., 1998). A zone devoid of myofibrils is seen around each central nucleus, which often appears as a hole with histological stains. This central zone contains mitochondria and glycogen so there is central aggregation of oxidative enzymes and periodic acid Schiff (PAS) staining. The periphery of the fibers may appear as a pale halo in young cases.
19
Type 1 fiber hypotrophy/atrophy and type 1 fiber predominance are also features. High levels of desmin and vimentin have been put forward as evidence of maturational delay (Sarnat, 1990, 1992), but the developmental transition from neonatal to fast or slow myosin occurs and central nuclei can be seen in fibers with fast or slow myosin (Sewry, 1998). Antibodies to myotubularin do not recognize native protein on sections of muscle from affected patients but an absence of protein has been shown using immunoprecipitation (Laporte et al., 2001b). Female carriers of the X-linked form may manifest to a varying degree and show pathological changes in muscle biopsies (Dahl et al., 1995; Tanner et al., 1999; Jungbluth et al., 2003), and the possibility of a mutation in the myotubularin gene should always be considered in a female with abundant central nuclei. Differential diagnosis in neonates should also include congenital myotonic dystrophy as the pathological appearance is identical to myotubular myopathy. 1.2.7.3. Genetics and molecular pathogenesis X-linked myotubular myopathy is caused by mutations in the myotubularin gene (Laporte et al., 1996). The mutations are nonsense, missense, and frameshift mutations. Myotubularin (OMIM 300415) is a putative tyrosine phosphatase that is a potent phosphatidylinositol 3-phosphate phosphatase (PI(3)P; Laporte et al., 2001a). The mutations have been suggested to prevent normal maturation of muscle fibers, although the normal transitions of myosin isoforms occur. Data from a myotubularin knockout mouse model in which myogenesis is normal suggest an abnormality in the maintenance of muscle fibers (Buj-Bello et al., 2002). 1.2.8. Centronuclear myopathy
Fig. 1.14. Biopsy from an 8-month-old child with X-linked myotubular myopathy stained with haematoxylin and eosin showing large central nuclei in many fibers.
1.2.8.1. Clinical aspects There are many reports in the literature of cases that do not link to Xp28, with probable autosomal inheritance (Wallgren-Pettersson and Thomas, 1994; Bertini et al., 2004). Autosomal centronuclear myopathies are characterized by chains of centrally located nuclei in a large number of muscle fibers on muscle biopsy. It is rare, and the age of onset is highly variable, ranging from infantile to adult. However, it does tend to present later than X-linked MTM. In a review of 29 individuals from 12 families, Jeannet and co-workers were able to categorize centronuclear myopathy into AD, AR, and sporadic forms (Jeannet et al., 2004). All three AD families had a relatively late onset of disease and a slow progression. One AD family had unusual diffuse muscle hypertrophy. In the two AR families and seven sporadic cases, three subgroups were identified, namely early onset with
20
N. G. LAING ET AL.
ophthalmoparesis, early onset without ophthalmoparesis, and late onset without ophthalmoparesis. The clinical features seen in most but not all groups were ptosis, restriction of eye movements, and diffuse weakness of all muscles with occasional proximal or distal predominance. In the AD families, onset could be at any age between infancy and adulthood, even in the same family. Loss of ambulation occurred in two patients, but not until their eighth decade of life. The early-onset AR or sporadic forms all tended to present in infancy or early childhood, and there were various combinations of the clinical features, as outlined above. Some patients had a reduction in respiratory function, but none required ventilation. The two patients in the AR late-onset subgroup had no facial weakness or restriction of eye movements, presenting only with diffuse mild limb weakness beginning in the third decade of life. Similarities did exist between the AD forms and the AR late-onset forms. Mutations in the dynamin 2 gene have recently been described as causing autosomal dominant centronuclear myopathy in two families (Bitoun et al., 2005). In the 10 patients described, 9 had bilateral ptosis, with 2-with eye movement abnormalities, 4 had mild facial weakness, and 3 had axial muscle weakness and/or hyperlordosis (Fischer et al., 2006). Eight patients had siginificant leg weakness, four distally, two proximally, and two diffusely. Six had arm weakness, all more distal than proximal. Tendo Achilles was tight in 9 of 10 patients. 1.2.8.2. Histopathology The main morphological features are similar to X-linked cases with central nuclei, some peripheral nuclei, type 1 fiber atrophy and/or predominance. Central areas again show accumulation of mitochondria and sometimes an absence of myofibrils. There may also be a spoke-like effect radiating from the center of the fibers that is seen with oxidative enzyme stains and the PAS technique for glycogen. Subsarcolemmal peripheral halos are also commonly seen with oxidative enzymes. Some fibers may also show core-like areas devoid of oxidative enzymes. A few fibers may show neonatal myosin but, as in X-linked cases, fibers with central nuclei do not show neonatal myosin and most fibers have either fast or slow myosin. Fibers with slow myosin (type 1 fibers) tend to be smaller in diameter and may be more predominant. The similarity of some features, in particular central nuclei and core-like areas, to those seen in cases with RYR1 mutations was recently discussed at a European Neuromuscular Center workshop on myotubular myopathy (Bertini et al., 2004) and the consortium agreed that in all cases of centronuclear myopathy both the DM1 and
RYR1 genes should be excluded. The large size of the latter, however, makes this difficult. 1.2.8.3. Genetics and molecular pathogenesis Recently mutations in dynamin 2 (DNM2), have been identified in a subset of patients with autosomal dominant centronuclear myopathy (Bitoun et al., 2005). Dynamins are a family of GTPases involved in vesicle trafficking. DNM2 has also been shown to be mutated in autosomal dominant intermediate Charcot–Marie–Tooth disease, associated in some cases with neutropenia, suggesting that DNM2 plays a role in maturation of neutrophils as well as peripheral nerves and muscle (Zuchner et al., 2005). Previously, mutation of the myogenic factor 6 gene (MYF6) had been suggested as the cause of autosomal centronuclear myopathy in one boy and to have modified the disease severity of Becker muscular dystrophy in his father who had a severe Becker muscular dystrophy, which should have been mild, based on the dystrophin deletion present (Kerst et al., 2000). In addition, mutations in the RYR1 gene have recently been identified in two females with centronuclear myopathy (Jungbluth et al., 2005b). Nevertheless, the genetic basis of the majority of cases of centronuclear myopathy remains to be clarified, though a locus on chromosome 10 has also been identified (Bertini et al., 2004). 1.2.9. Disorders with congenital contractures: arthrogryposis multiplex congenita/distal arthrogryposis; autosomal dominant inclusion body myopathy IBM3 1.2.9.1. Clinical aspects Arthrogryposis multiplex congenita (AMC) is a syndrome characterized clinically by congenital fixation of multiple joints. In distal arthrogryposis (DA) infants are born with congenital contractures of distal limbs (Sung et al., 2003a). Arthrogryposis multiplex congenita and DA can be secondary to a wide range of disorders, including disorders of the neuraxis such as lissencephaly, meningocele, sacral agenesis, anterior horn cell disorders such as spinal muscular atrophy, peripheral nerve hypomyelination, or disorders of the neuromuscular junction as in congenital myasthenia gravis. It also may complicate disorders of skin or connective tissue such as congenital ichthyosis or skeletal dysplasias, or be a consequence of impairment of the fetal environment as seen in oligohydramnios or uterine abnormalities, although they can complicate primary muscle diseases such as myotonic dystrophy (O’Flaherty, 2001). Arthrogryposis multiplex congenita and DA are not conventionally considered part of the “congenital myopathy” group of disorders. However, they are muscle diseases, present at birth,
CONGENITAL MYOPATHIES and we now know they can be caused by mutations in members of some of the same protein families that are mutated in congenital myopathies such as nemaline myopathy and myosin storage myopathy. The severe congenital form of nemaline myopathy has been described in conjunction with AMC (Bucher et al., 1985). It is also an uncommon but well-described presentation in central core disease. In order to facilitate genetic research into this condition, 10 different DAs were documented (Sung et al., 2003a). The most severe DA is the Freeman–Sheldon syndrome, and this has been shown to be caused principally by mutations in MYH3, the embryonic myosin heavy chain gene (Toydemir et al., 2006). Mutation of MYH3 is also responsible for one-third of the cases of the most common form of DA, Sheldon–Hall syndrome (Toydemir et al., 2006). The prototypic type 1 DA is characterized primarily by campylodactyly and clubfoot, with variable involvement of the shoulders and hips. Distal arthrogryposis type 2b has added dysmorphic features such as triangular facies, downward-slanting palpebral fissures, small mouth and mandible, and cervical webbing (Krakowiak et al., 1998). Mutations in fast-twitch contractile proteins have been found to cause a single case of each of these DA categories (Sung et al., 2003a, b). Another mutation in a sarcomeric protein, this time in the perinatal myosin heavy-chain (MYH8), was identified in a family with trismus-pseudocamptodactyly syndrome (Veugelers et al., 2004). Finally, an autosomaldominant myopathy (IBM3) associated with proximal muscle weakness, congenital joint contractures and ophthalmoplegia was found to have a mutation in the myosin expressed in fast IIa muscle fibers (Darin et al., 1998; Martinsson et al., 2000). 1.2.9.2. Histopathology The precise muscle histopathology in these diseases, except IBM3, is unclear. In IBM3 the pathology of rimmed vacuoles, cytoplasmic and intranuclear inclusions and accumulation of proteins characteristic of inclusion body myopathies were restricted to type 2a muscle fibers (Darin et al., 1998; Martinsson et al., 2000). 1.2.9.3. Genetics and molecular pathogenesis Mutations have been identified in distal arthrogryposis in b-tropomyosin (TPM2; Sung et al., 2003a), fast troponin I (TNNI2; Sung et al., 2003a), and fast skeletal troponin T (TNNT3; Sung et al., 2003b). It is perhaps significant that all these proteins are expressed in fast muscle fibers, whereas the mutations in similar thin filament proteins that cause nemaline myopathy are
21
expressed in slow muscle fibers (see section 1.2.1.4 and Table 1.1). b-tropomyosin is expressed in both fast and slow muscle fibers and different mutations in b-tropomyosin may cause either distal arthrogryposis (Sung et al., 2003a) or nemaline myopathy (Donner et al., 2002). Similarly the embryonic myosin heavy chain gene MYH3, which is mutated in both Freeman– Sheldon syndrome and Sheldon–Hall syndrome, tends to be expressed in myotubes that will become fast muscle fibers (Toydemir et al., 2006). The trismus pseudocamptodactyly syndrome (Veugelers et al., 2004) is caused by mutation in the perinatal myosin heavy chain gene (MYH8) expressed around birth and which is retained in muscles such as extraocular and masseter muscles and is re-expressed in regenerating muscles (Weiss et al., 1999). Interestingly the Arg674 residue mutated in MYH8 (Veugelers et al., 2004) is paralogous to the Arg672 residue most frequently mutated in MYH3 in Freeman–Sheldon syndrome (Toydemir et al., 2006). Autosomal dominant IBM3 with congenital joint contractures and ophthalmoplegia (Darin et al., 1998) is caused by a Glu706Lys mutation, in the SH1 domain of the fast myosin heavy chain gene expressed in IIa muscle fibers (MYH2; Martinsson et al., 2000). This mutation is likely to affect force generation but not incorporation of the mutant myosin into the thick filament (Tajsharghi et al., 2005a). One other MYH2 mutation has since been identified in a patient with autosomal dominant myopathy (Tajsharghi et al., 2005b). 1.2.10. Sarcotubular myopathy Jerusalem et al. (1973) described two brothers with a novel congenital myopathy, where the muscle biopsies demonstrated sarcotubular masses. The disease was therefore called sarcotubular myopathy. Subsequent to this, sarcotubular myopathy was identified in two brothers in a German family with a milder clinical phenotype (Muller-Felber et al., 1999). The brothers described by Jerusalem et al. (1973) were Hutterites; the brothers described by Muller-Felber et al. (1999) were not. Both sets of brothers have now been shown to have the same Asp487Asn mutation in the TRIM32 gene (Schoser et al., 2005) as Hutterites with autosomal recessive limb girdle muscular dystrophy LGMD2H (Frosk et al., 2002). This indicates that sarcotubular myopathy and LGMD2H are different manifestations of the same disease (Schoser et al., 2005). 1.2.11. Uniform fiber typing In the previous edition of the chapter on congenital myopathies, congenital myopathy with uniform fiber typing
22
N. G. LAING ET AL.
was given a separate heading (Goebel and Lenard, 1992). However, we now know that this fiber typing can be associated with a number of diseases such as nemaline myopathy with mutations in the nebulin gene (Sewry et al., 2001) or the actin gene (Fig. 1.7) and central core disease with mutations in the ryanodine receptor gene (Fig. 1.10; Sewry et al., 2002). Uniform fiber typing is therefore a common feature of various congenital myopathies and should be viewed as such. As might be expected, nemaline myopathy patients showing uniform fiber typing have been shown by array analysis to exhibit a unique and consistent pattern of protein expression (Sanoudou et al., 2004).
2000; Selcen et al., 2001; Gommans et al., 2003). All of these entities are excellently described by Goebel and Lenard (1992) and North (2004), or both, and little progress has been made in their elucidation. Since many of these entities are based on very small numbers of patients/observations, their classification and relationships to the other better-known congenital myopathies remain debatable. Clarification of the relationships would come through finding causative gene defects. However, finding the genes for diseases where there are only small numbers of patients, especially isolated patients, is not easy. Linkage analysis cannot be accomplished, and researchers are left with candidate gene approaches. Candidate gene approaches have been successful in some congenital myopathies where few patients were available, for example, identifying mutations in actin in actin myopathy (Nowak et al., 1999) and myosin in hyaline body myopathy/myosin storage myopathy (Tajsharghi et al., 2003; Laing et al., 2005). These successes came through careful analysis of the precise pathology in the muscle biopsies of these patients, identifying the accumulation of actin in actin myopathy and at least myosin heads in hyaline body myopathy/myosin storage myopathy. However, the best hope for finding the disease genes for these very rare
1.3. Congenital myopathies for which genes have not yet been identified There are a large number of congenital myopathies in the literature for which the genes have not yet been identified (Table 1.2; Engel et al., 1970; Brooke and Neville, 1972; Engel et al., 1972; Lake and Wilson, 1975; Fardeau et al., 1976; Ringel et al., 1978; Carpenter et al., 1979; Fidzianska et al., 1981; Goebel et al., 1981; Mrak et al., 1993; Mrak et al., 1996; Marbini et al., 1998; Bourque et al., 1999; Goebel and Anderson, 1999; Ikezoe et al.,
Table 1.2 Congenital myopathies for which the disease gene has not been identified Disease
OMIM
Locus
Inheritancea
Reference(s)
Nemaline myopathy with core like areas Broad A-Band disease Cap disease Cylindrical spirals myopathy Cytoplasmic or spheroid body myopathy Fingerprint body myopathy
NEM6 160990 305550
15q -
AD AD -
Lamellar body myopathy Myopathy with apoptotic changes Myopathy with hexagonally cross-linked tubular arrays Myopathy with mosaic fibers and interlacing sarcomeres Myopathy with muscle spindle excess Reducing body myopathy Trilaminar fiber myopathy Tubular aggregate myopathy Zebra body myopathy
-
-
?AD
(Gommans et al., 2003) (Mrak et al., 1993) (Mrak et al., 1996) (Fidzianska et al., 1981) (Carpenter et al., 1979) (Goebel et al., 1981) (Engel et al., 1972) (Fardeau et al., 1976) (Goebel and Anderson, 1999) (Ikezoe et al., 2000) (Bourque et al., 1999)
-
-
-
(Marbini et al., 1998)
160565 -
-
AD -
(Selcen et al., 2001) (Brooke and Neville, 1972) (Ringel et al., 1978) (Engel et al., 1970) (Lake and Wilson, 1975)
OMIM ¼ Online Mendelian Inheritance in Man, OMIM (TM). McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD), 2000. http://www.ncbi. nlm.nih.gov/omim/ a AD: autosomal dominant; AR: autosomal recessive; de novo: de novo dominant.
CONGENITAL MYOPATHIES congenital myopathies might be to track down the even rarer large families with these diseases. This certainly worked through the identification of linkage for central core disease initially only in one large family (Haan et al., 1990). Another successful strategy is to examine genes which have been shown to be mutated in similar disorders. Good examples of this are the identification of mutations in ACTA1 (Laing et al., 2004) and SEPN1 (Clarke et al., 2006) in patients diagnosed with CFTD and determining that sarcotubular myopathy is allelic to LGMD2H (Schoser et al., 2005). Finding the other genes for congenital myopathies where some genes have already been identified is also a daunting task. For example, tracking down the disease genes for the rare cases of nemaline myopathy not caused by mutations in the five known genes, is not going to be easy.
1.4. Molecular archaeology of muscle diseases Molecular archaeology is the study of ancient molecules. In the context of the congenital myopathies, it can be defined as the molecular analysis of samples from patients described in the older literature, before molecular diagnosis was available. This is achieved by molecular analysis of DNA isolated from paraffin blocks, frozen tissue or other remains from the cases described in the pre-DNA era. It is important to try to correlate the molecular aetiology with the clinical and histopathological descriptions of the cases that have been in the literature for many years and are in reality the foundation of the field. For example, it is extremely gratifying to have found an ACTA1 mutation in the first patient identified with what is now know as nemaline myopathy (Schnell et al., 2000) and a MYH7 mutation in the first family described with myosin storage myopathy (Dye et al., 2006). A de novo dominant ACTA1 mutation has also been identified (N.G. Laing, unpublished observations) in one of the nemaline myopathy families originally thought, on the basis of minor abnormalities in the muscle biopsies of both parents, to have recessive nemaline myopathy (Arts et al., 1978). As noted above (section 1.2.3.2), most of the early cases reported with minicores are molecularly unresolved and it would be useful to clarify which of the early cases were caused by mutations in which of the genes.
1.5. Magnetic resonance imaging in the congenital myopathies The clinical presentation of the congenital myopathies is often similar and somewhat non-specific, making them difficult to distinguish from each other. The tradi-
23
tional first investigation, once a clinician decides that an infant’s phenotype is compatible with a congenital myopathy, has been to proceed to muscle biopsy. However, researchers have turned to MRI to investigate whether there are identifiable patterns of muscle involvement that would allow differentiation between the various myopathies and guide which muscle to biopsy. Early MRI studies of the congenital myopathies as a group demonstrated that overall, muscles were significantly less affected than in cases of muscular dystrophy or polymyositis, with respect to changes in signal intensity denoting edema or fat replacement (Lamminen, 1990; Wallgren-Pettersson et al., 1990). Further MRI data has shown characteristic differential involvement of muscles in nemaline myopathy associated with both ACTA1 and NEB mutations, myopathies associated with RYR1 mutations (Fig. 1.15) and a single family with CFTD (Jungbluth et al., 2004a, 2004b; Sobrido et al., 2005). In nemaline myopathy, patients with NEB mutations had more pronounced muscle involvement in the lower leg, with variations in signal intensity according to clinical severity (Jungbluth et al., 2004a). Therefore, in Table 1.3, the NEB mutation patients have been split according to whether their disease was mild or moderate. Patients with ACTA1 mutations had diffuse involvement of thigh and lower leg muscles, without differentiation in clinical and MRI severity. In order to establish diagnostic criteria for the earlyonset congenital myopathies based on MRI findings, studies should be performed according to a standard protocol. The variables to be controlled for include which anatomical areas to scan, what levels of the limb or torso to examine, as well as MRI settings. The duration of disease will also have to be taken into account. However, the potential for useful clinical data from MRI studies in the future is high. Magnetic resonance imaging can also be useful in the milder congenital myopathies, to help decide which muscles are most likely to give a diagnostic result when biopsied. MRI of the thigh muscles of a patient with chromosome 15 rod-core myopathy (Gommans et al., 2003) shows symmetrical fatty atrophy of the vastus lateralis, intermedius and medialis, with sparing of the rectus femoris, hamstring and adductor muscles (Fig. 1.16). The shoulder girdle muscles were only slightly edematous. The biopsy of the vastus lateralis had more pathological changes than the deltoid muscle (P. Lamont, unpublished case). It may be that MRI can identify subsets of patients/ families with congenital myopathy with other patterns of muscle dysfunction and thus help identify cohorts for linkage, candidate gene studies and muscles for biopsy.
24
N. G. LAING ET AL.
Fig. 1.15. For full color figure, see plate section. Muscle MRI in the congenital myopathies, T1-weighted transverse images from the proximal thigh (A–C) and the lower leg (D–F). Central core disease secondary to dominant RYR1 mutations (A, D): in the thigh (A) abnormal signal is markedly increased within vasti, sartorius (S) and adductor magnus (AM) with relative sparing of rectus femoris (RF), adductor longus (AL), gracilis (G) and semitendinosus (St). In the lower leg (D), abnormal signal is increased in soleus (So), peroneal group (PG) and gastrocnemius medialis (Gm) with relative sparing of tibialis anterior (AT) and gastrocnemius lateralis (Gm). Nemaline myopathy secondary to recessive mutations in the NEB gene (B, E): the thigh is spared (B). In the lower leg (E), there is increase in abnormal signal in soleus (So) and tibialis anterior (AT) with relative sparing of the peroneal group (PG) and both heads of the gastrocnemius. Nemaline myopathy secondary to a dominant mutation in the ACTA1 gene (C, F): there is diffuse involvement of thigh muscles (C) with marked atrophy and fatty replacement. In the lower leg (F), there is marked and diffuse increase in abnormal signal within the anterior and posterior compartments and relatively milder involvement of the soleus (So). VL¼vastus lateralis, RF¼rectus femoris, S¼sartorius, G¼gracilis, AL¼Adductor longus, AM¼Adductor magnus, St¼semitendinosus, So¼Soleus, Gm¼gastrocnemius medialis, Gl¼gastrocnemius lateralis). Courtesy of Heinz Jungbluth.
1.6. Management of patients with congenital myopathies, with particular emphasis on respiratory support The degree of respiratory involvement in the congenital myopathies depends on the precise diagnosis. This has been outlined in the individual sections. Respiratory failure can occur at any age in a patient with a congenital myopathy, including adulthood. It can happen slowly, but more alarmingly, can be sudden and catastrophic. The latter often, but not always, happens in the setting
of an intercurrent respiratory tract infection. The likelihood of respiratory compromise cannot be judged from muscle strength elsewhere in the body, as the weakness of the intercostal muscles and diaphragm can be out of proportion. Therefore, surveillance is vitally important, and is best done by a respiratory physician as part of a multidisciplinary team. Comprehensive guidelines for the assessment of respiratory function in congenital neuromuscular disorders were outlined during the 117th ENMC workshop, and are recommended reading (Wallgren-Pettersson et al., 2004b). The focus is on
CONGENITAL MYOPATHIES
25
Table 1.3 Magnetic resonance imaging findings in genetically proven congenital myopathies Nemaline myopathy secondary to ACTA1
Nemaline myopathy secondary to NEB
Anterior thigh
Diffuse involvement of all muscles; S > G
AM > AL vasti > RF VL > RF S>G
Mild diffuse changes; mostly seen in VL
Posterior thigh
Diffuse involvement, without selectivity
Mild: no abnormality Moderate: RF ¼ severe; VL, VI > VM S, G, adductors ¼ mild Mild: no abnormality Moderate–severe
Less affected than anterior thigh SM > ST
Lower leg
Diffuse involvement, with relative sparing of the soleus
Changes less in anterior posterior; Soleus > gastrocnemius Lateral gastrocnemius > medial Peroneal > TA
Limb girdles
Not reported
Mild: TA and soleus selectively involved, TP and gastrocnemius relatively spared Moderate: diffuse involvement particularly of the soleus Not reported
Diffuse changes, less than anterior muscles; sparing of G; ST less affected Not reported
Region
RYR1
Not reported
CFTD (mutation unknown)
Increased fat and atrophy, proportional to duration of disease; particular involvement of lumber paraspinal muscles
RF: rectus femoris; VL: vastus lateralis; VI: vastus intermedius; VM: vastus medialis; S: sartorius; G: gracilis; TA: tibialis anterior; TP: tibialis posterior; gastroc: gastrocnemius; AM: adductor magnus; AL: adductor longus; SM: semimembranosus; ST: semitendinosus.
detecting change in respiratory muscle strength, ability to cough, overnight oximetry and the presence of subtle symptoms of sleep-disordered breathing. This allows safe prediction of the development of respiratory failure. Most patients will show restriction of their respiratory capacity, even if they are symptom-free. In addition, weak airway muscles can lead to obstructive sleep apnea, further complicating nocturnal hypoventilation. For this reason, overnight sleep studies are recommended. The need for ventilatory support in congenital myopathies can be either intermittent or constant, and during the day or night or both. The need to intervene can be in the acute situation, as well as in the long term. Respiratory tract infections are the commonest cause of hospital admission and death in patients with neuromuscular disorders (Bach et al., 1997). There is evidence, although only anecdotal at this stage, that physiotherapy-assisted coughing may play a key part in preventing the build-up of secretions, and thus reduce the occurrence and severity of respiratory tract infections (Wallgren-Pettersson et al., 2004b). This needs to be studied further. It seems that non-invasive ventilation is very effective in these
patients, and a clear consensus exists that ventilatory support is successful in the congenital myopathies. Detailed recommendations as to the timing and type of support are outlined in the ENMC guidelines (Wallgren-Pettersson et al., 2004b). Bulbar muscle involvement predisposes patients to aspiration of secretions, food, and stomach contents. This can precipitate respiratory deterioration. Also, swallowing difficulties lead to nutritional deficiencies, weight loss, subsequent increased susceptibility to infection, and constipation. The neonatal period is the time when swallowing difficulties are most prominent, sometimes necessitating gavage feeding. These difficulties improve in 50% of infants (Ryan et al., 2001). If they do not improve, or difficulties intervene later, assessment by a speech therapist as part of a multidisciplinary team is required. Insertion of a gastrostomy tube may be beneficial. Treatment of joint contractures and scoliosis is best undertaken by a specialized team, including physiotherapist, orthotist, and orthopedic surgeon. Aggressive physiotherapy of joint contractures, including splinting and
26
N. G. LAING ET AL.
Fig. 1.16. Magnetic resonance imaging in chromosome 15 rod-core disease. This shows symmetrical fatty atrophy of the vastus lateralis (arrow), intermedius and medialis muscle bilaterally, with sparing of the rectus femoris, hamstring and adductor muscles.
serial casting, should be the initial treatment. However, if contractures do not respond to this treatment, surgery should be considered, especially if it will assist the child to improve function or mobility. Treatment options for scoliosis include bracing and spinal fusion.
1.7. Future treatments Can effective treatments be developed for the congenital myopathies? Having found a large number of the gene defects that cause congenital myopathies, we are now able to investigate the molecular pathogenesis of the diseases starting from the mutant proteins, or the effect of missing proteins. Amongst the first mouse models of the congenital myopathies is the model of slow a-tropomyosin nemaline myopathy (Corbett et al., 2001). This model has been used to show a beneficial effect of endurance exercise (Joya et al., 2004; Nair-Shalliker et al., 2004), raising the possibility of exercise being useful in congenital myopathies, which do not have the same level of muscle fiber necrosis as is seen in the muscular dystrophies. There is also evidence of endurance exercise being beneficial in central core disease (Hagberg et al., 1980). Multiple different approaches are being pursued in attempts to develop successful therapies for the muscular dystrophies, with most work aimed at Duchenne muscular dystrophy. Techniques being investigated include
myoblast transfer, viral-based gene replacement, antisense-induced exon skipping, inducing readthrough of stop codons using aminoglycosides, and upregulation of alternative genes (Bogdanovich et al., 2004). For other dominant diseases, allele-specific siRNA is being investigated, e.g., Maxwell et al. (2004). A number of these approaches will not work for some of the congenital myopathies. For example, inducing exon skipping of one of the six coding exons of actin is likely to be disastrous. Upregulation therapy may be appropriate, if it can ever be made to work in a clinical setting for muscle diseases, since many of the mutated genes are members of gene families and there are therefore alternative genes ready to hand. Cardiac actin is upregulated in patients with recessive actin mutations (Agrawal et al., 2004) and in the skeletal actin knockout mouse model, keeping the mice, which have no skeletal muscle actin, alive to 9 days postnatal (Crawford et al., 2002). Cardiac actin is an obvious choice for attempting upregulation therapy (Ilkovski et al., 2005). The short-, medium- and long-term future for congenital myopathy research must be focused on trying to develop effective treatments. This should be a goal of all scientists working on the mutated proteins: actin, nebulin, tropomyosin, the ryanodine receptor and myotubularin.
1.8. Concluding remarks The congenital myopathies are rare disorders. Some clinicians may be confronted by very few in their working careers. A web-based database with video and histopathological data on the spectrum of phenotypes in genetically proven cases, described by the clinician expert in that disease, would be extremely useful. It would be especially helpful to have video of patients with genetically proven disease but unusual phenotypes. It remains to be seen how much lumping and splitting will occur following the identification of the genetic basis of the rarer congenital myopathies. Animal models may provide surprising insights. For example, the mouse model of autosomal dominant slow tropomyosin nemaline myopathy shows as well as nemaline bodies, cytoplasmic bodies similar to those seen in cytoplasmic body myopathy, and tubular aggregates similar to those seen in tubular aggregate myopathy (Corbett et al., 2001). Does this mean that tropomyosin genes should be screened for mutations in cases of cytoplasmic body myopathy and tubular aggregate myopathy or especially in human patients with both nemaline bodies and cytoplasmic bodies (Itakura et al., 1998; Suwa et al., 2002)? Many of the severe congenital myopathy patients have de novo mutations, which is to be expected for genetically lethal diseases: either de novo mutations or
CONGENITAL MYOPATHIES recessive disease with a heterozygote carrier advantage. The high incidence of de novo mutations means that the congenital myopathies will always be with us unless techniques for fetal screening for mutations can be developed. Knowledge of the congenital myopathies has progressed remarkably since the last chapter on congenital myopathies in the Handbook of Clinical Neurology in 1992. But many intriguing puzzles remain. Many disease genes still need to be found. Most of the pathophysiology needs to be clarified, and some old questions, such as why there is such a high susceptibility to congenital dislocation of the hips in central core disease, are not answered. The biggest difficulty is developing successful treatments. Hopefully, we shall be much further towards this goal by the time of the next series.
Acknowledgements Nigel G. Laing is supported by the Australian National Health and Medical Research Council Fellowship Grant 403904, Project Grants 403941, and the West Australian Medical and Health Research Infrastructure Fund. We thank Cheryl Wise for the illustration of the Ashkenazi nebulin deletion, Mark Davis for the figure of the RYR1 somatic mosaic mother, Ana Domazetovska and Ross Boadle for the figure of the intranuclear rod in a patient biopsy, Biljana Ilkovski and Sandra Cooper for the figure of the tissue culture intranuclear rod, and Heinz Jungbluth for the MRI figure.
References Afifi AK, Smith JW, Zellweger H (1965). Congenital nonprogressive myopathy. Central core disease and nemaline myopathy in one family. Neurology 15: 371–381. Agrawal PB, Strickland CD, Midgett C, et al. (2004). Heterogeneity of nemaline myopathy cases with skeletal muscle alpha-actin gene mutations. Ann Neurol 56: 86–96. Anderson SL, Ekstein J, Donnelly MC, et al. (2004). Nemaline myopathy in the Ashkenazi Jewish population is caused by a deletion in the nebulin gene. Hum Genet 115: 185–190. Arts WF, Bethlem J, Dingemans KP, et al. (1978). Investigations on the inheritance of nemaline myopathy. Arch Neurol 35: 72–77. Bach JR, Ishikawa Y, Kim H (1997). Prevention of pulmonary morbidity for patients with Duchenne muscular dystrophy. Chest 112: 1024–1028. Banwell BL, Russel J, Fukudome T, et al. (1999). Myopathy, myasthenic syndrome, and epidermolysis bullosa simplex due to plectin deficiency. J Neuropathol Exp Neurol 58: 832–846. Barohn RJ, Brumback RA, Mendell JR (1994). Hyaline body myopathy. Neuromuscul Disord 4: 257–262.
27
Bergen HR, 3rd, Ajtai K, Burghardt TP, et al. (2003). Mass spectral determination of skeletal/cardiac actin isoform ratios in cardiac muscle. Rapid Commun Mass Spectrom 17: 1467–1471. Bertini E, Biancalana V, Bolino A, et al. (2004). 118th ENMC International Workshop on Advances in Myotubular Myopathy. 26–28 September 2003, Naarden, The Netherlands. (5th Workshop of the International Consortium on Myotubular Myopathy). Neuromuscul Disord 14: 387–396. Bethlem J, Arts WF, Dingemans KP (1978). Common origin of rods, cores, miniature cores, and focal loss of crossstriations. Arch Neurol 35: 555–566. Biben C, Hadchouel J, Tajbakhsh S, et al. (1996). Developmental and tissue-specific regulation of the murine cardiac actin gene in vivo depends on distinct skeletal and cardiac muscle-specific enhancer elements in addition to the proximal promoter. Dev Biol 173: 200–212. Bitoun M, Maugenre S, Jeannet PY, et al. (2005). Mutations in dynamin 2 cause dominant centronuclear myopathy. Nat Genet 37: 1207–1209. Bogdanovich S, Perkins KJ, Krag TO, et al. (2004). Therapeutics for Duchenne muscular dystrophy: current approaches and future directions. J Mol Med 82: 102–115. Bohlega S, Lach B, Meyer BF, et al. (2003). Autosomal dominant hyaline body myopathy: clinical variability and pathologic findings. Neurology 61: 1519–1523. Bohlega S, Abu-Amero SN, Wakil SM, et al. (2004). Mutation of the slow myosin heavy chain rod domain underlies hyaline body myopathy. Neurology 62: 1518–1521. Bonnemann CG, Thompson TG, van der Ven PF, et al. (2003). Filamin C accumulation is a strong but nonspecific immunohistochemical marker of core formation in muscle. J Neurol Sci 206: 71–78. Bourque PR, Lach B, Carpenter S, et al. (1999). Myopathy with hexagonally cross-linked tubular arrays: a new autosomal dominant or sporadic congenital myopathy. Ann Neurol 45: 512–515. Brooke MH (1973). Congenital fiber type disproportion. In: BA Kakulas, (Ed.), Clinical Studies in Myology International Congress Series No 295.Excerpta Medica, Amsterdam, pp. 147–159. Brooke MH, Neville HE (1972). Reducing body myopathy. Neurology 22: 829–840. Bruno C, Minetti C (2004). Congenital myopathies. Curr Neurol Neurosci Rep 4: 68–73. Bucher HU, Boltshauser E, Briner J (1985). Neonatal nemaline myopathy presenting with multiple joint contractures. Eur J Pediatr 144: 288–290. Buj-Bello A, Laugel V, Messaddeq N, et al. (2002). The lipid phosphatase myotubularin is essential for skeletal muscle maintenance but not for myogenesis in mice. Proc Natl Acad Sci U S A 99: 15060–15065. Caforio AL, Rossi B, Risaliti R, et al. (1989). Type 1 fiber abnormalities in skeletal muscle of patients with hypertrophic and dilated cardiomyopathy: evidence of subclinical myogenic myopathy. J Am Coll Cardiol 14: 1464–1473.
28
N. G. LAING ET AL.
Cancilla PA, Kalyanaraman K, Verity MA, et al. (1971). Familial myopathy with probable lysis of myofibrils in type I fibers. Neurology 21: 579–585. Carpenter S, Karpati G, Robitaille Y, et al. (1979). Cylindrical spirals in human skeletal muscle. Muscle Nerve 2: 282–287. Ceuterick C, Martin JJ, Martens C (1993). Hyaline bodies in skeletal muscle of a patient with a mild chronic nonprogressive congenital myopathy. Clin Neuropathol 12: 79–83. Chahin N, Selcen D, Engel AG (2005). Sporadic late onset nemaline myopathy. Neurology 65: 1158–1164. Clarke NF, North KN (2003). Congenital fiber type disproportion—30 years on. J Neuropathol Exp Neurol 62: 977–989. Clarke NF, Kidson W, Quijano-Roy S, et al. (2006). SEPN1: associated with congenital fiber-type disproportion and insulin resistance. Ann Neurol 59: 546–552. Clarke NF, Smith RL, Bahlo M, et al. (2005). A novel Xlinked form of congenital fiber-type disproportion. Ann Neurol 58: 767–772. Conen PE, Murphy EG, Donohue WL (1963). Light and electron microscopic studies of “myogranules” in a child with hypotonia and muscle weakness. Can Med Assoc J 89: 983–986. Corbett MA, Robinson CS, Dunglison GF, et al. (2001). A mutation in alpha-tropomyosin (slow) affects muscle strength, maturation and hypertrophy in a mouse model for nemaline myopathy. Hum Mol Genet 10: 317–328. Corbett MA, Anthony Akkari P, Domazetovska A, et al. (2005). An alphatropomyosin mutation alters dimer preference in nemaline myopathy. Ann Neurol 57: 42–49. Costa CF, Rommelaere H, Waterschoot D, et al. (2004). Myopathy mutations in a-skeletal-muscle actin cause a range of molecular defects. J Cell Sci 117: 3367–3377. Crawford K, Flick R, Close L, et al. (2002). Mice lacking skeletal muscle actin show reduced muscle strength and growth deficits and die during the neonatal period. Mol Cell Biol 22: 5887–5896. Dahl N, Hu LJ, Chery M, et al. (1995). Myotubular myopathy in a girl with a deletion at Xq27-q28 and unbalanced X inactivation assigns the MTM1 gene to a 600-kb region. Am J Hum Genet 56: 1108–1115. Darin N, Kyllerman M, Wahlstrom J, et al. (1998). Autosomal dominant myopathy with congenital joint contractures, ophthalmoplegia, and rimmed vacuoles. Ann Neurol 44: 242–248. Davis M, Brown R, Dickson A, et al. (2002). Malignant hyperthermia associated with exercise-induced rhabdomyolysis or congenital abnormalities and a novel RYR1 mutation in New Zealand and Australian pedigrees. Br J Anaesth 88: 508–515. Davis MR, Haan E, Jungbluth H, et al. (2003). Principal mutation hotspot for central core disease and related myopathies in the C-terminal transmembrane region of the RYR1 gene. Neuromuscul Disord 13: 151–157. Donner K, Ollikainen M, Pelin K, et al. (2000). Mutations in the b-tropomyosin (TPM2) gene in rare cases of autosomal dominant nemaline myopathy. Neuromuscul Disord 10: 342–343.
Donner K, Ollikainen M, Ridanpa¨a¨ M, et al. (2002). Mutations in the b-tropomyosin (TPM2) gene—a rare cause of nemaline myopathy. Neuromuscul Disord 12: 151–158. Donner K, Sandbacka M, Lehtokari VL, et al. (2004). Complete genomic structure of the human nebulin gene and identification of alternatively spliced transcripts. Eur J Hum Genet 12: 744–751. Durling HJ, Reilich P, Muller-Hocker J, et al. (2002). De novo missense mutation in a constitutively expressed exon of the slow alpha-tropomyosin gene TPM3 associated with an atypical, sporadic case of nemaline myopathy. Neuromuscul Disord 12: 947–951. Dye DE, Azzarelli B, Goebel HH, et al. (2006). Novel slowskeletal myosin (MYH7) mutation in the original myosin storage myopathy kindred. Neuromuscul Disord 16: 357–360. Eisler T, Wilson JH (1978). Muscle fiber-type disproportion. Report of a family with symptomatic and asymptomatic members. Arch Neurol 35: 823–826. Engel AG, Gomez MR, Groover RV (1971). Multicore disease. A recently recognized congenital myopathy associated with multifocal degeneration of muscle fibers. Mayo Clin Proc 46: 666–681. Engel AG, Angelini C, Gomez MR (1972). Fingerprint body myopathy, a newly recognized congenital muscle disease. Mayo Clin Proc 47: 377–388. Engel WK (1961). Muscle target fibers, a newly recognized sign of denervation. Nature 191: 389–390. Engel WK, Foster JB, Hughes BP, et al. (1961). Central core disease—an investigation of a rare muscle cell abnormality. Brain 84: 167–185. Engel WK, Bishop DW, Cunningham GG (1970). Tubular aggregates in type II muscle fibers: ultrastructural and histochemical correlation. J Ultrastruct Res 31: 507–525. Fananapazir L, Dalakas MC, Cyran F, Cohn G, Epstein ND (1993). Missense mutations in the b-myosin heavy-chain gene cause central core disease in hypertrophic cardiomyopathy. Proc Natl Acad Sci U S A 90: 3993–3997. Fardeau M, Tome FM, Derambure S (1976). Familial fingerprint body myopathy. Arch Neurol 33: 724–725. Ferreiro A, Estournet B, Chateau D, et al. (2000). Multiminicore disease—searching for boundaries: phenotype analysis of 38 cases. Ann Neurol 48: 745–757. Ferreiro A, Monnier N, Romero NB, et al. (2002a). A recessive form of central core disease, transiently presenting as multi-minicore disease, is associated with a homozygous mutation in the ryanodine receptor type 1 gene. Ann Neurol 51: 750–759. Ferreiro A, Quijano-Roy S, Pichereau C, et al. (2002b). Mutations of the selenoprotein N gene, which is implicated in rigid spine muscular dystrophy, cause the classical phenotype of multiminicore disease: reassessing the nosology of early-onset myopathies. Am J Hum Genet 71: 739–749. Ferreiro A, Ceuterick-de GrooteC, Marks JJ, et al. (2004). Desmin-related myopathy with Mallory body-like inclusions is caused by mutations of the selenoprotein N gene. Ann Neurol 55: 676–686.
CONGENITAL MYOPATHIES Fidzianska A, Badurska B, Ryniewicz B, et al. (1981). “Cap disease”: new congenital myopathy. Neurology 31: 1113–1120. Fischer D, Herasse M, Bitoun M, et al. (2006). Characterization of the muscle involvement in dynamin 2-related centronuclear myopathy. Brain 129: 1463–1469. Frosk P, Weiler T, Nylen E, et al. (2002). Limb-girdle muscular dystrophy type 2H associated with mutation in TRIM32, a putative E3-ubiquitin-ligase gene. Am J Hum Genet 70: 663–672. Fujii J, Otsu K, Zorzato F, et al. (1991). Identification of a mutation in porcine ryanodine receptor associated with malignant hyperthermia. Science 253: 448–451. Gillard EF, Otsu K, Fujii J, et al. (1991). A substitution of cysteine for arginine 614 in the ryanodine receptor is potentially causative of human malignant hyperthermia. Genomics 11: 751–755. Glick B, Shapira Y, Stern A, et al. (1984). Congenital muscle fiber-type disproportion myopathy: a follow-up study of twenty cases. Ann Neurol 16: 405–406. Goebel HH (2003). Congenital myopathies at their molecular dawning. Muscle Nerve 27: 527–548. Goebel HH, Anderson JR (1999). Structural congenital myopathies (excluding nemaline myopathy, myotubular myopathy and desminopathies): 56th European Neuromuscular Centre (ENMC) sponsored International Workshop. December 12–14, 1997, Naarden, The Netherlands. Neuromuscul Disord 9: 50–57. Goebel HH, Lenard HG (1992). Congenital myopathies. In: LP Rowland, S DiMauro (Eds.), Handbook of Clinical Neurology, Vol 18(62): Myopathies. Elsevier Science, Amsterdam, pp. 331–367. Goebel HH, Schloon H, Lenard HG (1981). Congenital myopathy with cytoplasmic bodies. Neuropediatrics 12: 166–180. Gommans IM, van Engelen BG, ter Laak HJ, et al. (2002). A new phenotype of autosomal dominant nemaline myopathy. Neuromuscul Disord 12: 13–18. Gommans IM, Davis M, Saar K, et al. (2003). A locus on chromosome 15q for a dominantly inherited nemaline myopathy with core-like lesions. Brain 126: 1545–1551. Graziano C, Bertini E, Minetti C, et al. (2004). Alphaactin gene mutations and polymorphisms in Italian patients with nemaline myopathy. Int J Mol Med 13: 805–809. Grogan PM, Tanner SM, Orstavik KH, et al. (2005). Myopathy with skeletal asymmetry and hemidiaphragm elevation is caused by myotubularin mutations. Neurology 64: 1638–1640. Guis S, Figarella-Branger D, Monnier N, et al. (2004). Multiminicore disease in a family susceptible to malignant hyperthermia: histology, in vitro contracture tests, and genetic characterization. Arch Neurol 61: 106–113. Gurnett CA, Bodnar JA, Neil J, et al. (2004). Congenital myasthenic syndrome: presentation, electrodiagnosis, and muscle biopsy. J Child Neurol 19: 175–182. Haan EA, Freemantle CJ, McCure JA, et al. (1990). Assignment of the gene for central core disease to chromosome 19. Hum Genet 86: 187–190.
29
Hagberg JM, Carroll JE, Brooke MH (1980). Endurance exercise training in a patient with central core disease. Neurology 30: 1242–1244. Haltia M, Somer H, Rehunen S (1988). Congenital fiber type disproportion in an adult: a morphometric and microchemical study. Acta Neurol Scand 78: 65–71. Hammans SR, Robinson DO, Moutou C, et al. (2000). A clinical and genetic study of a manifesting heterozygote with X-linked myotubular myopathy. Neuromuscul Disord 10: 133–137. Heckmatt JZ, Sewry CA, Hodes D, et al. (1985). Congenital centronuclear (myotubular) myopathy. A clinical, pathological and genetic study in eight children. Brain 108 (Pt 4): 941–964. Helliwell TR, Ellis IH, Appleton RE (1998). Myotubular myopathy: morphological, immunohistochemical and clinical variation. Neuromuscul Disord 8: 152–161. Herman GE, Finegold M, Zhao W, et al. (1999). Medical complications in long-term survivors with X-linked myotubular myopathy. J Pediatr 134: 206–214. Hu L-J, Laporte J, Kress W, et al. (1996). Deletions in Xq28 in two boys with myotubular myopathy and abnormal genital development define a new contiguous gene syndrome in a 430kb region. Hum Mol Genet 5: 139–143. Hutchinson DO, Charlton A, Laing NG, et al. (2006). Autosomal dominant nemaline myopathy with intranuclear rods due to mutation of the skeletal muscle ACTA1 gene: clinical and pathological variability within a kindred. Neuromuscul Disord 16: 113–121. Iannaccone ST, Bove KE, Vogler CA, et al. (1987). Type 1 fiber size disproportion: morphometric data from 37 children with myopathic, neuropathic, or idiopathic hypotonia. Pediatr Pathol 7: 395–419. Ikezoe K, Yan C, Momoi T, et al. (2000). A novel congenital myopathy with apoptotic changes. Ann Neurol 47: 531–536. Ilkovski B, Cooper ST, Nowak K, et al. (2001). Nemaline myopathy caused by mutations in the muscle alpha-skeletal-actin gene. Am J Hum Genet 68: 1333–1343. Ilkovski B, Nowak KJ, Domazetovska A, et al. (2004). Evidence for a dominant-negative effect in ACTA1 nemaline myopathy caused by abnormal folding, aggregation and altered polymerization of mutant actin isoforms. Hum Mol Genet 13: 1727–1743. Ilkovski B, Clement S, Sewry C, et al. (2005). Defining alphaskeletal and alpha-cardiac actin expression in human heart and skeletal muscle explains the absence of cardiac involvement in ACTA1 nemaline myopathy. Neuromuscul Disord 15: 829–835. Itakura Y, Ogawa Y, Murakami N, et al. (1998). Severe infantile congenital myopathy with nemaline and cytoplasmic bodies: a case report. Brain Dev 20: 112–115. Jeannet PY, Bassez G, Eymard B, et al. (2004). Clinical and histologic findings in autosomal centronuclear myopathy. Neurology 62: 1484–1490. Jerusalem F, Engel AG, Gomez MR (1973). Sarcotubular myopathy. A newly recognized, benign, congenital, familial muscle disease. Neurology 23: 897–906.
30
N. G. LAING ET AL.
Jin JP, Brotto MA, Hossain MM, et al. (2003). Truncation by Glu180 nonsense mutation results in complete loss of slow skeletal muscle troponin T in a lethal nemaline myopathy. J Biol Chem 278: 26159–26165. Jockusch BM, Veldman H, Griffiths GW, et al. (1980). Immunofluorescence microscopy of a myopathy: a-actinin is a major constituent of nemaline rods. Exp Cell Res 127: 409–420. Johi RR, Mills R, Halsall PJ, et al. (2003). Anaesthetic management of coronary artery bypass grafting in a patient with central core disease and susceptibility to malignant hyperthermia on statin therapy. Br J Anaesth 91: 744–747. Johnston JJ, Kelley RI, Crawford TO, et al. (2000). A novel nemaline myopathy in the Amish caused by a mutation in troponin T1. Am J Hum Genet 67: 814–821. Joya JE, Kee AJ, Nair-Shalliker V, et al. (2004). Muscle weakness in a mouse model of nemaline myopathy can be reversed with exercise and reveals a novel myofiber repair mechanism. Hum Mol Genet 13: 2633–2645. Jungbluth H, Sewry CA, Brown SC, et al. (2001). Mild phenotype of nemaline myopathy with sleep hypoventilation due to mutation in the skeletal muscle a-actin (ACTA1) gene. Neuromuscul Disord 11: 35–40. Jungbluth H, Muller CR, Halliger-Keller B, et al. (2002). Autosomal recessive inheritance of RYR1 mutations in a congenital myopathy with cores. Neurology 59: 284–287. Jungbluth H, Sewry CA, Buj-Bello A, et al. (2003). Early and severe presentation of X-linked myotubular myopathy in a girl with skewed X-inactivation. Neuromuscul Disord 13: 55–59. Jungbluth H, Davis MR, Muller C, et al. (2004a). Magnetic resonance imaging of muscle in congenital myopathies associated with RYR1 mutations. Neuromuscul Disord 14: 785–790. Jungbluth H, Sewry CA, Counsell S, et al. (2004b). Magnetic resonance imaging of muscle in nemaline myopathy. Neuromuscul Disord 14: 779–784. Jungbluth H, Zhou H, Bertini E, et al. (2005a). Autosomal dominant mutations in the human ryanodine receptor (RYR1) gene associated with centronuclear myopathy. Neuromuscul Disord 15: 681. Jungbluth H, Zhou H, Hartley L, et al. (2005b). Minicore myopathy with ophthalmoplegia caused by mutations in the ryanodine receptor type 1 gene. Neurology 65: 1930–1935. Kaimaktchiev V, Goebel H, Laing N, et al. (2006). Intranuclear nemaline rod myopathy. Muscle Nerve 34: 369–372. Kaindl AM, Ruschendorf F, Krause S, et al. (2004). Missense mutations of ACTA1 cause dominant congenital myopathy with cores. J Med Genet 41: 842–848. Kalita D (1989). Nonprogressive nemaline myopathy. J Orthomolec Med 4: 70–74. Kausch K, Lehmann-Horn F, Janka M, et al. (1991). Evidence for linkage of the central core disease locus to the proximal long arm of human chromosome 19. Genomics 10: 765–769. Keller CE, Hays AP, Rowland LP, et al. (2006). Adult-onset nemaline myopathy and monoclonal gammopathy. Arch Neurol 63: 132–134.
Kerst B, Mennerich D, Schuelke M, et al. (2000). Heterozygous myogenic factor 6 mutation associated with myopathy and severe course of Becker muscular dystrophy. Neuromuscul Disord 10: 572–577. Klein HH, Muller R, Vestergaard H, et al. (1999). Implications of compound heterozygous insulin receptor mutations in congenital muscle fiber type disproportion myopathy for the receptor kinase activation. Diabetologia 42: 245–249. Krakowiak PA, Bohnsack JF, Carey JC, et al. (1998). Clinical analysis of a variant of Freeman–Sheldon syndrome (DA2B). Am J Med Genet 76: 93–98. Kristiansen M, Knudsen GP, Tanner SM, et al. (2003). X-inactivation patterns in carriers of X-linked myotubular myopathy. Neuromuscul Disord 13: 468–471. Krivosic-Horber R, Depret T, Wagner JM, et al. (2004). Malignant hyperthermia susceptibility revealed by increased serum creatine kinase concentrations during statin treatment. Eur J Anaesthesiol 21: 572–574. Laing NG, Majda BT, Akkari PA, et al. (1992). Assignment of a gene (NEM1) for autosomal dominant nemaline myopathy to chromosome 1. Am J Hum Genet 50: 576–583. Laing NG, Wilton SD, Akkari PA, et al. (1995). A mutation in the a-tropomyosin gene TPM3 associated with autosomal dominant nemaline myopathy. Nat Genet 9: 75–79. Laing NG, Clarke NF, Dye DE, et al. (2004). Actin mutations are one cause of congenital fiber type disproportion. Ann Neurol 56: 689–694. Laing NG, Ceuterick-de Groote C, Dye DE, et al. (2005). Myosin storage myopathy: slow skeletal myosin (MYH7) mutation in two isolated cases. Neurology 64: 527–529. Lake BD, Wilson J (1975). Zebra body myopathy. Clinical, histochemical and ultrastructural studies. J Neurol Sci 24: 437–446. Lamminen AE (1990). Magnetic resonance imaging of primary skeletal muscle diseases: patterns of distribution and severity of involvement. Br J Radiol 63: 946–950. Lamont PJ, Dubowitz V, Landon DN, Davis et al. (1998). Fifty year follow-up of a patient with central core disease shows slow but definite progression. Neuromuscul Disord 8: 385–391. Lamont PJ, Udd B, Mastaglia FL, et al. (2006). Laing early onset distal myopathy: slow myosin defect with variable abnormalities on muscle biopsy. J Neurol Neurosurg Psychiatry 77: 208–215. Laporte J, Hu LJ, Kretz C, et al. (1996). A gene mutated in X-linked myotubular myopathy defines a new putative tyrosine phosphatase family conserved in yeast. Nat Genet 13: 175–182. Laporte J, Blondeau F, Buj-Bello A, et al. (2001a). The myotubularin family: from genetic disease to phosphoinositide metabolism. Trends Genet 17: 221–228. Laporte J, Kress W, Mandel JL (2001b). Diagnosis of X-linked myotubular myopathy by detection of myotubularin. Ann Neurol 50: 42–46. Luther PK, Squire JM (2002). Muscle Z-band ultrastructure: titin Z-repeats and Z-band periodicities do not match. J Mol Biol 319: 1157–1164.
CONGENITAL MYOPATHIES Lyfenko AD, Goonasekera SA, Dirksen RT (2004). Dynamic alterations in myoplasmic Ca2þ in malignant hyperthermia and central core disease. Biochem Biophys Res Commun 322: 1256–1266. Magee KR, Shy GM (1956). A new congenital non-progressive myopathy. Brain 79: 610–621. Marbini A, Gemignani F, Badiali L, et al. (1998). Congenital myopathy with mosaic fibers and interlacing sarcomeres: a new structural myopathy. Acta Neuropathol 96: 643–650. Martinez AJ, Hay S, McNeer KW (1976). Extraocular muscles: light microscopy and ultrastructural features. Acta Neuropathol 34: 237–253. Martinsson T, Oldfors A, Darin N, et al. (2000). Autosomal dominant myopathy: missense mutation (Glu-706 -> Lys) in the myosin heavy chain IIa gene. Proc Natl Acad Sci USA 97: 14614–14619. Masuzugawa S, Kuzuhara S, Narita Y, et al. (1997). Autosomal dominant hyaline body myopathy presenting as scapuloperoneal syndrome: clinical features and muscle pathology. Neurology 48: 253–257. Matthews K (2004). Multiminicore myopathy, central core disease, malignant hyperthermia susceptibility, and RYR1 mutations. One disease with many faces? Arch Neurol 61: 27–29. Maxwell MM, Pasinelli P, Kazantsev AG, et al. (2004). RNA interference-mediated silencing of mutant superoxide dismutase rescues cyclosporin A-induced death in cultured neuroblastoma cells. Proc Natl Acad Sci U S A 101: 3178–3183. McElhinny AS, Kazmierski ST, Labeit S, et al. (2003). Nebulin: the nebulous, multifunctional giant of striated muscle. Trends Cardiovasc Med 13: 195–201. McEntagart M, Parsons G, Buj-Bello A, et al. (2002). Genotype-phenotype correlations in X-linked myotubular myopathy. Neuromuscul Disord 12: 939–946. Meredith C, Herrmann R, Parry C, et al. (2004). Mutations in the slow skeletal muscle fiber myosin heavy chain gene (MYH7) cause Laing early-onset distal myopathy (MPD1). Am J Hum Genet 75: 703–708. Michele DE, Albayya FP, Metzger JM (1999). A nemaline myopathy mutation in alpha-tropomyosin causes defective regulation of striated muscle force production. J Clin Invest 104: 1575–1581. Millevoi S, Trombitas K, Kolmerer B, et al. (1998). Characterization of nebulette and nebulin and emerging concepts of their roles for vertebrate Z-discs. J Mol Biol 282: 111–123. Moghadaszadeh B, Petit N, Jaillard C, et al. (2001). Mutations in SEPN1 cause congenital muscular dystrophy with spinal rigidity and restrictive respiratory syndrome. Nat Genet 29: 17–18. Monnier N, Romero NB, Lerale J, et al. (2000). An autosomal dominant congenital myopathy with cores and rods is associated with a neomutation in the RYR1 gene encoding the skeletal muscle ryanodine receptor. Hum Mol Genet 9: 2599–2608. Monnier N, Romero NB, Lerale J, et al. (2001). Familial and sporadic forms of central core disease are associated
31
with mutations in the C-terminal domain of the skeletal muscle ryanodine receptor. Hum Mol Genet 10: 2581–2592. Monnier N, Ferreiro A, Marty I, et al. (2003). A homozygous splicing mutation causing a depletion of skeletal muscle RYR1 is associated with multi-minicore disease congenital myopathy with ophthalmoplegia. Hum Mol Genet 12: 1171–1178. Moraczewska J, Greenfield NJ, Liu Y, et al. (2000). Alteration of tropomyosin function and folding by a nemaline myopathy-causing mutation. Biophys J 79: 3217–3225. Mrak RE, Lange B, Brodsky MC (1993). Broad A bands of striated muscle in Leber’s congenital amaurosis: a new congenital myopathy? Neurology 43: 838–841. Mrak RE, Griebel M, Brodsky MC (1996). Broad A band disease: a new benign congenital myopathy. Muscle Nerve 19: 587–594. Muller-Felber W, Schlotter B, Topfer M, et al. (1999). Phenotypic variability in two brothers with sarcotubular myopathy. J Neurol 246: 408–411. Muntoni F, Sewry CA (2003). Central core disease: new findings in an old disease. Brain 126: 2339–2340. Nair-Shalliker V, Kee AJ, Joya JE, et al. (2004). Myofiber adaptational response to exercise in a mouse model of nemaline myopathy. Muscle Nerve 30: 470–480. North K (2004). Congenital myopathies. In: AG Engel, L Franzini-Armstrong (Eds.), Myology, Vol 2, McGraw-Hill, New York, pp. 1473–1533. Nowak KJ, Wattanasirichaigoon D, Goebel HH, et al. (1999). Mutations in the skeletal muscle alpha-actin gene in patients with actin myopathy and nemaline myopathy. Nature Genet 23: 208–212. Nowak KJ, Laing NG (2002). Sarcomeric protein congenital myopathies — can successful treatments be developed? In: J Bohl, (Ed.). Neuropathology — Back to the Roots Festschrift for Prof Dr Hans Goebel. Shaker Verlag, Aachen chapter 17. O’Flaherty P (2001). Arthrogryposis multiplex congenita. Neonatal Netw 20: 13–20. Osada H, Masuda K, Seki K, et al. (2004). Multi-minicore disease with susceptibility to malignant hyperthermia in pregnancy. Gynecol Obstet Invest 58: 32–35. Pallagi E, Molnar M, Molnar P, et al. (1998). Central core and nemaline rods in the same patient. Acta Neuropathol 96: 211–214. Pelin K, Hilpela P, Donner K, et al. (1999). Mutations in the nebulin gene associated with autosomal recessive nemaline myopathy. Proc Natl Acad Sci USA 96: 2305–2310. Petit N, Lescure A, Rederstorff M, et al. (2003). Selenoprotein N: an endoplasmic reticulum glycoprotein with an early developmental expression pattern. Hum Mol Genet 12: 1045–1053. Phillips MS, Fujii J, Khanna VK, et al. (1996). The structural organization of the human skeletal muscle ryanodine receptor (RYR1) gene. Genomics 34: 24–41. Pierson CR, Tomczak K, Agrawal P, et al. (2005). X-linked myotubular and centronuclear myopathies. J Neuropathol Exp Neurol 64: 555–564.
32
N. G. LAING ET AL.
Pourmand R, Azzarelli B (1994). Adult-onset of nemaline myopathy, associated with cores and abnormal mitochondria. Muscle Nerve 17: 1218–1220. Quane KA, Healy JMS, Keating KE, et al. (1993). Mutations in the ryanodine receptor gene in central core disease and malignant hyperthermia. Nature Genet 5: 51–55. Quane KA, Keating KE, Healy JMS, et al. (1994). Mutation screening of the RYR1 gene in malignant hyperthermia: detection of a novel tyr-ser mutation in a pedigree with associated central cores. Genomics 23: 236–239. Quinlivan RM, Muller CR, Davis M, et al. (2003). Central core disease: clinical, pathological, and genetic features. Arch Dis Child 88: 1051–1055. Riggs JE, Bodensteiner JB, Schochet SSJr. (1994). The dropped head sign: an unusual presentation of congenital myopathy. J Child Neurol 9: 330–331. Ringel SP, Neville HE, Duster MC, et al. (1978). A new congenital neuromuscular disease with trilaminar muscle fibers. Neurology 28: 282–289. Romero NB, Barois A, Leroy J-P, et al. (2003a). Homozygous nonsense mutation of the ACTA1 gene—clinical phenotype and muscle pathology. Neuromuscul Disord 13: 619. Romero NB, Monnier N, Viollet L, et al. (2003b). Dominant and recessive central core disease associated with RYR1 mutations and fetal akinesia. Brain 126: 2341–2349. Ryan MM, Schnell C, Strickland CD, Shield CD, et al. (2001). Nemaline myopathy: a clinical study of 143 cases. Ann Neurol 50: 312–320. Ryan MM, Ilkovski B, Strickland CD, et al. (2003). Clinical course correlates poorly with muscle pathology in nemaline myopathy. Neurology 60: 665–673. Sanoudou D, Haslett JN, Kho AT, et al. (2003). Expression profiling reveals altered satellite cell numbers and glycolytic enzyme transcription in nemaline myopathy muscle. Proc Natl Acad Sci U S A 100: 4666–4671. Sanoudou D, Frieden LA, Haslett JN, et al. (2004). Molecular classification of nemaline myopathies: “nontyping” specimens exhibit unique patterns of gene expression. Neurobiol Dis 15: 590–600. Sarnat HB (1990). Myotubular myopathy: arrest of morphogenesis of myofibers associated with persistence of fetal vimentin and desmin. Four cases compared with fetal and neonatal muscle. Can J Neurol Sci 17: 109–123. Sarnat HB (1992). Vimentin and desmin in maturing skeletal muscle and developmental myopathies. Neurology 42: 1616–1624. Sasaki T, Shikura K, Sugai K, et al. (1989). Muscle histochemistry in myotubular (centronuclear) myopathy. Brain Dev 11: 26–32. Scacheri PC, Hoffman EP, Fratkin JD, et al. (2000). A novel ryanodine receptor gene mutation causing both cores and rods in congenital myopathy. Neurology 55: 1689–1696. Schnell C, Kan A, North KN (2000). “An artefact gone awry”: identification of the first case of nemaline myopathy by Dr R.D.K. Reye. Neuromuscul Disord 10: 307–312. Schoser BG, Frosk P, Engel AG, et al. (2005). Commonality of TRIM32 mutation in causing sarcotubular myopathy and LGMD2H. Ann Neurol 57: 591–595.
Schroder R, Reimann J, Salmikangas P, et al. (2003). Beyond LGMD1A: myotilin is a component of central core lesions and nemaline rods. Neuromuscul Disord 13: 451–455. Seitz RJ, Toyka KV, Wechsler W (1984). Adult-onset mixed myopathy with nemaline rods, minicores, and central cores: a muscle disorder mimicking polymyositis. J Neurol 231: 103–108. Selcen D, Kupsky WJ, Benjamins D, et al. (2001). Myopathy with muscle spindle excess: a new congenital neuromuscular syndrome? Muscle Nerve 24: 138–143. Sewry CA (1998). The role of immunocytochemistry in congenital myopathies. Neuromuscul Disord 8: 394–400. Sewry CA (2002). Pathology in the congenital myopathies. Adv Clin Neurosci 12: 401–410. Sewry CA, Brown SC, Pelin K, et al. (2001). Abnormalities in the expression of nebulin in chromosome-2 linked nemaline myopathy. Neuromuscul Disord 11: 146–153. Sewry CA, Muller C, Davis M, et al. (2002). The spectrum of pathology in central core disease. Neuromuscul Disord 12: 930–938. Shafiq SA, Gorycki MA, Asiedu SA, et al. (1969). Tenotomy. Effect on the fine structure of the soleus of the rat. Arch Neurol 20: 625–633. Shingde MV, Spring PJ, Maxwell A, et al (2006). Myosin storage (hyaline body) myopathy: a case report. Neuromuscul Disord 16: 882–886. Shy GM, Engel WK, Somers JE, et al. (1963). Nemaline myopathy: a new congenital myopathy. Brain 86: 793–810. Smith ER, Heffernan LP, Sangalang VE, Vaughan VE, et al. (1976). Voluntary muscle involvement in hypertrophic cardiomyopathy. A study of eleven patients. Ann Intern Med 85: 566–572. Sobrido MJ, Fernandez JM, Fontoira E, et al. (2005). Autosomal dominant congenital fiber type disproportion: a clinicopathological and imaging study of a large family. Brain 128: 1716–1727. Sparrow JC, Nowak KJ, Durling HJ, et al. (2003). Muscle disease caused by mutations in the skeletal muscle alpha-actin gene (ACTA1). Neuromuscul Disord 13: 519–531. Sung SS, Brassington AM, Grannatt K, et al. (2003a). Mutations in genes encoding fast-twitch contractile proteins cause distal arthrogryposis syndromes. Am J Hum Genet 72: 681–690. Sung SS, Brassington AM, Krakowiak PA, et al. (2003b). Mutations in TNNT3 cause multiple congenital contractures: a second locus for distal arthrogryposis type 2B. Am J Hum Genet 73: 212–214. Sutton IJ, Winer JB, Norman AN, et al. (2001). Limb girdle and facial weakness in female carriers of X-linked myotubular myopathy mutations. Neurology 57: 900–902. Suwa K, Mizuguchi M, Momoi MY, et al. (2002). Co-existence of nemaline and cytoplasmic bodies in muscle of an infant with nemaline myopathy. Neuropathology 22: 294–298. Tajsharghi H, Thornell LE, Lindberg C, et al. (2003). Myosin storage myopathy associated with a heterozygous missense mutation in MYH7. Ann Neurol 54: 494–500.
CONGENITAL MYOPATHIES Tajsharghi H, Darin N, Rekabdar E, et al. (2005a). Mutations and sequence variation in the human myosin heavy chain IIa gene (MYH2). Eur J Hum Genet 13: 617–622. Tajsharghi H, Pilon M, Oldfors A (2005b). A Caenorhabditis elegans model of the myosin heavy chain IIa E706K mutation. Ann Neurol 58: 442–448. Takeshima H, Iino M, Takekura H, et al. (1994). Excitationcontraction uncoupling and muscular degeneration in mice lacking functional skeletal muscle ryanodine-receptor gene. Nature 369: 556–559. Tan P, Briner J, Boltshauser E, et al. (1999). Homozygosity for a nonsense mutation in the alpha-tropomyosin gene TPM3 in a patient with severe infantile nemaline myopathy. Neuromuscul Disord 9: 573–579. Tanner SM, Orstavik KH, Kristiansen M, et al. (1999). Skewed X-inactivation in a manifesting carrier of X-linked myotubular myopathy and in her non-manifesting carrier mother. Hum Genet 104: 249–253. Tilgen N, Zorzato F, Halliger-Keller B, et al. (2001). Identification of four novel mutations in the C-terminal membrane spanning domain of the ryanodine receptor 1: association with central core disease and alteration of calcium homeostasis. Hum Mol Genet 10: 2879–2887. Toydemir RM, Rutherford A, Whitby FG, et al. (2006). Mutations in embryonic myosin heavy chain (MYH3) cause Freeman–Sheldon syndrome and Sheldon–Hall syndrome. Nat Genet 38: 561–565. Tsai TC, Horinouchi H, Noguchi S, et al. (2005). Characterization of MTM1 mutations in 31 Japanese families with myotubular myopathy, including a patient carrying 240 kb deletion in Xq28 without male hypogenitalism. Neuromuscul Disord 15: 245–252. Venance SL, Koopman WJ, Miskie BA, et al. (2005). Rigid spine muscular dystrophy due to SEPN1 mutation presenting as cor pulmonale. Neurology 64: 395–396. Vestergaard H, Klein HH, Hansen T, et al. (1995). Severe insulin-resistant diabetes mellitus in patients with congenital muscle fiber type disproportion myopathy. J Clin Invest 95: 1925–1932. Veugelers M, Bressan M, McDermott DA, et al. (2004). Mutation of perinatal myosin heavy chain associated with a Carney complex variant. N Engl J Med 351: 460–469. Wallgren-Pettersson C, Laing NG (1996). Report on the 40th ENMC sponsored international workshop: nemaline myopathy. Neuromuscul Disord 6: 389–391. Wallgren-Pettersson C, Laing NG (2000). Report of the 70th ENMC International Workshop: Nemaline myopathy June 11–13 1999, Naarden, The Netherlands. Neuromuscul Disord 10: 299–306. Wallgren-Pettersson C, Laing NG (2001). 83rd ENMC International Workshop: 4th Workshop on Nemaline Myopathy. September 22–24 2000, Naarden, The Netherlands. Neuromuscul Disord 11: 589–595.
33
Wallgren-Pettersson C, Thomas NS (1994). Report on the 20th ENMC sponsored international workshop: myotubular/ centronuclear myopathy. Neuromuscul Disord 4: 71–74. Wallgren-Pettersson C, Kivisaari L, Jaaskelainen J, et al. (1990). Ultrasonography, CT, and MRI of muscles in congenital nemaline myopathy. Pediatr Neurol 6: 20–28. Wallgren-Pettersson C, Avela K, Marchand S, et al. (1995). A gene for autosomal recessive nemaline myopathy assigned to chromosome 2q by linkage analysis. Neuromuscul Disord 5: 441–443. Wallgren-Pettersson C, Pelin K, Hilpela P, et al. (1999). Clinical and genetic heterogeneity in autosomal recessive nemaline myopathy. Neuromuscul Disord 9: 564–572. Wallgren-Pettersson C, Donner K, Sewry C, et al. (2002). Mutations in the nebulin gene can cause severe congenital nemaline myopathy. Neuromuscul Disord 12: 674–679. Wallgren-Pettersson C, Bushby K, Mellies U, et al. (2004a). 117th ENMC workshop: ventilatory support in congenital neuromuscular disorders—congenital myopathies, congenital muscular dystrophies, congenital myotonic dystrophy and SMA (II) April 4–6 2003, Naarden, The Netherlands. Neuromuscul Disord 14: 56–69. Wallgren-Pettersson C, Pelin K, Nowak KJ, et al. (2004b). Genotype–phenotype correlations in nemaline myopathy caused by mutations in the genes for nebulin and skeletal muscle alpha-actin. Neuromuscul Disord 14: 461–470. Wattanasirichaigoon D, Swoboda KJ, Takada F, et al. (2002). Mutations of the slow muscle a-tropomyosin gene, TPM3, are a rare cause of nemaline myopathy. Neurology 59: 613–617. Weeks DA, Nixon RR, Kaimaktchiev V, et al. (2003). Intranuclear rod myopathy, a rare and morphologically striking variant of nemaline rod myopathy. Ultrastruct Pathol 27: 151–154. Weiss A, Schiaffino S, Leinwand LA (1999). Comparative sequence analysis of the complete human sarcomeric myosin heavy chain family: implications for functional diversity. J Mol Biol 290: 61–75. Yamaguchi M, Robson RM, Stromer MH, et al. (1982). Nemaline myopathy rod bodies: structure and composition. J Neurol Sci 56: 35–56. Yu S, Manson J, White S, Bourne S, et al. (2003). X-linked myotubular myopathy in a family with three adult survivors. Clin Genet 64: 148–152. Zhang Y, Chen HS, Khanna VK, et al. (1993). A mutation in the human ryanodine receptor gene associated with central core disease. Nat Genet 5: 46–50. Zuchner S, Noureddine M, Kennerson M, et al. (2005). Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot–Marie–Tooth disease. Nat Genet 37: 289–294.
Handbook of Clinical Neurology, Vol. 86 (3rd series) Myopathies F. L. Mastaglia, D. Hilton-Jones, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 2
Myopathies with early contractures MARIANNE DE VISSER* Department of Neurology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
2.1. Introduction A contracture is defined as fixed tightening of muscle, tendons, ligaments, or skin. It prevents normal movement of the associated body part and can cause permanent deformity. This chapter is confined to skeletal muscle contractures although there is no certainty about the nature of the contractures in the collagen VI myopathies, Bethlem myopathy and Ullrich congenital muscular dystrophy. In chronic progressive myopathies, contractures will ultimately develop due to longstanding muscle weakness. However, this chapter will focus on the early occurrence of contractures in myopathies. Readers are referred to chapter 1 on congenital myopathies, which includes a comprehensive discussion on those diseases associated with early contractures. Early-onset contractures, hypotonia, and muscle weakness in infants suggest a neuromuscular disease rather than central nervous system (CNS) dysfunction for which impaired visual alertness, convulsions, and abnormal movements are generally suggestive. A retrospective study of infants with hypotonia associated with muscle weakness (revealed by absent or reduced antigravity movements spontaneously or on stimulation) and/or contractures (Vasta et al., 2005) showed that the former was mainly found in infants with neuromuscular disorders (sensitivity and specificity: 97.4% and 75%, respectively). Contractures were also mainly found in infants with primary neuromuscular disorder, but sensitivity and specificity were lower than for weakness (sensitivity 69.2%, specificity 61.3%) as contractures were relatively frequent in infants with genetic or metabolic syndromes or in those who suffered a prenatal brain injury. Both isolated (mainly talipes) and multiple contractures could be found equally in neuromuscular disorders.
2.2. Muscular dystrophies 2.2.1. Dystrophinopathies In Duchenne and Becker muscular dystrophy Achilles tendon contractures are an early sign and considered a compensatory mechanism for weakness of the gluteus maximus muscles. Pes cavus was found in patients described by Becker (1962) and Bradley et al. (1978). Other contractures and scoliosis are usually seen only in advanced stages of the disease. Amongst the unusual phenotypes of dystrophinopathy a rare congenital-onset form has been described with floppiness at birth, delayed motor milestones, and calf hypertrophy (Kyriakides et al., 1994). By the age of 3 years there was severe proximal muscle and mild facial weakness and contractures of hips and knees. This phenotype is closer to congenital muscular dystrophy (CMD) than Duchenne muscular dystrophy (DMD), although calf hypertrophy is rare in CMD. 2.2.2. Limb girdle muscular dystrophies In most limb girdle muscular dystrophies (LGMD) contractures develop late in the course of the disease as in Duchenne and Becker muscular dystrophies. Since there is a clear relationship between weakness and the occurrence of contractures, patients with early-onset LGMD are tip-toe walkers associated with ankle contractures. 2.2.2.1. Autosomal recessive LGMD In the so-called contracted type of LGMD2A, caused by mutations in the calpain-3 gene, primary contractures of the finger flexors, hips, elbows and paraspinal muscles were most striking in young-onset patients (Fardeau
*Correspondence to: Dr. Marianne De Visser MD, PhD, Department of Neurology, Academic Medical Centre, Meibergdreef 9, NL - 1105 AZ Amsterdam, The Netherlands. Email:
[email protected], Tel: þ31-20-566-3445, Fax: þ31-20-697-1438.
36
M. DE VISSER
et al., 1996; Pollit et al., 2001; Mercuri et al., 2005). Diagnostic workup is mostly restricted to protein testing, and subsequently mutation analysis takes place in patients shown to have a protein deficiency. However, Fanin et al. (2004) point out that calpain-3 protein testing lacks complete specificity and sensitivity since calpain-3 protein deficiency may be found in patients with mutations in the dysferlin or titin gene and in patients with poorly conserved tissue samples (Anderson et al., 1998). Conversely, 20% of the patients with normal calpain-3 protein expression were found to have mutations (Fanin et al., 2004). Mercuri et al. (2005a) demonstrate that muscle imaging may be helpful in the differential diagnosis of patients with the contracted type of LGMD2A who show a significant overlap with autosomal dominant Emery– Dreifuss muscular dystrophy and Bethlem myopathy. Usually limb girdle muscular dystrophy type 2E, caused by mutations in the b-sarcoglycan (SBCB) gene, manifest with progressive muscle weakness. Cardiomyopathy may be present (Fanin et al., 2005), but early contractures are notably absent. Kaindl et al. (2005) describe a consanguineous East-Anatolian family suffering from a severe limb-girdle muscular dystrophy manifesting with delayed motor milestones and loss of ambulation in early childhood. In addition, some patients showed facial musculature involvement, and had facial dysmorphic features. All patients had scoliosis and joint contractures, in most of them combined with hyperlaxity of proximal metacarpophalangeal joints. The patients became wheelchair-dependent around the age of 10 years, and three patients died of heart failure. Muscle biopsy of the index patient revealed a severe dystrophic picture with normal dystrophin labeling and complete absence of both a-sarcoglycan and b-sarcoglycan due to a large (approximately 400 kb) microdeletion of chromosome 4q11–q12 including the SGCB gene. a-dystroglycan is a heavily glycosylated peripheral membrane component of the dystrophin-associated glycoprotein complex serving as a linker to the extracellular basal lamina, whereas b-dystroglycan is a transmembrane protein that interacts with dystrophin. Thus, dystroglycan plays an essential role in linking the intracellular cytoskeleton to components of the extracellular matrix. Disruption of this linkage is associated with several forms of muscular dystrophy (Michele et al., 2002). Mutations of a gene encoding a putative glycosyltransferase, fukutin-related protein (FKRP) were found to cause both limb girdle muscular dystrophy (LGMD2I) and congenital muscular dystrophy. In the former virtually no contractures are found, whereas this is a frequently observed feature in the latter (see section 2.3.2.3) A novel form of autosomal recessive slowly progressive limb girdle muscular dystrophy with mental
retardation and abnormal expression of a-dystroglycan was described by Dinc¸er et al. (2003). Half of the ambulant patients showed contractures of the Achilles tendons and one also had slight contractures at the elbows. All patients had microcephaly and mild to severe mental retardation, but none of them had epilepsy and morphological changes were not found on brain imaging. Mutations in the FKRP gene were not identified. Serum CK (sCK) activity was markedly elevated and muscle histology showed dystrophic changes and significantly reduced labeling for a-dystroglycan. 2.2.2.2. Autosomal dominant LGMD An autosomal-dominantly inherited mild late-onset form of LGMD (1G) mapping to chromosome 4q21 and associated with progressive finger and toe flexion limitation was found in a Brazilian-Caucasian family (Starling et al., 2004). Most of the patients showed these contractures in early stages of the disease. Although the reduced mobility hampered proper evaluation of muscle strength, the authors concluded that finger and toe extension was normal, as were the intrinsic hand muscles. The clinical phenotype of this new form of muscular dystrophy was otherwise comparable to that of other known forms of autosomal dominant LGMDs. Serum CK activity ranged from normal to 10 times the upper limit of normal. Muscle biopsy showed fiber size variation, necrotic fibers, rimmed vacuoles and scattered groups of small atrophic angulated fibers. Tanaka et al. (1998) reported a small Japanese family in which four males were affected in two generations compatible with an autosomal-dominant mode of inheritance. Consanguinity was not mentioned. All patients manifested with ankle joint contractures in the second or third decade and subsequently developed slowly progressive limb girdle muscle weakness and wasting leading to wheelchair dependency around the age of 40–50 years. In all sCK was markedly elevated (14–50 times the upper limit of normal). There was no cardiac involvement. Muscle biopsy was consistent with a muscular dystrophy. Linkage studies could not be performed. The authors compared the clinical picture in this family with LGMDs described in the literature and concluded that it had some features in common with LGMD1A, LGMD1B and Bethlem myopathy. At the time of publication of the paper, mutation analysis for neither disorder could be performed. 2.2.3. Bethlem myopathy This autosomal-dominantly inherited myopathy, first described by Jaap Bethlem and George van Wijngaarden, is characterized by early-onset slowly progressive
MYOPATHIES WITH EARLY CONTRACTURES muscle weakness and wasting associated with early contractures of multiple joints (Bethlem and Van Wijngaarden, 1976; Arts et al., 1978). In 1996, after a genome-wide search, Jo¨bsis et al. (1996a) found significant linkage with the COL6A1 and COL6A2 loci on 21q22.3. Subsequently, Speer et al. (1996) demonstrated that a French-Canadian family previously described by Mohire et al. (1988) was linked to the COL6A3 locus on 2q37. Subsequently, missense mutations in the COLVI genes either in regions encoding the triple helical or N-terminal globular domains (Jo¨bsis et al., 1996b) that were presumed to exert a dominant negative effect and frameshifting single base deletions resulting in haploinsufficiency of the a1(VI) subunit and hence in reduced expression of a structurally normal protein (Lamande´ et al., 1998) were identified. The number of causative mutations is rapidly expanding due to a new sequencing method (Lampe et al., 2005). 2.2.3.1. Clinical aspects There is a spectrum with prenatal onset with decreased fetal movements or congenital presentation with hypotonia and arthrogryposis, dislocated hips and/or torticollis at one end (Jo¨bsis et al., 1999) and presentation as late as the sixth decade (Somer et al., 1991) at the other. In most families the first symptoms occur in the first or second decade (Pepe et al., 2002). Childhood-onset Bethlem myopathy includes mildly delayed motor
37
milestones, atypical crawling, difficulty in rising from a squatting position, clumsy or waddling gait, toe walking, easy tripping with frequent falls, a diminished inability to run and climb stairs, and difficulty with school gymnastics (Arts et al., 1988; Mohire et al., 1988; Jo¨bsis et al., 1999; Scacheri et al., 2002). There is gradual progression of muscle weakness resulting in wheelchair dependency in two-thirds of the patients over the age of 50 years (Jo¨bsis et al., 1999; Scacheri et al., 2002). A minority of the patients with a severe form of Bethlem myopathy may stop walking as early as age 12 years (Mercuri et al., 2005). Both Haq et al. (1999) and Jo¨bsis et al. (1999b) described a patient who developed respiratory insufficiency, necessitating night-time ventilatory support. Autopsy studies (Bethlem and Van Wijngaarden, 1976; Mohire et al., 1988) revealed that the diaphragm is involved in the myopathic proces. Life expectancy is usually normal. The characteristic clinical picture includes mild, generalized, more or less symmetric muscle atrophy and weakness, proximal more than distal, and extensors weaker than flexors. Some patients are asymptomatic (Merlini et al., 1994). Flexion contractures at the interphalangeal joint of the last four fingers due to shortening of the flexor digitorum profundus muscle which are most striking when the wrists are fully extended are a hallmark of the disease (Fig. 2.1A). Contractures may appear at various joints in the upper and lower
Fig. 2.1. (A) Male patient with Bethlem myopathy. Note finger flexor contractures. (Reproduced from De Visser et al., 2004 with permission from McGraw-Hill). (B) Elbow contracture and wasting of the upper arm muscles in a male with Bethlem myopathy.
38
M. DE VISSER
extremities, but most commonly affect the deep finger flexors, the biceps brachii muscles (Fig. 2.1B) and the Achilles tendons. If patients show contractures of the erector spinae or posterior neck muscles leading to a rigid spine, or neck and elbow contractures, distinction from Emery–Dreifuss muscular dystrophy may be difficult (Lampe et al., 2005). Congenital dorsiflexion contractures at the ankles may appear in the congenitalonset form and are observed to disappear within several weeks to months (Jo¨bsis et al., 1999). In contrast, hypermobility of the wrists and fingers later evolving into contractures has also been observed in children. Several children exhibited laxity of the hip joints with an increased range of internal rotation (Jo¨bsis et al., 1999). Torticollis due to contracture of the sternocleidomastoid is present at birth or develops during the first years of life in 15% of the patients (Jo¨bsis et al., 1999). Some patients only show weakness and this may give rise to confusion with limb-girdle muscular dystrophy if it appears in sporadic patients (Pepe et al., 2002; Scacheri et al., 2002). Conversely, patients with a clinical picture dominated by contractures have also been described (Pepe et al., 1999a; Lucioli et al., 2005). Muscle hypertrophy is usually absent. Keloid formation is frequently observed (Lampe and Bushby, 2005). Cutaneous hyperlaxity is rare (Pepe et al., 1999a). Various cardiac investigations, including two autopsy studies (Bethlem and Van Wijngaarden, 1976; Mohire et al., 1988) revealed no significant abnormalities. 2.2.3.2. Laboratory features Additional laboratory tests, including estimation of serum sCK activity, electromyography (EMG), and histopathological examination of a muscle biopsy specimen usually yield non-specific results. Serum CK can be normal or slightly elevated (two- to five-fold above the upper limit of normal). Sometimes, an increase up to 15 times above the upper normal value is observed, particularly in young patients (Merlini et al., 1994). Electromyography is usually myopathic with an increased proportion of polyphasic potentials. Occasionally, there is spontaneous muscle fiber activity at rest (Scacheri et al., 2002). Imaging studies of muscle reveal diffuse replacement of skeletal muscle by fat starting at the periphery of individual muscles. Imaging studies showed selective and early involvement of the quadriceps with relative sparing of the gracilis, sartorius and adductor longus muscles (Somer et al., 1991; Nielsen and Jakobsen 1994; Mercuri et al., 2005a). The vastus lateralis muscle was the most frequently affected thigh muscle with a rim of abnormal signal at the periphery of each muscle and relative sparing of the central part. Another frequent finding was
the presence of a central area of abnormal signal within the rectus femoris muscle (Mercuri et al., 2005b). Muscle biopsy findings include abnormal variation in muscle fiber diameter, a moderate increase in fibers with internal nuclei, and increase fatty and fibrous connective tissue (Bethlem and Van Wijngaarden, 1976). The occasional necrotic fiber may be encountered (Merlini et al., 1994; Nielsen and Jakobsen 1994; Scacheri et al., 2002). Immunostains for collagen VI reveal no abnormality. In most fibroblast cultures from patients with Bethlem myopathy the immunofluorescence labeling pattern of type VI collagen is normal, but, in some cases there is reduced expression of collagen VI (Pepe et al., 1999a, 2002). In the chromosome 21-linked Bethlem myopathy there is a striking myofiber-specific deficiency of b1-laminin, a component of the basal lamina (Merlini et al., 1999). 2.2.3.3. Genetics Since all the above tests are non-specific and the clinical picture may show overlap with Emery–Dreifuss muscular dystrophy or limb-girdle muscular dystrophy, it is necessary to rely on genetic testing for a definite diagnosis. Recently, Lampe et al. (2005) have been able to identify 61% of all Bethlem myopathy cases using single-condition amplification/internal primer (SCAIP) sequencing. However, this method was also found to have limitations, namely the inability to detect large large exonic deletions (Pepe et al., 2006), and mutations located more distantly in the intron which cause altered splicing. There was a comparatively low detection rate in patients with mild Bethlem myopathy (22%) according to the authors, possibly due to overlap with other muscular dystrophies. Approximately 75% of the mutations are located in COL6A1, 10% in COL6A2 and 15% in COL6A3 (Jo¨bsis et al., 1996a; Pan et al., 1998; Pepe et al., 1999b; Lucioli et al., 2005). 2.2.3.4. Genotype–phenotype correlations Patients with the so-called classic Dutch phenotype, consisting of relatively benign childhood-onset progressive limb-girdle muscle wasting and weakness associated with early contractures were found to have mutations, in particular splicing mutations, localized in a “hot spot” between exon 3 and 14 corresponding to the COOH end of the NH2 globular domain and the NH2 end of the triple helix of the COL6A1 gene resulting in reduced amounts of collagen VI protein and microfibrils (Merlini et al., 1994; Lucioli et al., 2005). Virtually no Bethlem myopathy mutations have been documented in the C-terminal part of the triple helix. Conversely, a large number of recessively acting in-frame deletions in Ullrich congenital muscular
MYOPATHIES WITH EARLY CONTRACTURES dystrophy (UCMD) patients appear to cluster in the C-terminal triple helix (Lampe and Bushby, 2005). 2.2.3.5. Molecular pathogenesis (See reviews by De Visser et al., 2004 and by Lampe and Bushby, 2005.) Collagen VI is unique within the collagen superfamily in that the three a-chains associate intracellularly to form triple helical monomers, then form 6-chain dimers and 12-chain tetramers that are secreted from the cell. The triple helical monomers have large N- and C-terminal globules of several von Willebrand factor type A modules. After secretion, tetramers aggregate extracellularly into beaded collagen microfibrils with a distinctive 100-nm periodicity, in an end-to-end association by interaction of the globular domains with each other and with the triple helical domains (Kuo et al., 1995; Knupp et al., 2001). The assembly of microfibrils requires the presence of all three constituent chains. In the triple helix domain every third amino acid is a glycine enabling the tight turns of the peptides to form a helix. Breaking of the repeating Gly-Xaa-Yaa pattern by a single amino acid mutation results in subtle conformational alteration with local untwisting of the triple helix that interferes with proper network formation. The mechanism by which collagen VI mutations gives rise to Bethlem myopathy remains to be clarified. Missense mutations, involving single amino acid substitutions disrupting the Gly-Xaa-Yaa motif of the triple helical domain in COL6A1, COL6A2, or COL6A3 constitute a frequent pathogenic mechanism. These glycine mutations in the triple helix do not prevent association and folding of individual chains in the triple helix, or intracellular assembly of collagen VI monomers, dimers, or tetramers assembly, or the secretion of the assembled molecules, but cause a kink in the normally straight triple helix (Lamande´ et al., 2002). In addition, the formation of microfibrils from tetramers is impaired so that the amount of collagen VI in the extracellular matrix is reduced, reflecting a dominant negative effect. Splice-site mutations of COL6A1 result in premature stop codons or exon skipping and may cause haploinsufficiency when they are localized within domains flanking the triple helical domain (Lamande´ et al., 1998, 1999; Pepe et al., 1999b). Reduced synthesis of the a1(VI) chain limits the amount of collagen VI that can be assembled intracellularly into triple helical molecules that comprise a1(VI), a2(VI), and a3(VI) chains, and ultimately leads to a matrix containing reduced amounts of structurally normal collagen VI. Collagen VI has cell adhesion properties and interacts with several extracellular matrix proteins. The extended microfilament network formed by secreted collagen VI is abundant and close to the cells, consis-
39
tent with its role of anchoring the basement membrane to the underlying connective tissue (see reviews by De Vissar et al., 2004 and by Lampe and Bushby, 2005). Collagen VI is ubiquitously present in virtually all connective tissues, but patients with a collagen VI mutation exhibit only muscle weakness and contractures. Targeted disruption of COL6A1 in the mouse results in undetectable mRNA for a1(VI) but has no effect on mRNA levels for a2(VI) or a3(VI) mRNA. The cola1/ mice have a myopathy with abnormal variation in the size of muscle fibers, an increase in internal nuclei, necrosis and phagocytosis, and regeneration. However, these mice develop normally and showed no overt signs of disease (Bonaldo et al., 1998). The histologic abnormalities develop at an early stage and do not progress noticeably. The diaphragm is the most affected muscle, showing loss of contractile strength associated with ultrastructural abnormalities of the sarcoplasmatic reticulum and mitochondria, and spontaneous apoptosis (Irwin et al., 2003). The authors found a latent mitochondrial dysfunction in the myofibers of the mouse model that was reversible by addition of ciclosporin. The authors postulate that collagen VI myopathies may have a mitochondrial pathogenesis that could be exploited for therapeutic interventions. 2.2.3.6. Management Many patients receive physical therapy to prevent worsening of contractures although its efficacy has not been evaluated. Due to the dynamic nature of contractures in infancy, corrective surgery should be delayed unless the contractures interfere with development. Progressive weakness ultimately leads to disability necessitating additional aids, like a cane, adjustments at home, and wheelchair justifying consultation by a rehabilitation physician. Involvement of the respiratory muscles must be monitored during the disease. A proportion of ambulant patients may have diaphragmatic involvement, and therefore monitoring of the vital capacity, also measured in a supine position, and overnight pulse oximetry studies have to be performed on a regular basis (WallgrenPettersson et al., 2004). Symptoms of nocturnal hypoventilation respond well to non-invasive respiratory support such as mask ventilation. Prophylaxis with influenza and pneumococcal vaccination and physiotherapy, as well as early and aggressive use of antibiotics, may prevent chest infections (Wallgren-Pettersson et al., 2004). 2.2.4. Emery–Dreifuss muscular dystrophy 2.2.4.1. X-linked recessive form In 1961 and later in 1966 an unusual variant of the wellknown X-linked muscular dystrophies (Duchenne and Becker-type) was described with conspicuous atrophy
40
M. DE VISSER
of the upper arms, contractures at the elbows, absence of calf hypertrophy and intellectual impairment, and distinctive cardiac features (Dreifuss and Hogan, 1961; Emery and Dreifuss, 1966). It is likely that the first descriptions of the disease date back to the beginning of the 20th century (http://www.affari.com/smanet/edmd. htm). The gene locus for this entity, which is known as Emery–Dreifuss muscular dystrophy (EDMD), is located at Xq28, and the gene (STA) which is 2100 bp in length and consists of six exons, encodes a 254 amino acid serine-rich protein, identified as emerin (Bione et al., 1994). 2.2.4.1.1. Clinical aspects The disorder is characterized by the following set of clinical features (Yates, 1991; Emery, 2000): 1. Early contractures, often before there is any significant weakness, of the Achilles tendons, elbows and postcervical muscles (with subsequent limitation of neck flexion, but later forward flexion of the entire spine becomes limited). 2. Slowly progressive muscle wasting and weakness with a distinctive humero-peroneal distribution in the early stages of the disease. Weakness later extends to the proximal limb girdle musculature. Weakness is rarely profound. 3. Cardiomyopathy with cardiac conduction defects (ranging from sinus bradycardia to prolongation of the PR interval on electrocardiography to complete heart block). Atrial paralysis is almost pathognomonic of EDMD. The finding of a dilated right atrium on echocardiography and isolated atrial paralysis with absent “p” waves on electrocardiography should always prompt the exclusion of EDMD (Buckley et al., 1999). The intra- and interfamilial variability of the disease is broader than initially appreciated (Wehnert and Muntoni, 1999). The variability of the clinical severity in individual members of the same family appears to be much greater as compared to other forms of muscular dystrophy (even compared to Becker muscular dystrophy). Onset in the first few years of life is not exceptional (Wehnert and Muntoni, 1999; Talkop et al., 2002). Only very rarely is ambulation lost as a result of muscle weakness or contractures (Wehnert and Muntoni, 1999). Scoliosis is a rare feature but may occur (Wehnert and Muntoni, 1999). Very rare cases seem to be completely asymptomatic still in the fourth decade of life (Wehnert and Muntoni, 1999). The severity of heart disease does not correlate with the degree of skeletal muscle involvement. Sakata et al. (2005) described a Japanese family with X-linked recessive Emery–Dreifuss muscular dystrophy in which
patients died suddenly without prior cardiac or neuromuscular complaints. The living patients with cardiac involvement showed either no or mild muscle weakness and contractures were not present. Cardiac features usually occur in patients’ (early) teens or twenties, but a boy as young as age 5 in whom the heart was involved has been reported (Wehnert and Muntoni, 1999). Female carriers may have cardiac involvement as well (even causing sudden death), albeit usually at a later stage than male subjects (Fishbein et al., 2003; Sakata et al., 2005). There appears not to be an association with any sign of muscle weakness, wasting or contractures (Wehnert and Muntoni, 1999). Rare cases of females with the complete EDMD phenotype, as a result of skewed X-inactivation, can occur. Emery–Dreifuss muscular dystrophy affects the atria, and right heart involvement predominates. There is progressive replacement of the normal myocardium by fibrous and adipose tissue, which results in the loss of atrial contractility (atrial paralysis) and atrial dilatation. In due course the ventricles may become involved in the disease process, leading to progressive ventricular dilatation and, ultimately, ventricular failure (Fishbein et al., 2003). However, evidence of left ventricular dysfunction (in addition to the invariable involvement of the conduction system) was reported by some groups but not by others (Wehnert and Muntoni, 1999). 2.2.4.1.2. Laboratory features Serum CK activity is moderately to markedly elevated, but can be normal. Electromyography does not contribute to the diagnosis. Muscle histology may occasionally reveal frank dystrophic changes, but often there are only mild non-specific myopathic changes. Immunohistochemistry of muscle biopsy tissue, leucocytes, fibroblasts, or exfoliative buccal cells for emerin (XL-EDMD) can confirm the diagnosis. Reduction of laminin-b1 may be detected. In some cases electronmicroscopy showed abnormal distribution of heterochromatin in the nuclei (Sewry et al., 2001). 2.2.4.1.3. Genetics In 1999, a mutation database contained about a hundred mutations in the STA gene (Yates and Wehnert, 1999). Emerin mutations identified to date include a few missense mutations, and the majority are nonsense, splice site or small deletions/insertions that ultimately result in premature translation termination and complete absence of emerin expression on both Western blotting and immunohistochemistry. Rare cases with a reduced amount of the protein (due to a missense mutation) may have a milder phenotype (Yates et al., 1999). A complete
MYOPATHIES WITH EARLY CONTRACTURES deletion of the gene can result from an inversion within the Xq28 region (Small and Warren, 1998). Even normal residual expression of the protein has been reported in tissues other than skeletal muscle in patients with missense and promoter mutations. A normal emerin expression in skin and leukocytes does not therefore invariably rule out X-linked EDMD (Wehnert and Muntoni, 1999). 2.2.4.1.4. Molecular pathogenesis The biological function of the 34-kDa emerin protein which is expressed in different tissues (Manilal et al., 1996) and in all vertebrates remains to be elucidated. Emerin is conserved in evolution and is a LEM (lamina-associated polypeptide-emerin-MAN1) domain protein. The LEM-domain is a motif shared by a group of lamin-interacting proteins in the inner nuclear membrane and in the nucleoplasm. A major shared function of all characterized LEM-domain proteins is their binding (via the LEM domain) to a small protein named barrier-to-autointegration factor (BAF), a highly conserved chromatin-associated protein that cross-bridges DNA molecules and prevents viral autointegration (Zheng et al., 2000). Emerin binds not only directly to BAF, but also to MAN1, another LEM protein, and has a growing number of structural or anchoring partners, including a spectrin-repeat (SR) membrane protein named nesprin-1a, lamins A and C, and lamin B (see Holaska et al., 2004; and review by Hayashi, 2005). Dabauvalle et al. (1999) have shown that emerin, like lamin A, is involved in the early steps of nuclear envelope reassembly after mitosis. In order to understand the pathophysiology of emerin deficiency the same group (Gareiss et al., 2005) have chosen Xenopus laevis as a model organism to study the role of two emerin homologs (Xemerin1 and Xemerin2) in the nuclear envelope. The results showed that emerin is not relevant for organ development, particularly not of heart and skeletal muscle. The same authors hypothesize that MAN1, another transmembrane protein of the inner nuclear membrane, could functionally overlap with emerin and may rescue the lack of emerin. Holaska et al. (2004) showed that emerin is a pointedend F-actin-binding protein which implies a role of emerin in stabilization and formation of a nuclear actin cortical network contributing to the structural integrity of the nuclear envelope. There is also evidence that emerin may play a role in regeneration of muscle fibers (Squarzoni et al., 2005). In an animal model immunofluorescence, immunoblotting and mRNA analysis demonstrated that emerin level is increased in regenerating rat muscle.
41
2.2.4.1.5. Management With respect to the neuromuscular component of the disease the measures are rather non-specific and include physiotherapy, and referral to a rehabilitation physician for orthoses, occupational therapy to adjust to disabilities, surgery (Achilles tendons and scoliosis), and the preservation of respiratory function. The contractures in EDMD occur early and are not the result of prolonged immobilization, as in other dystrophies, which hampers treatment by physiotherapy and surgery. Since life expectancy is mainly determined by the cardiac complications, early detection of cardiac conduction defects and careful monitoring is of utmost importance. The insertion of a pacemaker may be lifesaving. However, in autosomal dominant (AD-EDMD caused by mutations of the LMNA gene, sudden death despite pacemaker implantation, presumably from ventricular arrhythmias has been described (van Berlo et al., 2005). Likewise, an implantable cardioverter-defibrillator may well be required for prevention of sudden death in some patients with the STA gene mutation. Heart transplantation has been used successfully in end-stage cardiomyopathy in EDMD (Kichuk Chrisant et al., 2004). Patients who display conduction disturbances or atrial cardiomyopathy, even when skeletal myopathy is absent, and at-risk family members are possible candidates for mutations in the STA gene, and it may prove worthwhile to screen such individuals for this condition. Carriers of the genetic abnormality should have a resting ECG, 24-hour ambulatory Holter monitoring, and echocardiography. If no cardiac abnormalities are found, repeat screening should take place, although there is no certainty as regards the optimal frequency. 2.2.4.2. Autosomal dominant form Autosomal dominant (and recessive) Emery–Dreifuss muscular dystrophy (AD-EDMD or EDMD2) is less frequent than X-EDMD and is caused by mutations in the LMNA gene on chromosome 1q11–q23 (Bonne et al., 1999; Di Barletta et al., 2000). Mutations in the LMNA gene encoding lamins A and C by alternative splicing cause primary laminopathies including various types of lipodystrophies, muscular dystrophies (EDMD2 and LGMD1B) and progeroid syndromes, mandibuloacral dysplasia, dilated cardiomyopathies, neuropathy, restrictive dermopathy, and arthropathy with tendinous calcifications. The secondary laminopathies are due to mutations in ZMPSTE24 gene which encodes for a zinc metalloproteinase involved in processing of prelamin A into mature lamin A and cause mandibuloacral dysplasia and restrictive dermopathy (see review by Jacob and Garg, 2006). Overlapping phenotypes have also been described (Van der Kooi et al., 2002).
42
M. DE VISSER
Lamins are the main components of the intermediate filament lamina, which lines the inner nuclear membrane. Lamin proteins have been shown to bind to chromatin and to several inner nuclear membrane proteins. The lamins are similar to cytoplasmic intermediate filaments such as keratins, neurofilaments, vimentin, and desmin. Like other intermediate filament proteins, lamins polymerize to form filaments. Similar to other cytoskeletal proteins, lamins are believed to play an important structural role. There are two major classes of lamins: A-type and B-type, which differ in their biochemical and structural properties. B-type lamins are essential for cell viability, and A-type lamins are only expressed in differentiated cells. In mammals, A-type lamins are different splice forms encoded by the LMNA gene. The main forms of A-type lamins in mammals are lamin A and lamin C (see review by Somech et al., 2005). 2.2.4.2.1. Clinical aspects Patients with AD-EDMD have a phenotype that is indistinguishable from that of XL-EDMD. The first reported patients with LGMD1B had no or only limited contractures and showed a limb-girdle distribution of muscle weakness (Van der Kooi et al., 1996). However, it is not unusual to find contractures in patients with LGMD1B indicating that there is a spectrum of muscle phenotypes due to mutations in the lamina A/C gene (Fig. 2.2). However, amongst a kindred with family members showing a LGMD1B-phenotype manifesting with limb-girdle pattern of muscle weakness associated with age-related rhythm disturbances necessitating pacemaker insertion and little or no contractures, a newborn from a consanguineous marriage with both parents affect was found to have severe contractures and muscle weakness causing his death immediately after birth (Van Engelen et al., 2005). The causative mutation was a LMNA nonsense mutation in a heterozygous state, except for the newborn child who had the mutation Y259X in a homozygous state. Not only do overlapping phenotypes occur, but intrafamilial variability also can be found with patients showing only cardiac involvement whereas the other family members had the full-blown EDMD picture (Bonne et al., 2000). Description of the other phenotypes caused by LMNA mutations are beyond the scope of this chapter (see review by Somech et al., 2005). 2.2.4.2.2. Laboratory features Serum creatine kinase is nomal or moderately elevated. Muscle biopsy shows non-specific myopathic or
dystrophic features. At the ultrastructural level structural abnormality of the inner nuclear membrane and that of adjacent fibrous lamina causing indistinctness of the inner nuclear membrane was found (Matsubara and Kitaguchi, 2004). 2.2.4.2.3. Genetics and genotype–phenotype correlations About 60–70% of the curently known LMNA gene mutations lead to striated muscle involvement (Decostre et al., 2005), including diseases affecting both skeletal and cardiac muscles and isolated cardiac muscle. Most of the approximately 40 different mutations in the LMNA gene known to cause EDMD2 are missense mutations, generally altering evolutionary conserved amino acids resulting in misfolding of the protein or failure to correctly assemble it, leading to partial or com¨ stlund plete loss of protein function (see review by O and Worman, 2003). There are also a few small in-frame deletions, a frameshift mutation, and one mutation changing amino acid 6 to a stop codon (see Leiden muscular dystrophy pages: www.dmd.nl).
Fig. 2.2. Female with LGMD1B. Note the rigid neck and exaggerated and fixed lumbar lordosis. (Courtesy of Dr Anneke J. van der Kooi, Academic Medical Centre, Department of Neurology, Amsterdam, The Netherlands).
MYOPATHIES WITH EARLY CONTRACTURES Emery–Dreifuss muscular dystrophy-2 mutations are found throughout the first 10 exons of LMNA, in regions encoding the 566 amino acids common to both lamin A and lamin C, with no clear correlation between the site of the mutation and the severity of the disease. There is as yet insufficient evidence to explain the complex pathogenesis of the various phenotypes with on the one hand mutations in the same gene giving rise to a wide spectrum of diseases, and on the other hand ubiquitously expressed genes giving rise to tissue-specific phenotypes. 2.2.4.2.4. Molecular pathogenesis (See review by Somech et al., 2005.) Homozygous knockout mice lacking LMNA are normal at birth but soon show signs of muscular dystrophy, with an abnormal gait and a hunched posture (Sullivan et al., 1999). The regional distribution of myopathy is similar to that seen in patients in EDMD, albeit that certain muscle groups, such as perivertebral muscles and those surrounding the femur are preferably affected. The mice also exhibit growth defects and cardiomyopathy. Within 8 weeks, all the homozygous knockout mice die. Heterozygous mice with one normal LMNA allele are indistinguishable from wild-type mice indicating that lamins are not necessary for development. Histological studies on muscle fibers from LMNA knockout mice show a phenotype similar to that in human subjects with EDMD. The LMNA-null mice exhibit tissue-specific alterations to their nuclear envelope integrity and mislocalization of emerin to the endoplasmatic reticulum, suggesting that lamin A/C plays a major role in retaining emerin at the inner membrane. A-type lamin is essential for maintaining the architecture and structural integrity of the nuclear envelope, and the observation that loss of A-type lamins causes both mechanical weakness and defects in mechanical-stress-dependent gene expression in vivo fed the mechanotransduction hypothesis. However, it does not explain the pathology of other tissues caused by LMNA mutations such as abnormal fat distribution in lipodystrophy and peripheral neuropathy in Charcot– Marie–Tooth disease. It may well be that mutations in a muscle-specific inner nuclear envelope protein, called nesprin-1a, which interacts with Lamin A/C and binds in vitro with emerin are also responsible for distortion of the cytoskeleton of the skeletal and cardiac muscle. Lamins seem to be important for the attachment of chromatin to the nuclear envelope, as heterochromatin is lost from the nuclear periphery in fibroblasts and myocytes from LMNA-knockout mice, and in
43
fibroblasts from patients with Hutchinson–Gilford progeria syndrome. Recent studies suggest that the mechanically stressed pathogenic cells first develop chromatin and nuclear envelope damage followed by alterations in the transcriptional activation of tissue specific genes.
2.3. Congenital muscular dystrophies Congenital muscular dystrophies (CMD) constitute a group of disorders characterized by early-onset muscular weakness and joint contractures, as well as dystrophic features identified by the morphological analysis of skeletal muscle. CMD is a common neuromuscular disorder based on epidemiological figures from a study in the north-east of Italy yielding an incidence of 4.65105 and a prevalence of 8106 (Mostacciuolo et al., 1996). The classification of CMD is a matter of debate (see review by Muntoni and Voit, 2004). CMD is usually subdivided on the basis of clinical features and country of origin. However, recent molecular genetic developments reveal that there is genetic heterogeneity in seemingly homogeneous phenotypes. Conversely, allelic mutations of one single gene can cause phenotypic variability. Therefore, Muntoni and Voit propose the following biochemical classification with the understanding that a number of CMD-variants are still in search of a gene: 1. Genes encoding for structural proteins of the basal membrane of the extracellular matrix of the skeletal muscle fibers. This includes: collagen VI genes causing Ullrich syndrome; laminin a2 chain causing merosin-deficient CMD, also known as MCDC1A, and integrin a7, giving rise to an extremely rare cause of CMD. Both Ullrich congenital muscular dystrophy and MCDC1A are characterized by muscle weakness and early contractures. 2. Genes encoding for putative or demonstrated glycosyltransferases, that in turn affect the glycosylation of dystroglycan, an external membrane protein of the basal membrane. Genes belonging to this category include: POMTGnT1 causing muscle–eye–brain disease and Walker–Warburg syndrome; fukutin causing Fukuyama CMD; fukutin-related protein (FKRP) causing MCD1C; LARGE causing MCD1D. Fukuyama disease and Walker–Warburg syndrome have early-onset contractures in addition to several other features. 3. Selenoprotein I, which encodes an endoplasmic reticulum protein of unknown function and gives rise to rigid spine syndrome with muscular dystrophy type 1 (RSMD1).
44
M. DE VISSER
2.3.1. Genes encoding for structural proteins of the basal membrane of the extracellular matrix of the skeletal muscle fibers 2.3.1.1. Ullrich congenital muscular dystrophy (UCMD) In 1930, Ullrich described a clinical picture characterized by a combination of congenital contractures of the proximal joints (Fig. 2.3A), hyperlaxity of the distal joints (Fig. 2.3C), kyphoscoliosis (Fig. 2.3B), muscle weakness, torticollis, and normal intelligence. This disorder was defined as scleroatonic muscular dystrophy. Italian research focused on molecular defects in the COL6 genes since the combination of joint contractures and distal hyperlaxity resembled clinical features observed in patients with Bethlem myopathy (Jo¨bsis
et al., 1999). The identification of recessive collagen VI mutations in patients with Ullrich CMD (Camacho Vanegas et al., 2001) led to the recognition of an increasing number of patients. 2.3.1.1.1. Clinical aspects Onset is either in the neonatal period with hypotonia or contractures or in the first months of life. Extended talipes, hip dislocation and torticollis may also be present (see review by Muntoni and Voit, 2004). There is great variability in motor function irrespective of the quantity of collagen VI on immunolabeling (Mercuri et al., 2000). Some are never able to walk (Mercuri et al., 2000; Ishikawa et al., 2002; Demir et al., 2004), others eventually achieve this motor milestone (Mercuri
Fig. 2.3. A–C Girl with Ullrich congenital muscular dystrophy. Note the elbow contracture, hyperlaxity and kyphoscoliosis for which she underwent surgery.
MYOPATHIES WITH EARLY CONTRACTURES et al., 2000; Baker et al., 2005), or are late walkers (Mercuri et al., 2000; Baker et al., 2005), but lose the ability to walk in due course, and there are less severe patients who are even able to run (Demir et al., 2004). Other features that have been described include peculiarities in facial appearance such as a round face, small chin and lips, irregular crowded teeth, large round eyes and prominent ears (Mercuri et al., 2000; Baker et al., 2005), but in contrast small eyes can also be observed. Other dysmorphic features include: high-arched palate, chest deformities (pectus excavatum or carinatum), posterior protrusion of the calcaneus, low-set anteverted ears and short neck (Demir et al., 2004). Signs of skin abnormalities, including abnormal scarring, mild hyperkeratosis and a reddish papular rash have often been noticed (Demir et al., 2004; Baker et al., 2005). Keloid formation at the site of suturing after surgery and softening of the skin in the palms and soles can also occur (Mercuri et al., 2000). Congenital contractures may improve or even disappear (Muntoni and Voit, 2004) with intense physiotherapy during the first years of life. However, they always recur and tend to worsen in proximal joints, especially in lower limbs (Demir et al., 2004). Ankle and feet hyperlaxity can convert into ankle contractures and/or equinovarus feet, requiring surgical correction and eventually leading to loss of ambulation. In milder cases contractures develop during the first decade (Demir et al., 2004). Progressive kyphoscoliosis that may require surgical correction is a frequent complication (Fig. 2.3B). In addition to contractures of the joints a rigid spine owing to contractures of the paraspinal extensors can often be encountered (Mercuri et al., 2000; Demir et al., 2004). All patients had generalized muscle weakness and wasting affecting the limbs (distal more than proximal), but also the neck musculature. Facial weakness is frequently present (Demir et al., 2004). Patients with severe muscle weakness almost invariably develop weakness of respiratory muscles necessitating ventilatory support in the first or second decade. If respiratory insufficiency escapes attention a pulmonary infection may well cause death (Demir et al., 2004). The severely weak and “dystrophic” patients develop a failure to thrive, which becomes more evident after age 10 and some require gastrostomy (Mercuri et al., 2000). Cardiac investigations including electrocardiography and echocardiography show no abnormalities (Mercuri et al., 2000). 2.3.1.1.2. Laboratory features Serum creatine kinase activity is usually normal or at the most four times the upper limit of normal (Mercuri et al., 2000; Demir et al., 2004; Baker et al., 2005).
45
Muscle pathology ranges from mildly myopathic to overtly dystrophic showing variation in size of the muscle fibers, signs of regeneration, necrotic fibers and an increase in endomysial connective tissue. Reduced or absent collagen VI labeling suggests a diagnosis of Ullrich CMD. Absence of collagen VI from the sarcolemma with presence of this protein in the interstitium has been observed in patients in whom no mutation in the COL6 genes could be identified (Ishikawa et al., 2004). These findings suggest that in these patients it is not the total absence of collagen VI from the muscle but the failure of collagen VI to anchor the basal lamina to the interstitium that is the cause of Ullrich disease. The authors suggest that the primary abnormality in most of the patients involved some other molecules, or alternatively non-coding regions of the collagen 6 gene. In contrast, normal collagen VI labeling can also be found in patients with the Ullrich CMD phenotype (Mercuri et al., 2000). Collagen VI immunolabeling studies on dermal fibroblast cultures appear to be more sensitive than muscle immunohistochemistry and can be a useful adjunct to diagnosis (Demir et al., 2004). Muscle imaging showed a pattern of muscle involvement which was different from Bethlem myopathy but there was a significant overlap between the two forms. In Ullrich CMD, there was diffuse involvement of the thigh muscles with relative sparing of sartorius, gracilis, and adductor longus and preservation of the central part of the vastus lateralis muscle. Another feature in common to the two forms of collagen VI related disorders is the presence, at calf level, of a rim of peripheral involvement between the soleus and the gastrocnemius muscles (Mercuri et al., 2005b). 2.3.1.1.3. Genetics and genotype–phenotype correlation (See review by Lampe and Bushby, 2005.) A large number of the mutations reported for patients with UCMD appear to result in premature termination codons with consequent nonsense-mediated mRNA decay and loss of the mutated chain. The premature termination codons occur either by direct introduction of a stop codon at the genomic level or through frameshift-inducing deletions, insertions, duplications and splice changes. Missense mutations substituting glycine in the triple helical GlyXaa-Yaa motif, other missense changes within the triple helical and C-terminal domains of COL6A2 and the N-terminal domains of COL6A3 and splice mutations leading to in-frame exonic deletions as well as in-frame genomic deletions located in the triple helical domains of COL6A1-3 as well as the C-terminal domains of COL6A2 have been reported (see review by Lampe and
46
M. DE VISSER
Bushby, 2005). The concept that UCMD is an autosomal-recessively inherited disease was challenged by the finding of a heterozygously occurring de novo large genomic deletion in COL6A1, which causes an in-frame deletion near the N-terminus of the triple helical domain exerting a dominant negative mechanism on microfibrillar assembly resulting in a dramatic reduction in the amount of extracellular collagen VI accounting for the classical UCMD phenotype (Pan et al., 2003). Currently, the number of dominant mutations is increasing (Baker et al., 2005). There are patients in whom no second mutation has been found. It may well be that these cases carry a second yet unidentified mutation, but an alternative explanation is that they have to be considered “severe Bethlem myopathy” which is of paramount importance with regard to genetic counseling (Lampe and Bushby, 2005). Thus, collagenVI myopathies seem to form a spectrum with the classical Dutch phenotype of Bethlem myopathy on the one end and classical Ullrich congenital muscular dystrophy on the other. 2.3.1.1.4. Management (See review by Lampe and Bushby, 2005). Active management as soon as the diagnosis is established is required to promote mobility and independence. Early mobilization in a standing frame and regular stretching and splinting are important to achieve upright posture and protect against the development of scoliosis and other contractures, although there is no evidence for the efficacy of these measures. The contractures tend to be relentlessly progressive and may require surgical release. Scoliosis often develops in the first or second decade of life and may require active management including spinal surgery to prevent progression. Respiratory failure is a common complication. Respiratory support with nocturnal ventilation usually becomes necessary in the first or second decade and can be effective in reducing symptoms, promoting quality of life, and allowing normal schooling. Prophylaxis with influenza and pneumococcal vaccination and physiotherapy, as well as early and aggressive use of antibiotics, may prevent chest infections and thus further respiratory problems. In addition, feeding difficulties can manifest as failure to thrive or excessive time taken to finish eating a meal. Consultation with a nutrition specialist may be needed; for serious problems, feeding by gastrostomy may be the best solution to promote a normal weight gain (Mercuri et al., 2000; Lampe and Bushby, 2005). 2.3.1.1.5. Prenatal diagnosis Haplotype analysis in combination with immunocytochemistry on chorion villus samples is a rapid and reliable
method for prenatal diagnosis of UCMD, provided the family is genetically informative and reduced collagen VI expression in the proband has been demonstrated (Brockington et al., 2004). 2.3.1.2. Congenital muscular dystrophy type MDC1A Primary deficiency of laminin a2 (merosin) accounts for approximately 30–40% of all patients with CMD in European countries and only 6% in Japan (Pegoraro et al., 1996; Allamand and Guicheny, 2002; Muntoni and Voit, 2004). This variant was initially identified by Fernando Tome´ and associates (1994) and called the classical, occidental-type CMD, or merosin-deficient CMD indicating the deficiency of the trimer formed by the combined expression of laminin a2, laminin b1 and laminin g1. Subsequent studies localized the disorder to the region of the laminin a2 (LAMA2) gene on chromosome 6q2 (Hillaire et al., 1994), and mutations in the corresponding gene were found shortly thereafter (Helbling-Leclerc et al., 1995). 2.3.1.2.1. Clinical aspects Congenital muscular dystrophy (CMD, MDCD1A) is an autosomal-recessive disorder which presents at birth or in the first 6 months of life with hypotonia and weakness (Philpot et al., 1995). Respiratory and feeding problems can also be present although not so severe as to require the need for ventilatory support at birth (Muntoni and Voit, 2004). Contractures can occur, but severe arthrogryposis is rare. In the early phases of the disorder calves may be firm, but the phenotype is more commonly an atrophic one. Weakness affects the limbs more proximally than distally, and axial muscles are severely affected as well (Fig. 2.4A). Limited ocular movements resulting in partial external ophthalmoplegia can be observed in the later stages (Muntoni and Voit, 2004). There is a delay or rather arrest in motor milestones. In rare cases, the maximum motor ability is walking with support. Often the children can stand with support and sit unsupported (Philpot et al., 1995; Muntoni and Voit, 2004). The disease course does not deteriorate change significantly in most cases; however, there is great variability between affected children (Philpot et al., 1995). Increased flexion deformity at the hips, knees, elbows and ankles, followed by rigidity and scoliosis of the spine occur almost invariably (Fig. 2.4A; Muntoni and Voit, 2004). Frequent complications in MDC1A include respiratory failure, feeding problems and failure to thrive (Muntoni and Voit, 2004). Severe restrictive respiratory syndrome and an increased risk of aspiration pneumonias determine the morbidity and mortality in this disorder. A mild to moderate left
MYOPATHIES WITH EARLY CONTRACTURES
47
Fig. 2.4. A Boy with MCDC1A; pectoral folds with severe shoulder weakness and multiple contractures. B MRI of the brain from the same patient showing prominent white matter changes.
ventricular hypokinesia is observed in a proportion of cases (Muntoni and Voit, 2004). 2.3.1.2.2. Laboratory features Serum creatine kinase activity is usually markedly elevated. Absence of laminin a2 from skeletal muscle gives rise to a dystrophic picture with massive muscle fiber necrosis and regeneration combined with an increase in endo- and perimysial connective tissue fibrosis that can be detected already immediately after birth (Tome´ et al., 1994). Prominent inflammatory infiltrate can lead to the erroneous diagnosis of congenital inflammatory myopathy (Pegoraro et al., 1996). From a diagnostic point of view, a wider panel of antibodies to different regions of the protein is required to avoid false positive or negative results, especially in cases where residual expression of the protein is found (Sewry et al., 1997). The C-terminal 80-kDa fragment of laminin a2 may be preserved whereas pronounced reduction of the 300kDa fragment can be demonstrated (Sewry et al., 1997). In patients with complete laminin a2 deficiency, a concomitant reduction of a-dystroglycan, laminin b2 and integrin a7 and upregulation of a4 and a5 chains in the basal lamina surrounding myofibers is found (see review by Muntoni and Voit, 2004). Abnormal expression of laminin a2 on Western blots occurs also in patients with fukutin related-protein gene defects who also show partial immunocytochemical
reduction of a-dystroglycan and laminin a2 (Bushby et al., 1998; Brockington et al., 2001). Similar secondary changes in laminin a2 chain expression can be found also in Walker–Warburg syndrome and Fukayama CMD. For reaching a diagnosis in patients with partial laminin a2 reduction it is necessary to therefore integrate clinical (brain imaging; motor nerve conduction velocity assessment) and molecular data into the diagnostic approach. Laminin a2 is also expressed at basement membrane at the junction of the dermis and epidermis in skin, and can therefore be used for diagnostic purposes (Sewry et al., 1996). Brain magnetic resonance imaging (MRI) studies invariably show white matter changes in patients with MDC1A after the age of 6 months (Lamer et al., 1998). Alterations consist of bilateral, symmetric, diffuse periventricular involvement of the white matter with white intensity on T2-weighted images (Fig. 2.4B). The arcuate fibers are involved to a lesser extent. Occipital areas are better preserved. High signal intensity can be seen in the external capsule. The internal capsule, corpus callosum, basal ganglia, and cerebellar white matter are spared. Using fast-spin echo MRI sequence, these changes can be demonstrated to be present at birth (Muntoni and Voit, 2004). To date, no patient with mutation-proven complete laminin a2 deficiency and normal white matter after age of 6 months has been reported
48
M. DE VISSER
(Muntoni and Voit, 2004), and therefore, brain MRI is a powerful diagnostic tool. In addition to the white-matter abnormalities, structural brain changes have been reported in some patients with complete or mutationproven partial laminin a2 deficiency. These included ventricular dilatation at the supratentorial level, cortical atrophy, and brainstem and vermis hypoplasia (Lamer et al., 1998) and occipital polymicrogyria/agyria (Philpot et al., 1999). Whenever present (about 5% of cases), occipital agyria is associated with mental retardation (cognitive function is otherwise normal in MDC1A) and epilepsy. This latter is a frequent complication of MDC1A and in the experience of Muntoni and Voit (2004) it can affect up to 30% of cases. Visual function is normal. Electrophysiological studies have however shown that visual and somatosensory evoked responses are usually abnormal in MDC1A (Muntoni and Voit, 2004). Children with MDC1A have a motor demyelinating neuropathy (Mercuri et al., 1996). Sensory nerve function is unaffected in young children (Muntoni and Voit, 2004), but involvement of these nerves can be demonstrated in older patients. 2.3.1.2.3. Genetics and genotype–phenotype correlations The LAMA2 gene mapped to chromosome 6q22–23 is composed of 64 exons. The resulting heterotrimeric protein laminin is a major component of the extracellular matrix and is composed of three different subunits: one heavy chain (a), and two light chains (b, g). The muscle-specific laminin isoform is a2b1g1 or laminin 2. The a2-chain consists of six domains: the N-terminal domain VI participates in polymerization and is important for integrin binding; domains V, IIIb and IIIa contain cystein-rich EGF-like repeats resulting in rigid, rod-like structures domain III is important for entactin/ nidogen binding; domains Vb and IVa are predicted to form globular structures while the laminin long arm binds to agrin. The coiled-coil forming domains II and I are important for the assembly of the heterotrimer, while the C-terminal end is formed by the G-domain, composed of five globular LG-modules which are important for binding cell-surface receptors. In particular, the LG domains 1–3 and 4–5 bind to a-dystroglycan, and this binding is also important for the induction of acetylcholine receptor clustering. In addition, the LG 4–5 modules are required for basement membrane assembly (reviewed in Muntoni and Voit, 2004). The laminin a2 chain is expressed in numerous tissues including skeletal muscle fibers, Schwann cells, synaptic basal lamina of peripheral nerves, heart, trophoblast and skin. The major role of laminin-a2 in the muscle is to interconnect the myofiber extracellular basal lamina
with the plasma membrane, mainly through dystroglycans. In laminin-a2-deficient individuals, the basal lamina is corrupted and the transmembrane cytoskeletal structure is lost, which leads to a dystrophic phenotype (Qiao et al., 2005). A wide spectrum of mutations including stop, missense, nonsense, splice and deletion mutations of the LAMA2 gene spread over the entire length of the gene and leading to complete or partial laminin a2 deficiency has been reported (Allamand and Guicheny, 2002; Muntoni and Voit, 2004). Most of the mutations are localized in the N-terminal domain (exons 1 – 31; Allamand and Guicheny, 2002) and are predicted to produce truncated proteins. According to Muntoni and Voit (2004) mutations precluding the synthesis of domains I and II, and/or of the G-domain, typically result in a severe phenotype. In total laminin a2 deficiency, many loss-of-function mutations have been reported, whereas in partial laminin a2 deficiency, many missense mutations are compatible with the production of a mutated laminin a2 protein in skeletal muscle (Allamand and Guicheny, 2002). However, there is a rare exception to the rule with a case with a homozygous loss-of-function mutation in the LAMA2 gene having a particularly mild clinical phenotype (Prandini et al., 2004). Conversely, disease in a small proportion of patients with partial laminin a2 deficiency follows a severe course, indistinguishable from complete deficiency (Muntoni and Voit, 2004). 2.3.1.2.4. Molecular pathogenesis The two commonly used animal models for laminin a2-deficient CMD are the result of spontaneous mutation including the ReJ dy/dy mouse which lacks laminin a2, and the C57BL6J/dy2J dystrophia muscularis mouse which has a truncated form of the laminin a2. This truncation results in a protein which lacks a portion of the domain VI, which is involved in laminin polymerization. Targeted null alleles have also been described recently (reviewed by Connolly et al., 2001). The mouse models present muscle pathology and dysmyelination of the peripheral nervous system due to a complete and partial deficiency in the a2 chain of laminin, respectively (Sunada et al., 1994; Connolly et al., 2001). The dy/dy mouse mimics both the genotype and clinical phenotype of children with CMD secondary to laminin a2 deficiency. Absence of laminin a2 from the skeletal muscle of mice results in a disruption of normal intracellular calcium homeostasis as well as deformities in skeletal muscle fibers (reviewed by Anderson et al., 2005). Laminin a2 immunoreactivity has been shown to be associated with neuronal processes, most evidently with
MYOPATHIES WITH EARLY CONTRACTURES neuronal fibers and punctate, potentially synaptic structures of the limbic brain region, and in neurite outgrowth and neuronal migration. Laminin a2 antigens are also reported to be present in dendritic spines in the hippocampus, with the first appearance in the developing rat brain corresponding to active synaptogenesis (reviewed by Anderson et al., 2005). A lack of laminin a2 in the cerebellum of dy2J mice is associated with a disruption in long-term synaptic plasticity. Since the cerebellum plays a role in motor function and in a variety of perceptual and cognitive functions, the functional deficit at the level of the synapse may play a role in the phenotypic signs of CNS origin in laminin a2-deficient patients (Anderson et al., 2005). Recent experiments show that overexpression of mini-agrin in skeletal muscle increases muscle integrity and regenerative capacity in laminin a2 mice regardless of the residual expression of laminin a2 (Bentzinger et al., 2005). Subsequently, Qiao et al. (2005) demonstrated that overexpression of a mouse mini-agrin gene by AAV vectors in two different mouse models of laminin-a2-deficient CMD ameliorated muscle pathology, decreased fibrosis, and restored the structure of the muscle myofiber basal lamina. Moreover, the dystrophic mice treated by somatic gene delivery obtained significant improvement in body growth, locomotor functions, and survival time. 2.3.1.2.5. Management There is no effective therapy currently available. Conservative management is usually preferred to orthopedic procedures and spinal surgery is often not a realistic option for these children. Treatment with night-time non-invasive positive pressure ventilation delivered by facemask relieves the symptoms of nocturnal hypoventilation which usually occurs at ages ranging from 5 years to early teens (Muntoni and Voit, 2004). Early speech and language and dietician input are indicated; gastrostomy should be considered in children who are failing to thrive or have swallowing difficulty (Muntoni and Voit, 2004). Prenatal diagnosis is available following molecular genetic studies and the immunostaining of the trophoblast, a tissue also expressing laminin a2 chain (Vainzof et al., 2005). 2.3.2. Genes encoding for putative or demonstrated glycosyltransferases 2.3.2.1. Fukuyama congenital muscular dystrophy (FCMD) Fukuyama congenital muscular dystrophy, an autosomal recessive disorder, was first described by Yukio Fukuyama from Japan in 1960. The disorder is
49
particularly frequent in Japan where its incidence is 40% of that of Duchenne muscular dystrophy, but is rare in Western countries (Toda et al., 2000). The molecular basis for the high frequency of FCMD in Japan is secondary to a founder mutation. 2.3.2.1.1. Clinical aspects The classical picture is the combination of generalized muscle weakness, severe brain involvement with mental retardation, frequent occurrence of seizures, and abnormal eye function. There is variability in clinical manifestations. First symptoms may occur in utero, with poor fetal movements, or at birth where asphyxia is not uncommon. At the other end of the spectrum are children who walk and live longer. Most of the children develop their symptoms before 9 months of age. The child is floppy, exhibits motor developmental delay and shows wasting and weakness of facial, neck and limb muscles. Severe arthrogryposis is unusual. Proximal muscles are relatively more affected than distal in the upper part of the body, and conversely, distal muscles, especially the calf muscles, worse than proximal in the lower extremities. Poor sucking and a mildly weak cry during the neonatal period have been noticed in about half of the cases, but severe feeding difficulty and respiratory distress are rare (Toda et al., 2000). Hip, knee, and ankle contractures generally appear before 1 year of age, and scoliosis develops around the age of 9 after the loss of independent sitting (Muntoni and Voit, 2004). Enlargement of the calves, forearms, quadriceps muscles and tongue is common (Toda et al., 2000; Muntoni and Voit, 2004). A tendency for the mouth to remain partially open is apparent from infancy. Functional disability is more severe in FCMD patients than in DMD patients; usually the maximum level of motor function achieved is sliding while sitting on the buttocks, and most FCMD patients are never able to walk unassisted. However, Muntoni and Voit (2004) often observe functional improvement and they state that most patients achieve standing with support. Patients usually become bedridden before 10 years of age due to generalized muscle atrophy and weakness and joint contractures, and most of them die by 20 years of age due to respiratory failure. Cardiac involvement (dilated cardiomyopathy) is observed in almost all patients and typically develops in the second decade of life (Muntoni and Voit, 2004). The brain abnormalities are more or less similar to those in other forms of a-dystroglycanopathy which include micropolygyria, pachygyria, (and agyria at the most severe end of the spectrum) of the cerebrum and cerebellum (type II lissencephaly) lacking neuronal lamination of the normal six-layered cortex. In addition,
50
M. DE VISSER
focal interhemispheric fusion, fibroglial proliferation of the leptomeninges, mild to moderate ventricular dilatation, and hypoplasia of the corticospinal tracts are also often observed. In all cases there is severe mental retardation with IQ scores between 30 and 50. Seizures occur in nearly half of the cases, in association with abnormal electroencephalograms (EEGs). About half of the patients with classical disease have ophthalmologic lesions including myopia, cataract, abnormal eye movements, pale optic disc and retinal detachment, though the patients are capable of making visual contact (Toda et al., 2000). 2.3.2.1.2. Laboratory features Serum creatine kinase is invariably markedly elevated. The skeletal muscle shows a combination of a degenerative process, with fibrosis from early infancy. Laminin a2 and several proteins of the dystrophin-associated glycoprotein complex were found to be abnormal in skeletal muscle of FCMD patients. Following the suggestion that fukutin was a glycosyltransferase, Hayashi et al. (2001) demonstrated a complete loss of glycosylated a-dystroglycan from FCMD muscle, identifying the involvement of this molecule as a possible substrate for the deficiency of a putative glycolsytransferase. In addition, abnormally glycosylated a-dystroglycan in FCMD has lost most of its laminin a2-, neurexin- and agrin-binding abilities. Electron microscopy confirms a disruption of the muscle fiber basal lamina (Ishii et al., 1997). Brain MRI shows always pachygyria in the cerebral cortex and transient T2-weighted high intensity in the white matter; and variable hypoplasia of the pons and cerebellar cysts. The high intensity in the white matter is thought to be due to delayed myelination that tends to diminish gradually with age (Barkovich, 1998; Muntoni and Voit, 2004). 2.3.2.1.3. Genetics Fukuyama congenital muscular dystrophy is caused by mutations of the fukutin gene on chromosome 9q31 (Kobayashi et al., 1998). Its protein product, fukutin, has sequence homologies with bacterial glycosyltransferase, but its precise function is unknown. A retrotransposal 3-kb insertion into the 30 non-coding region of the gene accounts for 87% of FCMD chromosomes and is considered to be a relatively mild mutation as it only partially reduces the stability of the full length mRNA. 2.3.2.1.4. Genotype–phenotype correlations The vast majority of patients have at least one copy of the founder fukutin mutation, the 3kb-retrotransposal insertion.
Fukutin-deficient chimeric mice show a severe phenotype which closely resembles Walker–Warburg syndrome (Takeda et al., 2003). In keeping with this interpretation, combined heterozygotes between this mutation and deletions or nonsense mutations have a more severe phenotype than individuals homozygous for the retrotransposon (Toda et al., 2000). Recently two non-Japanese patients with a severe Walker–Warburg syndrome-like phenotype due to functional null mutations in a homozygous state were reported illustrating that complete loss of fukutin function is compatible with life (Silan et al., 2003; Beltra´n-Valero de Bernabe´ et al., 2003). Remarkably, no FCMD patients with non-founder (point) mutations on both alleles of the gene were detected. Considering the fact that point mutations have been seen to render the FCMD phenotype rather severe, inactivation of both alleles by point mutations might be embryonic-lethal. This could explain why few FCMD cases are reported in non-Japanese populations 2.3.2.1.4. Molecular pathogenesis Targeted homozygous germline disruption of the fukutin gene in mice leads to lethality at embryonic day 9.5, prior to development of skeletal muscle, cardiac muscle or mature neurons, suggesting that fukutin is essential for early embryonic development (see review by Toda et al., 2005). The authors postulate that basement fragility may underlie embryonic lethality (Kobayashi et al., 2005). Mutant mice deficient in fukutin caused by targeted gene disruption developed neuronal migration disorder and ocular abnormality in addition to severe muscular dystrophy with selective deficiency of a-dystroglycan similar to FCMD patients. In these mice, Takeda et al. (2003) showed that fukutin is necessary for the maintenance of muscle integrity, cortical histiogenesis and normal ocular development. Injection of fukutin by electroporation showed restoration of a-dystroglycan suggesting the functional linkage between fukutin and a-dystroglycan. The brains of FCMD fetuses obtained after prenatal diagnosis, but also adult FCMD brains, were found to show extrusion of neuroglial tissue into the subarachnoid space through breaches in the glia limitans–basal lamina complex and this gives rise to the characteristic polymicrogyria. Histological and immunohistochemical examination of the developing forebrain of fukutindeficient chimeric mice showed ectopias as early as the 14th embryonic day and at the same time pial basement membrane defects could be detected (Toda et al., 2005). Immunohistochemical analysis of glycosylated a-dystroglycan showed progressive defects coinciding with the disruption of the pial basement membrane. Neuronal migration was not affected in chimeras. Therefore,
MYOPATHIES WITH EARLY CONTRACTURES the authors conclude that disruption of the pial basment membrane plays a key role in the pathogenesis of cortical dysplasia in Fukuyama CMD. Fukutin mRNA is expressed specifically in neurons within the prenatal developing brain, but not in glial cells (Chiyonobu et al., 2005) and predominant expression of fukutin in neurons of the normal developing brain was also found by immunohistochemistry. The immunoreactivity of fukutin was markedly reduced in brain from FCMD patients indicating that fukutin may play a role in the termination of neuronal migration (Saito et al., 2003). Saito et al. recently (2006) found altered glycosylation of a-dystroglycan in hippocampal neurons in FCMD brains. Fukutin immunolabeling was also decreased in these neurons. According to the authors these observations suggest that a fukutin protein defect may result in hypoglycosylation of neurons and that the pathogenesis of morphological and functional abnormalities in the FCMD brain should be explored in terms of the functional role of glycosylated a-dystroglan in neurons of developing and mature brains. 2.3.2.1.5. Management and prenatal diagnosis Treatment is supportive (see also section 2.3.1.1.4). Proper treatment of epilepsy in cases suffering from seizures is of course warranted. Genetic counseling is recommended for parents at risk of having a child with FCMD. In Japanese families, haplotype analysis using microsatellite markers is available. In non-Japanese families, DNA sequence analysis is available. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed (Saito, 2006). 2.3.2.2. Walker–Warburg syndrome Walker–Warburg syndrome (WWS) is the most severe a-dystroglycanopathy and associated with a life expectancy of less than 3 years (average 0.8 years; Van Reeuwijk et al., 2004). It is an autosomal recessive disorder described for the first time in 1942 by Walker, and later by Warburg in 1978. Characteristic features are congenital muscular dystrophy in combination with type II lissencephaly and eye abnormalities. Recent genetic data show a high degree of genetic heterogeneity (Beltra´n-Valero de Bernabe´ et al., 2002, 2003; Van Reeuwijk et al., 2005). So far four genes (POMT1, POMT2, fukutin and FKRP gene) have been implicated in WWS, but they account for only 30% of the cases (Van Reeuwijk et al., 2004). 2.3.2.2.1. Clinical aspects Walker–Warburg syndrome is an extremely severe condition. Characteristic brain anomalies include
51
hydrocephalus, neuronal overmigration causing a cobblestone cortex, lissencephaly, agenesis of the corpus callosum, fusion of the hemispheres, dilatation of the fourth ventricle, pontocerebellar hypoplasia and occasionally occipital encephalocele (Cormand et al., 2001). Hydrocephalus may require shunting when seizures occur frequently. In addition to the brain phenotype, patients are blind or have severe visual impairment resulting from a number of congenital ocular abnormalities, such as unilateral or bilateral microphthalmia, hypoplastic or absent optic nerves, ocular colobomas usually involving the retina and other retinal changes including retinal detachment. Anterior chamber malformations include cataracts, iris malformation or hypoplasia, and congenital or infantile glaucoma secondary to an abnormal anterior chamber angle (Muntoni and Voit, 2004). Patients with WWS have virtually no active movements due to the severe congenital muscular dystrophy. There is usually muscle hypoplasia and floppiness, and contractures may be present at birth or develop rapidly thereafter (Muntoni and Voit, 2004). Severe feeding difficulties are invariable and tube or gastrostomy feeding is required. Many children die within the first months of life (Cormand et al., 2001). 2.3.2.2.2. Laboratory features Serum creatine kinase activity is usually markedly elevated. Histopathological features of muscular dystrophy may be present at birth but in a few cases these changes were subtle and only became evident after a few months of life (Muntoni and Voit, 2004). Severe depletion of a-dystroglycan is found in skeletal muscle tissue of patients with WWS (Beltra´n-Valero de Bernabe´ et al., 2002; Jimene´z-Mallebrera et al., 2003) and also in nerve (Sabatelli et al., 2003). Laminin a2 chain, perlecan and integrin a7B can be reduced in muscle fibers, but are normally expressed in intramuscular peripheral nerve (Sabatelli et al., 2003). The same group found alterations in the basal lamina and the nucleus at the ultrastructural level including detachment from the plasma membrane, focal loss and interruptions, and alterations of heterochromatin organization and they suggest that a complex pathogenetic mechanism, affecting several subcellular compartments, underlies the degenerative process in WWS muscle. On MRI there is a severe diffuse cobblestone aspect of the cortex, complete absence of cerebral and cerebellar myelin, cerebellar polymicrogyria (with or without cysts), pontine and cerebellar vermal hypoplasia, hydrocephalus, and variable callosal hypogenesis (Barkovich, 1998).
52
M. DE VISSER
Pathological studies confirm the cobblestone type of lissencephaly, resulting from a large number of undifferentiated neurons migrating through the pial surface, forming leptomeningeal heterotopia in the subarachnoid space, complete loss of cortical layering accompanied by a markedly abnormal vascular architecture both on the surface of the brain and in the cortex. Differentiation between WWS, MEB and FCMD can be made by examination of the brain architecture using imaging techniques like MRI and computerized tomography (CT) scanning or by post-mortem examination (Barkovich, 1998; Cormand et al., 2001). 2.3.2.2.3. Genetics The presumptive diagnosis of WWS is based on clinical (congenital hypotonia and weakness, retinal malformation), radiological (type II lissencephaly, cerebellar malformation) and pathological observations (congenital muscular dystrophy; Jime´nez-Mallebrera et al., 2003). Patients with WWS can be diagnosed prenatally by ultrasound because of severe hydrocephalus (Cormand et al., 2001). Mutations in the O-mannosyltransferase 1 (POMT1) gene were first identified (Beltra´n-Valero de Bernabe´ et al., 2002). The incidence can be as high as 20% (Beltra´n-Valero de Bernabe´ et al., 2002) and as low as 7% (Currier et al., 2005). Protein glycosylation is a highly complex mechanism by which sugars are sequentially added to proteins at the endoplasmic reticulum and the Golgi apparatus. This post-translational process modulates protein stability, conformation, and function and has been implicated in cell adhesion, growth and differentiation. The proteinattached glycans are divided into two groups on the basis of their linkage site: the N-glycans are linked to an asparagine residue of the target protein, whereas the O-glycans are attached through a serine or a threonine. Among the O-mannosylated proteins that have been identified is a-dystroglycan. All of the O-mannosyl glycans sequences identified, although diverse, share the common motif galactose-b-1, 4-N-acetylglucosamine-b-1, 2-mannose-O-Ser/Thr (Galb1 4GlcNAcb1 2Man-OSer/Thr; O-mannose-linked core). So far, O-mannose-linked glycosylation has been observed only in brain, peripheral nerve and muscle glycoproteins. POMT1 catalyses the first step in O-mannosyl glycan synthesis. A second putative O-mannosyltransferase, POMT2, shows an expression pattern in adults that overlaps with POMT1. Both POMT1 and POMT2 form a complex which confers the enzymatic O-mannosyltransferase activity. a-Dystroglycan immunolabeling is severely reduced in patients with POMT1 and POMT2-linked WWS (Beltra´n-Valero de Bernabe´
et al., 2002; Jime´nez-Mallebrera et al., 2003; Van Reeuwijk et al., 2005). Among other genes responsible for WWS, there are both the fukutin (Silan et al., 2003; Beltra´n-Valero de Bernabe´ et al., 2003; see section 2.3.2.1.4) and FKRP gene (Beltra´n-Valero de Bernabe´ et al., 2004; see section 2.3.2.3.3), but they only account for a fraction of WWS cases. Recently homozygous mutations in the POMT2 gene at 14q24.3 were reported, resulting in a phenotype similar to that caused by POMT1 mutations and in severely reduced levels of glycosylated a-dystroglycan (Van Reeuwijk et al., 2005). Genome-wide linkage analyses by the Nijmegen group conducted on consanguineous WWS families point to further genetic heterogeneity (Van Reeuwijk et al., 2005). 2.3.2.3. FKRP gene-related congenital muscular dystrophy/congenital muscular dystrophy 1C The FKRP gene is a homolog of the fukutin gene encoding for fukutin-related protein. It has been localized in the Golgi apparatus and is involved in the glycosylation processing of a-dystroglycan. It is ubiquitously expressed. Mutations in the fukutin-related protein gene (FKRP) located on chromosome 19q13 give rise to a spectrum of phenotypes, including a form of congenital muscular dystrophy (MDC1C), WWS phenotype and a relatively mild form of limb-girdle muscular dystrophy (LGMD2I). FKRP is a putative glycosyltransferase whose function is uncertain. There is strong evidence that FKRP is involved in the glycosylation of a-dystroglycan on the basis of abnormal glycosylation of a-dystroglycan expression on skeletal muscle biopsy specimens. The degree of abnormal glycosylation roughly correlates with the disease severity. In Western countries, and in particular in the UK, FKRP-related myopathies are very common. 2.3.2.3.1. Clinical aspects of MDC1C Children present at birth or in the first few weeks of life with hypotonia, weakness and feeding difficulties. Motor milestones are usually not achieved, or at best the child is able to take a few steps if supported. Weakness and wasting are often more pronounced in the shoulder girdle and proximal arm muscles as compared to the legs and facial muscles and sternomastoid muscles are often affected. Calf muscles and sometimes quadriceps muscles are hypertrophic. The tongue can become enlarged in due course, usually in the second decade. Although there is no arthrogryposis, Achilles tendons and hip flexors are often tight (Mercuri et al., 2003). Respiratory muscle involvement is the rule rather than the exception and can result in respiratory failure necessitating assisted ventilation or even lead to sudden
MYOPATHIES WITH EARLY CONTRACTURES death due to respiratory infections, typically in the second decade. Feeding difficulties may necessitate gastrostomy (Brockington et al., 2001). Cognitive development is usually normal. However, recently reported cases of MDC1C with mental deterioration and white matter changes and/or cerebellar structural abnormalities (cysts, atrophy) have been described (Topaloglu et al., 2003; Louhichi et al., 2004). Cardiac involvement, manifesting with impairment of the left ventricle function leading to dilated cardiomyopathy, is observed in a proportion of cases. 2.3.2.3.2. Laboratory features Serum CK activity is markedly elevated. Brain MRI is usually normal, but both Topaloglu et al. (2003) and Mercuri et al. (2006) have described patients with structural changes on MRI including cerebellar cysts, either isolated or in combination with vermal hypoplasia and white matter abnormalities, or other structural changes in the posterior fossa, cortex or both. Muscle biopsy shows severe dystrophic changes and reduction of laminin a2. There is severe reduction or absence of a-dystroglycan and preservation of b-dystroglycan, dystrophin and perlecan both by immunohistochemistry and on immunoblot analysis. Muntoni’s group (Mercuri et al., 2000) identified 10 different mutations, nonsense and missense, in the FKRP-gene. 2.3.2.3.3. Genetics and phenotype-genotype correlations Patients with MCD1C were found to be either compound heterozygotes of one missense and one nonsense mutation or harboring a homozygous nonsense mutation, whereas the patients with LGMD2I with onset from 1.5 years onwards usually had missense mutations, although rarely a compound heterozygote with a missense and a nonsense mutation could also be found. The missense mutations causing MDC1C associated with brain abnormalities were found to reside in sequences encoding the putative catalytic (C-terminal) domain of the gene where other mutations giving rise to severe MDC1C cases without brain involvement have also been identified (Louhichi et al., 2004). In contrast, the equally severely affected cases described by Topaloglu et al. (2003) were found outside this catalytic domain. In patients with MCD1C there is typically a more severe reduction in a-dystroglycan, as compared to LGMD2I, with a Duchenne-like severity. Individuals with the milder form of LGMD2I showed a variable but subtle alteration in a-dystroglycan immunolabeling (Brown et al., 2004). Recently Beltra´n-Valero de Bernabe´ et al. (2004) reported two cases with mutations in the FKRP-gene
53
which had a phenotype indistinguishable from muscle– eye–brain disease and Walker–Warburg syndrome, respectively, thus demonstrating that some FKRPmutations can give rise to structural brain and eye abnormalities. The same holds true for Topaloglu’s cases of congenital muscular dystrophy with mental retardation and cerebellar cysts (2003). 2.3.2.3.4. Management See section 2.3.1.1.4 2.3.2.4. Congenital muscular dystrophy with severe mental retardation and abnormal glycosylation/ MDC1D The spontaneously arising mutation in the LARGE gene encoding a putative bifunctional glycosyltransferase, Large, found in the myodystrophy (myd; now renamed Largemyd) mouse causes loss of function reflected by a profound loss of muscle a-dystroglycan. Homozygous Largemyd mice display a severe, autosomal-recessively inherited progressive muscular dystrophy including involvement of the diaphragm and the tongue, and a mild cardiomyopathy associated with a reduced lifespan, in addition to retinal abnormalities, sensorineural deafness, and central nervous system involvement. Abnormalities in neuronal migration are observed in the brain particularly the cortex and cerebellum which is similar to that seen in fukutin-deficient mice (Holzfeind et al., 2002; Grewal et al., 2003; Muntoni and Voit, 2004). So far, one human with mutations in the human homolog of this gene (LARGE) mapped to chromosome 22q13 has been reported, and the disease was named MDC1D. The patient presented at age 5 months with hypotonia and profound psychomotor retardation. Clinical examination showed a limb-girdle distribution of muscle weakness, muscle hypertrophy, flexion contractures of the fingers and elbows, adduction of the thumbs and tight Achilles tendons, involvement of the facial muscles, and pyramidal features including spasticity. Vision was normal, but electroretinography was abnormal. Cardiac function was not impaired. Brain MRI showed extensive periventricular white-matter changes and mild structural changes of the brainstem and of the gyral surface indicative of a neuronal migration disorder (Longman et al., 2003). Serum creatine kinase was markedly elevated. The patient was found to harbor compound heterozygote mutations within the putative catalytic domain of the LARGE gene giving rise to reduction of a-dystroglycan in the muscle biopsy specimen. 2.3.2.5. CMD variants For characteristics of CMD variants without identified genetic defects, see review by Muntoni and Voit (2004).
54
M. DE VISSER
2.4. Miscellaneous 2.4.1. Congenital myotonic dystrophy Myotonic dystrophy may have a congenital onset with neonatal hypotonia and weakness, talipes (club feet) at birth and thin ribs. The disease is usually transmitted by the mother. However, if (subtle) clinical features of the disease in the mother are not appreciated diagnosis in the newborn can be difficult. Hydramnios and reduced fetal movements during pregnancy are frequent. Swallowing and respiratory symptoms can be lifethreatening post partum. Prognosis is determined by the duration of artificial ventilation. If the children survive the neonatal period they initially follow a static course, and eventually learn to walk, but with significant mental retardation in 60–70% of cases. By age 10 they develop myotonia and in adulthood develop the additional complications described for the adultonset disease. Roig et al. (1994) reported long-term follow-up of 18 patients diagnosed with congenital myotonic dystrophy. Three of the 18 had died, and five were lost to follow-up. The remaining 10 had IQs of less than 65. Universal findings were language delay, hypotonia, and delayed motor development. 2.4.2. Congenital myopathy with muscle spindle excess Selcen et al. (2001) reported a weak and hypotonic neonate with arthrogryposis (flexion contractures at the wrists, adducted thumbs with metacarpophalangeal joint contractures and bilateral club feet) who developed respiratory insufficiency and hypertrophic cardiomyoapthy and succumbed at the age of 14 months. Serum creatine kinase activity was normal. Muscle biopsy revealed marked excess of muscle spindles with atrophy of extrafusal fibers. At autopsy other skeletal muscles were shown to have similar findings although the deltoids and quadriceps femoris muscles were the most affected. Additional findings were enlargement of brain, liver and kidneys and a congenital neuroblastoma which had been surgically removed. The authors identified one such case in the literature, albeit that the patient in question had Noonan syndrome which was not the case in the case described by Selcen et al. 2.4.3. Tel Hashomer camptodactyly syndrome (THCS) Tel Hashomer camptodactyly syndrome (THCS) is a rare disorder comprising camptodactyly, hypotonia and muscle hypoplasia, skeletal dysplasia, inguinal hernia and mitral valve prolapse and abnormal dermatoglyphics.
Melegh et al. (2005) described a mentally retarded Hungarian boy who was diagnosed with THCS at age 4 months. Features compatible with skeletal muscle and/ or connective tissue involvement include high-arched palate, hypoplastic and hypotonic muscles, scapulae alatae, thoracic scoliosis, clubfeet, and rigid campodactyly of fingers 2–5. Serum creatine kinase activity was two times the upper limit of normal. Muscle biopsy showed only abnormalities at the ultrastructural level, i.e., irregularities of the transverse tubuli of the sarcoplasmic reticulum and some morphological abnormalities of mitochondria. 2.4.4. Reducing body myopathy Goebel et al. (2001) described a bedridden 21-year old man who developed a rigid spine at the age of 7 years. At that time he was also found to have tight Achilles tendons. Muscle strength was normal. Ancillary investigations revealed a slightly elevated serum creatine kinase activity and a myopathic electromyogram. Subsequently, his muscle strength deteriorated and at the age of 8 years he became wheelchair-bound. Thereafter, he developed contractures of all his major joints. Heart was normal and so was mentation. His maternal grandmother had late-onset distal muscle weakness and wasting starting in the legs. The boy’s muscle biopsy, taken at age 7, showed a myopathy, type I fibers were smaller than the hypertrophic type 2 fibers and multiple fibers showed inclusions including reducing bodies. Inclusions were found in his grandmother’s muscle biopsy, but reducing bodies were not present. His asymptomatic mother’s muscle biopsy showed a non-specific myopathy.
References Allamand V, Guicheny P (2002). Merosin-deficient congenital muscular dystrophy, autosomal recessive (MDC1A, MIM#156225, LAMA2 gene coding for a2 chain of laminin). Eur J Hum Genet 10: 91–94. Anderson LVB, Davison K, Moss JA, et al. (1998). Characterisation of monoclonal antibodies to calpain 3 and protein expression in muscle from patients with limb girdle muscular dystrophy type 2A. Am J Pathol 153: 1169–1179. Anderson JL, Head SI, Morley JW (2005). Synaptic plasticity in the dy2J mouse model of laminin a2-deficient congenital muscular dystrophy. Brain Res 1042: 23–28. Arts WF, Bethlem J, Volkers WS (1978). Further investigations on benign myopathy with autosomal dominant inheritance. J Neurol 217: 201–206. Baker NL, Mo¨rgelin M, Peat R, et al. (2005). Dominant collagen VI mutations are a common cause of Ullrich congenital muscular dystrophy. Hum Mol Genet 14: 279–293.
MYOPATHIES WITH EARLY CONTRACTURES Barkovich AJ (1998). Neuroimaging manifestations and classification of congenital muscular dystrophies. Am J Neuroradiol 19: 1389–1396. Becker PE (1962). Two families of benign sex-linked recessive muscular dystrophy. Rev Can Biol 21: 551–566. Beltra´n-Valero de Bernabe´ D, Currier S, Steinbrecher A, et al. (2002). Mutations in the O-Mannosyltransferase Gene POMT1 give rise to the severe neuronal migration disorder Walker–Warburg syndrome. Am J Hum Genet 71: 1033–1043. Beltra´n-Valero de Bernabe´ D, van Bokhoven H, van Beusekom E, et al. (2003). A homozygous nonsense mutation in the fukutin gene causes a Walker–Warburg syndrome phenotype. J Med Genet 40: 845–848. Beltra´n-Valero de Bernabe´ D, Voit T, Longman C, et al. (2004). Mutations in the FKRP gene can cause muscle– eye–brain disease and Walker–Warburg syndrome. J Med Genet 41: e61. Bentzinger CF, Barzaghi P, Lin S, et al. (2005). Overexpression of mini-agrin in skeletal muscle increases muscle integrity and regenerative capacity in laminin-a-2-deficient mice. FASEB J 19: 934–942. Bethlem J, van Wijngaarden GK (1976). Benign myopathy, with autosomal dominant inheritance. A report on three pedigrees. Brain 99: 91–100. Bione S, Maestrini E, Rivella S, et al. (1994). Identification of a novel X-linked gene responsible for Emery–Dreifuss muscular dystrophy. Nat Genet 8: 323–327. Bonaldo P, Braghetta P, Zanetti M, et al. (1998). Collagen VI deficiency induces early onset myopathy in the mouse: an animal model for Bethlem myopathy. Hum Mol Genet 7: 2135–2140. Bonne G, Di Barletta MR, Varnous S, et al. (1999). Mutations in the gene encoding lamin A/C cause autosomal dominant Emery–Dreifuss muscular dystrophy. Nat Genet 21: 285–288. Bonne G, Mercuri E, Muchir A, et al. (2000). Clinical and molecular genetic spectrum of autosomal dominant Emery–Dreifuss muscular dystrophy due to mutations of the lamin A/C gene. Ann Neurol 48: 170–180. Bradley WG, Jones MZ, Mussini JM, et al. (1978). Beckertype muscular dystrophy. Muscle Nerve 1: 111–132. Brockington M, Blake DJ, Prandini P, et al. (2001). Mutations in the fukutin-related protein gene (FKRP) cause a form of congenital muscular dystrophy with secondary laminin a2 deficiency and abnormal glycosylation of adystroglycan. Am J Hum Genet 69: 1198–1209. Brockington B, Brown SC, Lampe A, et al. (2004). Prenatal diagnosis of Ullrich congenital muscular dystrophy using haplotype analysis and collagen VI immunocytochemistry. Prenat Diagn 24: 440–444. Brown SC, Torelli S, Brockington M, et al. (2004). Abnormalities in alpha-dystroglycan expression in MDC1C and LGMD2I muscular dystrophies. Am J Pathol 164: 727–737. Buckley AE, Dean J, Mahy IR (1999). Cardiac involvement in Emery Dreifuss muscular dystrophy: a case series. Heart 82: 105–108.
55
Bushby K, Anderson LV, Pollit C, et al. (1998). Abnormal merosin in adults. A new form of late onset muscular dystrophy not linked to chromosome 6q2. Brain 121: 581–588. Camacho Vanegas O, Bertini E, Zhang RZ, et al. (2001). Ullrich scleroatonic muscular dystrophy is caused by recessive mutations in collagen type VI. Proc Natl Acad Sci U S A 98: 7516–7521. Chiyonobu T, Sasaki J, Nagai Y, et al. (2005). Effects of fukutin deficiency in the developing mouse brain. Neuromuscul Disord 15: 416–426. Connolly AM, Keeling RM, Mehta S, et al. (2001). Three mouse models of muscular dystrophy: the natural history of strength and fatigue in dystrophin-, dystrophin/utrophin-, and laminin a2-deficient mice. Neuromuscul Disord 11: 703–712. Cormand B, Pihko H, Baye´s M, et al. (2001). Clinical and genetic distinction between Walker–Warburg syndrome and muscle–eye–brain disease. Neurology 56: 1059–1069. Currier SC, Lee CK, Chang BS, et al. (2005). Mutations in POMT1 are found in a minority of patients with Walker– Warburg syndrome. Am J Med Genet 133A: 53–57. Dabauvalle MC, Mu¨ller E, Ewald A, et al. (1999). Distribution of emerin during the cell cycle. Eur J Cell Biol 78: 749–756. Decostre V, Ben Yaou R, Bonne G (2005). Laminopathies affecting skeletal and cardiac muscles: clinical and pathophysiological aspects. Acta Myol 24: 104–109. Demir E, Ferreiro A, Sabatelli P, et al. (2004). Colagen VI status and clinical severity in Ullrich muscular dystrophy: phenotype analysis of 11 families linked to the COL6 loci. Neuropediatrics 35: 103–112. De Visser M, van der Kooi A, Jo¨bsis GJ (2004). Bethlem myopathy. In: AG Engel, C Franzini-Armstrong (Eds.), Myology. McGraw-Hill, New York, pp. 1135–1146. Di Barletta RM, Ricci E, Galluzzi G, et al. (2000). Different mutations in the LMNA gene cause autosomal dominant and autosomal recessive Emery–Dreifuss muscular dystrophy. Am J Hum Genet 66: 1407–1412. Dinc¸er P, Balci B, Yuva Y, et al. (2003). A novel form of recessive limb girdle muscular dystrophy with mental retardation and abnormal expression of a-dystroglycan. Neuromuscul Disord 13: 771–778. Dreifuss FE, Hogan GH (1961). Survival in X-chromosomal muscular dystrophy. Neurology 11: 734–737. Emery AE (2000). Emery–Dreifuss muscular dystrophy — a 40 year retrospective. Neuromuscul Disord 10: 228–232. Emery AEH, Dreifuss FE (1966). Unusual type of benign Xlinked muscular dystrophy. J Neurol Neurosurg Psychiatry 29: 338–342. Fanin M, Fulizio L, Nascimbeni AC, et al. (2004). Molecular diagnosis in LGMD2A: mutation analysis or protein testing? Hum Mutat 24: 52–62. Fardeau M, Eymard B, Mignard C, et al. (1996). Chromosome 15-linked limb-girdle muscular dystrophy: clinical phenotypes in Re´union Island and French metropolitan communities. Neuromuscul Disord 6: 447–453. Fishbein MC, Siegel RJ, Thompson CE, et al. (1993). Sudden death of a carrier of X-linked Emery–Dreifuss muscular dystrophy. Ann Intern Med 119: 900–905.
56
M. DE VISSER
Gareiss M, Eberhardt K, Kruger E, et al. (2005). Emerin expression in early development of Xenopus laevis. Eur J Cell Biol 84: 295–309. Gacos KN, Garg A (2006). Lammopathies: multi system dystrophy syndromes. Mol genet Metab 87: 289–302. Goebel HH, Halbig LE, Goldfarb L, et al. (2001). Reducing body myopathy with cytoplasmic bodies and rigid spine syndrome: a mixed congenital myopathy. Neuropediatrics 32: 196–205. Haq RU, Speer MC, Chu ML, et al. (1999). Respiratory muscle involvement in Bethlem myopathy. Neurology 52: 174–176. Hayashi YK (2005). X-linked form of Emery–Dreifuss muscular dystrophy. Acta Myol 24: 98–103. Hayashi YK, Ogawa M, Tagawa K, et al. (2001). Selective deficiency of alpha-dystroglycan in Fukuyama-type congenital muscular dystrophy. Neurology 57: 115–121. Helbling-Leclerc A, Zhang X, Topaloglu H, et al. (1995). Mutations in the laminin alpha 2-chain gene (LAMA2) cause merosin-deficient congenital muscular dystrophy. Nat Genet 11: 216–218. Hillaire D, Leclerc A, Faure´ S, et al. (1994). Localization of merosin-negative congenital muscular dystrophy to chromosome 6q2 by homozygosity mapping. Hum Mol Genet 3: 1657–1661. Holaska JM, Kowalski AK, Wilson KL (2004). Emerin caps the pointed end of actin filaments: evidence for an actin cortical network at the nuclear inner membrane. PLoS Biol 2: e231. Holzfeind PJ, Grewal PK, Reitsamer HA, et al. (2002). Skeletal, cardiac and tongue muscle pathology, defective retinal transmission, and neuronal migration defects in the Largemyd mouse defines a natural model for glycosylation-deficient muscle–eye–brain disorders. Hum Mol Genet 11: 2673–2687. Irwin WA, Bergamin N, Sabatelli P, et al. (2003). Mitochondrial dysfunction and apoptosis in myopathic mice with collagen VI deficiency. Nat Genet 35: 367–371. Ishii H, Hayashi YK, Nonaka I, et al. (1997). Electron microscopic examination of basal lamina in Fukuyama congenital muscular dystrophy. Neuromuscul Disord 7: 191–197. Ishikawa H, Sugie K, Murayama K, et al. (2002). Ullrich disease: collagen VI deficiency: EM suggests a new basis for muscular weakness. Neurology 59: 920–923. Ishikawa H, Sugie K, Murayama K, et al. (2004). Ullrich disease due to deficiency of collagen VI in the sarcolemma. Neurology 62: 620–623. Jacob KN, Garg A (2006). Laminopathies: multi-system dystrophy syndromes. Mol Genet Metab 87: 289–302. Jime´nez-Mallebrera C, Torelli S, Brown SC, et al. (2003). Profound skeletal muscle depletion of a-dystroglycan in Walker–Warburg syndrome. Eur J Paediatr Neurol 7: 129–137. Jo¨bsis GJ, Bolhuis PA, Boers JM, et al. (1996). Genetic localization of Bethlem myopathy. Neurology 46: 779–782. Jo¨bsis GJ, Keizers H, Vreijling JP, et al. (1996). Type VI collagen mutations in Bethlem myopathy, an autosomal dominant myopathy with contractures. Nat Genet 14: 113–115.
Jo¨bsis GJ, Boers JM, Barth PG, et al. (1999). Bethlem myopathy: a slowly progressive congenital muscular dystrophy with contractures. Brain 122: 649–655. Kichuk Chrisant MR, Drummond-Webb J, Hallowell S, et al. (2004). Cardiac transplantation in twins with autosomal dominant Emery–Dreifuss muscular dystrophy. J Heart Lung Transplant 23: 496–498. Kobayashi K, Nakahori Y, Miyake M, et al. (1998). An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy. Nature 394: 388–392. Kyriakides T, Gabriel G, Drousioutou A, et al. (1994). Dytrophinopathy presenting as congenital muscular dystrophy. Neuromuscul Disord 4: 387–392. Lamande´ SR, Sigalas E, Pan TC, et al. (1998). The role of the alpha 3(VI) chain in collagen VI assembly. J Biol Chem 273: 7423–7430. Lamande´ SR, Morgelin M, Selan C, et al. (2002). Kinked collagen VI tetramers and reduced microfibril formation as a result of Bethlem myopathy and introduced triple helical glycine mutations. J Biol Chem 277: 1849–1856. Lamer S, Carlier R-Y, Pinard J-M, et al. (1998). Congenital muscular dystrophy: use of brain MR imaging findings to predict merosin deficiency. Radiology 206: 811–816. Lampe AK, Bushby KMD (2005). Collagen VI related muscle disorders. J Med Genet 42: 673–685. Lampe AK, Hoogendijk JE, Eagle M, et al. (2005). Bethlem myopathy, autosomal dominant and X-linked Emery Dreifuss muscular dystrophy — comparison of contractural phenotypes. Neuromuscul Disord 15: 729. Louhichi N, Triki C, Quijano-Roy S, et al. (2004). New FKRP mutations causing congenital muscular dystrophy associated with mental retardation and central nervous system abnormalities. Identification of a founder mutation in Tunesian families. Neurogenetics 5: 27–34. Lucioli S, Giusti B, Mercuri E, et al. (2005). Detection of common and private mutations in the COL6A1 gene of patients with Bethlem myopathy. Neurology 64: 1931–1937. Manilal S, Nguyen TM, Sewry CA, et al. (1996). The Emery– Dreifuss muscular dystrophy protein, emerin, is a nuclear membrane protein. Human Molecular Genetics 5: 801–808. Matsubara S, Kitaguchi T (2004). Pathological changes of the myonuclear fibrous lamina and internal nuclear membrane in two cases of autosomal dominant limb-girdle muscular dystrophy with atrioventricular conduction disturbance (LGMD1B). Acta Neuropathol 107: 111–118. Melegh B, Hollo´dy K, Aszmann M, et al. (2005). Tel Hashomer camptodactyly syndrome: 12-year follow-up of a Hungarian patient and review. Am J Med Genet 135A: 320–323. Mercuri E, Pennock J, Goodwin F, et al. (1996). Sequential study of central and peripheral nervous system involvement in an infant with merosin-deficient congenital muscular dystrophy. Neuromuscul Disord 6: 425–429. Mercuri E, Sewry CA, Brown SC (2000). Congenital muscular dystrophy with secondary merosin deficiency and normal brain MRI: a novel entity? Neuropediatrics 31: 186–189. Mercuri E, Brockington M, Straub V, et al. (2003). Phenotypic spectrum associated with mutations in the fukutinrelated protein gene. Ann Neurol 53: 537–542.
MYOPATHIES WITH EARLY CONTRACTURES Mercuri E, Bushby K, Ricci E, et al. (2005a). Muscle MRI findings in patients with limb girdle muscular dystrophy with calpain 3 deficiency (LGMD2A) and early contractures. Neuromuscul Disord 15: 164–171. Mercuri E, Lampe A, Allsop J, et al. (2005b). Muscle MRI in Ullrich congenital muscular dystrophy and Bethlem myopathy. Neuromuscul Disord 15: 303–310. Mercuri AE, Topaloglu H, Brockington M, et al. (2006). Spectrum of brain changes in patients with congenital muscular dystrophy and FKRP gene mutations. Arch Neurol 63: 251–257. Merlini L, Morandi L, Granata C, et al. (1994). Bethlem myopathy: early-onset benign autosomal dominant myopathy with contractures. Description of two new families. Neuromuscul Disord 4: 503–511. Merlini L, Villanova M, Sabatelli P, et al. (1999). Decreased expression of laminin beta 1 in chromosome 21-linked Bethlem myopathy. Neuromuscul Disord 9: 326–329. Michele DE, Barresi R, Kanagawa M, et al. (2002). Posttranslational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies. Nature 418: 417–422. Mohire MD, Tandan R, Fries TJ, et al. (1988). Early onset benign autosomal dominant limb-girdle myopathy with contractures (Bethlem myopathy). Neurology 38: 573–580. Mostacciuolo ML, Miorin M, Martinello F, et al. (1996). Genetic epidemiology of congenital muscular dystrophy in a sample from north-east Italy. Hum Genet 97: 277–279. Muntoni F, Voit T (2004). The congenital muscular dystrophies in 2004: a century of exciting progress. Neuromuscul Disord 14: 635–649. Nielsen JF, Jakobsen J (1994). A Danish family with limbgirdle muscular dystrophy with autosomal dominant inheritance. Neuromuscul Disord 4: 139–142. ¨ stlund C, Worman HJ (2003). Nuclear envelope proteins O and neuromuscular diseases. Muscle Nerve 27: 393–406. Pan T-C, Zhang R-Z, Pericak-Vance MA, et al. (1998). Missense mutation in a von Willebrand facor type A domain of the a3(VI) collagen gene (COL6A3) in a family with Bethlem myopathy. Hum Mol Genet 7: 807–812. Pan T-C, Zhang R-Z, Sudano DG, et al. (2003). New molecular mechanism for Ullrich congenital muscular dystrophy: a heterozygous in-frame deletion in the COL6A1 gene causes a severe phenotype. Am J Hum Genet 73: 355–369. Pegoraro E, Mancias P, Swerdlow SH, et al. (1996). Congenital muscular dystrophy with primary laminin alpha2 (merosin) deficiency presenting as inflammatory myopathy. Ann Neurol 40: 782–791. Pepe G, Giusti B, Bertini E, et al. (1999a). A heterozygous splice site mutation in COL6A1 leading to an in-frame deletion of the alpha1(VI) collagen chain in an italian family affected by Bethlem myopathy. Biochem Biophys Res Commun 258: 802–807. Pepe G, Bertini E, Giusti B, et al. (1999b). A novel de novo mutation in the triple helix of the COL6A3 gene in a twogeneration Italian family affected by Bethlem myopathy.
57
A diagnostic approach in the mutations’ screening of type VI collagen. Neuromuscul Disord 9: 264–271. Pepe G, de Visser M, Bertini E, et al. (2002). Bethlem myopathy (BETHLEM) 86th ENMC International Workshop, 10–11 November 2000, Naarden, the Netherlands. Neuromuscul Disord 12: 296–305. Pepe G, Lucarini L, Zhang R-Z, et al. (2006). COL6A1 genomic deletions in Bethlem myopathy and Ullrich muscular dystrophy. Ann Neurol 59: 190–195. Philpot J, Sewry C, Pennock J, et al. (1995). Clinical phenotype in congenital muscular dystrophy: correlation with expression of merosin in skeletal muscle. Neuromuscul Disord 5: 301–305. Philpot J, Cowan F, Pennock J, et al. (1999). Merosin-deficient congenital muscular dystrophy: the spectrum of brain involvement on magnetic resonance imaging. Neuromuscul Disord 9: 81–85. Prandini P, Berardinelli A, Fanin M, et al. (2004). LAMA2 loss-of-function mutation in a girl with a mild congenital muscular dystrophy. Neurology 63: 1118–1121. Qiao C, Li J, Zhu T, et al. (2005). Amelioration of laminina2-deficient congenital muscular dystrophy by somatic gene transfer of miniagrin. Proc Natl Acad Sci U S A 102: 11999–12004. Roig M, Balliu PR, Navarro C, et al. (1994). Presentation, clinical course, and outcome of the congenital form of myotonic dystrophy. Pediatr Neurol 11: 208–213. Sabatelli P, Columbaro M, Mura I, et al. (2003). Extracellular matrix and nuclear abnormalities in skeletal muscle of a patient with Walker–Warburg syndrome caused by POMT1 mutation. Biochim Biophys Acta 1638: 57–62. Saito K (2006). Prenatal diagnosis of Fukuyama congenital muscular dystrophy. Prenat Diagn 26: 415–417. Saito Y, Kobayashi M, Itoh M, et al. (2003). Aberrant neuronal migration in the brainstem of Fukuyama-type congenital muscular dystrophy. J Neuropathol Exp Neurol 62: 497–508. Saito Y, Yamamoto T, Mizuguchi M, et al. (2006). Altered glycosylation of alpha-dystroglycan in neurons of Fukuyama congenital muscular dystrophy brains. Brain Res 1075: 223–228. Sakata K, Shimizu M, Ino H, et al. (2005). High incidence of sudden cardiac death with conduction disturbances and atrial cardiomyopathy caused by a nonsense mutation in the STA gene. Circulation 111: 3352–3358. Scacheri PC, Gillanders EM, Subramony SH, et al. (2002). Novel mutations in collagen VI genes: expansion of the Bethlem myopathy phenotype. Neurology 58: 593–602. Selcen D, Kupsky W, Benjamins D (2001). Myopathy with muscle spindle excess: a new congenital neuromuscular syndrome? Muscle Nerve 24: 138–143. Sewry CA, Philpot J, Sorokin LM, et al. (1996). Diagnosis of merosin (laminin-2) deficient congenital muscular dystrophy by skin biopsy. Lancet 347: 582–584. Sewry CA, Naom I, D’Alessandro M, et al. (1997). Variable clinical phenotype in merosin-deficient congenital muscular dystrophy associated with differential immunolabeling
58
M. DE VISSER
of two fragments of the laminin a2 chain. Neuromuscul Disord 7: 169–175. Sewry CA, Brown SC, Mercuri E, et al. (2001). Skeletal muscle pathology in autosomal dominant Emery–Dreifuss muscular dystrophy with lamin A/C mutations. Neuropathol Appl Neurobiol 27: 281–290. Silan F, Yoshioka M, Kobayashi K, et al. (2003). A new mutation of the fukutin gene in a non-Japanese patient. Ann Neurol 53: 392–396. Small K, Warren ST (1998). Emerin deletions occurring on both Xq28 inversion backgrounds. Hum Mol Genet 7: 135–139. Somech R, Shaklai S, Amariglio N, et al. (2005). Nuclear envelopathies — raising the nuclear veil. Pediatric Res 57: 8R–15R. Somer H, Laulumaa V, Paljarvi L, et al. (1991). Benign muscular dystrophy with autosomal dominant inheritance. Neuromuscul Disord 1: 267–273. Speer MC, Tandan R, Rao PN, et al. (1996). Evidence for locus heterogeneity in the Bethlem myopathy and linkage to 2q37. Hum Mol Genet 5: 1043–1046. Squarzoni S, Sabatelli P, Capanni C, et al. (2005). Emerin increase in regenerating muscle fibers. Eur J Histochem 49: 355–362. Starling A, Kok F, Passos-Bueno MR, et al. (2004). A new form of autosomal dominant limb-girdle muscular dystrophy (LGMD1G) with progressive fingers and toes flexion limitation maps to chromosome 4p21. Eur J Hum Genet 12: 1033–1040. Sullivan T, Escalante-Alcalde D, Bhatt H, et al. (1999). Loss of A-type lamin expression compromises nuclear envelope integrity leading to muscular dystrophy. J Cell Biol 147: 913–919. Sunada Y, Bernier SM, Kozak CA, et al. (1994). Deficiency of merosin dy mice and genetic linkage of laminin M chain gene to dy locus. J Biol Chem 19: 13729–13732. Takeda S, Kondo M, Sasaki J, et al. (2003). Fukutin is required for maintenance of muscle integrity, cortical histiogenesis and normal eye development. Hum Mol Genet 12: 1449–1459. ¨ , Talvik I, So˜najalg M, et al. (2002). Early onset of Talkop U cardiomyopathy in two brothers with X-linked Emery– Dreifuss muscular dystrophy. Neuromuscul Disord 12: 878–881. Toda T, Kobayashi K, Kondo-Iida E, et al. (2000). The Fukuyama congenital muscular dystrophy story. Neuromuscul Disord 10: 153–159. Toda T, Chiyonobu T, Xiong H, et al. (2005). Fukutin and alpha-dystroglycanopathies. Acta Myol 24: 60–63. Tome´ FM, Evangelista T, Leclerc A, et al. (1994). Congenital muscular dystrophy with merosin deficiency. C R Acad Sci III 317: 351–357. Topaloglu H, Brockington M, Yuva Y, et al. (2003). FKRP gene mutations cause congenital muscular dystrophy, mental retardation, and cerebellar cysts. Neurology 60: 988–992. Ullrich O (1930). Kongenitale, atonisch-sklerotische muskeldystrophie. Monatsschr Kinderheilkd 47: 502–510.
Vainzof M, Richard P, Herrmann R, et al. (2005). Prenatal diagnosis in laminin alpha2 chain (merosin)-deficient congenital muscular dystrophy: a collective experience of five international centers. Neuromuscul Disord 15: 588–594. Van Berlo JH, de Voogt WG, van der Kooi AJ, et al. (2005). Meta-analysis of clinical characteristics of 299 carriers of LMNA gene mutations: do lamin A/C mutations portend a high risk of sudden death? J Mol Med 83: 79–83. Van der Kooi AJ, Ledderhof TM, de Voogt WG, et al. (1996). A newly recognized autosomal dominant limb girdle muscular dystrophy with cardiac involvement. Ann Neurol 39: 636–642. Van der Kooi AJ, Bonne G, Eymard B, et al. (2002). Lamin A/C mutations with lipodystrophy, cardiac abnormalities, and muscular dystrophy. Neurology 59: 620–623. Van Engelen BGM, Muchir A, Hutchison CJ, et al. (2005). The lethal phenotype of a homozygous nonsense mutation in the lamin A/C gene. Neurology 64: 374–376. Van Reeuwijk J, Brunner HG, van Bokhoven H (2004). Glyc-O-genetics of Walker–Warburg syndrome. Clin Genet 67: 281–289. Van Reeuwijk J, Janssen M, van den Elzen C, et al. (2005). POMT2 mutations cause a-dystroglycan hypoglycosylation and Walker–Warburg syndrome. J Med Genet 42: 907–912. Vasta I, Kinali M, Messina S, et al. (2005). Can clinical signs identify newborns with neuromuscular disorders? J Pediatr 146: 73–79. Wallgren-Pettersson C, Bushby K, Mellies U, et al. (2004). 117th ENMC Workshop: Ventilatory support in congenital neuromuscular disorders — congenital myopathies, congenital muscular dystrophies, congenital myotonic dystrophy and SMA. (II)4–6 April 2003, Naarden, the Netherlands. Neuromuscul Disord 14: 56–69. Wehnert M, Muntoni F (1999). 60th ENMC International Workshop: Non X-linked Emery–Dreifuss Muscular Dystrophy. Neuromuscul Disord 9: 115–121. Yates JRW (1991). European Workshop on Emery–Dreifuss Muscular Dystrophy 1991. Neuromuscul Disord 1: 393–396. Yates JR, Wehnert M (1999). The Emery–Dreifuss Muscular Dystrophy Mutation Database. Neuromuscul Disord 9: 199. Yates JRW, Bagshaw J, Aksmanovic VMA, et al. (1999). Genotype–phenotype analysis in X-linked Emery–Dreifuss muscular dystrophy and identification of a missense mutation associated with a milder phenotype. Neuromuscul Disord 9: 159–165. Zheng R, Ghirlando R, Lee MS, et al. (2000). Barrier-toautointegration factor (BAF) bridges DNA in a discrete, higher-order nucleoprotein complex. Proc Natl Acad Sci USA 97: 8997–9002.
Further Reading Grewal PK, Holzfeind PJ, Bittner RE, et al. (2001). Mutant glycosyltransferase and altered glycosylation of a dystro-
MYOPATHIES WITH EARLY CONTRACTURES glycan in the myodystrophy mouse. Nat Genet 28:: 151–154. Kaindl AM, Jakubiczka S, Lucke T, et al. (2005). Homozygous microdeletion of chromosome 4q11-q12 causes severe limb-girdle muscular dystrophy type 2E with joint hyperlaxity and contractures. Hum Mutat 26: 279–280. Knupp C, Squire JM (2001). A new twist in the collagen story — the type VI segmented supercoil. EMBO J 20: 372–376. Kobayashi K, Nakahori Y, Miyake M, et al. (2005). Basement membrane fragility underlies embryonic lethality in fukutin-null mice. Neurobiol Dis 19: 208–217. Kuo HJ, Keene DR, Glanville RW (1995). The macromolecular structure of type-VI collagen. Formation and stability of filaments. Eur J Biochem 232: 364–372. Lamande´ SR, Bateman JF, Hutchison W, et al. (1998). Reduced collagen VI causes Bethlem myopathy: a heterozygous COL6A1 nonsense mutation results in mRNA decay and functional haploinsufficiency. Hum Mol Genet 7: 981–989. Lamande´ SR, Shields KA, Kornberg AJ, Shield AJ, et al. (1999). Bethlem myopathy and engineered collagen VI triple helical deletions prevent intracellular multimer assembly and protein secretion. J Biol Chem 274: 21817–21822. Longman C, Brockington M, Torelli S, et al. (2002). Mutations in the human LARGE gene cause MDC1D, a novel
59
form of congenital muscular dystrophy with severe mental retardation and abnormal glycosylation of a-dystroglycan. Hum Mol Genet 12: 2853–2861. Mercuri E, Yuva Y, Brown SC, et al. (2002). Collagen VI involvement in Ullrich syndrome. A clinical, genetic, and immunohistochemical study. Neurology 58: 1354–1359. Nakagome Y, Kanazawa I, Nakamura Y, et al. (1998). An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy. Nature 394: 388–392. Nonaka I, Nakagome Y, Kanazawa I, et al. (1998). An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy. Nature 394: 388–392. Pollitt C, Anderson LVB, Pogue R, et al. (2001). The phenotype of calpainopathy: diagnosis based on a multidisciplinary approach. Neuromuscul Disord 11: 287–296. Richard I, Broux O, Allamand V, et al. (1995). Mutations in the proteolytic enzyme calpain 3 cause limb-girdle muscular dystrophy type 2A. Cell 81: 27–40. Saito Y, Mizuguchi M, Oka A, et al. (2000). Fukutin protein is expressed in neurons of the normal developing human brain but is reduced in Fukuyama-type congenital muscular dystrophy brain. Ann Neurol 47: 756–764. Tanaka K, Yamada T, Kikuchi H, et al. (1998). Autosomal dominant limb-girdle muscular dystrophy with ankle joint contracture. Acta Neurol Scand 100: 199–201.
Handbook of Clinical Neurology, Vol. 86 (3rd series) Myopathies F. L. Mastaglia, D. Hilton-Jones, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 3
Myotonic disorders FRANK LEHMANN-HORN* AND KARIN JURKAT-ROTT Ulm University, Ulm, Germany
3.1. A glossary of myotonia By definition, myotonia is a feature of muscle fiber dysfunction. Proof of this can be achieved with curare. This differentiates the myotonia from neuromyotonia, which is caused by spontaneous motor unit activity due to hyperexcitability of the terminal motor nerve branches. Myotonia is characterized by an involuntary muscle tension that is caused by a lowered electrical threshold and action potentials which repetitively fire because of a hyperexcitability of the muscle fiber membrane. Usually myotonia does not occur spontaneously but depends on the patient’s past activity. Myotonia is most prominent in muscles that are strenuously activated for a few seconds after they have rested for >10 minutes. Under these conditions, muscle relaxation is severely slowed due to the involuntary after-activity. If the myotonia is severe, transient weakness can occur. The myotonia decreases with continued activity, a phenomenon called warm-up. Also the weakness, if present at all, resolves. On the contrary, paradoxical myotonia or paramyotonia worsens with exercise in the cold. Paradoxical myotonia of the eyelid muscles may also occur in the warmth; it is indicative of sodium-channel myotonia. The lid lag phenomenon is positive when the white sclera between the iris and the lagging upper lid are visible after a sudden downward gaze following a several-second-lasting upward gaze. Percussion myotonia is the reaction to a blow with the reflex hammer characterized by an indentation along the muscle fibers. In contrast, myoedema shows a transverse bulging of the percussed muscle. Myotonia may or may not be aggravated by ingestion of potassium. The former is called potassium-aggravated myotonia, a symptom that is indicative of sodium-channel myotonia, a syndrome caused by a sodium-channel mutation. On electromyographic (EMG) examination, myotonic
muscles exhibit myotonic runs, i.e., action potentials characterized by a modulation of frequency and amplitude. In mild cases myotonia may not be evident on clinical examination, yet EMG may reveal the typical myotonic bursts. This is termed latent myotonia.
3.2. Membrane excitability Voltage-gated ion channels regulate the membrane excitability of muscle and nerve. It is therefore not surprising that mutant channels can cause diseases of these tissues, so-called channelopathies. Muscle channelopathies are characterized by either transient membrane hyperexcitability (i.e., myotonia) or hypoexcitability (i.e., paralysis) or both (Jurkat-Rott and Lehmann-Horn, 2005a). Lossof-function mutations of the inhibitory chloride channel as well as gain-of-function mutations of the excitatory sodium channel cause membrane hyperexcitability such as in the classical congenital myotonias and in potassium-aggravated myotonia. The inward current through the mutant sodium channels is associated with a sustained membrane depolarization that can inactivate the remaining sodium channels and render the membrane unexcitable. This happens in paramyotonia in the cold and in hyperkalemic periodic paralysis at elevated serum potassium levels.
3.3. Chloride-channel myotonias 3.3.1. Thomsen and Becker myotonias The two classical forms of myotonia are distinguished by their mode of inheritance and the severity of their clinical features: the relatively mild dominant myotonia congenita (or Thomsen disease, MIM 160800) and the more severe recessive myotonia congenita (or Becker
*Correspondence to: Professor Frank Lehmann-Horn, Department of Applied Physiology, University of Ulm, Albert-EinsteinAllee 11, 89069 Ulm, Germany. E-mail:
[email protected].
62
F. LEHMANN-HORN AND K. JURKAT-ROTT
myotonia, MIM 255700). Both disorders progress slowly during childhood and adolescence, neither form present as muscular dystrophy, and both forms are caused by mutations in the gene, CLCN1, coding for the voltagegated chloride channel of the plasma membrane (Koch et al., 1992; George et al., 1993). For this reason, they are also referred to as chloride-channel myotonias. The prevalence of Thomsen disease has turned out to be much lower than thought in the premolecular era (1:23 000; Becker, 1977); it is now estimated at 1:400 000. Families with an apparent dominant trait were later found to have Becker myotonia with pseudodominant inheritance and others were identified as carriers of a sodium-channel mutation. Conversely, the prevalence of Becker myotonia is likely higher than Becker’s original estimate of 1:50 000 (Becker, 1977). Generally, the stiffness in patients with Thomsen and Becker myotonia is initiated by a forceful muscle contraction, particularly after rest for at least 10 minutes. This does not necessarily pertain to the first contraction which may be relatively unimpeded. The myotonic muscle stiffness becomes increasingly obvious following a second and third short but forceful contraction. Further contractions typically dampen the myotonia gradually. This “warm-up” phenomenon then lasts for several minutes. Its pathomechanism remains unclear. Upon examination, patients with Thomsen myotonia may present with hypertrophic muscles and an athletic appearance. Their muscle strength is normal or even greater than normal and they can be quite successful in sports that require strength more than speed. Percussion myotonia and lid lag are usually present and, in some patients, the lid muscle myotonia results in blepharospasm after forceful eye closure. The muscle stretch reflexes are normal and muscle pain is usually not present. The myotonic signs persist throughout life. The clinical picture of Becker myotonia resembles that of Thomsen disease. A few special points are worth mentioning. In many patients with Becker myotonia, the stiffness is not manifest until the age of 10–14 years or even later, but in a few it is already obvious at the age of 2–3 years. The severity of the myotonia may slowly increase for a number of years, but usually not after the age of 25–30. The myotonia is more severe than in Thomsen disease. Thus, patients with Becker myotonia are more handicapped in daily life, and especially by myotonic stiffness of the leg muscles that causes gait problems. Situations requiring rapid motor control may provoke severe generalized stiffness causing these patients to fall to the ground without being able to protect themselves, and to be injured or rendered unconscious through head injury. This has previously led to the misdiagnosis of epilepsy, prompting the use of antiepileptic drugs which improved the myotonia.
Muscle shortening due to continuous contractions may limit dorsiflexion of the wrist or foot. Severely affected patients with Becker myotonia tend to toe-walk and develop a compensatory lordosis. The leg and gluteal muscles are often markedly hypertrophic. In some patients, especially older ones, the neck, shoulder and arm muscles appear poorly developed resulting in a characteristic disproportionate figure. Also very disabling is a peculiar transient weakness affecting especially the hand and arm muscles (Deymeer et al., 1998). This lasts only a few seconds following initial contraction and may be interpreted as clumsiness by the affected individual. Patients with severe Becker myotonia are limited in their choice of occupation and are unsuited for military service. A few patients with Becker myotonia show permanent weakness in some muscle groups, distal muscle atrophy, and unusually high serum creatine kinase (CK) levels, making the differentiation from myotonic dystrophies difficult. Life expectancy is normal. 3.3.1.1. EMG The electrophysiological correlate of myotonia, regardless of the type of channel affected, is involuntary repetitive firing of muscle fiber action potentials. The impressive electrical activity following a voluntary contraction is too painful to monitor. Instead, the EMG needle is usually inserted into the resting muscle. Needle insertion itself elicits myotonic bursts. In patients with Thomsen and Becker myotonia, the myotonic bursts can be observed in all routinely examined skeletal muscles. Typically, short bursts of action potentials appear as triphasic spikes or as positive sharp waves with amplitude and frequency modulation. Most frequent are short bursts characterized by a rising frequency and a falling spike amplitude (Fig. 3.1). An often mentioned, but actually rare, pattern is a short discharge characterized first by an increase in frequency and decrease in amplitude and then by a decrease in frequency and increase in amplitude. It resembles the sound of a dive-bomber when recorded in the acoustic EMG. In a few recessive myotonia congenita families, latent myotonia can be demonstrated in the heterozygous parents of affected offspring; that is, repetitive action potentials are seen on EMG without clinical features of myotonia (Deymeer et al., 1999). Motor unit potentials are usually normal. Myopathic changes such as multiphasic or lowamplitude potentials can be observed in the rare patients with Becker myotonia who have permanent weakness (Nagamitsu et al., 2000). Compound muscle action potiential (CMAP) amplitudes are reduced during transient weakness and upon repetitive stimulation (Fournier et al., 2004). Consistent with the less
MYOTONIC DISORDERS
63
Fig. 3.1. Myotonic runs and transient weakness in a patient with Becker myotonia. A. The two EMG traces show typical myotonic runs of short duration, waxing frequency and waning amplitude. The final high-frequency phase of some runs causes a tetanic contraction of the spiking muscle fiber which induces another discharge in a surrounding fiber. B. Surface EMG of biceps brachii muscle (upper trace) and voluntary isometric force (in Newton) of the forearm flexors (lower trace) show a pattern characteristic for transient weakness. Modified after Ricker et al. (1978b).
pronounced transient weakness in patients with Thomsen than those with Becker myotonia, a higher stimulation frequency is necessary to induce the same effect (Deymeer et al., 1998). Multichannel surface EMG reveals a gradually developing decrease in peak-to-peak amplitude of the motor unit action potentials from endplate towards tendon in parallel with the force decline. This deteriorating membrane function leads transiently to a complete intramuscular conduction block (Drost et al., 2001). 3.3.1.2. Microscopy Muscle biopsy, which is not part of the diagnostic process, is usually normal. In some, slight myopathic changes with increased occurrence of central nuclei and pathological variation of fiber diameter may be found. Muscle fiber hypertrophy, especially of type 2A fibers, and fiber atrophy may be present. Finally, there may be reduction or complete absence of type 2B fibers (Jurkat-Rott et al., 2002). 3.3.1.3. Molecular genetics and pathogenesis The causative gene for dominant Thomsen and recessive Becker myotonia is CLCN1 on chromosome 7q encoding the voltage-gated chloride channel of the skeletal muscle fiber membrane. The chloride channel protein, ClC-1, forms homodimeric double-barrel complexes (Mindell et al., 2001; Dutzler et al., 2002) with two ion-conducting pores (Saviane et al., 1999; for review see Fahlke, 2001). Over 70 ClC-1 mutations have been identified (Fig. 3.2; Koch et al., 1992; George et al., 1993; Heine et al., 1994; Lorenz et al., 1994; Lehmann-Horn et al., 1995; Koty et al., 1996; Maila¨nder et al., 1996; Sangiuolo et al., 1998; Brugnoni et al., 1999; Sasaki et al., 1999, 2001; Wu et al., 2002; reviewed in Pusch, 2002), making genetic studies quite arduous. While nonsense and splicing mutations usually lead to the recessive phenotype, missense mutations are found in both Thomsen and Becker myotonia. After the first description as dominant, several mutations — all of which were functionally
expressed and shown to have a “dominant-negative effect” on coexpressed wildtype (Meyer-Kleine et al., 1995; Pusch et al., 1995; Kubisch et al., 1998; Zhang et al., 2000) — were also found in families with a recessive mode of inheritance or in a homozygous state (George et al., 1994; Meyer-Kleine et al., 1995; Zhang et al., 1996; Sloan-Brown and George, 1997; Esteban et al., 1998; Plassart-Schiess et al., 1998). According to our own data, some seemingly dominant pedigrees can be explained by pseudodominant transmission by multiple recessive mutations (Mao et al., unpublished data). Hitherto, only three families with pseudodominant transmission have been described (Papponen et al., 1999; Sun et al., 2001). If mutation screening is negative, linkage analysis that includes a sufficient number of informative additional family members may confirm the diagnosis. 3.3.2. Myotonia associated with muscle dystrophies Myotonic dystrophy (DM) is a progressive multisystemic disease with muscle wasting, myotonia, subcapsular cataracts, cardiac conduction defects, gonadal atrophy, mild deafness and cognitive deficits. There are two clinically distinguished types: DM1 with the classical phenotype and a milder DM2 type with a more proximal pattern of weakness. 3.3.2.1. Myotonic dystrophy type 1 Myotonic dystrophy type 1 (DM1; MIM 160900) is an autosomal dominant multiorgan disease and the most common inherited muscle disorder in adults. Myotonia is only one of the many symptoms of this progressive disease, the most severe symptom being muscle weakness that begins in the distal limb and cranial muscles (myopathic face). Subcapsular cataracts with a characteristic iridescent appearance, gonadal atrophy, cardiac conduction abnormalities, mild deafness and cognitive deficits are evident to varying degrees. The mutation of DM1 is an expansion of an unstable CTG trinucleotide repeat in
64
F. LEHMANN-HORN AND K. JURKAT-ROTT 445 503 499 496
Q
329 I
433 −
R 338
327 V 150
Y
F
136
V D
161 165 167
232 230 236
218
285 286 R
G
F
S3 S2 S4
A
V
S5
S6
200 G
$ G V
S7
+
T
I E
Y
261 213
S1
415 413
317 313
A
552 Q
S15
S13 $ M
F
S10
531
− G R
I 424
S12
A
−
I
S16
P C G
S11
F
556
V
A
300 R 307
268
491 485
429 +
387
563
480 481 S18 482
289 290 291
658 Q A 659 R
105 R
669
F 708
Dominant myotonia congenita (DMC) 74 Q
Recessive myotonia congenita (RMC)
68 Q 67 +
N $
R
−
837 + $
E 717
755
$ Splice -- Deletion
A
Myotonic mice Myotonic goat
R 894
C
+ Insertion
P
932
Fig. 3.2. Membrane topology of the chloride channel. The model shows the skeletal muscle chloride channel monomer, ClC-1. The functional channel is a homodimer encoded by the CLCN1 gene. The different symbols used for the known mutations leading to either dominant or recessive myotonia in man, mouse and goat are explained on the bottom. Conventional one-letter abbreviations are used for replaced amino acids.
the 30 untranslated region of the myotonic dystrophy protein kinase (DMPK) gene on chromosome 19q13.3 (for review see Conne et al., 2000). A phenotype not found in Thomsen or Becker myotonia is a severe congenital form of DM1 characterized by generalized muscle weakness at birth (floppy infant) and retarded motor and mental development. Myotonia is absent in infancy. The diagnosis is readily established by detecting signs of dystrophy in the patient’s mother and by genetic analysis that reveals a large CTG expansion in the infant. In adults with myotonic dystrophy, myotonic EMG activity is less striking than in the non-dystrophic myotonias and is unevenly distributed between muscles. Distal muscles of the upper extremity and orbicularis oris muscles show the highest incidence of electrical myotonia. Long-lasting discharges of 2–30 s duration with falling or unchanging frequency and amplitude occur more often than the typical short myotonic runs typically observed in non-dystrophic myotonia. The maximal frequency of the discharges is 40–60 Hz and thus lower than in chloride-channel myotonia. Positive sharp waves and complex repetitive discharges are also very common.
3.3.2.2. Myotonic dystrophy type 2 or PROMM A second dominant multisystemic myotonic disorder, similar to classical myotonic dystrophy but with no DMPK gene involvement, was originally described as proximal myotonic myopathy or PROMM (Ricker et al., 1994a). Since some patients exhibited distal muscle weakness and dystrophy (Ranum et al., 1998), the disease was later renamed myotonic dystrophy type 2, a broader category that also includes PROMM (DM2; OMIM 602668). The disease locus for DM2 is on chromosome 3q (Ranum et al., 1998; Ricker et al., 1999). The mutation is an expansion of an unstable CCTG tetranucleotide repeat in intron 1 of the ZNF9 gene coding for zinc finger protein 9. Parallels between mutations in DM1 and DM2 indicate that repeat expansions in RNA can be pathogenic and cause multisystemic deficits in both diseases (Liquori et al., 2001). In most patients, DM2 progresses very slowly, with weakness developing typically after the age of 40. Some patients have troublesome, sometimes disabling, muscle pains, especially in the thighs. The pain is not related to myotonic stiffness and is most apparent at night. In other patients the early onset of cataract may be the first recognized manifestation of the disorder. The cataract
MYOTONIC DISORDERS is posterior capsular and, during early stages, iridescent as in myotonic dystrophy. Many patients first complain of intermittent stiffness. When this is present, it is typically focal, involving one thigh or one hand. The movements are jerky and stepwise, especially in the thumb and the index finger and show the warm-up phenomenon. Because the severity of the myotonia is variable and the disorder is usually mild in the initial stages, it is not unusual for the signs of myotonia to elude clinical detection. Electromyographic investigation usually reveals myotonic discharges, even in those patients without obvious clinical myotonia. These myotonic discharges are often scarce and difficult to detect. A myopathic EMG pattern may be detectable in the most affected muscles. For all the myotonias discussed above, genetic analysis is available to confirm the diagnosis. 3.3.3. Animal models About 30 years after the first description of myotonia in man, White and Plaskett (1904) described a breed of “fainting” goats raised in Tennessee, USA. The animals tended to have attacks of extreme muscle stiffness when attempting a quick forceful motion, so that they often fell to the ground for 5–20 seconds with extended neck and limbs. Clark et al. (1939) were the first to refer to the disease as “a form of congenital myotonia in goats”. Much later, susceptibility to malignant hyperthermia was excluded (Newberg et al., 1983). In the late 1970s, two spontaneous mouse mutations were detected, one in the A2G strain in London, UK, the other in the SWR/J strain in Bar Harbor/Maine, USA. The behavioral abnormalities of the affected animals were very similar, and in both mutants the sign was transmitted as an autosomal recessive trait. The British scientists were struck by the observation that from days 10–12 onwards, the affected animals had difficulty in righting themselves when placed supine and therefore called the mutation adr for “arrested development of righting response”. The Americans observed that shaking the cage provoked sustained extension of an animal’s hind limbs, and since electrical myotonia was recorded in the EMG from the stiff muscles, this strain was called mto for “myotonic”. As far as the phenotype is concerned, the two models of myotonia are virtually indistinguishable. 3.3.4. Molecular pathogenesis of the chloride-channel myotonias In contrast to most cells, the chloride conductance of muscle fibers is very high, making up 80% of the total membrane conductance at rest. This high chloride conductance stabilizes the resting membrane potential and
65
inhibits potential deviations. Therefore, a decrease of the chloride conductance should cause membrane hyperexcitability. This hypothesis has been proven by experiments on myotonic goat muscle fibers which showed no, or a strikingly reduced, chloride conductance (Bryant, 1969) and later confirmed for human myotonia congenita (Lipicky et al., 1971; Rudel et al., 1988). The myotonic goat did not play a role in the identification of the gene defect responsible for the reduced chloride conductance. The mutation in the homologous goat gene was detected (Beck et al., 1996) long after CLCN1 was localized and cloned for mouse (Steinmeyer et al., 1991) and man (Koch et al., 1992). The mutation in the goat gene predicts an Ala-885-Pro substitution in the C terminus of the chloride channel protein (Fig. 3.2) that right-shifts the activation curve of the chloride current, much like the dominant mutations do in man. As in the myotonic goat and in human myotonia congenita, the reason for the abnormal excitability in the myotonic mice is a reduced chloride conductance. Homology cloning of the chloride channel gene expressed in skeletal muscle of the adr mouse identified an insertion that destroys the gene’s coding potential for several membrane spanning domains (Steinmeyer et al., 1991). Later, it was found that the mto allele carries a stop codon, leading to a truncation of the N-terminus (Fig. 3.2). In heterologous expression systems, the most common feature of mutant human chloride channels is a shift of the activation threshold towards more positive membrane potentials almost out of the physiological range (Pusch et al., 1995; Wagner et al., 1998). As a consequence of this, the chloride conductance is drastically reduced in the crucial vicinity of the resting membrane potential (Fig. 3.3). This leads to a reduced membrane conductance for chloride and decreases the stability of the membrane potential, especially following an action potential. Coexpression studies showed that dominant mutations exert a dominant-negative effect on the dimeric channel complex. This means that mutant/ mutant complexes, i.e., 25%, and mutant/wildtype, i.e., 50% of the complexes, are malfunctional. The resulting chloride conductance is reduced to 25% (wildtype/ wildtype), so that clinical myotonia develops (Palade and Barchi, 1977). In contrast, the gene product altered by a nonsense mutation is unstable so that neither mutant/mutant nor mutant/wildtype complexes are formed. The wildtype/wildtype complexes establish 50% of the normal chloride conductance in the heterozygous mutation carriers, a value that is sufficient for an almost stable membrane potential. Therefore Becker myotonia requires mutations on both alleles. The pathogenesis of myotonia in the myotonic dystrophies is not fully understood. In DM1, the ion channel
66
F. LEHMANN-HORN AND K. JURKAT-ROTT 1
WT
0.5
Gly-200-Arg
paralysis (HypoPP type 2; Jurkat-Rott et al., 2000) and a subtype of the congenital myasthenic syndromes (Tsujino et al., 2003) are not associated with myotonia but with hypoexcitability due to a reduced channel function. The acronyms for the periodic paralyses follow the recommendation of an international expert consortium (Lehmann-Horn et al., 1993). The periodic paralyses are discussed in detail in Chapter 4 and therefore mentioned here only as far as needed for better comprehension. 3.4.1. Potassium-aggravated myotonias
0
−100
0 Membrane voltage (mV)
100
Fig. 3.3. Voltage dependence of open probability of a dominant ClC-1 mutation. Behavior of human skeletal muscle ClC-1 channels expressed in a mammalian cell line. Compared are the relative open probabilities of normal (WT) and mutant (Gly-200-Arg) channels, the latter causing Thomsen myotonia. Note that the open probability of the mutant channel is strikingly reduced in the physiological potential range. All mutations that cause such a voltage shift have dominant effects. Adapted from Wagner et al. (1998).
disturbance likely stems from increased or alternative splicing leading to non-functional chloride channel gene products. The most abundantly occurring variants are retention of intron 2 and insertion of two accessory exons 6b and 7a (Charlet et al., 2002; Mankodi et al., 2002). Two splice variants, leading to a truncated protein of 283 amino acids, exerted a dominant-negative effect on coexpressed wildtype ClC1 channel in Xenopus oocytes (Berg et al., 2004). In DM2, exclusion of exons 6 and 7 is the most abundant variant (S-F Ursu et al., unpublished data). The truncated protein of 236 amino acids, did not exert a truly dominant-negative effect on co-expressed wildtype ClC1, but only a slightly suppressive effect. Confocal laser microscopy suggested that a ClC1236X interaction with ClC1 may occur, though not regularly. In agreement with this observation, nonsense mutations of ClC1 resulting in early truncations nearby, such as fs231X, fs258X, or fs289X, are all inherited in a recessive manner.
3.4. Sodium-channel myotonias Three dominantly inherited skeletal muscle sodiumchannel myotonias have been delineated in humans on the basis of their clinical phenotype: potassiumaggravated myotonia (PAM, MIM 608390); paramyotonia congenita (MIM 168300), and hyperkalemic periodic paralysis (HyperPP, MIM 170500; JurkatRott and Lehmann-Horn, 2005b). Two other skeletal muscle sodium channelopathies, hypokalemic periodic
In 1994, the term potassium-aggravated myotonia was coined by Mitrovic et al. (1994) for sodium channel myotonias characterized by an exacerbation of muscle stiffness by potassium ingestion and/or cold environment. The name has been approved by international experts at a European Neuromuscular Centre Workshop on Paramyotonia, Potassium-aggravated Myotonia and Periodic Paralyses (Rudel and Lehmann-Horn, 1997). The potassium-aggravated myotonias (PAM) include myotonia fluctuans, myotonia permanens, acetazolamide-responsive myotonia and painful myotonia, i.e., a spectrum of diseases with overlapping clinical features which have in common, in contrast to paramyotonia congenita and hyperPP, no weakness. In the mildest form, the affected individuals might not be aware of a muscle problem. These patients may present with a severe generalized muscle stiffness after intravenous administration of depolarizing muscle relaxants. Others experience stiffness that tends to fluctuate from day to day, hence the name myotonia fluctuans (Ricker et al., 1990). Usually, the patients become stiff 10–30 min after strenuous work (Fig. 3.4). This delayed myotonia should not be confused with paradoxical myotonia. Usually, the limb muscles show a warm-up phenomenon, and paradoxical myotonia is restricted to the eyelid muscles. The patients do not experience muscle weakness and their muscles are not substantially sensitive to cold. They develop severe stiffness also following oral ingestion of potassium and administration of other depolarizing agents such as anticholinesterases. The sometimes painful stiffness may hinder the patient’s movements for several hours. The sodium channel mutations S804F and G1306A (Fig. 3.5) have been identified to cause myotonia fluctuans (Ricker et al., 1994b). Anesthetic complications of G1306A carriers have also been reported by others (Vita et al., 1995). The intermediate form of PAM is similar to Thomsen’s disease. However, in contrast to patients with Thomsen’s disease is the patients respond very well to acetazolamide (acetazolamide-responsive myotonia; Trudell et al., 1987; Ptacek et al., 1994), develop stiffness not
MYOTONIC DISORDERS
67
Fig. 3.4. Delayed myotonia in a myotonia fluctuans patient. The upper trace shows the surface EMG and the lower trace the myogram of the finger flexors. The first two forceful isometric contractions (lasting 10 s and a second shorter period) were not associated with myotonia. However, short contractions, performed after a rest of 2 and 10 minutes, elicited severe electrical myotonia and slowed relaxation (delayed myotonia). Adapted from Ricker et al. (1990).
Fig. 3.5. Membrane topology model of the voltage-gated sodium channel. A. The skeletal muscle a-subunit functions as an ion-conducting channel and consists of four highly homologous domains (repeats I–IV) containing six transmembrane segments each (S1–S6). The S6 transmembrane segments and the S5–S6 loops form the ion-selective pore, and the S4 segments contain positively charged residues conferring voltage dependence to the protein. The repeats are connected by intracellular loops; one of them, the III–IV linker, contains the supposed inactivation particle of the channel. B. When inserted in the membrane, the four repeats of the protein fold to generate a central pore as indicated schematically. C. The different symbols used for the known mutations leading to potassium-aggravated myotonia, paramyotonia congenita and two types of periodic paralysis.
only after potassium ingestion but also after exposure to cold (V1589M: Heine et al., 1993; Mitrovic et al., 1994; V1293I: Koch et al., 1995; L266V: Wu et al., 2001; F1705I: Wu et al., 2005), and/or suffer from exercise-induced painful muscle cramping (V445M: Rosenfeld et al., 1997; V1589M: Orrell et al., 1998; L266V:
Wu et al., 2001). In contrast to paramyotonia, no cold-induced weakness occurs. The most severe type of sodium-channel myotonia is characterized by persistent and severe myotonia and is therefore called myotonia permanens. Molecular biology has revealed that this condition is caused by a specific
68
F. LEHMANN-HORN AND K. JURKAT-ROTT
mutation (G1306E, Fig. 3.5) in the SCN4A gene product (Lerche et al., 1993; Mitrovic et al., 1995). The continuous electrical myotonia leads to a generalized muscle hypertrophy that also involves muscles of face, neck and shoulders. When the myotonia is aggravated, as by intake of potassium-rich food or by exercise, ventilation can be impaired by stiffness of the thoracic muscles. Children are particularly at risk of suffering acute hypoventilation leading to cyanosis and unconsciousness. This has led to confusion with epileptic seizures and resulted in treatment with anticonvulsants which block sodium channels. The severely affected patients could probably not survive without continuous treatment. One patient was misdiagnosed as having the “myogenic type” of Schwartz-Jampel syndrome (Spaans et al., 1990), until electrophysiological studies revealed impaired sodium-channel inactivation (Lehmann-Horn et al., 1990b) and finally, molecular genetics showed a SCN4A mutation (Lehmann-Horn et al., 2004). A further indication of the severity of the myotonia is that all patients reported to date are sporadic. There are no reports of familial cases and affected patients have not had children. Because of the severity of the disease, ingestion of potassium or exposure to cold may cause further worsening and should be avoided. 3.4.1.1. Electromyography In addition to the short-lasting myotonic bursts found in the chloride-channel myotonias, long-lasting runs of fibrillation-like activity with slow or no changes in action potential frequency and amplitude are found in sodium channel PAM. In myotonia fluctuans, the EMG demonstrates myotonic bursts even when clinical myotonia is absent. As to be expected, muscles of myotonia permanens patients reveal continuous myotonic activity. 3.4.1.2. Microscopy Despite the seemingly drastic differences in clinical severity, the histological findings do not systematically differ (Jurkat-Rott et al., 2002). In myotonia fluctuans, light microscopy may show a normal appearance or increased central nuclei and fiber diameter variation. Subsarcolemmal vacuoles representing a nonspecific enlargement of the T-tubular system may by found by electron microscopy (Ricker et al., 1990). In myotonia permanens, the subsarcolemmal myoplasmic space and mitochondria may be increased, and focal disarray or interruption of myofibrils and disappearance of Z-disks, involving one or more sarcomeres, may be seen. In these areas, glycogen particles and elongated or branched mitochondria can be found. Between the bundles of myofibrils, membranebound vacuoles may be visible which are empty, or filled with fine granular material or electron-dense whorls.
3.4.2. Paramyotonia congenita Paramyotonia congenita (PC) is inherited as an autosomal dominant (MIM 168300). Signs are present at birth and often remain unchanged throughout life. The cardinal symptom is cold-induced muscle stiffness that increases with continued activity (paradoxical myotonia). On repeated strong contractions of the orbicularis oculi, the opening of the eyelids is increasingly impeded; finally the eyes cannot be opened to more than a slit. As a rule, muscles are bilaterally and symmetrically affected. Many patients exhibit the lid-lag phenomenon and some have percussion myotonia. The motility of the eyeballs may be hampered, which may lead to short bouts of diplopia. Also, swallowing may be impeded for short periods of time. These symptoms, however, tend to be transient. In rare cases, the paramyotonic muscles seem to be somewhat swollen. Muscle atrophy or hypertrophy are not typical for the disease. In the cold (even in just a cool wind), the face may appear mask-like, and the eyes cannot be opened for several seconds or minutes (Fig. 3.6). Working in the cold makes the fingers so stiff that the patient cannot move them for several minutes. Under warm conditions, most patients have no complaints because impaired muscle relaxation improves at higher temperatures. Other patients have stiff limb muscles in a warm environment; the stiffness improves on continued exercise and displays the paradoxical reaction only on cooling. On the whole, the duration and degree of the paramyotonic reaction of muscles depends on the duration and intensity of cooling, but there are also individual differences in susceptibility. A few patients claim that emotional factors or hunger aggravate their condition. In many cases alcohol has an obvious beneficial effect. Some patients believe that they are more susceptible to paramyotonia when they have a cold. Paramyotonia may become more severe during pregnancy, so that the leg muscles stiffen even under warm conditions. Hypothyroidism also causes generalization of paramyotonia and aggravates both muscle stiffness and weakness. All movements are then severely hampered, even independently of cooling. An estimate of the prevalence of paramyotonia congenita seems almost impossible to obtain, because most of the affected individuals never consult a doctor for their symptoms. Moreover, when a paramyotonic patient requires medical help for another reason, they hardly mention their paramyotonic symptoms. Although paramyotonia can be troublesome, it is often a harmless abnormality or a familiar peculiarity that the sufferer simply tolerates. Patients feel that they must make the best of their condition, as did their ancestors, an opinion reinforced when they encounter medical ignorance. On the whole, patients tend to hide their
MYOTONIC DISORDERS
69
Fig. 3.6. Effects of local cooling on a paramyotonia congenita patient. After the patient’s right eye was cooled for 10 min, she was asked to close her eyes forcefully (A) and the open them fast (B). The cooled right eyelid remained involuntarily closed for almost a minute.
family anomaly as much as possible, even from close relatives, because they have often experienced embarrassing situations and been ridiculed. On the other hand, paramyotonia patients readily share their experiences with each other. Older patients report that their paramyotonia improved with age. In many of these cases, however, it was not clear whether the paramyotonia had really improved or whether the patients had learned to adapt to it by avoiding exposure to cold and by taking advantage of improving standards of living. Life expectancy is not decreased by paramyotonia. In most families, the stiffness gives way to flaccid weakness or even to paralysis on intensive exercise and cooling (Fig. 3.7; Haass et al., 1981). Some, but not all, families with PC also have attacks of generalized hyperkalemic periodic paralysis for an hour or less (see below), provoked by rest after strong exercise or by potassium ingestion. In contrast, the cold-induced weakness usually lasts for several hours even when the muscles are promptly rewarmed. During a severe paralytic attack, the muscle stretch reflexes are diminished or absent. Paramyotonia mutations are situated either in the inactivation gate, the intracellular loop connecting domains III and IV (T1313M: McClatchey et al., 1992; T1313A: Bouhours et al., 2004), in the voltage sensor of repeat IV (R1448H/C/S/P: Ptacek et al., 1992; Chahine et al., 1994; Lerche et al., 1996; Bendahhou et al., 1999) or in the intracellular S4-S5 loops (F1473S: Lerche et al., 1997; A1152D: Bouhours et al., 2005). Paramyotonia families with R1448 substitutions (Fig. 3.5) also have
Fig. 3.7. Contractions of a paramyotonia patient at different temperatures. Periods of voluntary isometric muscle contractions (in Newton) and the corresponding surface EMG activity underneath (modified from Haass et al., 1981). The patient was asked to maximally contract his muscles for about 3–5 s and then to relax. The upper two traces show the warm-up phenomenon at 37 C, the lower two traces the paradoxical myotonia, i.e., slowed relaxation during exercise after 30-min cooling of the forearm in water of 15 C. Note the reduced muscle strength after cooling.
attacks of generalized hyperkalemic periodic paralysis, provoked by rest or ingestion of potassium, lasting for an hour or less. In contrast to the short-lasting spontaneous weakness in hyperkalemimc periodic paralysis and
70
F. LEHMANN-HORN AND K. JURKAT-ROTT
paramyotonia, the cold-induced paramyotonic weakness usually lasts several hours even when the muscles are immediately rewarmed. Also, carriers of other mutations show overlapping features: in a Japanese pedigree, the mutation M1370V resulted in paramyotonia in one family member and in hyperkalemic periodic paralysis in others (Okuda et al., 2001). Also, with hyperkalemic periodic paralysis mutations such as M1360V, T704M and M1592V (Fig. 3.5), paramyotonic signs have been reported in single families (Kelly et al., 1997; Wagner et al., 1997; Kim et al., 2001; Brancati et al., 2003). I693T has been published as a paramyotonia mutation (Plassart et al., 1996) although it causes weakness in the absence of stiffness and would therefore be compatible with a hyperkalemic periodic paralysis mutation. 3.4.2.1. Electromyography Electrical discharges may be absent at normal or increased temperatures, but cooling elicits fibrillationlike spontaneous activity (Haass et al., 1981). Depending on the temperature and the resulting membrane potential between the action potentials, the electrical activity may vary between myotonic discharges and long-lasting repetitive complex discharges (Weiss and Mayer, 1997). In the transient phase, during which periodic paralysis emerges from the paramyotonic state, silent contractures can accompany the myotonic contractions. Extracellular recordings from excised muscle bundles, with electrodes that detect all electrical activity, reveal that part of the slowed relaxation following direct electrical stimulation and cooling are not caused by action potentials (Ricker et al., 1986). The most likely explanation is that sustained membrane depolarization evokes a long-lasting contracture and also blocks subsequent action potentials generation. This process finally leads to lack of insertional and voluntary EMG activity. 3.4.2.2. Microscopy In paramyotonia, light microscopy may be unremarkable except for non-specific changes such as occasional central nuclei, variation of fiber diameter and occasional hypertrophic, atrophic, split and regenerating fibers (Jurkat-Rott et al., 2002). ATPase type 2A fibers may be hypertrophied and the number of type 2B fibers may be decreased as in the chloride channelopathies. However, normal muscle fiber area and distribution of fiber types 1, 2A and 2B have also been described. In some areas, there may be focal myofibrillar degeneration with myelin bodies, lipid deposits, occasional subsarcolemmal vacuoles (without periodic acid-Schifff (PAS)-positive material) and tubular aggregates. Muscle fiber degeneration followed by phagocyte invasion and fatty replacement may occur, perhaps induced by
the cold-induced attacks of weakness (see also periodic paralysis) and structural alterations due to electrolyte shifts or periods of muscle inexcitability. 3.4.3. Hyperkalemic periodic paralysis Hyperkalemic periodic paralysis (hyperPP) is characterized by attacks of transient myotonic stiffness which are followed by flaccid weakness and hyperkalemia. Between attacks, serum potassium and muscle strength are normal, but a chronic progressive proximal myopathy may develop in older patients. The paralytic attacks usually begin in the first decade of life and increase in frequency and severity over time into adulthood. After about the age of 45 years, the frequency of attacks declines considerably. Potassium-rich food or rest after exercise can precipitate an attack. Cold environment and emotional stress also provoke or worsen the attacks. A spontaneous attack commonly starts in the morning before breakfast, lasts for 15 minutes to an hour, and then disappears. Usually, cardiac arrhythmia or respiratory insufficiency do not occur. Between attacks, hyperPP is usually associated with a mild myotonia which may be detectable only by EMG. If myotonia is aggravated by cold and exercise, the diagnosis of paramyotonia congenita is preferred. HyperPP mutations are situated at several disseminated intracellularly faced positions of the sodiumchannel protein potentially involved in the formation of the inactivation apparatus (Lehmann-Horn and JurkatRott, 1999). They lead to incomplete channel inactivation and a pathologically increased sodium current which is associated with a sustained muscle-fiber depolarization. The degree of depolarization determines the clinical symptoms: the non-inactivating mutant channels open the normal channels of a slightly depolarized membrane thereby generating repetitive muscle action potentials (hyperexcitability); at stronger depolarizations, the population of genetically normal sodium channels is inactivated and the muscle paralyzed as no action potentials can be generated. Although myotonia and paralysis are clinically the opposite the pathomechanism is qualitatively the same. The dominance of the mutation results from the fact that the mutation is decisive for the cell excitability. Elevation of extracellular potassium triggers an attack because is depolarizes the membrane. Detailed information on this disease is given in chapter 4 (Periodic paralysis). 3.4.4. Animals with sodium- channel myotonias A condition equivalent to human hyperkalemic periodic paralysis in man has been identified in the Quarter horse, a common breed of racehorse in the USA (Cox,
MYOTONIC DISORDERS 1985). It has the highest incidence of all known inherited disorders of horses. The symptoms are similar to those described above for the human disease, but the condition seems to be more serious than in man as some affected horses have died during attacks. The hyperexcitability of muscles causes hypertrophy, and the resulting aesthetic makes them show winners rather than race winners. A sodium-channel mutation was identified in the equine muscle sodium channel (Rudolph et al., 1992) that causes functional alterations comparable to that observed in human hyperPP at the molecular level (Cannon et al., 1995; Hanna et al., 1996). All affected horses (4.4% of the Quarter horses in the USA) trace to the sire Impressive as first-, second- or third-generation descendants. This is an ideal model for the study of the cellular and physiological factors dictating the onset and severity of attacks and the relationship between exercise, serum potassium levels, catecholamines and other factors influencing muscle metabolism. Study of hyperkalemic horses revealed the first correlation of mutant relative to normal mRNA level as a likely determinant of clinical severity in a dominantly inherited disease (Zhou et al., 1994). Accordingly, homozygous animals have laryngeal and pharyngeal dysfunction during exercise while heterozygous animals do not, even though their weakness and myotonia are comparable (Carr et al., 1996).
3.4.5. Diagnosis and molecular pathogenesis Potassium-aggrevated myotonias, paramyotonia and hyperPP have a similar pathogenesis, involving the voltage-gated sodium channel which is essential for the generation of the muscle action potential. Gain of function mutations cause a gating defect of the sodium channel that leads to slowed and/or incomplete channel inactivation (for review see Lehmann-Horn and JurkatRott, 1999) and an uncoupling of inactivation from activation (Chahine et al., 1994). As a result of the increased membrane permeability, more sodium ions than normal are conducted and the fibers depolarize (Lehmann-Horn et al., 1987; Lerche et al., 1993). The pathologically increased inward sodium current through the mutant channels generates repetitive action potentials and myotonia (PAM). Cooling increases the inactivation defect of paramyotonia channels (Fig. 3.8; Mohammadi et al., 2003). Stronger sustained depolarizations, as in paramyotonia, lead to inactivation of the remaining sodium channels, abolition of action potentials and hence muscle weakness. The sodium pump, which is partly blocked by cooling, cannot compensate for this large inward sodium current, which becomes osmotically relevant and draws water into the fibers
71
(Weber et al., 2006). The resulting electrolyte imbalance prolongs the weakness, which usually lasts several hours even when the muscle has been immediately rewarmed. In contrast, PAM fibers tend to repolarize to normal membrane potentials and therefore do not become paralyzed (Weber et al., 2006). Given a clinical or EMG diagnosis of myotonia, the first step is to exclude myotonic dystrophy. Although other clinical features may be suggestive, this can only be achieved with certainty by molecular genetics (exclusion of DM1 and DM2 nucleotide repeat expansions). If exclusion is successful, further clarification is based on provocation tests (potassium ingestion, cooling) and molecular genetics (screening for mutations in SCN4A and CLCN1). The identification of a specific mutation may aid advising about prognosis. As histology is not specific, and a muscle biopsy should only be considered in those patients whose diagnosis remains unclear after all other diagnostic tools have been used.
3.4.6. Therapy Most patients with Thomsen and some with Becker myotonia can manage well without medication. They tend to keep their muscles in the warmed-up state by continuous slight movements. However, many patients with Becker myotonia require long-term medication. The myotonic stiffness responds to local anesthetics and class 1 antiarrhythmic drugs, the lidocaine analogs. Of the many drugs tested that can be administered orally, mexiletine is the drug of choice (up to 200 mg mexiletine three times daily). As the therapeutic index of mexiletine is narrow, patients and doctors must monitor for symptoms and signs indicating drug toxicity. An ECG should be performed before and after starting treatment, and after dose increases. At higher doses, the serum level should be checked whenever the dose is increased. Complications include nausea, paresthesia, tremor, seizures, alterations in cardiac excitability and conduction, hypotension and coma. Mexiletine can be administered to children provided they are kept well-hydrated at all times. Mexiletine preferentially blocks the non-inactivating mutant sodium channels that reopen abnormally frequently (Mohammadi et al., 2005). Thus, mexiletine has a much greater beneficial effect in sodium-channel myotonias than in chloride-channel myotonia. Patients with myotonia permanens need long-term continuous therapy. The drug is also very effective in preventing and reducing the degree of cold-induced stiffness and weakness in PC. These patients may wish to prevent the cold-induced stiffness and weakness at special events, e.g., winter sports. For this purpose, a temporary use of mexiletine, beginning 2–3 days before the event,
72
F. LEHMANN-HORN AND K. JURKAT-ROTT
Fig. 3.8. Superimposed whole-cell current traces for a depolarization from 100 mV to 0 mV for wild-type (WT) and the R1448H and M1360V mutant channels at (A) 15 C, (B) 25 C, (C) 35 C. M1360V causes temperature-insensitive hyperPP; R1448H causes temperature-sensitive paramyotonia congenita. Adapted from Mohammadi et al. (2003).
can be sufficient. The antimyotonic drugs have no effect on the spontaneous attacks of weakness associated with hyperkalemia that also occur in patients with PC (Ricker et al., 1983). Carbonic anhydrase inhibitors, such as acetazolamide and dichlorophenamide, are an alternative treatment for patients with sodium-channel myotonias. The benefit of these drugs can be judged from the fact that one of the sodium-channel myotonias was dubbed acetazolamide-responsive myotonia (Tru¨dell et al., 1987). Acetazolamide can improve paramyotonic stiffness (Benstead et al., 1987) but may induce weakness
in PC patients (Griggs et al., 1978) and — like fenoterol — exacerbate chloride-channel myotonia (Ricker et al., 1978a; Bretag et al., 1980). Independent of the molecular etiology of the myotonia, pregnancy (Risseeuw et al., 1997; Lacomis et al., 1999; Newman et al., 1999) and hypothyroidism (Sansone et al., 2000) can unmask subclinical myotonia; vice versa, myotonia that occurs in hypothyroid patients responds to thyroxin. Fasting and stress aggravate myotonic stiffness. A myotonic reaction can be also exacerbated by depolarizing agents such as potassium, suxamethonium and anticholinesterases (Mastaglia, 1982; Lehmann-Horn and Iaizzo, 1990a). Administration of depolarizing muscle relaxants usually causes isolated masseter spasm. Respiratory and occasionally other skeletal muscles may also become stiff. Subsequent impaired intubation and mechanical ventilation may result in a life-threatening situation. As myotonia is aggravated by hypothermiainduced muscle shivering, the patients should be kept warm in the operation theatre. Of the various types of sodium channel myotonia, the incidence of anesthetic events seems to be highest in families with myotonia fluctuans (Ricker et al., 1990; Heine et al., 1993; Ricker et al., 1994b; Vita et al., 1995). Most likely, it relates to the frequent absence of clinical signs prior to the operation. Thus, the anesthesiologist is not aware of the condition. In the other diseases, patients report that they have myotonia or attacks of weakness, and depolarizing agents can be avoided thereby lowering the risk of an adverse event. PC patients may be paralyzed for several hours upon awakening from general anesthesia. Preventive therapy before surgery, and maintaining a normal body temperature will help to prevent such attacks (Ashwood et al., 1992). As myotonic patients may develop local or generalized muscle spasms, and such spasms can cause an increase in body temperature and elevated CK values, they are often considered to be susceptible to malignant hyperthermia. However, the specific clinical details and the results of in vitro contracture testing have not been detailed in case reports suggesting an association with malignant hyperthermia (Paasuke and Brownell, 1986; Thomas et al., 1988; Heiman-Patterson et al., 1988). Most likely, these anesthesia-related episodes are caused simply by severe myotonic reactions (Lehmann-Horn and Iaizzo, 1990a; Allen, 1993; Iaizzo and Lehmann-Horn, 1995). In contrast to the silent muscle contractures in malignant hyperthermia (JurkatRott et al., 2000) which well respond to dantrolene, myotonic contractions result from bursts of action potentials and theoretically are more likely to be relieved by lidocaine than by dantrolene. The latter may reduce the contraction force but not the primary hyperexcitability of the membrane.
MYOTONIC DISORDERS
References Allen GC (1993). Paramyotonia and MH. Can J Anaesth 40: 580–581. Ashwood EM, Russell WJ, Burrow DD (1992). Hyperkalaemic periodic paralysis and anaesthesia. Anaesthesia 47: 579–584. Beck CL, Fahlke C, George AL Jr (1996). Molecular basis for decreased muscle chloride conductance in the myotonic goat. Proc Natl Acad Sci U S A 93: 11248–11252. Becker PE (1977). Myotonia Congenita and Syndromes Associated with Myotonia, Thieme Press Inc, Stuttgart. Bendahhou S, Cummins TR, Kwiecinski H, et al. (1999). Characterization of a new sodium channel mutation at arginine 1448 associated with moderate paramyotonia congenita in humans. J Physiol 518: 337–344. Benstead TJ, Camfield PR, King DB (1987). Treatment of paramyotonia congenita with acetazolamide. Can J Neurol Sci 14: 156–158. Berg J, Jiang H, Thornton CA, et al. (2004). Truncated ClC1 mRNA in myotonic dystrophy exerts a dominant-negative effect on the Cl current. Neurology 63: 2371–2375. Bouhours M, Sternberg D, Davoine CS, et al. (2004). Functional characterization and cold sensitivity of T1313A, a new mutation of the skeletal muscle sodium channel causing paramyotonia congenita in humans. J Physiol 554: 635–647. Bouhours M, Luce S, Sternberg D, et al. (2005). A1152D mutation of the Naþ channel causes paramyotonia congenita and emphasizes the role of DIII/S4-S5 linker in fast inactivation. J Physiol 565: 415–427. Brancati F, Valente EM, Davies NP, et al. (2003). Severe infantile hyperkalaemic periodic paralysis and paramyotonia congenita: broadening the clinical spectrum associated with the T704M mutation in SCN4A. J Neurol Neurosurg Psychiatry 74: 1339–1341. Bretag AH, Dawe SR, Kerr DI, et al. (1980). Myotonia as a side effect of diuretic action. Br J Pharmacol 71: 467–471. Brugnoni R, Galantini S, Confalonieri P, et al. (1999). Identification of three novel mutations in the major human skeletal muscle chloride channel gene (CLCN1), causing myotonia congenita. Hum Mutat 14: 447. Bryant SH (1969). Cable properties of external intercostal muscle fibres from myotonic and nonmyotonic goats. J Physiol 204: 539–550. Cannon SC, Hayward LJ, Beech J, et al. (1995). Sodium channel inactivation is impaired in equine hyperkalemic periodic paralysis. J Neurophysiol 73: 1892–1899. Carr EA, Spier SJ, Kortz GD, et al. (1996). Laryngeal and pharyngeal dysfunction in horses homozygous for hyperkalemic periodic paralysis. J Am Vet Med Assoc 209: 798–803. Chahine M, George ALJr, Zhou M, et al. (1994). Sodium channel mutations in paramyotonia congenita uncouple inactivation from activation. Neuron 12: 281–294. Charlet N, Savkur RS, Singh G, et al. (2002). Loss of the muscle-specific chloride channel in type 1 myotonic dystrophy due to misregulated alternative splicing. Mol Cell 10: 45–53.
73
Clark SL, Luton FH, Cutler JT (1939). A form of congenital myotonia in goats. J Nerv Ment Dis 90: 297–309. Conne B, Stutz A, Vassalli JD (2000). The 30 untranslated region of messenger RNA: a molecular ‘hotspot’ for pathology? Nat Med 6: 637–641. Cox JH (1985). An episodic weakness in four horses associated with intermittent serum hyperkalemia and the similarity of the disease to hyperkalemic periodic paralysis in man. Proc Am Assoc Equine Pract 31: 383–390. Deymeer F, Cakirkaya S, Serdaroglu P, et al. (1998). Transient weakness and compound muscle action potential decrement in myotonia congenita. Muscle Nerve 21: 1334–1337. Deymeer F, Lehmann-Horn F, Serdaroglu P, et al. (1999). Electrical myotonia in heterozygous carriers of recessive myotonia congenita. Muscle Nerve 22: 123–125. Drost G, Blok JH, Stegeman DF, et al. (2001). Propagation disturbance of motor unit action potentials during transient paresis in generalized myotonia: a high-density surface EMG study. Brain 124: 352–360. Dutzler R, Campbell EB, Cadene M, et al. (2002). X-ray structure of a ClC chloride channel at 3.0 A reveals the molecular basis of anion selectivity. Nature 415: 287–294. Esteban J, Neumeyer AM, McKenna-Yasek D, et al. (1998). Identification of two mutations and a polymorphism in the chloride channel CLCN-1 in patients with Becker’s generalized myotonia. Neurogenetics 1: 185–188. Fahlke C (2001). Ion permeation and selectivity in ClC-type chloride channels. Am J Physiol Renal Physiol 280: F748–F757. Fournier E, Arzel M, Sternberg D, et al. (2004). Electromyography guides toward subgroups of mutations in muscle channelopathies. Ann Neurol 56: 650–661. George AL Jr, Crackower MA, Abdalla JA, et al. (1993). Molecular basis of Thomsen’s disease (autosomal dominant myotonia congenita). Nat Genet 3: 305–310. George AL Jr, Sloan-Brown K, Fenichel GM, Mitchell GM, et al. (1994). Nonsense and missense mutations of the muscle chloride channel gene in patients with myotonia congenita. Hum Mol Genet 3: 2071–2072. Griggs RC, Moxley RT3, Riggs JE, et al. (1978). Effects of acetazolamide on myotonia. Ann Neurol 3: 531–537. Haass A, Ricker K, Rudel R, et al. (1981). Clinical study of paramyotonia congenita with and without myotonia in a warm environment. Muscle Nerve 4: 388–395. Hanna WJ, Tsushima RG, Sah R, et al. (1996). The equine periodic paralysis Naþ channel mutation alters molecular transitions between the open and inactivated states. J Physiol 497: 349–364. Heiman-Patterson T, Martino C, Rosenberg H, et al. (1988). Malignant hyperthermia in myotonia congenita. Neurology 38: 810–812. Heine R, Pika U, Lehmann-Horn F (1993). A novel SCN4A mutation causing myotonia aggravated by cold and potassium. Hum Mol Genet 2: 1349–1353. Heine R, George AL Jr, Pika U, et al. (1994). Proof of a nonfunctional muscle chloride channel in recessive myotonia congenita (Becker) by detection of a 4 base pair deletion. Hum Mol Genet 3: 1123–1128.
74
F. LEHMANN-HORN AND K. JURKAT-ROTT
Iaizzo P, Lehmann-Horn F (1995). Anesthetic complications in muscle disorders. Anesthesiology 82: 1093–1096. Jurkat-Rott K, McCarthy T, Lehmann-Horn F (2000). Genetics and pathogenesis of malignant hyperthermia. Muscle Nerve 23: 4–17. Jurkat-Rott K, Mitrovic N, Hang C, et al. (2000). Voltagesensor sodium channel mutations cause hypokalemic periodic paralysis type 2 by enhanced inactivation and reduced current. Proc Natl Acad Sci U S A 97: 9549–9554. Jurkat-Rott K, Muller-Ho¨cker J, Pongratz D, et al. (2002). Diseases associated with ion channel and ion transporter defects: chloride and sodium channel myotonias. In: G Karpati, (Ed.), Structural and Molecular Basis of Skeletal Muscle Diseases. ISN Neuropath Press, Basel, pp. 90–94. Jurkat-Rott K, Lehmann-Horn F (2005a). Muscle channelopathies and critical points in functional and genetic studies. J Clin Invest 115: 2000–2009. Jurkat-Rott K, Lehmann-Horn F (2005b). Hyperkalemic periodic paralysis type I. In: Gene Reviews at GeneTests: Medical Genetics Information Resource [database online], University of Washington, SeattleFunded by NIH. Copyright, Available athttp://www.genetests.org. Kelly P, Yang WS, Costigan D, et al. (1997). Paramyotonia congenita and hyperkalemic periodic paralysis associated with a Met 1592 Val substitution in the skeletal muscle sodium channel alpha subunit — a large kindred with a novel phenotype. Neuromuscul Disord 7: 105–111. Kim J, Hahn Y, Sohn EH, et al. (2001). Phenotypic variation of a Thr704Met mutation in skeletal sodium channel gene in a family with paralysis periodica paramyotonica. J Neurol Neurosurg Psychiatry 70: 618–623. Koch MC, Steinmeyer K, Lorenz C, et al. (1992). The skeletal muscle chloride channel in dominant and recessive human myotonia. Science 257: 797–800. Koch MC, Baumbach K, George AL, et al. (1995). Paramyotonia congenita without paralysis on exposure to cold: a novel mutation in the SCN4A gene (Val1293Ile). Neuroreport 6: 2001–2004. Koty PP, Pegoraro E, Hobson G, et al. (1996). Myotonia and the muscle chloride channel: dominant mutations show variable penetrance and founder effect. Neurology 47: 963–968. Kubisch C, Schmidt-Rose T, Fontaine B, et al. (1998). ClC-1 chloride channel mutations in myotonia congenita: variable penetrance of mutations shifting the voltage dependence. Hum Mol Genet 7: 1753–1760. Lacomis D, Gonzales JT, Giuliani MJ (1999). Fluctuating clinical myotonia and weakness from Thomsen’s disease occurring only during pregnancies. Clin Neurol Neurosurg 101: 133–136. Lehmann-Horn F, Iaizzo PA (1990). Are myotonias and periodic paralyses associated with susceptibility to malignant hyperthermia? Br J Anaesth 65: 692–697. Lehmann-Horn F, Jurkat-Rott K (1999). Voltage-gated ion channels and hereditary disease. Physiol Rev 79: 1317–1372. Lehmann-Horn F, Rudel R, Ricker K (1987). Membrane defects in paramyotonia congenita (Eulenburg). Muscle Nerve 10: 633–641.
Lehmann-Horn F, Iaizzo PA, Franke C, et al. (1990). Schwartz-Jampel syndrome: II. Naþ channel defect causes myotonia. Muscle Nerve 13: 528–535. Lehmann-Horn F, Rudel R, Ricker K (1993). Non-dystrophic myotonias and periodic paralyses. Neuromuscul Disord 3: 161–168. Lehmann-Horn F, Maila¨nder V, Heine R, et al. (1995). Myotonia levior is a chloride channel disorder. Hum Mol Genet 4: 1397–1402. Lehmann-Horn F, Rudel R, Jurkat-Rott K (2004). Nondystrophic myotonias and periodic paralyses. In: AG Engel, C Franzini-Armstrong (Eds.), Myology.3rd edn., McGraw-Hill, New York, pp. 1257–1300. Lerche H, Heine R, Pika U, et al. (1993). Human sodium channel myotonia: slowed channel inactivation due to substitutions for a glycine within the III–IV linker. J Physiol 470: 13–22. Lerche H, Mitrovic N, Dubowitz V, et al. (1996). Paramyotonia congenita: the R1448P Naþ channel mutation in adult human skeletal muscle. Ann Neurol 39: 599–608. Lerche H, Peter W, Fleischhauer R, et al. (1997). Role in fast inactivation of the IV/S4-S5 loop of the human muscle Naþ channel probed by cysteine mutagenesis. J Physiol (Lond) 505: 345–352. Lipicky RJ, Bryant SH, Salmon JH (1971). Cable parameters, sodium, potassium, chloride, and water content, and potassium efflux in isolated external intercostal muscle of normal volunteers and patients with myotonia congenita. J Clin Invest 50: 2091–2103. Liquori CL, Ricker K, Moseley ML, et al. (2001). Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science 293: 864–867. Lorenz C, Meyer-Kleine C, Steinmeyer K, et al. (1994). Genomic organization of the human muscle chloride channel ClC-1 and analysis of novel mutations leading to Becker-type myotonia. Hum Mol Genet 3: 941–946. Maila¨nder V, Heine R, Deymeer F, et al. (1996). Novel muscle chloride channel mutations and their effects on heterozygous carriers. Am J Hum Genet 58: 317–324. Mankodi A, Takahashi MP, Jiang H, et al. (2002). Expanded CUG repeats trigger aberrant splicing of ClC-1 chloride channel pre-mRNA and hyperexcitability of skeletal muscle in myotonic dystrophy. Mol Cell 10: 35–44. Mastaglia FL (1982). Adverse effects of drugs on muscle. Drugs 24: 304–321. McClatchey AI, Van den Bergh P, Pericak-Vance MA, et al. (1992). Temperature-sensitive mutations in the III–IV cytoplasmic loop region of the skeletal muscle sodium channel gene in paramyotonia congenita. Cell 68: 769–774. Meyer-Kleine C, Steinmeyer K, Ricker K, et al. (1995). Spectrum of mutations in the major human skeletal muscle chloride channel gene (CLCN1) leading to myotonia. Am J Hum Genet 57: 1325–1334. Mindell JA, Maduke M, Miller C, et al. (2001). Projection structure of a ClC-type chloride channel at 6.5 A resolution. Nature 409: 219–223. Mitrovic N, George ALJr, Heine R, et al. (1994). Kþ-aggravated myotonia: destabilization of the inactivated state of the
MYOTONIC DISORDERS human muscle Naþ channel by the V1589M mutation. J Physiol 478: 395–402. Mitrovic N, George AL Jr, Lerche H, et al. (1995). Different effects on gating of three myotonia-causing mutations in the inactivation gate of the human muscle sodium channel. J Physiol 487: 107–114. Mohammadi B, Mitrovic N, Lehmann-Horn F, et al. (2003). Mechanisms of cold sensitivity of paramyotonia congenita mutation R1448H and overlap syndrome mutation M1360V. J Physiol 547: 691–698. Mohammadi B, Jurkat-Rott K, Alekov AK, et al. (2005). Preferred mexiletine block of human sodium channels with IVS4 mutations and its pH-dependence. Pharmacogenet Genomics 15: 235–244. Nagamitsu S, Matsuura T, Khajavi M, et al. (2000). A “dystrophic” variant of autosomal recessive myotonia congenita caused by novel mutations in the CLCN1 gene. Neurology 55: 1697–1703. Newberg LA, Lambert EH, Gronert GA (1983). Failure to induce malignant hyperthermia in myotonic goats. Br J Anaesth 55: 57–60. Newman B, Meola G, O’Donovan DG, et al. (1999). Proximal myotonic myopathy (PROMM) presenting as myotonia during pregnancy. Neuromuscul Disord 9: 144–149. Okuda S, Kanda F, Nishimoto K, et al. (2001). Hyperkalemic periodic paralysis and paramyotonia congenita — a novel sodium channel mutation. J Neurol 248: 1003–1004. Orrell RW, Jurkat-Rott K, Lehmann-Horn F, et al. (1998). Familial cramp due to potassium-aggravated myotonia. J Neurol Neurosurg Psychiatry 65: 569–572. Paasuke RT, Brownell AK (1986). Serum creatine kinase level as a screening test for susceptibility to malignant hyperthermia. JAMA 255: 769–771. Palade PT, Barchi RL (1977). On the inhibition of muscle membrane chloride conductance by aromatic carboxylic acids. J Gen Physiol 69: 879–896. Papponen H, Toppinen T, Baumann P, et al. (1999). Founder mutations and the high prevalence of myotonia congenita in northern Finland. Neurology 53: 297–302. Plassart E, Eymard B, Maurs L, et al. (1996). Paramyotonia congenita: genotype to phenotype correlations in two families and report of a new mutation in the sodium channel gene. J Neurol Sci 142: 126–133. Plassart-Schiess E, Gervais A, Eymard B, et al. (1998). Novel muscle chloride channel (CLCN1) mutations in myotonia congenita with various modes of inheritance including incomplete dominance and penetrance. Neurology 50: 1176–1179. Ptacek LJ, George AL Jr, Barchi RL, et al. (1992). Mutations in an S4 segment of the adult skeletal muscle sodium channel cause paramyotonia congenita. Neuron 8: 891–897. Ptacek LJ, Tawil R, Griggs RC, et al. (1994). Sodium channel mutations in acetazolamide-responsive myotonia congenita, paramyotonia congenita, and hyperkalemic periodic paralysis. Neurology 44: 1500–1503. Pusch M (2002). Myotonia caused by mutations in the muscle chloride channel gene CLCN1. Hum Mutat 19: 423–434.
75
Pusch M, Steinmeyer K, Koch MC, et al. (1995). Mutations in dominant human myotonia congenita drastically alter the voltage dependence of the ClC-1 chloride channel. Neuron 15: 1455–1463. Ranum LP, Rasmussen PF, Benzow KA, et al. (1998). Genetic mapping of a second myotonic dystrophy locus. Nat Genet 19: 196–198. Ricker K, Haass A, Glo¨tzner F (1978a). Fenoterol precipitating myotonia in a minimally affected case of recessive myotonia congenita. J Neurol 219: 279–282. Ricker K, Haass A, Hertel G, et al. (1978b). Transient muscular weakness in severe recessive myotonia congenita. Improvement of isometric muscle force by drugs relieving myotonic stiffness. J Neurol 218: 253–262. Ricker K, Bo¨hlen R, Rohkamm R (1983). Different effectiveness of tocainide and hydrochlorothiazide in paramyotonia congenita with hyperkalemic episodic paralysis. Neurology 33: 1615–1618. Ricker K, Rudel R, Lehmann-Horn F, et al. (1986). Muscle stiffness and electrical activity in paramyotonia congenita. Muscle Nerve 9: 299–305. Ricker K, Lehmann-Horn F, Moxley RT3 (1990). Myotonia fluctuans. Arch Neurol 47: 268–272. Ricker K, Koch MC, Lehmann-Horn F, et al. (1994a). Proximal myotonic myopathy: a new dominant disorder with myotonia, muscle weakness, and cataracts. Neurology 44: 1448–1452. Ricker K, Moxley RT3, Heine R, et al. (1994b). Myotonia fluctuans. A third type of muscle sodium channel disease. Arch Neurol 51: 1095–1102. Ricker K, Grimm T, Koch MC, et al. (1999). Linkage of proximal myotonic myopathy to chromosome 3q. Neurology 52: 170–171. Risseeuw JJ, Oudshoorn JH, van der Straaten PJ, et al. (1997). Myotonic dystrophy in pregnancy: a report of two cases within one family. Eur J Obstet Gynecol Reprod Biol 73: 145–148. Rosenfeld J, Sloan-Brown K, George AL Jr (1997). A novel muscle sodium channel mutation causes painful congenital myotonia. Ann Neurol 42: 811–814. Rudel R, Lehmann-Horn F (1997). Paramyotonia, potassiumaggravated myotonias and periodic paralyses. 37th ENMC International Workshop, Naarden, The Netherlands, 8–10 December 1995, Neuromuscul Disord 7: 127–132. Rudel R, Ricker K, Lehmann-Horn F (1988). Transient weakness and altered membrane characteristic in recessive generalized myotonia (Becker). Muscle Nerve 11: 202–211. Rudolph JA, Spier SJ, Byrns G, et al. (1992). Periodic paralysis in quarter horses: a sodium channel mutation disseminated by selective breeding. Nat Genet 2: 144–147. Sangiuolo F, Botta A, Mesoraca A, et al. (1998). Identification of five new mutations and three novel polymorphisms in the muscle chloride channel gene (CLCN1) in 20 Italian patients with dominant and recessive myotonia congenita. Hum Mutat 11: 331. Sansone V, Griggs RC, Moxley RT3 (2000). Hypothyroidism unmasking proximal myotonic myopathy. Neuromuscul Disord 10: 165–172.
76
F. LEHMANN-HORN AND K. JURKAT-ROTT
Sasaki R, Ichiyasu H, Ito N, et al. (1999). Novel chloride channel gene mutations in two unrelated Japanese families with Becker’s autosomal recessive generalized myotonia. Neuromuscul Disord 9: 587–592. Sasaki R, Ito N, Shimamura M, et al. (2001). A novel CLCN1 mutation: P480T in a Japanese family with Thomsen’s myotonia congenita. Muscle Nerve 24: 357–363. Saviane C, Conti F, Pusch M (1999). The muscle chloride channel ClC-1 has a double-barreled appearance that is differentially affected in dominant and recessive myotonia. J Gen Physiol 113: 457–468. Sloan-Brown K, George AL Jr (1997). Inheritance of three distinct muscle chloride channel gene (CLCN1) mutations in a single recessive myotonia congenita family. Neurology 48: 552–553. Spaans F, Theunissen P, Reekers AD, et al. (1990). SchwartzJampel syndrome: I. Clinical, electromyographic, and histologic studies. Muscle Nerve 13: 516–527. Steinmeyer K, Klocke R, Ortland C, et al. (1991). Inactivation of muscle chloride channel by transposon insertion in myotonic mice. Nature 354: 304–308. Sun C, Tranebjaerg L, Torbergsen T, et al. (2001). Spectrum of CLCN1 mutations in patients with myotonia congenita in Northern Scandinavia. Eur J Hum Genet 9: 903–909. Thomas A, Leopold U, Winkler H (1988). Maligne hyperthermie bei paramyotonia congenita. Anaesthesiol Reanim 13: 295–300. Trudell RG, Kaiser KK, Griggs RC (1987). Acetazolamideresponsive myotonia congenita. Neurology 37: 488–491. Tsujino A, Maertens C, Ohno K, et al. (2003). Myasthenic syndrome caused by mutation of the SCN4A sodium channel. Proc Natl Acad Sci U S A 100: 7377–7382. Vita GM, Olckers A, Jedlicka AE, et al. (1995). Masseter muscle rigidity associated with glycine1306-to-alanine mutation in the adult muscle sodium channel a-subunit gene. Anesthesiology 82: 1097–1103.
Wagner S, Lerche H, Mitrovic N, et al. (1997). A novel sodium channel mutation causing a hyperkalemic paralytic and paramyotonic syndrome with variable clinical expressivity. Neurology 49: 1018–1025. Wagner S, Deymeer F, Kurz LL, et al. (1998). The dominant chloride channel mutant G200R causing fluctuating myotonia: clinical findings, electrophysiology, and channel pathology. Muscle Nerve 21: 1122–1128. Weber M-A, Nielles-Vallespin S, Essig M, et al. (2006). Na flux in muscle sodium channelopathies in vitro and by 23 Na MRI in vivo. Neurology 67: 1151–1158. Weiss MD, Mayer RF (1997). Temperature-sensitive repetitive discharges in paramyotonia congenita. Muscle Nerve 20: 195–197. White GR, Plaskett J (1904). “Nervous”, “stiff-legged”, or “fainting” goats. Am Vet Rev 28: 556–560. Wu FF, Takahashi MP, Pegoraro E, et al. (2001). A new mutation in a family with cold-aggravated myotonia disrupts Na(þ) channel inactivation. Neurology 56: 878–884. Wu FF, Ryan A, Devaney J, et al. (2002). Novel CLCN1 mutations with unique clinical and electro-physiological consequences. Brain 125: 2392–2407. Wu FF, Gordon E, Hoffman EP, et al. (2005). A C-terminal skeletal muscle sodium channel mutation associated with myotonia disrupts fast inactivation. J Physiol 565: 371–380. Zhang J, George AL Jr, Griggs RC, et al. (1996). Mutations in the human skeletal muscle chloride channel gene (CLCN1) associated with dominant and recessive myotonia congenita. Neurology 47: 993–998. Zhang J, Bendahhou S, Sanguinetti MC, et al. (2000). Functional consequences of chloride channel gene (CLCN1) mutations causing myotonia congenita. Neurology 54: 937–942. Zhou J, Spier SJ, Beech J, et al. (1994). Pathophysiology of sodium channelopathies: correlation of normal/mutant mRNA ratios with clinical phenotype in dominantly inherited periodic paralysis. Hum Mol Genet 3: 1599–1603.
Handbook of Clinical Neurology, Vol. 86 (3rd series) Myopathies F. L. Mastaglia, D. Hilton-Jones, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 4
Periodic paralysis DOREEN FIALHO AND MICHAEL G. HANNA* Institute of Neurology, London, UK
4.1. Introduction Periodic paralysis is a disorder of skeletal muscle in which patients experience attacks of muscle weakness of variable duration and severity. The attacks can last from a few minutes to several days. The weakness in an attack can be generalized or focal. Early in the natural history of the disease muscle strength returns to normal after an attack, but later significant fixed muscle weakness often develops. The variability of the symptoms often leads to delays in accurate diagnosis and treatment. Although the clinical phenotype of periodic paralysis has been recognized for many years, it is only in recent times that the underlying pathophysiology has been deduced at a molecular genetic level. In all forms of this disorder, electrophysiological examination during an attack reveals that the skeletal muscle fiber membrane is in a partially depolarized and inexcitable state. Muscle membrane excitability depends on the coordinated interplay of key voltage-gated ion channels. It is now known that in both genetic and acquired forms of periodic paralysis dysfunction of these key membranebound ion channels underlies the pathophysiology and explains the altered muscle excitability. Periodic paralysis was one of the first neurological channelopathies to be characterized at a genetic and cellular level. To a certain extent the current detailed molecular knowledge about periodic paralysis represents a paradigm for our understanding of subsequently discovered muscle and brain channelopathies. Historically, periodic paralysis was classified according to serum potassium abnormalities during attacks into hypo- and hyperkalemic periodic paralysis (hypoPP and hyperPP). This classification depending on serum potassium is still of use clinically but has
now been supplemented by the newer molecular genetic classification which we describe here. In this chapter we provide a detailed review of current knowledge regarding clinical features, investigations, treatment, genetics and molecular pathophysiology of the periodic paralyses.
4.2. Clinical features 4.2.1. Familial hypokalemic periodic paralysis (hypoPP) Most of the early original publications on periodic paralysis were probably describing hypoPP, as this is the commonest form of periodic paralysis. Talbott published an extensive review of the literature on periodic paralysis in 1941 (Talbott, 1941). This paper summarized many of the characteristic features of periodic paralysis including age of onset, male predilection, development of fixed weakness and provoking factors. Talbott cites Musgrave’s interesting observation from 1727 of a 21year-old woman who presented with attacks of weakness, and suggests this may be the first description of periodic paralysis (Musgrave, 1727). However, some of the features in Musgrave’s original case were atypical, including loss of speech and attacks always occurring on the same day of the week. From the beginning of the 19th century a number of reports started to appear describing cases of sporadic periodic paralysis and the first familial case of an affected father and son was reported by Shakhnowitsch in 1882. Early hypotheses on the pathogenesis of periodic paralysis included the theory of muscle ischemia as the underlying pathology (Westphal, 1885; Holtzapple, 1905; Schmidt, 1919; Mankowsky, 1929). Goldflam (Goldflam, 1890) and others (Crafts,
*Correspondence to: Dr. M.G. Hanna, Centre for Neuromuscular Disease, National Hospital for Neurology and Neurosurgery, University College London Foundation NHS Trust, and Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, UK. E-mail:
[email protected], Tel: þ44-(0)207837-3611, Fax: þ44-(0)207-6921-2085.
78
D. FIALHO AND M. G. HANNA
1900; Singer and Goodbody, 1901) suggested that an autotoxin was responsible. Hartwig (1874) was the first to describe electrical inexcitability of muscles during an attack of paralysis. Indeed, Hartwig was so surprised by the lack of response to electrical stimulation that he initially thought that his apparatus was malfunctioning. Biemond and Daniels (1934) provided the first report of low potassium levels during a spontaneous attack. This was confirmed in another case a year later when Walker (1935) reported convincing evidence that there was a 50% decrease of serum potassium during an attack. It is now known that hypoPP is the most common form of familial periodic paralysis with a prevalence of 0.4–1:100 000 in Europe (Kantola and Tarssanen, 1992; Fontaine, 1994). The inheritance is autosomal dominant with reduced penetrance in women giving a male:female ratio of ~3:1 (Elbaz et al., 1995). There are currently three genes implicated in familial hypoPP including CACNA1S, SCN4A and KCNJ2. Mutations in the voltage-gated calcium channel gene CACNA1S account for the majority of cases (~70%; Fouad et al., 1997; Miller et al., 2004). In less than 10% of cases mutations in the voltage-gated sodium channel gene SCN4A are reported (Bulman et al., 1999; Davies et al., 2001; Sternberg et al., 2001; Miller et al., 2004). Mutations in KCNJ2 encoding an inwardrectifying potassium channel can cause Andersen– Tawil syndrome (Plaster et al., 2001). Since this condition is distinct and can present with both hypo- and hyperkalemic periodic paralysis it will be discussed separately. A mutation in KCNE3 reported as pathogenic in hypoPP was later found to be a benign polymorphism
(Abbott et al., 2001; Sternberg et al., 2003; Jurkat-Rott and Lehmann-Horn, 2004). Hypokalemic periodic paralysis generally presents later than hyperkalemic paralysis, usually between the ages of 5 and 20, typically in the teenage years (Fouad et al., 1997; Miller et al., 2004; see Table 4.1). However, onset over the age of 20 has been reported (Miller et al., 2004). Attacks tend to last from several hours up to 2–3 days. It is often difficult for patients to give a precise estimate of attack duration as both onset and resolution tend to be gradual. A sudden onset of weakness leading to a collapse would argue against a diagnosis of periodic paralysis. It is generally considered that in hypoPP attacks are longer and more severe than in hyperPP. Although this is our experience, a recent retrospective study did not confirm this. It is possible the use of medication by patients in the study may have influenced attack duration (Miller et al., 2004). In a typical hypoPP episode the patient wakes in the night or in the morning with generalized severe weakness being “unable to move”. Often intake of a carbohydrate-rich meal or strenuous exercise the preceding day or night can be identified as a triggering factor. Focal episodes of weakness may be triggered by exercise only involving one limb but are more common in hyperPP. Tendon reflexes are diminished or absent. Even in a severe attack cranial muscles are spared so that speech and eye opening remain intact. Impairment of speech, visual symptoms or alterations in consciousness are not expected and should trigger consideration of other diagnostic possibilities. Respiratory muscles are mostly spared but a reduction in vital capacity and consequent
Table 4.1 Clinical features of hyperkalemic periodic paralysis and hypokalemic periodic paralysis
Onset of symptoms Triggers Time of attack Duration of attack Severity of attack Additional symptoms Serum potassium Interictal electromyography Treatment Gene/ion channel
Hyperkalemic periodic paralysis
Hypokalemic periodic paralysis
First decade Rest after exercise, cold, fasting, potassium-rich food Any time of the day Minutes to hours Mild to moderate, may be focal Myotonia or paramyotonia Usually high, may be normal Myotonic discharges in some, positive McManis test Acetazolamide, dichlorphenamide, thiazide, beta-agonist SCN4A: Nav1.4 (sodium channel subunit), KCNJ2: Kir2.1 (potassium channel subunit)
Second decade Rest after exercise, carbohydrate load Typically when waking up in the morning Hours to days Moderate to severe Low Never myotonic discharges, positive McManis test Acetazolamide, dichlorphenamide, potassium supplementation, potassium-sparing diuretics CACNA1S: Cav1.1 (calcium channel subunit), SCN4A: Nav1.4 (sodium channel subunit), KCNJ2: Kir2.1 (potassium channel subunit)
PERIODIC PARALYSIS respiratory failure has rarely been reported to occur in severe attacks (Ziegler and McQuarrie, 1952; Rowley and Kliman, 1960; Resnick and Engel, 1967). Strength gradually improves over the course of the next day or two although some patients indicate that it takes up to a week to recover. Even when the patient is not complaining of clear clinical attacks careful quantitative strength measurement has suggested that there is diurnal variation of muscle power, being lowest in the early hours of the morning and highest in the afternoon and evening (Engel et al., 1965). Attacks often become less frequent and severe in later life and in common with hyperPP a permanent myopathy may develop (Biemond and Daniels, 1934). Interestingly fixed weakness has been described to occur even in patients without a strong history of frequent paralytic attacks (Sternberg et al., 2001). For example, in some females the lateonset myopathy may be the only manifestation without any clinically evident paralytic attacks (Links et al., 1990). A study of a large kindred with hypoPP showed that nearly all subjects over the age of 50 years had evidence of fixed muscle weakness (Links et al., 1994). It remains unproven whether active treatment to reduce the frequency of paralytic attacks might reduce the development of fixed weakness later. A useful feature to distinguish between hypo- and hyperkalemic periodic paralysis clinically is the absence of (true) myotonia in hypoPP. The only exception to this rule so far is the SCN4A mutation P1158S which has been described in a Japanese kindred causing myotonia and cold-induced hypoPP (Sugiura et al., 2000). Previously in the literature only a single case was reported with myotonia and periodic paralysis where the potassium level was low (1.9 mEq/l) during the attack. However the patient was from a family with typical myotonic dystrophy and the precise diagnosis is unclear (Leyburn and Walton, 1960). There are a handful of other reports of apparent clinical myotonia (mostly myotonic lid lag) in association with hypokalemic periodic paralysis (Odor et al., 1967; Resnick et al., 1967; Griggs et al., 1970). Here the explanation may be that the lid lag was not due to true electrical myotonia, which explains why no EMG myotonia could be demonstrated in any of these patients. Although lid lag is a sensitive marker of myotonia it does not appear to be very specific as it has been found even in healthy volunteers (Odor et al., 1967) and should therefore be interpreted with caution. A number of factors may induce or exacerbate attacks. These include ingestion of carbohydrates, administration of insulin and epinephrine injections (Ziegler and McQuarrie, 1952; Rowley and Kliman, 1960; Engel et al., 1965). Stress and excitement and exposure to cold are also often listed by patients as triggers (Miller et al.,
79
2004). Menstruation and pregnancy have been reported to cause an increase in frequency and severity of attacks (Bender, 1936; Links et al., 1994). Although serum potassium levels are often reduced, especially at the beginning of an attack, they may not be below the normal range. The original studies of periodic paralysis in the early 20th century reported a number of other electrolyte changes (for review see Talbott 1941), including a decrease in serum phosphate in parallel with potassium and reduced urinary excretion of sodium, potassium, chloride and water. Serum creatine kinase (CK) may be normal or slightly elevated in between attacks. During paralytic attacks there can be a moderate rise in CK (De Keyser et al., 1987). Electrocardiogram (ECG) changes have been observed with very low potassium including prominent U waves, flattening of T waves and ST depression. Interictal ECG is usually normal although affected members of a kindred with hypokalemic periodic paralysis carrying the R528H CACNA1S mutation were reported to suffer from cardiac arrhythmias (Fouad et al., 1997). The presence of prominent U waves, frequent ventricular ectopic beats or arrhythmias should alert the clinician to the possibility of Andersen–Tawil syndrome (ATS) (see later section). Familial hypokalemic periodic paralysis is not associated with clinical or echocardiographic evidence of cardiomyopathy (Schipperheyn et al., 1978).
4.2.2. Familial hyperkalemic periodic paralysis (hyperPP) In the early 1950s the Swedish pediatric neurologist Gamstorp recognized a new form of periodic paralysis associated with an elevated serum potassium. In her thesis in 1956 she coined the term “adynamia episodica hereditaria” (Gamstorp, 1956) but later it was referred to as hyperkalemic periodic paralysis. Familial hyperPP is due to mutations in SCN4A encoding the a-subunit of the skeletal muscle voltagegated sodium channel Nav1.4. The clinical presentation of hyperPP includes attacks of limb weakness lasting minutes to hours. In contrast to hypoPP the attacks frequently happen during daytime but nocturnal attacks may occur (Gamstorp, 1956; Layzer et al., 1967). From a clinical diagnostic perspective, frequent short daytime attacks favor a diagnosis of hyperPP and nocturnal prolonged attacks may slightly favor hypoPP. The onset of symptoms is typically within the first decade and attacks tend to become milder and less frequent with age. A persistent mild myopathy may develop later in the course of the disease and reports indicate that this is independent of the number of attacks (Saunders et al., 1968; Bradley et al., 1990; Ptacek et al., 1991a).
80
D. FIALHO AND M. G. HANNA
The rise of potassium during attacks may be subtle and transient, frequently not exceeding the normal range and can therefore be easily missed (Plassart et al., 1994). For many years normokalemic periodic paralysis was considered to be a distinct disorder based on descriptions of a limited number of families (Poskanzer and Kerr, 1961; Meyers et al., 1972; Danowski et al., 1975). However, the status of normokalemic PP as a distinct entity now looks uncertain. We had the opportunity to analyze the original 1961 family from the northeast of England and showed that they harbored the common M1592V hyperPP SCN4A mutation (Chinnery et al., 2002). It seems likely that normokalemic periodic paralysis should be considered a variant of hyperPP. HyperPP, potassium aggravated myotonia (PAM) and paramyotonia congenita (PMC) are allelic sodium channel disorders and their phenotypes overlap to varying degrees (Layzer et al., 1967; de Silva et al., 1990). In hyperPP and paramyotonia congenita women may be less severely affected (Layzer et al., 1967). Many patients who have both periodic paralysis and myotonia find it difficult to distinguish between stiffness and weakness and attacks are often initially dominated by stiffness leading to paralysis later. EMG myotonia can be demonstrated in at least 50% of patients with the two most common SCN4A mutations T704M and M1592V (Plassart et al., 1994; Miller et al., 2004; Fournier et al., 2004) but myotonia on examination is detected in a smaller percentage (Plassart et al., 1994). Interestingly myotonic symptoms are frequently experienced and easily elicited in the cranial musculature (myotonic lid lag, eye closure myotonia) which is not usually involved in the paralytic attack. Consciousness is preserved and respiratory and cranial musculature is usually spared. A number of factors have been identified that can trigger or exacerbate attacks. These include rest following exercise, fasting, cold, stress, intercurrent infection and anesthesia. Hormonal changes may also play a role as menstruation, oral contraception and pregnancy have been associated with an increase in symptoms (Layzer et al., 1967; Ptacek et al., 1993; Kim et al., 2001). 4.2.3. Andersen–Tawil syndrome (ATS) Andersen–Tawil syndrome first fully described by Andersen et al. (1971) is characterized by a triad of periodic paralysis, ventricular arrhythmia and distinctive physical features. Many patients do not have all of these features and there can be marked intrafamilial variation and evidence of incomplete penetrance (Plaster et al., 2001). It is the rarest form of periodic paralysis and no reliable data exist on prevalence.
Mutations in KCNJ2 encoding the inward-rectifying potassium channel Kir2.1 have been identified in about two-thirds of kindreds with ATS (Plaster et al., 2001; Tristani-Firouzi et al., 2002). Up to 20% of individuals carrying pathogenic mutations may not exhibit any phenotypic features (Andelfinger et al., 2002; Tristani-Firouzi et al., 2002; Donaldson et al., 2003). De novo mutations are frequent (Donaldson et al., 2003). The original case described by Andersen et al. (1971) had quite marked physical abnormalities with low-set ears, hypertelorism, mandibular hypoplasia, scaphocephalic cranium, clinodactyly, single transverse palm crease, central defect of soft and hard palate and cryptorchidism. Many patients with Andersen–Tawil syndrome have only subtle skeletal or facial abnormalities which become more obvious when the patient’s appearance is compared with unaffected family members. The most common features are mandibular hypoplasia, hypertelorism, broad-based nose, low-set ears, clinodactyly and syndactyly (Fig. 4.1; Canun et al., 1999). Other possible associated features described in a small number of cases include hypoplastic kidney (Andelfinger et al., 2002), renal tubular acidosis, dysphonia, cognitive impairment (Davies et al., 2005), valvular heart defects (Andelfinger et al., 2002) and vaginal atresia (Canun et al., 1999). Symptomatic onset with episodic weakness is typically in the first or second decade. The periodic paralysis is most commonly hypokalemic but may also be hyper- or normokalemic (Donaldson et al., 2003). Electrocardiography may show bidirectional or polymorphic ventricular tachycardia, prolonged corrected QT interval, bigeminy, frequent ventricular ectopy or may be normal (Fig. 4.2). A particularly frequent finding is a prominent ‘U’ wave even in the presence of a normal serum potassium (Tristani-Firouzi et al., 2002). Due to the cardiac abnormalities Andersen– Tawil syndrome is also classified as long-QT syndrome 7 (LQT7). In comparison to other long-QT syndromes the arrhythmias in Andersen–Tawil syndrome are less malignant (Tristani-Firouzi et al., 2002). However sudden cardiac death does occur and patients require careful cardiac evaluation (Andelfinger et al., 2002; Tristani-Firouzi et al., 2002; Donaldson et al., 2003). A more recent study of ECGs from a large cohort of ATS patients established a distinct T-U-wave pattern that reliably distinguished between KCNJ2 mutation positive ATS patients and those where no mutation could be found (Zhang et al., 2005). The authors also point out that in many ATS patients the QT interval is in fact within the normal limits and the designation of LQT7 should therefore not be used.
PERIODIC PARALYSIS
81
Fig. 4.1. ATS patient with distinctive physical features including hypoplastic maxilla and mandible, hypertelorism, low set ears, webbed neck, clinodectyly, shortened digits and mild syndactyly of the 2nd and 3rd toes.
4.2.4. Thyrotoxic periodic paralysis (TPP) The occurrence of periodic paralysis in association with hyperthyroidism was reported as early as 1902 (Rosenfeld, 1902). This form of periodic paralysis is more common in Asia, particularly China, Korea and Japan, where more than 10% of male thyrotoxic patients may be affected (Chen et al., 1965; McFadzean and Yeung, 1967; Ober, 1992; Kung et al., 2004). The overall incidence in thyrotoxic patients from these populations is approximately 2% (McFadzean and Yeung, 1967) while the incidence in Caucasians has been estimated at only 0.1–0.2% (Kelley et al., 1989). Due to migration, cases of TPP are now increasingly seen in the Western world (Ober, 1992). It is also recognized in Caucasians (Linder, 1955), native American Indians (Conway et al., 1974), Blacks (Kilpatrick et al., 1994), Aborigines (Ghose et al., 1996) and Maoris (Wild, 2004). The male-to-female predominance is much more marked in TPP (between 20:1 and 76:1) (Okinaka et al.,
1957; McFadzean and Yeung, 1967) compared to hypoPP (3:1; Elbaz et al., 1995). This is even more significant given that the prevalence of thyrotoxicosis is so much higher in females. Most cases of TPP are sporadic but a few familial cases have been described (Kufs et al., 1989; Dias da Silva et al., 2002a). The onset of symptoms is most frequently between the second and fourth decade in parallel to the highest incidence of hyperthyroidism. A significant proportion of patients have only subtle clinical signs of hyperthyroidism (McFadzean and Yeung, 1967; Kelley et al., 1989). Autoimmune thyrotoxicosis (Graves’ disease) is the most common underlying disorder but TPP may be caused by any form of hyperthyroidism in susceptible patients including excessive administration of thyroid hormone replacement. Thyrotoxic periodic paralysis bears phenotypic resemblance to familial hypokalemic periodic paralysis. It is associated with low serum potassium during attacks, may be triggered by glucose/insulin administration and
82
D. FIALHO AND M. G. HANNA
A
B Fig. 4.2. ECG traces from patients with ATS. (A) Frequent polymorphic ventricular ectopy with bidirectional ventricular ectopics detectable in the lateral chest leads. QTc interval borderline prolonged. (B) Prominent U-wave.
may also be triggered by rest following exercise. Focal weakness can develop in more strenuously exercised muscles and attacks typically occur at night or on wakening in the morning (McFadzean and Yeung, 1967). Rare cases with associated normo- or hyperkalemia have been reported, although this was prior to the availability of DNA testing for familial periodic paralysis (Adachihara and Takagi, 1974; Mehta et al., 1990). The respiratory and cranial musculature tend to be spared. Morbidity and mortality is low but significant arrhythmias associated with severe hypokalemia have been reported (McFadzean and Yeung, 1967; Fisher, 1982).
4.2.5. Secondary periodic paralysis A number of secondary causes of periodic paralysis should to be considered when evaluating a patient with periodic paralysis. Both hypo- and hyperkalemia of any origin can result in muscle weakness or paralysis. Usually the patient remains weak until the underlying cause of potassium alteration is identified and treated. Occasionally patients with a secondary cause may
present with intermittent attacks of weakness and this may make the distinction with sporadic genetic periodic paralysis more difficult. In general the electrolyte disturbance tends to be more severe than seen in the familial forms of periodic paralysis. Usually potassium levels have to decline to <3 mmol/l or rise to >7 mmol/l before significant muscle symptoms are experienced. With the exception of barium poisoning and insulin excess there is a loss or excess of total body potassium in secondary periodic paralysis rather than a shift between intraand extracellular space as is the case in the familial forms and in TPP. Metabolic abnormalities often persist between attacks and this gives an important clue to the underlying diagnosis. The treatment is aimed at correcting the primary abnormality. A number of conditions mainly causing urinary or gastrointestinal potassium loss leading to hypokalemia have been reported in association with episodic weakness (Table 4.2). With severe hypokalemia there is an associated risk of significant arrhythmias, paralytic ileus and rhabdomyolysis in addition to respiratory failure secondary to muscle paralysis (Weiss-Guillet et al., 2003). The presentation of patients with muscle
PERIODIC PARALYSIS
83
Table 4.2 Causes of secondary periodic paralysis
Endocrine
Renal
Conditions leading to hyperkalemia
Conditions leading to hypokalemia
Addison’s disease (Pollen and Williams, 1960) Hypoaldosteronism and hyporeninaemia (Daughaday and Rendleman, 1967)
Hyperaldosteronism (primary/secondary) (Conn et al., 1964; Ishikawa et al., 1985; Ma et al., 1986) Cushing’s disease/syndrome
Gordon’s syndrome: pseudohypoaldosteronism type II (Pasman et al., 1989)
Hyperreninism (Umeki et al., 1986) 17a-hydroxylase deficiency (CYP17) (Yazaki et al., 1982) Hyperinsulinemia Bartter’s syndrome (Shiah et al., 1994) Liddle syndrome Gitelman syndrome (Lin et al., 2003) Distal tubular acidosis type 1 and 2 þ/ Sjo¨gren’s syndrome (Owen and Verner, 1960; Raskin et al., 1981) Severe diarrhea and vomiting (Ortuno et al., 2002; Haddad et al., 2004) Ileostomy Uterosigmoidostomy (Angeloni and Scott, 1960; Sataline and Simonelli, 1961) Villous adenoma (Keyloun and Grace, 1967) Licorice (Cumming et al., 1980; Ishikawa et al., 1985) Laxative abuse (Basser, 1979)
Chronic renal failure (Cumberbatch and Hampton, 1999)
Gastro-intestinal
Drugs/Toxins
Potassium load (Muensterer, 2003) Potassium-sparing diuretics (Udezue and Harrold, 1980) High-dose angiontensin-converting (ACE) inhibitor (Dutta et al., 2001)
paralysis secondary to hyperkalemia is much less common than hypokalemia (Evers et al., 1998). Most cases of secondary hyperPP are due to potassiumsparing diuretics (spironolactone) often on a background of renal impairment. There have been many case reports of primary and secondary renal tubular acidosis (RTA) associated with hypoPP (Koul et al., 1993; Bresolin et al., 2005). Renal tubular acidosis probably due to autoimmune tubulointerstitial nephritis may occur in Sjo¨gren’s syndrome and an association with periodic paralysis has been described (Raskin et al., 1981). In some of these cases the muscle symptoms were the presenting complaints (Soy et al., 2005), even leading to respiratory arrest (Poux et al., 1992; Fujimoto et al., 2001). Habitual toluene inhalation (glue sniffing) can also cause RTA and may present with paralysis (Bennett and Forman, 1980).
Potassium-wasting diuretics (Cohen, 1959) Amphotericin B (McChesney and Marquardt, 1964) Barium poisoning (Lewi and Bar-Khayim, 1964) Toluene exposure (Bennett and Forman, 1980) Cocaine (Nalluri et al., 2000; Lajara-Nanson, 2002) Gossypol (Wang and Chen, 1991; Waites et al., 1998)
The first cases of barium poisoning were referred to as Pa Ping disease due to endemic periodic paralysis in the Pa Ping area of the Szechwan province of China caused by ingestion of table salt contaminated by barium (Allen, 1943). Accidental ingestion of barium salts used as rat poison, industrial accidents, suicidal attempts and administration of barium carbonate instead of the insoluble sulphate in radiodiagnosis have been reported (Lewi and Bar-Khayim, 1964; Berning, 1975; Layzer, 1982; Shankle and Keane, 1988; Ahlawat and Sachdev, 1999). Manifestations of toxicity include hemorrhagic gastroenteritis with vomiting, colic and diarrhea, hypertension, cardiac arrhythmias, muscle twitching, seizures, hypokalemia and muscle paralysis (Johnson and VanTassell, 1991). The hypokalemia in barium poisoning occurs due to a shift of potassium from the extracellular to intracellular compartments. Barium competitively blocks potassium channels causing reduction in potassium
84
D. FIALHO AND M. G. HANNA
permeability leading to membrane depolarization and finally inexcitability (Sperelakis et al., 1967; Gallant, 1983). The potassium channels affected include the inward-rectifying channel Kir2.1 which is mutated in the familial periodic paralysis Andersen–Tawil syndrome (Schram et al., 2003). The main treatment consists of oral or intravenous potassium which displaces barium and allows it to be excreted. 4.2.6. Differential diagnosis Other neuromuscular disorders should also be considered in the differential diagnosis of episodic weakness. The difference between myasthenia and periodic paralysis appears straight forward at first glance. Attacks of weakness are more distinct in PP versus a more longterm fluctuation of muscle strength in myasthenia. Gentle exercise helps to lessen or abort PP attacks while exertion worsens symptoms in myasthenia. The distribution of muscles affected is different (bulbar and extraocular muscles frequently affected in myasthenia and spared in PP). Investigations (neuromuscular junction transmission deficit on repetitive nerve stimulation and single fiber EMG, acetylcholine receptor antibodies, genetic testing) should also easily distinguish between these two disorders. However, diagnostic difficulty may sometimes arise when distinguishing between the limb girdle presentation of myaesthenia and periodic paralysis. In this context it is interesting to note the discovery of a mutation in SCN4A leading to loss of sodium channel Nav1.4 function in a patient with attacks of bulbar and respiratory paralysis associated with ptosis and a neuromuscular junction transmission deficit on neurophysiological investigations (Tsujino et al., 2003). This finding indicates that an overlap between periodic paralysis and myasthenia gravis may occur at a molecular level. Of interest is also an Australian family with episodic weakness affecting extraocular, facial, trunk and limb muscles lasting weeks to months (Ryan et al., 1999). The disorder has been linked to the X chromosome but the gene involved has not been identified. Patients with both myotonia congenita and paramyotonia/hyperPP can experience intermittent weakness. In myotonia congenita this is termed transient weakness and presents with brief loss of muscle strength at initiation of movement particularly after a period of rest. Attacks of weakness in patients with hyperPP and paramyotonia congenita are usually more profound and of longer duration. Most other disorders causing acute or subacute muscle weakness (e.g., McArdle’s disease, Guillain-Barre´ syndrome, acute intermittent porphyria) are normally straightforward to exclude by appropriate history, clinical examination and investigations.
4.3. Examination and investigations 4.3.1. General examination and laboratory investigations General examination of patients between attacks is often normal. Muscle strength testing may reveal evidence of persistent proximal weakness. Patients with hyperPP may show signs of action and percussion myotonia. Lid lag often proves to be the most sensitive indicator of myotonia but it can also be seen in healthy volunteers. Patients with periodic paralysis and myotonia may also exhibit a degree of muscle hypertrophy (McArdle, 1962; Layzer et al., 1967). Attention should be paid to detect any subtle dysmorphic features which may indicate ATS. Laboratory investigations are directed to establish potassium levels during attacks (ideally soon after the onset of attack) and exclude secondary causes of periodic paralysis. All patients with hypokalemic periodic paralysis should have their thyroid function checked to exclude the possibility of TPP. Routine 12-lead electrocardiography (ECG) should be undertaken in all PP cases since the cranioskeletal features of ATS may be subtle. There is also a risk of cardiac arrhythmias during severe attacks when potassium levels are excessively deranged. Patients with suspected ATS should undergo more thorough cardiological work-up including prolonged ECG recordings, echocardiography and exercise testing. In the past patients were often subjected to a range of provocative tests, many of which have now been superseded by the availability of genetic analysis and specialized neurophysiological investigations. The principle aim was to induce a clinical focal or generalized attack of paralysis. For hyperPP administration of potassium (orally or intravenously), cooling of limbs and exercise, or a combination has been used. In cases of suspected hypoPP a glucose load with or without additional insulin was the preferred method of inducing attacks. The glucose-insulin test needs to be interpreted with caution as apparent weakness (although without change in reflexes) has also been induced in patients with hyperkalemic periodic paralysis (Layzer et al., 1967). Cardiac monitoring and frequent testing of the serum potassium and glucose level are essential. Another provocative test involved intra-arterial epinephrine together with EMG monitoring. 4.3.2. Genetic testing DNA testing is now a major diagnostic tool in familial periodic paralysis. However, even with extensive DNA sequencing of the ion channel genes known to be
PERIODIC PARALYSIS involved in periodic paralysis, mutations are not detected in one-third of patients with either hyper- or hypokalemic periodic paralysis (Miller et al., 2004). Both CACNA1S and SCN4A are large genes containing 44 and 24 exons respectively. The genetic testing generally available in DNA diagnostic-service laboratories often only encompasses gene regions containing common mutations. It is therefore important to note that a negative genetic result from such a laboratory reduces the likelihood but does not exclude a diagnosis of familial periodic paralysis. The potassium channel gene KCNJ2 mutated in ATS is a relatively small single exon gene and direct sequencing analysis of the whole gene is more feasible in the diagnostic laboratory setting. In ATS more than 30 mutations have been identified (Table 4.3) but approximately 30% of kindreds do not harbor mutations in KCNJ2. This could be partly because there may be undetected mutations in the promoter or intronic regions of the KCNJ2 gene (Tristani-Firouzi et al., 2002). In patients with clear evidence of hypoPP, analysis for the known mutations in CACNA1S should be undertaken first. Mutations have so far only been described at residues 528 (R528H and R528G) and 1239 (R1239G and R1239H) and testing is therefore
85
relatively straightforward. The R528H or R1239H mutations are each found in 40–50% of genotyped hypoPP, patients while the R1239G mutation is much rarer (Ptacek et al., 1994; Elbaz et al., 1995; Fouad et al., 1997; Davies et al., 2001; Sternberg et al., 2001; Miller et al., 2004). The R528G mutation has only been reported in a single Chinese kindred (Wang et al., 2005). Less commonly (<10%) changes are found in SCN4A in hypoPP and exon 12 appears to be a hotspot (Bulman et al., 1999; Davies et al., 2001; Sternberg et al., 2001; Miller et al., 2004). Testing of KCNJ2 may also be helpful even in the absence of cardiac or distinctive physical features as some patients only present with one of the three typical features of ATS. DNA of patients with definite hyperkalemic periodic paralysis and/or with evidence of myotonia should be analysed for mutations in SCN4A. The two most commonly occurring mutations are T704M and M1592V (Rojas et al., 1991; Ptacek et al., 1991a) accounting for 30–70% and 15–30% respectively of all genotyped patients with hyperPP depending on the population (Plassart et al., 1994; Miller et al., 2004). There are a number of other mutations (Table 4.4). Patients with Andersen syndrome may less commonly suffer from
Table 4.3 KCNJ2 mutations in Andersen–Tawil syndrome Amino acid change
Functional domain
References
Functional effect
R67W
N-terminal
Y68D D71N D71V
N-terminal N-terminal N-terminal
Strong dominant-negative effect, affinity to PIP2 affected
T74A T75A T75R T75M D78G R82Q Del 95–98
N-terminal N-terminal N-terminal N-terminal N-terminal M1 M1
C101R V123G S136F
M1 Extra-cellular loop P
Andelfinger et al., 2002 (genþfunct); Donaldson et al., 2003 (gen) Davies et al., 2005 (gen) Donaldson et al., 2003 (gen) Plaster et al., 2001 (genþfunct); Lange et al., 2003 (funct); Bendahhou et al., 2003 (funct) Zhang et al., 2005 (gen) Fodstad et al., 2004 (genþfunct) Donaldson et al., 2003 (gen) Davies et al., 2005 (genþfunct) Davies et al., 2005 (genþfunct) Davies et al., 2005 (genþfunct) Plaster et al., 2001 (gen); Tristani-Firouzi et al., 2002 (genþfunct); Lange et al., 2003 (funct); Bendahhou et al. 2003 (funct) Chun et al., 2004 (genþfunct) Davies et al., 2005 (gen) Plaster et al., 2001 (gen); Tristani-Firouzi et al., 2002 (genþfunct); Lange et al., 2003 (funct); Bendahhou et al., 2003 (funct)
Equivalent to D74Y mutation in Bartter’s syndrome; strong dominantnegative effect No clear dominant-negative effect Dominant-negative Dominant-negative Dominant-negative Dominant-negative
effect effect effect effect
Dominant-negative effect Dominant-negative effect
(continued)
86
D. FIALHO AND M. G. HANNA
Table 4.3 (Continued) Amino acid change
Functional domain
References
Functional effect
G144S
P
First G of GYG motif; weak dominantnegative effect
G146D C154F Del 163–164 P186L
P Extra-cellular loop M2 C-terminal
Plaster et al., 2001 (gen); Tristani-Firouzi et al., 2002 (genþfunct); Lange et al., 2003 (funct); Bendahhou et al., 2003 (funct) Donaldson et al., 2003 (gen) Bendahhou et al., 2005 (genþfunct) Fodstad et al., 2004 (genþfunct) Tristani-Firouzi et al., 2002 (genþfunct)
R189I T192A
C-terminal C-terminal
Donaldson et al., 2003 (gen) Ai et al., 2002 (genþfunct)
G215D N216H
C-terminal C-terminal
Hosaka et al., 2003 (genþfunct) Tristani-Firouzi et al., 2002 (genþfunct); Bendahhou et al., 2003 (funct)
L217P R218W
C-terminal C-terminal
R218Q
C-terminal
G300D
C-terminal
Davies et al., 2005 (genþfunct) Plaster et al., 2001 (genþfunct); Donaldson et al., 2003 (gen); Lange et al., 2003 (funct) Plaster et al., 2001 (gen); Tristani-Firouzi et al., 2002 (genþfunct); Lopes et al., 2002 (funct); Bendahhou et al., 2003 (funct) Donaldson et al., 2003 (gen); Davies et al., 2005 (genþfunct)
G300V
C-terminal
V302M
C-terminal
E303K
C-terminal
T309I R312C Del 314–315
C-terminal C-terminal C-terminal
Plaster et al., 2001 (gen), Tristani-Firouzi et al., 2002 (genþfunct), Lopes et al., 2002 (funct), Lange et al., 2003 (funct), Bendahhou et al., 2003 (funct) Tristani-Firouzi et al., 2002 (genþfunct), Bendahhou et al., 2003 (funct)
Plaster et al., 2001 (gen); Tristani-Firouzi et al., 2002 (genþfunct); Lopes et al., 2002 (funct); Lange et al., 2003 (funct); Bendahhou et al., 2003 (funct) Bendahhou et al., 2005 (genþfunct) Donaldson et al., 2003 (gen) Plaster et al., 2001 (gen); Tristani-Firouzi et al., 2002 (genþfunct); Lange et al., 2003 (funct); Bendahhou et al., 2003 (funct)
gen: genetic; funct: functional; del: deletion; PIP2: phosphatidylinositol 4,5-bisphosphate
Second G of GYG motif Dominant-negative effect No clear dominant-negative effect Alters PKKKR motif (AA 186–9) implicated in PIP2 binding Affinity to PIP2 Region 175–206 binding of PIP2; also region necessary for multimerization, only minimal dominant-negative effect Dominant-negative effect Region 207–246 thought to be involved in PIP2 interaction; weak dominantnegative effect Dominant-negative effect Affinity to PIP2; weak dominantnegative effect Dominant-negative effect, decreases PIP2 binding
Dominant-negative effect, affinity to PIP2 probably through allosteric interaction Weak dominant-negative effect, decreases PIP2 binding
Affects trafficking and/or assembly, mutant channels don’t reach membrane; effect through haploinsufficiency Strong dominant-negative, decreases PIP2 binding
Dominant-negative effect Affinity to PIP2 Strong dominant-negative effect, trafficking of channels containing mutant subunits impaired
Table 4.4 SCN4A mutation causing periodic paralysis and/or myotonia Amino acid change
Domain/ segment
Exon
Phenotype
References
Functional effect; comments
L266V V445M
DI/S5 DI/S6
6 9
Cold-aggravated myotonia Myotonia
R669H
DII/S4
12
HypoPP
Impaired fast inactivation Impaired fast inactivation, enhanced slow inactivation Enhanced fast and slow inactivation
R672G
DII/S4
12
HypoPP
Wu et al., 2001 (genþfunct) Rosenfeld et al., 1997 (gen); Takahashi and Cannon, 1999 (funct) Bulman et al. 1999 (gen); Struyk et al., 2000 (funct); Kuzmenkin et al., 2002 (funct) Jurkat-Rott et al., 2000b (genþfunct); Sternberg et al., 2001 (gen); Kuzmenkin et al., 2002 (funct) Bendahhou et al., 2001 (genþfunct); Sternberg et al., 2001 (gen); Davies et al., 2001 (gen) Jurkat-Rott et al., 2000b (genþfunct); Sternberg et al., 2001 (gen); Kuzmenkin et al., 2002 (funct) Kim et al., 2004 (gen); Miller et al., 2004 (gen) Vicart et al., 2004 (gen) Vicart et al., 2004 (gen) Vicart et al., 2004 (gen) Miller et al., 2004 (gen) Bendahhou et al., 2002 (genþfunct) Plassart et al., 1996 (gen); Hayward et al., 1999 (funct) Ptacek et al., 1991a (gen); Cannon and Strittmatter, 1993 (funct); Hayward et al., 1999 (funct) Baquero et al., 1995 (gen); Miller et al., 2004 (gen); Green et al., 1997 (funct) McClatchey et al., 1992a (gen); Green et al., 1998 (funct) McClatchey et al., 1992a (gen); Yang et al., 1994 (funct); Hayward et al., 1999 (funct) Sugiura et al., 2000 (gen); 2003 (funct)
R672S
HypoPP
R672H
HypoPP
R672C R675G R675W R675Q L689V L689I I693T T704M
DII/S4
13
DII/S4–5
12
DII/S4–5 DII/S5
13 13
HypoPP PP PP PP PP HyperPP PMC; PP HyperPP
V781I
DII/S6
13
HyperPP
S804F
DII-III
14
Myotonia
A1156T
DIII/S4–5
19
HyperPP
P1158S
DIII/S4–5
19
I1160V V1293I
DIII/S4–5 DIII/S6
19 21
Cold-induced hypoPP þ heat-induced myotonia PAM PMC
G1306V
DIII-IV
22
PMC
Richmond et al., 1997b (genþfunct) Koch et al., 1995 (gen); Green et al., 1998 (funct) McClatchey et al., 1992b (gen); Mitrovic et al., 1995 (funct)
Enhanced fast and slow inactivation Enhanced fast and slow inactivation Enhanced fast inactivation
Impaired slow inactivation, enhanced activation Impaired slow activation Impaired slow inactivation ?benign polymorphism Impaired fast inactivation Impaired fast inactivation Temperature-dependent shift of voltage dependence Impaired fast inactivation Impaired fast inactivation and enhanced activation Impaired fast inactivation
(continued)
88 Table 4.4 (Continued) Amino acid change
Domain/ segment
Exon
G1306E
Phenotype
References
Functional effect; comments
Myotonia
Lerche et al., 1993 (gen); Mitrovic et al., 1995 (funct) Lerche et al., 1993 (gen); Mitrovic et al., 1995 (funct) McClatchey et al., 1992b (gen); Richmond et al., 1997a (funct) Lehmann-Horn et al., 1993 (gen); Wagner et al., 1997 (genþfunct) Miller et al., 2004 (gen) Okuda et al., 2001(gen) Ptacek et al., 1993 (gen); Yang et al., 1994 (funct) Tsujino et al., 2003 (genþfunct)
Impaired fast inactivation and enhanced activation Impaired fast inactivation Impaired fast inactivation
G1306A T1313M
DIII-IV
22
Myotonia PMC
M1360V
DIV/S1
23
HyperPP
I1363T M1370V L1433R V1442E
DIV/S1 DIV/S1 DIV/S3 DIV/S3–4
23 23 24 24
? HyperPP and PMC PMC; hyperPP Myasthenic syndrome
R1448C
DIV/S4
24
PMC; PMC þ hyperPP
DIV/S4 DIV/S4 DIV/S4–5 DIV/S5
24 24 24 24
PMC PMC PMCþPP PMC PMC PMC HyperPP
Ptacek et al., 1992 (gen); Chahine et al., 1994 (funct), Richmond et al., 1997a (funct) Bendahhou et al., 1999a (genþfunct) Wang et al., 1995 (gen); Mitrovic et al., 1999 (funct) Ptacek et al., 1992 (gen); Chahine et al., 1994 (funct) Sasaki et al., 1999 (gen) Lehmann-Horn et al., 1993 (gen) Fleischhauer et al., 1998 (genþfunct) Bendahhou et al., 2000 (genþfunct)
DIV/S5
24
HyperPP
Bendahhou et al., 1999b (genþfunct)
V1589M M1592V
DIV/S6 DIV/S6
24 24
Myotonia HyperPP
E1702K F1705I
C-terminal C-terminal
24 24
PMC PMC
Heine et al., 1993 (gen); Mitrovic et al., 1994 (funct) Rojas et al., 1991 (gen); Cannon and Strittmatter, 1993 (funct); Hayward et al., 1999 (funct) Miller et al., 2004 (gen) Wu et al., 2005 (genþfunct)
R1448S R1448P R1448H G1456E V1458F F1473S F1490L þ M14931 I1495F
gen: genetic; funct: functional, PMC: paramyotonia congenita
Impaired inactivation
Impaired inactivation Enhanced fast inactivation, found together with S246L (possible benign polymorphism) Impaired fast inactivation Impaired fast inactivation Impaired inactivation Impaired fast inactivation Impaired fast inactivation Enhanced slow activation Impaired fast inactivation, enhanced activation and enhanced slow inactivation Impaired fast inactivation Impaired slow activation
Impaired fast inactivation
PERIODIC PARALYSIS hyperkalemic periodic paralysis (without myotonia) and testing of KCNJ2 may be indicated in selected cases. In patients where the clinical data is insufficient to decide whether the patient is suffering from hypo- or hyperkalemic periodic paralysis testing for the common mutations in both SCN4A and CACNA1S is a reasonable strategy. 4.3.3. Neurophysiological examination Routine nerve conduction studies between attacks are normal. EMG may show myopathic changes, particularly in those patients who have developed fixed weakness. In patients with hyperPP evidence of sarcolemmal hyperexcitability in the form of myotonic discharges, increased insertional activity and spontaneous fibrillation and positive sharp waves may be found. Myotonic discharges can be present even in the absence of clinical symptoms or signs of (para)myotonia but the degree of abnormality tends to correlate with the clinical picture. The presence of myotonic discharges has important implications as they are not seen in hypokalemic periodic paralysis regardless of the underlying genetic defect (CACNA1S, SCN4A or KCNJ2) (Fournier et al., 2004). The detection of myotonia is therefore helpful in directing gene analysis to SCN4A. During an attack the compound motor action potential (CMAP) amplitude and area are reduced. Needle EMG shows fibrillation potentials and positive sharp waves, a decrease in insertional activity, and there is an increased proportion of polyphasic motor unit potentials (Engel et al., 1965). With severe paralysis the muscle may become completely inexcitable. More specific tests include the use of provocation such as exercise, rest and cold, all in combination with EMG or CMAP monitoring. McManis et al. introduced the long exercise test in 1986 (McManis et al., 1986). This involves sustained maximal isometric exercise for 2–5 min (with a short rest period every 15–30 s) in one of the small hand muscles (typically abductor digiti minimi; ADM) with CMAP monitoring every 1–2 minutes during and after the exercise for approximately 30–40 minutes or until no further decrement occurs. The authors observed a significant delayed CMAP amplitude decline in 75% of patients with clinically definite or possible familial periodic paralysis with positive family history using a cutoff point of 40% CMAP decrement. In this study the decline was greater and more frequently seen in patients with hyperPP compared to hypoPP. When familial and secondary causes of periodic paralysis are considered together the long exercise test has been found highly specific (97.8%) in one study (Kuntzer et al., 2000). Prior to the availability of genetic testing McManis et al. (1986)
89
found a sensitivity of approximately 73% for the long exercise test (including acquired and familial periodic paralysis). Kuntzer et al. (2000) quoted a sensitivity of 81% for periodic paralysis caused by sodium- or calcium-channel mutations. In a study of two families with hypoPP the long exercise test only identified 55% of subjects who where found to carry the CACNA1S mutation R528H (Tengan et al., 2004). All subjects who were mutation positive but had a negative exercise test were either asymptomatic carriers or had not had an attack of paralysis in the year prior to the examination. This indicates that the exercise test reflects disease activity, which needs to be taken into account when assessing patients. Patients with frequent or recent attacks of paralysis and a normal exercise test are unlikely to suffer from periodic paralysis. With less recent attacks a negative exercise test has to be interpreted with caution. In hyperPP the CMAP decrement in response to exercise may become more profound after cooling. Successful treatment, such as with mexiletine, can lead to an improvement in the neurophysiological abnormality (Kim et al., 2001). In thyrotoxic periodic paralysis the exercise test normalizes after correction of the hyperthyroidism (Jackson and Barohn, 1992). Simple limb immobilization can lead to a decline in CMAP in affected patients. The effect seems to be slightly delayed compared to post-exercise measurements but the percentage decline after 1 hour was not significantly different in a group of three patients (Subramony and Wee, 1986). This phenomenon may also explain why it is impossible at times to obtain a stable baseline CMAP in some patients (McManis et al., 1986). The short exercise test was originally described by Streib and colleagues (1982) investigating patients with myotonia. The technique involves a short period (10 s) of isometric contraction of one of the small hand muscles followed by CMAP monitoring every 10 s usually up to one minute. In normal individuals a transient small increase in CMAP amplitude may be observed (Streib et al., 1982; Fournier et al., 2004). The short exercise test has been found helpful in the evaluation of patients with myotonia congenita where a transient decrease in CMAP amplitude mirrors the transient weakness elicited clinically (Streib et al., 1982; Fournier et al., 2004). In paramyotonia congenita there is a decrease in CMAP following exercise which is exacerbated or may only become apparent after cooling (Streib et al., 1983; Jackson et al., 1994). Not many reports exist on the use of the short exercise test in periodic paralysis. Fournier et al. (2004) tested six patients with hyperkalemic periodic paralysis with the common T704M SCN4A mutation and found a more pronounced and sustained CMAP increase compared to normal controls (23% 3% vs 51%). Further increase in CMAP amplitude
90
D. FIALHO AND M. G. HANNA
was seen with repeated short exercise test (þ64% 11%). This correlates well with the experience of patients that light activity may improve or even abort an attack of paralysis. In the same study patients with paramyotonia congenita (SCN4A mutations T1313M and R1448C) showed a moderate decrease in CMAP amplitude which in contrast to patients with myotonia congenita persisted for at least one minute and worsened with repeated exercise. Patients with hypokalemic periodic paralysis (13 with CACNA1S mutation and 2 with SCN4A mutation) showed no abnormalities in the short exercise test. In a different study no changes were demonstrated in two subjects with ATS (Bendahhou et al., 2005). Exposure to cold may trigger attacks of weakness in patients with hyperPP, typically in those who suffer with an overlap of paramyotonia and periodic paralysis. This phenomenon is exploited in the cooling test. Different methods of limb cooling have been applied. Bathing the hand or forearm in ice water is the quickest way but can be uncomfortable. It is important to note that the aim is to reduce the muscle temperature which is usually only indirectly measured through surface temperature. Using a cold water bath which is kept at a constant temperature may achieve more even cooling with less discomfort to the patient but takes much longer than the ice-bath method. In normal subjects CMAP amplitude and duration increases with lower temperatures. In general the cooling test is most helpful in patients with paramyotonia congenita where a significant drop in CMAP amplitude or EMG signal or complete electrical silence may be observed. Similar findings can be seen in some subjects with hyperPP particularly those who have additional signs or symptoms of myotonia (de Silva et al., 1990; Kim et al., 2001). In addition the CMAP amplitude decrement seen during the long exercise test may be exacerbated by cold exposure (Kim et al., 2001). A reduction of average muscle fiber conduction velocity (MFVC) between attacks in familial hypoPP was found by Troni et al. (1983) using needle EMG and direct muscle stimulation. Similar changes were later seen in familial and sporadic hypoPP utilizing high-resolution surface EMG signals (Zwarts et al., 1988; Brouwer et al., 1992; Cruz-Martinez and Arpa, 1997). This technique is less invasive and involves the estimation of MFVC computed from the delay between surface EMG signals detected from at least two different muscle locations along the fiber direction during voluntary contraction. Although initially considered promising as a non-invasive test, a major disadvantage has been the poor reproducibility (Rainoldi et al., 2001). Reproducibility can be improved by recording from multiple channels using a linear electrode array
(Farina et al., 2004). Abnormalities in MFVC are not specific for muscle channelopathies but can be detected in other neuromuscular disorders (van der Hoeven et al., 1993; Huppertz et al., 1997). These factors, together with the need for specialist equipment, have prevented this technique from becoming widely accepted as a major diagnostic tool in clinical practice. 4.3.4. Histopathology Muscle biopsy is not usually indicated in making the diagnosis of periodic paralysis. Commonly observed changes in muscle biopsies include vacuolar changes and tubular aggregates. Histopathological features generally do not distinguish between the subtypes of periodic paralysis. Occasionally, a biopsy with typical changes may be helpful in patients who are evaluated with prominent myopathy in the absence of paralytic attacks. The changes appear to be more closely related to the degree of fixed weakness rather than the number of attacks. Histopathological abnormalities including glycogen accumulation have been reported in the absence of paralytic attacks or clinical myopathy (Buruma and Bots, 1978). Vacuolization of muscle fibers in familial periodic paralysis first discovered by Goldflam (1895, 1897) has been shown repeatedly in cases with the hypo- and hyperkalemic variants of the disorder. Studies on histopathological and ultrastructural abnormalities prior to 1970 where extensively reviewed by Engel, who also summarized his own observations (Engel, 1970). The vacuoles are usually empty but at times contain granular material with an affinity for glycogen staining. Periodic acid-Schiff (PAS)-positive material occasionally fills the entire vacuole but is more frequently located in one of the vacuolar compartments or in small subsarcolemmal or intermyofibrillar spaces. Regions with increased acid phosphatase activity may be seen associated with vacuoles. The same regions often also show NADH dehydrogenase and cytochrome oxidase activity. Engel studied the development of vacuoles in detail and concluded that they originated from proliferated T tubules and dilated sarcoplasmic reticulum components. Tubular aggregates consisting of subsarcolemmal proliferations of longitudinal components of the sarcoplasmic reticulum are another feature described in periodic paralysis (Engel, 1970). They may be particularly frequent finding in Andersen–Tawil syndrome (Tawil et al., 1994). However, tubular aggregates can be a nonspecific feature seen in a number of other neuromuscular disorders (Morgan-Hughes, 1998). Many other non-specific findings, including variation in fiber diameter, excess of internal nuclei and regional rarefaction, have been described (Engel, 1970).
PERIODIC PARALYSIS
4.4. Treatment 4.4.1. Treatment of familial periodic paralysis 4.4.1.1. Lifestyle and dietary advice Simple advice on lifestyle changes to avoid recognized triggering factors can be helpful and should be given to all patients. In all patients with periodic paralysis excessive exertion, particularly when followed by a long period of rest, such as sleep overnight, should be avoided. During an attack gentle physical activity can be helpful in aborting symptoms. Many patients benefit from “warming down” after exercise. Dietary advice includes regular meals (to prevent fasting) and avoidance of potassium-rich foods (banana, melon and a number of other fruits) in hyperPP. Ingestion of carbohydrate-containing drinks or snacks may abort attacks in hyperPP while patients with hypoPP should avoid large carbohydrate-rich meals, particularly late in the evening. 4.4.1.2. Medication options Potassium chloride can be used in the treatment of an acute attack in hypoPP. Oral preparations are preferable as there is a higher risk of rebound hyperkalemia with intravenous administration. Regular use may reduce the frequency of attacks. Agents that reduce urinary potassium loss such as spironolactone (100 mg/day) or triamterene (150 mg/day) can also improve symptoms in hypoPP. Patients with hyperPP may benefit from treatment to prevent hyperkalemia including thiazide diuretics (McArdle, 1962) and inhaled b-agonists (Wang and Clausen, 1976; Bendheim et al., 1985; Hanna et al., 1998). Inhibitors of carbonic acid anhydrase (acetazolamide, dichlorphenamide) are useful in both hypoPP and hyperPP (McArdle, 1962; Resnick et al., 1968). Studies in hypoPP suggest that interictal low-grade weakness may also improve (Griggs et al., 1970; Dalakas and Engel, 1983). However, at present none of the treatments used in periodic paralysis have been proven to prevent the progressive myopathy seen in both hypoPP and hyperPP. The exact mechanism underlying the beneficial effect of carbonic anhydrase inhibitors remains unclear. One of several possibilities includes acidification of the channel microenvironment. The channel defect may be alleviated by a reduction in the muscle pH as shown in expression studies for some mutations (Kuzmenkin et al., 2002). A similar mechanism may explain why gentle exercise (known to cause transient hyperkalemia) can improve symptoms during a mild attack. In vitro studies also show that carbonic anhydrase inhibitor improve weakness in Kþ-deficient
91
rats (an animal model for hypoPP) through activation of calcium-activated potassium channels rather than direct inhibition of carbonic anhydrase (Tricarico et al., 2000, 2004). Acetazolamide has been evaluated in a number of case studies although evidence from a randomized double-blind placebo-controlled trial is lacking. The dosage should be started low at 62.5 or 125 mg daily and increased gradually until a satisfactory response is achieved but usually not higher than 1000 mg/day given in two or three divided doses. Distal paresthesiae, headaches and occasionally mood disturbance including depression can be experienced. An important long-term complication is the development of renal calculi in 10 –20% of patients (Tawil et al., 1993). Therefore, all patients should undergo baseline and yearly follow-up renal imaging to enable early detection and treatment of nephrolithiasis. Regular intake of citrus drinks reduces the development of renal calculi. The efficacy of dichlorphenamide (50–300 mg/day) was demonstrated in a double-blind placebo-controlled crossover trial (Tawil et al., 2000). Despite the limitations of this study such as the dropout rate and unblinding of patients and investigators, the effectiveness of dichlorphenamide to prevent or reduce the severity and frequency of attacks in both hyperPP and hypoPP was clearly shown. Side-effects and consequent precautions are similar to acetazolamide. Some reports suggest that acetazolamide can exacerbate symptoms in patients with hypoPP due to sodium channel mutations (Bendahhou et al., 2001; Sternberg et al., 2001) but others report benefit (Kuzmenkin et al., 2002; Kim et al., 2004). Treatment-induced worsening with carbonic anhydrase inhibitors can also occur with other mutations and patient should be warned and monitored accordingly. Patients with hyperPP and myotonia may also benefit from antimyotonic agents such as mexiletine (200–600 mg/day in two or three divided doses). Due to its cardiac side-effects mexiletine should be monitored with baseline and follow-up ECGs. Potassium-channel openers have been investigated as potential treatment agents in hypoPP. Theoretically, by increasing potassium conductance, the muscle membrane could be repolarized and attacks prevented. Diazoxide, cromakalim and pinacidil, drugs with an antihypertensive vasodilator effect, are known to directly activate ATP-sensitive potassium channels. Diazoxide was initially effective in preventing attacks in patients with hypoPP but became ineffective after a few months (Johnsen, 1977). In vitro studies in human hypoPP muscle fibers showed that cromakalim did repolarize the muscle membrane and restore twitch force (Grafe et al., 1990). Ligtenberg et al. (1996) found
92
D. FIALHO AND M. G. HANNA
some increase in muscle strength following carbohydrate challenge in two out of four hypoPP patients after using pinacidil. Clinically the use of K-ATP openers has been limited due to severe side-effects including hypotension and hyperglycaemia. Nevertheless more selective channel modulators may improve management in the future. 4.4.2. Periodic paralysis and anesthesia There are case reports of patients with periodic paralysis having episodes of malignant hyperthermia (Paasuke and Brownell, 1986; Lambert et al., 1994; Rajabally and El Lahawi, 2002). In one of these patients a mutation in the ryanodine receptor has been identified (Marchant et al., 2004). Whether another unidentified mutation in a voltage-gated channel is responsible for the periodic paralysis in this particular case is uncertain. From a practical point of view it is advisable to avoid volatile anesthetics although there is no definite evidence of an increased risk of malignant hyperthermia in this patient group. The more frequent anesthetic complication is an attack of paralysis following an intervention (Fouad et al., 1997). This is not unexpected given the known trigger factors (stress, immobility, cold, exertion during labor) in addition to anesthetic drugs. The management plan should take these factors into account (avoidance or minimization of pain, carbohydrate loads in hypoPP, fasting and cold in hyperPP, sympathomimetics, prolonged labor, etc.). Non-depolarizing muscle relaxants, propofol, and regional anesthesia have been found to be relatively safe (Aarons et al., 1989; Ashwood et al., 1992; Cone and Sansome, 1992; Weller et al., 2002). 4.4.3. Treatment of Andersen–Tawil syndrome Treatment of ATS presents a particular problem as muscle and cardiac symptoms often occur independently and treatment of one may exacerbate the other. Carbonic anhydrase inhibitors appear to be beneficial and are probably the first line treatment for the muscle symptoms. A single report suggested efficacy of terbutaline, a ß2-agonist, reducing the frequency of paralytic attacks (Djurhuus et al., 1998). The same patient had also responded to potassium and spironolactone. It is curious that a b2-agonist, usually helpful in hyperPP, and medication often given in hypoPP, should be beneficial in the same patient. The lack of evidence from randomized controlled trials in this rare condition is unlikely to change soon. The management of cardiac arrhythmias can range between simple monitoring to necessity of pacemaker or implantable cardioverter defibrillator. Case reports
exist on the successful use of amiodarone (Junker et al., 2002) and imipramine (Gould et al., 1985; Tawil et al., 1994). Imipramine does not interact with Kir2.1 channels (Kobayashi et al., 2004) but it has inhibitory effects on many other cardiac potassium, sodium and calcium channels (Garcia-Ferreiro et al., 2004). Beta-blockers have been tried (Sansone et al., 1997). Verapamil has been found beneficial in one patient (Kannankeril et al., 2004) but worsened muscle symptoms in another (Sansone et al., 1997). 4.4.4. Treatment of thyrotoxic periodic paralysis Effective treatment of TPP requires the correction of the endocrine abnormality. Once the patient becomes euthyroid the paralytic attacks cease and neurophysiological abnormalities disappear (Jackson and Barohn, 1992). The underlying susceptibility however remains and excessive thyroid supplementation may induce recurrence of attacks. Correcting thyrotoxicosis can sometimes take weeks or months during which time prevention and treatment of acute attacks may be desirable in severely affected patients. In contrast to the familial periodic paralyses no convincing benefit from carbonic anhydrase inhibitors has been described in TPP (Norris, et al., 1971; Yeung and Tse, 1974). Most centers use potassium supplementation, a beta-blocker, or a combination to treat acute attacks. Lu et al. (2004) conducted a small study comparing intravenous potassium chloride in 20 patients with no potassium chloride administration in 12 patients. Patients in the untreated group all recovered spontaneously but took twice as long as the treated cohort (13.57.5 vs 6.33.8 hours, p<0.01). However, in 40% of patients receiving potassium rebound hyperkalemia developed with Kþ>5.5 mmol/l. Intravenous potassium chloride for the acute treatment of paralysis in TPP should therefore probably be reserved for severe cases with associated cardiac arrhythmias where rapid normalization of serum potassium level is required. In other cases oral potassium supplement or simple monitoring with no potassium supplementation may suffice. Beta-blockers can be used both in acute attacks as well as a preventive measure. It has been postulated that hyperadrenergia during thyrotoxicosis contributes to the muscle weakness. Indeed, a 6-day course of propranolol (40 mg four times daily) prevented or lessened the severity of paralysis induced by a high carbohydrate diet in five out of seven patients with TPP (Yeung and Tse, 1974). Oral propranolol without potassium supplementation has been found by other authors to be beneficial (Conway et al., 1974; Lin and Lin, 2001). Intravenous propranolol together with potassium supplementation has also been described (Payne et al.,
PERIODIC PARALYSIS 1979; Shayne and Hart, 1994; Birkhahn et al., 2000). Again, rebound hyperkalemia with cardiac arrhythmias was observed.
4.5. Genetic and in vitro electrophysiological characteristics 4.5.1. Calcium channel periodic paralysis Missense mutations in the pore-forming a-subunit of the dihydropyridine-sensitive (L-type) calcium channel Cav1.1 of skeletal muscle are the main cause of familial hypokalemic periodic paralysis. In 1994, in a genomewide search in three affected European families, Fontaine et al. (1994) discovered linkage to chromosome 1q31–q32. They also established that the CACNA1S gene mapped to the same region and cosegregated with the disease with no recombinants in two families. The first mutations were identified by Ptacek et al. (1994) and Jurkat-Rott et al. (1994). A founder effect has not been established (Elbaz et al., 1995; Grosson et al., 1996). The Cav1.1 gene spans about 73 kb, and consists of 44 exons (Drouet et al., 1993). Similarly to other voltage-gated sodium and calcium channels, Cav1.1 is made up of the main pore-forming a-subunit which is associated with accessory units (a2, d, b and g). Within the a-subunit four homologous domains can be distinguished (DI–IV). Each domain correlates to a single subunit of the voltage-gated potassium channel, which requires four subunits to assemble a complete poreforming channel. Evolutionarily, the a-subunit of the calcium and sodium channels developed through gene duplication from these potassium channels. Each domain of Cav1.1 is made up of six transmembrane segments. The fourth transmembrane segment (S4) contains regularly-spaced positively charged amino acids and functions as the voltage sensor. This segment is thought to move outward upon depolarization and channel openings (Mannuzzu et al., 1996; Yang et al., 1996). Other important structures are the loops between segments five and six of each domain which re-enter the membrane and come together to provide the lining of the pore and determine the ion selectivity. In skeletal muscle conformational changes of Cav1.1 have been shown to activate the ryanodine receptor, facilitating calcium release from the sarcoplasmic reticulum, thus mediating excitation-contraction coupling. Some controversy exists regarding the precise subunit topology and voltage sensor movement, following the crystallization of a bacterial voltage-gated potassium channel (Jiang et al., 2003). Two main models for the voltage sensor movement exist (Ahern and Horn, 2004). In the conventional model, which seems to be
93
more in keeping with most of the experimental data obtained so far, S4 moves in a helical screw or in a helical twist pattern inside the densely packed channel protein. However, the “paddle” model assumes that the S4-charged helical segment and portions of S3 form a paddle that lies at the periphery of the channel, parallel to the intracellular membrane–water interface. During depolarization, the paddle-like motif moves across the membrane toward the extracellular side, thus triggering channel opening. All four mutations identified in CACNA1S causing periodic paralysis occur at positively charged arginines in the voltage-sensing region of the channel. Interestingly, the sodium channel mutations identified causing hypoPP also affect positively charged arginines in the voltage sensing region of SCN4A. Two other changes in CACNA1S have been identified in a few families causing malignant hyperthermia. These mutations (R1086H and R1086C) occur in the loop connecting domains III and IV (Monnier et al., 1997; Jurkat-Rott et al., 2000a). The exact mechanism through which mutations in CACNA1S cause periodic paralysis is unknown. The channel does not contribute on its own to membrane excitability. Expression studies of mutant channels as well as primary cultures of affected muscle have shown only moderate functional changes. These range from reduced current density, slowing in activation rate to enhanced rate of closing (Lapie et al., 1996; Jurkat-Rott et al., 1998; Morrill and Cannon, 1999). The effect of these changes is a reduction in calcium influx into the muscle. It has been suggested that an indirect effect on other channels is responsible for the clinical presentation. In keeping with this, patch recordings from fibers with the R528H mutation showed a loss of potassium conductance of an ATP-sensitive Kþ channel (Tricarico et al., 1999). Ruff (1999) also reported an insulininduced reduction in potassium currents. How this is linked to the calcium channel remains unclear. One hypothesis for the pathogenesis of hypoPP is that a disruption of the calcium homeostasis due to mutant Cav1.1 channels alters the transcription, expression or regulation of other ion channels including potassium channels. A reduced potassium current in turn could then explain the depolarized resting potential and the intracellular trapping of potassium during attacks. Even at baseline the resting potential in hypoPP muscle is depolarized by 5–10 mV compared to normal (Rudel et al., 1984; Ruff, 1999). Hypokalemia in hypoPP results from the physiological effect of glucose intake and the release of insulin which in turn stimulates the sodium–potassium pump and shifts potassium from the extracellular to the intracellular space. In normal muscle fibers this leads to hyperpolarization. In contrast, in hypoPP muscle fibers hypokalemia
94
D. FIALHO AND M. G. HANNA
causes depolarization and induces an attack of paralysis (Rudel et al., 1984; Minaker et al., 1988). 4.5.2. Sodium-channel periodic paralysis Clinically the sodium channelopathies of skeletal muscle can be divided into three main allelic disorders: hyperkalemic periodic paralysis, paramyotonia congenita and potassium-aggravated myotonia. Patients with sodium channel hyperPP may also complain of symptoms suggestive of paramyotonia congenita or potassiumaggravated myotonia as these conditions frequently overlap (Sasaki et al., 1999). The pioneering work on muscle specimens from myotonic goat by Bryant and colleagues (Bryant, 1962; Lipicky and Bryant, 1966) identified the loss of resting chloride conductance as the primary underlying defect, which was later confirmed in myotonia congenita in humans (Lipicky and Bryant, 1973). In the early 1980s Lehmann-Horn and colleagues undertook a series of in-vitro electrophysiological studies on human intercostals muscle fibers to see whether patients with both myotonia and periodic paralysis also had a chloridechannel defect (Lehmann-Horn et al., 1981, 1983). Unlike in muscle with myotonia congenita, chloride conductance was normal but they identified an anomalous persistent inward cation current. This current was blocked by tetrodotoxin which implicated the voltagegated skeletal-muscle sodium channel. An isoform of the a-subunit of this channel was first cloned from rat by Trimmer et al. (1989). The human gene SCN4A maps to 17q23–q24, spans 35 kb, contains 24 exons and codes for a 1836-amino-acid protein (George et al., 1991, 1992, 1993). Linkage for hyperkalemic periodic paralysis to SCN4A was found in 1990 by Fontaine et al.
DI
DII
(1990). This was confirmed by Ptacek et al. (1991b) and Koch et al. (1991a). Several groups found linkage of paramyotonia congenita to SCN4A establishing the fact that these are allelic disorders (Ebers et al., 1991; Koch et al., 1991b; Ptacek et al., 1991c). The structure of the channel subunit encoded by SCN4A is analogous to the a-subunit of the skeletalmuscle voltage-gated calcium channel (Fig. 4.3). Four domains each composed of six transmembrane segments form the main channel. The S4 segment acts as a voltage sensor and the S5–S6 loop lines the pore. Channel function is modulated by small b-subunits. All pathogenic changes identified so far have been missense mutations of conserved amino acids of the a-subunit, resulting in periodic paralysis and myotonia. No mutations have been identified in the b1-subunit associated with neuromuscular disorder but a missense mutation has been found to be a rare cause of generalized epilepsy with febrile seizures (Wallace et al., 1998). Three main conformations exist for the sodium channel. After membrane depolarization the sodium channels open within a fraction of a millisecond and the resulting inward flux of sodium ions accounts for the rapid upstroke of the action potential. The sodium channels then become rapidly inactivated even if depolarization continues. The linker between domains III and IV is thought to act as a hinged lid, which occludes the channel on fast inactivation. Only membrane repolarization allows sodium channels to change from the inactivated state to the resting state from which further activation is possible. The majority of mutations in SCN4A lead to a gainof-function defect. In response to depolarization mutant sodium channels open normally and maintain selectivity
DIII
DIV Extracellular
+ 1 2 3 4 5 +
6
+ + +
+ + +
+ + +
Intracellular COO− NH3+
Fig. 4.3. Membrane-spanning topology of the a-subunit of the skeletal muscle sodium channel Nav1.4. Each domain (DI–IV) contains six transmembrane segments (S1–6). The structure of the a-subunit of the L-type skeletal muscle calcium channel Cav1.1 is homologous.
PERIODIC PARALYSIS for sodium ions, but they inactivate less completely, too slowly, recover too quickly or have a shifted voltage dependence. Some mutations (including the most common hyperPP mutation T704M) shift the activation to more hyperpolarized potentials (Cummins et al., 1993). Both inactivation and activation defects result in an increase in sodium current conducted by the mutant channels compared to the wild-type. The question arises how gain-of-function mutations in the sodium channel gene can lead to seemingly opposite clinical presentations with increase in excitability (myotonia) on the one hand and loss of excitability (paralysis) on the other. In-vitro experiments and computer modeling have provided an answer to this problem. A toxin-based subtle disruption of sodium channel inactivation of about 2% in rat muscle in vitro can cause myotonia (Cannon and Corey, 1993). A computer simulation of a model fiber confirmed that a small defect of inactivation produces repetitive discharges following a single pulse stimulation (Cannon et al., 1993). An increase of failed inactivation to only about 3% induces a susceptibility for a depolarizing shift of the resting membrane potential after stimulation. This depolarized membrane potential of 40mV is maintained by the sodium channels which have failed to inactivate while at the same time the majority of sodium channels (both mutant and wild type) are inactivated, which leads to inexcitability and paralysis. In keeping with these findings expression studies have shown that paralysis-associated mutations tend to cause a more severe disruption of gating compared to those leading to myotonia (Cannon, 2000). The toxin-based model also demonstrated a common mechanism between chloride- and sodium-channel myotonia. Each action potential in skeletal muscle leads to outward flow of potassium into the extracellular space. In skeletal muscle this includes the T-tubule system which consists of long narrow invaginations of the cell membrane and allows propagation of action potentials into the core of the fiber. Although these T-tubules communicate with the extracellular space they also present a significant diffusion barrier. During sustained contraction activity-dependent potassium accumulation occurs and in the presence of reduced chloride conductance or sodium-channel inactivation defect this increase in potassium is sufficient to trigger myotonic discharges. Another feature of sodium-channel function is the presence of fast inactivation (milliseconds) and slow inactivation (seconds to minutes) mechanisms which are operated through different molecular gates. Ruff (1994) suggested that a defect in slow inactivation must be present for paralysis-associated mutations as the slow inactivation mechanism would otherwise lead to a shutdown of the mutant sodium channels which
95
have failed to close down and thus allow repolarization of the membrane. This has been confirmed in invitro expression systems for the two most common mutations that lead to hyperkalemic periodic paralysis (T704M and M1592V) and a mutation associated with cold-induced weakness (I693T; Hayward et al., 1999). Some rare mutations exist that cause periodic paralysis without impairment of slow inactivation. In contrast to the above, SCN4A loss-of-function defects have been identified in a subset of patients with hypokalemic periodic paralysis (Bulman et al., 1999; Jurkat-Rott et al., 2000b; Bendahhou et al., 2001). All of the mutations are located in the voltage-sensing segment S4 of domain II and all neutralize positively charged arginines in analogy to the hypoPP calcium-channel mutations. The phenotype of patients with calcium-channel compared to sodium-channel hypokalemic periodic paralysis is identical (Jurkat-Rott et al., 2000b). Electrophysiologically, these mutations attenuate sodium current due to excess fast and slow inactivation and reduced density of sodium channels (Struyk et al., 2000; JurkatRott et al., 2000b; Bendahhou et al., 2001; Kuzmenkin et al., 2002). The production and insertion of normal sodium channels did not compensate for the reduced sodium current, which raises the question of how skeletal muscle fibers regulate the expression of sodium channels to control membrane excitability. Interestingly, muscle fibers with a calcium-channel mutation associated with hypoPP have also been shown to have a reduction in sodium current (Ruff and Al-Mudallal, 2000). The distinction between SCN4A mutations associated with hyper- or hypoPP may not always be so clear. Vicart et al. (2004) reported four kindreds with three new SCN4A mutations affecting an arginine at position 675, located in the S4 voltage sensor of domain II adjacent to residues R669 and R672 where mutations causing hypoPP have been identified. Administration of corticosteroids resulted in severe weakness associated with hypokalemia in two affected individuals from different families, in one of them in the presence of thyrotoxicosis. Repeated ictal testing however did not reveal consistent potassium abnormalities in a number of affected subjects during attacks. The presence of EMG myotonia in one individual together with symptoms of muscle cramps and stiffness and provocation by cold and fasting may point towards a defect similar to hyperPP mutations but functional expression data is awaited. The P1158S mutation located in the linking loop between segments 4 and 5 of domain III was identified in a single kindred with cold-induced hypoPP and myotonia (Sugiura et al., 2000). This is the only mutation where a true combination of hypoPP and myotonia exists. Functional expression identified a slowing of
96
D. FIALHO AND M. G. HANNA
inactivation and cold-induced shift of activation and inactivation to more hyperpolarized potentials (Sugiura et al., 2003). In a computer model these abnormalities accounted fully for myotonia regardless of the temperature. Taking hypokalemia into account the electrical activities of P1158S cells in the computer model ceased at a depolarized potential at 22 C, reproducing coldinduced paralysis. This might be related to a general reduction in membrane potassium conductance associated with low temperature as well as specifically reduced potassium current through inward-rectifying potassium channels due to low extracellular potassium. In a unique case with congenital myasthenic syndrome including fatigable generalized weakness, recurrent attacks of respiratory and bulbar paralysis since birth and rapid decrement of compound muscle action potential on high frequency repetitive stimulation, Tsujino et al. (2003) identified a loss-of-function SCN4A mutation which caused a left-shift in the voltage dependence of fast inactivation. This defect is compounded by enhanced cumulative use-dependent inactivation. A conclusion on the inheritance pattern could not be drawn due to lack of data from other family members. However, in the same subject a second mutation was identified on the other allele of SCN4A which also had detectable changes in biophysical properties when tested in the heterologous expression system. This mutation caused no clinical manifestation when found alone in the patient’s mother and sister and thus may indicate a recessive inheritance, but this is by no means proven. Interestingly, the patient responded both to pyridostigmine as well as acetazolamide therapy. Cardiac arrhythmias are not thought to be a major part of this form of periodic paralysis. Baquero et al., (1995) reported a patient with periodic paralysis in whom the SCN4A mutation V781I was identified. He was later investigated for presyncope attacks and found
to have ventricular tachycardia and multiform ventricular ectopy on electrocardiography. This particular mutation has only been reported in one other paper (Miller et al., 2004) without any details of the patient’s characteristics. Functional expression suggests that this might be a benign polymorphism (Green et al., 1997). A mutation in KCNJ2 was not excluded in Baquero’s subject. The main voltage-gated sodium channel in cardiac tissue is an isoform of Nav1.5. However, Nav1.4 RNA is detectable in human cardiac tissue at about 30% compared to skeletal muscle (Pereon et al., 2003). Cardiac expression of Nav1.4 has also been demonstrated in mice (Zimmer et al., 2002; Haufe et al., 2005).
4.5.3. Potassium-channel periodic paralysis (Andersen–Tawil syndrome) Plaster et al. (2001) showed that mutations in KCNJ2, a gene encoding a voltage-independent potassium channel (Kir2.1) located on chromosome 17q23, are causative in the majority of patients with Andersen–Tawil syndrome. All potassium channels belonging to the Kir family consist of an intracellular N- and C-terminal domain, two a-helical transmembrane segments (M1 and M2) and the loop connecting M1 and M2 (H5 or P-loop) which contains the pore-forming elements and the Gly-Tyr-Gly signature sequence conferring potassium selectivity (Fig. 4.4). A complete channel is formed by assembly of four homo- or heteromeric subunits (Yang et al., 1995). The recently resolved crystallographic structure of the prokaryotic Kir channel KirBac1.1 has helped to refine the structural model of the channel (Kuo et al., 2003). Kir2.1 is an inwardrectifying channel highly expressed in heart, skeletal muscle and brain (Kubo et al., 1993; Raab-Graham et al., 1994). It is known to be important for stabilizing
Pore
M1
M2
NH3+ COO−
Fig. 4.4. Structure of a Kir2.1 subunit encoded by the KCNJ2 gene. It contains two transmembrane segments (M1 and M2). The majority of mutations causing ATS are located in the C- and N-terminal regions. Four subunits are required to assemble to form a complete channel.
PERIODIC PARALYSIS the resting potential in cardiac muscle and thought to contribute to the late-repolarization phase in both skeletal and cardiac muscle. Inward rectification refers to the fact that the channel permits inward flux of potassium at membrane potentials negative to the potassium reversal potential more easily compared to outward flux at more positive potentials. This prevents excess potassium loss during the plateau phase of the cardiac action potential but allows participation in the late repolarization. The closure of Kir2 channels occurs due to binding of intracellular magnesium or cationic polyamines at potentials positive to the potassium reversal potential (Lopatin and Nichols, 2001). The open state of Kir2.1 and other inward-rectifying channels is facilitated by phosphatidylinositol 4,5-bisphosphate (PIP2; Huang et al., 1998). PIP2 is a membrane-bound phospholipid which acts as a precursor for secondary messengers. It binds directly to Kir channels through interaction between positively charged amino acids of the Kir channel and negatively charged phosphate groups of the lipid. Three putative PIP2 binding sites exist within the C-terminal domain of Kir2.1 (Soom et al., 2001). In rat embryos mRNA is detectable in cardiac and skeletal muscle, brain, metanephrons and developing bony structures of the cranium, extremities and vertebrae (Karschin and Karschin, 1997). This closely mirrors the organ systems affected in ATS. A Kir2.1 knockout mouse showed developmental craniofacial abnormalities in analogy with ATS (Zaritsky et al., 2000). Functional expression of the majority of mutations so far has demonstrated a dominant-negative effect on wild-type subunits in the tetrameric channel. The clinical severity of symptoms does not seem to be correlated with the degree of dominant negative effect in expression studies (Tristani-Firouzi et al., 2002). At least half of the mutations impair interaction with PIP2 (Tristani-Firouzi et al., 2002; Lopes et al., 2002; Donaldson et al., 2003). The delS314–Y315 mutation has been shown to interfere with protein trafficking leading to intracellular trapping of the channel containing one or more mutant subunit (Bendahhou et al., 2003). The same study suggested that the mutation V302M disrupts both channel trafficking or folding as well as assembly trapping only mutant subunits in the cell and causing ATS through a haploinsufficiency mechanism. Preisig-Muller et al. (2002) demonstrated the ability of Ki2.1 to form heteromeric channels with potassium channel subunits from the Kir2 subfamily (Kir 2.2 and 2.3). They also showed a dominant-negative effect of mutant Kir2.1 subunits on these heteromers. This finding may provide a possible explanation of the phenotypic variation within and between families with ATS. Of interest also is the recent discovery of two gain-offunction mutations in KCNJ2 underlying familial atrial
97
fibrillation in a Chinese kindred (Xia et al., 2005) and short QT syndrome in another family (Priori et al., 2005). Neither of the two families had any dysmorphic features or skeletal muscle symptoms.
4.5.4. Thyrotoxic periodic paralysis Although TPP typically occurs sporadically, the heavily skewed ethnic distribution suggests a genetic component. It is suspected that in thyrotoxic periodic paralysis a genetically determined susceptibility to abnormal membrane excitability exists that is only unmasked in the presence of hyperthyroidism. It is not clear whether the primary abnormality is associated with one of the voltage-gated skeletal muscle ion channel genes or a gene that has a secondary effect. Screening for mutations in CACNA1S and SCN4A known to be associated with hypokalemic periodic paralysis has been negative (Dias da Silva et al., 2002b; Kung et al., 2004). The associated hypokalemia in TPP is thought to be due to a rapid influx of potassium into cells similarly to the familial periodic paralyses (Feely, 1981). The sodium–potassium ATPase is an important transporter that allows potassium to be pumped into the cells. Thyrotoxicosis causes an increase in number and activity of the sodium-potassium ATPase per se, but this effect is more pronounced in patients with TPP (Oh et al., 1990; Chan et al., 1991). The difference between thyrotoxic patients with and without TPP disappears after restoration of the euthyroid status. Many recent genetic studies in TPP have concentrated on detection of polymorphisms with potential functional effects in membrane channel or transporter genes. Dias da Silva et al. (2002a) discovered two polymorphisms in CACNA1S at nucleotides 1551 and 1564 at higher frequency in 13 cases of sporadic thyrotoxic periodic paralysis compared to normal controls (77% and 31% vs 18% and 8.6%). This was not confirmed in a larger study including 97 male Chinese patients with TPP who were screened for polymorphisms in the coding and promoter region of CACNA1S in addition to microsatellite markers in the region of the Na/K-ATPase subunits a1, a2 and b1 (Kung et al., 2004). However, the latter study identified two intronic and one 50 -flanking region single nuclear polymorphisms (SNPs) in CACNA1S which occurred with significantly different frequencies compared to groups of normal controls and thyrotoxic patients without periodic paralysis. All three SNPs are located at or near putative thyroid hormone response elements but whether they have any functional effect remains to be seen. The authors hypothesized that these SNPs may modulate the effect of thyroid hormones on the expression of CACNA1S. Polymorphisms in the b2-adrenergic receptor
98
D. FIALHO AND M. G. HANNA
gene were not found to be associated with TPP (Kim et al., 2005). Dias da Silva et al. (2002b) also described the mutation R83H in KCNE3 in a patient with TPP. KCNE3 encodes the MinK-related peptide 2 (MiRP2) which coassembles with Kv3.4 to form the human skeletalmuscle voltage-gated potassium channel. This change had been reported previously in a case of familial HypoPP (Abbott et al., 2001). However more detailed studies later showed that it was in fact a polymorphism (Sternberg et al., 2003; Jurkat-Rott and Lehmann-Horn, 2004). Human leukocyte antigen (HLA) markers have been extensively studied. Various associations with TPP have been reported which differ according to the population studied (Yeo et al., 1978; Hawkins et al., 1985; Tamai et al., 1987; Cavan et al., 1994), but no consistent marker has emerged.
Acknowledgements Doreen Fialho is a CINCH-NIH fellow. Research in our laboratory is supported by the Wellcome Trust UK and MRC UK. Our clinical and DNA diagnostic service is funded by the UK NHS Department of Health through the National Specialist Commissioning Advisory group — NSCAG.
References Aarons JJ, Moon RE, Camporesi EM (1989). General anesthesia and hyperkalemic periodic paralysis. Anesthesiology 71: 303–304. Abbott GW, Butler MH, Bendahhou S, et al. (2001). MiRP2 forms potassium channels in skeletal muscle with Kv3.4 and is associated with periodic paralysis. Cell 104: 217–231. Adachihara K, Takagi Y (1974). [Case of thyrotoxic paralysis associated with hyperkalemic and hypokalemic paralytic attacks]. Rinsho Shinkeigaku 14: 369–375. Ahern CA, Horn R (2004). Stirring up controversy with a voltage sensor paddle. Trends Neurosci 27: 303–307. Ahlawat SK, Sachdev A (1999). Hypokalaemic paralysis. Postgrad Med J 75: 193–197. Ai T, Fujiwara Y, Tsuji K, et al. (2002). Novel KCNJ2 mutation in familial periodic paralysis with ventricular dysrhythmia. Circulation 105: 2592–2594. Allen AS (1943). Pa Ping or Kiating paralysis. Chin Med J (Engl) 61: 296–301. Andelfinger G, Tapper AR, Welch RC, et al. (2002). KCNJ2 mutation results in Andersen syndrome with sex-specific cardiac and skeletal muscle phenotypes. Am J Hum Genet 71: 663–668. Andersen ED, Krasilnikoff PA, Overvad H (1971). Intermittent muscular weakness, extrasystoles, and multiple developmental anomalies. A new syndrome? Acta Paediatr Scand 60: 559–564.
Angeloni JM, Scott GW (1960). Flaccid quadriplegia following ureteric transplant. Lancet 1: 1005–1006. Ashwood EM, Russell WJ, Burrow DD (1992). Hyperkalaemic periodic paralysis and anaesthesia. Anaesthesia 47: 579–584. Baquero JL, Ayala RA, Wang J, et al. (1995). Hyperkalemic periodic paralysis with cardiac dysrhythmia: a novel sodium channel mutation? Ann Neurol 37: 408–411. Basser LS (1979). Purgatives and periodic paralysis. Med J Aust 1: 47–48. Bendahhou S, Cummins TR, Kwiecinski H, et al. (1999a). Characterization of a new sodium channel mutation at arginine 1448 associated with moderate Paramyotonia congenita in humans. J Physiol 518 (Pt 2): 337–344. Bendahhou S, Cummins TR, Tawil R, et al. (1999b). Activation and inactivation of the voltage-gated sodium channel: role of segment S5 revealed by a novel hyperkalaemic periodic paralysis mutation. J Neurosci 19: 4762–4771. Bendahhou S, Cummins TR, Hahn AF, et al. (2000). A double mutation in families with periodic paralysis defines new aspects of sodium channel slow inactivation. J Clin. Invest 106: 431–438. Bendahhou S, Cummins TR, Griggs RC, et al. (2001). Sodium channel inactivation defects are associated with acetazolamide-exacerbated hypokalemic periodic paralysis. Ann Neurol 50: 417–420. Bendahhou S, Cummins TR, Kula RW, et al. (2002). Impairment of slow inactivation as a common mechanism for periodic paralysis in DIIS4-S5. Neurology 58: 1266–1272. Bendahhou S, Donaldson MR, Plaster NM, et al. (2003). Defective potassium channel Kir2.1 trafficking underlies Andersen–Tawil syndrome. J Biol Chem 278: 51779–51785. Bendahhou S, Fournier E, Sternberg D, et al. (2005). In vivo and in vitro functional characterization of Andersen’s syndrome mutations. J Physiol 565: 731–741. Bender JA (1936). Family periodic paralysis in a girl aged seventeen. Arch Neurol Psychiatry 35: 131–135. Bendheim PE, Reale EO, Berg BO (1985). Beta-adrenergic treatment of hyperkalemic periodic paralysis. Neurology 35: 746–749. Bennett RH, Forman HR (1980). Hypokalemic periodic paralysis in chronic toluene exposure. Arch Neurol 37: 673. Berning J (1975). Letter: Hypokalaemia of barium poisoning. Lancet 1: 110. Biemond A, Daniels AP (1934). Familial periodic paralysis and its transition into spinal muscular atrophy. Brain 57: 91–108. Birkhahn RH, Gaeta TJ, Melniker L (2000). Thyrotoxic periodic paralysis and intravenous propranolol in the emergency setting. J Emerg Med 18: 199–202. Bradley WG, Taylor R, Rice DR, et al. (1990). Progressive myopathy in hyperkalemic periodic paralysis. Arch Neurol 47: 1013–1017. Bresolin NL, Grillo E, Fernandes VR, et al. (2005). A case report and review of hypokalemic paralysis secondary to renal tubular acidosis. Pediatr Nephrol 20: 818–820. Brouwer OF, Zwarts MJ, Links TP (1992). Muscle fiber conduction velocity in the diagnosis of sporadic hypokale-
PERIODIC PARALYSIS mic periodic paralysis. Clin Neurol Neurosurg 94: 149–151. Bryant SH (1962). Muscle membrane of normal and myotonic goats in normal and low external chloride. Fed Proc 21: 312. Bulman DE, Scoggan KA, van Oene MD, et al. (1999). A novel sodium channel mutation in a family with hypokalemic periodic paralysis. Neurology 53: 1932–1936. Buruma OJ, Bots GT (1978). Myopathy in familial hypokalaemic periodic paralysis independent of paralytic attacks. Acta Neurol Scand 57: 171–179. Cannon SC (2000). Spectrum of sodium channel disturbances in the nondystrophic myotonias and periodic paralyses. Kidney Int 57: 772–779. Cannon SC, Corey DP (1993). Loss of Naþ channel inactivation by anemone toxin (ATX II) mimics the myotonic state in hyperkalaemic periodic paralysis. J Physiol 466: 501–520. Cannon SC, Brown RH Jr, Corey DP (1993). Theoretical reconstruction of myotonia and paralysis caused by incomplete inactivation of sodium channels. Biophys J 65: 270–288. Cannon SC, Strittmatter SM (1993). Functional expression of sodium channel mutations identified in families with periodic paralysis. Neuron 10: 317–326. Canun S, Perez N, Beirana LG (1999). Andersen syndrome autosomal dominant in three generations. Am J Med Genet 85: 147–156. Cavan DA, Penny MA, Jacobs KH, et al. (1994). The HLA association with Graves’ disease is sex-specific in Hong Kong Chinese subjects. Clin Endocrinol (Oxf) 40: 63–66. Chahine M, George AL, Jr, Zhou M, et al. (1994). Sodium channel mutations in paramyotonia congenita uncouple inactivation from activation. Neuron 12: 281–294. Chan A, Shinde R, Chow CC, et al. (1991). In vivo and in vitro sodium pump activity in subjects with thyrotoxic periodic paralysis. BMJ 303: 1096–1099. Chen KM, Hung TP, Lin TY (1965). Periodic paralysis in Taiwan. Clinical study of 28 cases. Arch Neurol 12: 165–171. Chinnery PF, Walls TJ, Hanna MG, et al. (2002). Normokalemic periodic paralysis revisited: does it exist? Ann Neurol 52: 251–252. Chun TU, Epstein MR, Dick M, et al. (2004). Polymorphic ventricular tachycardia and KCNJ2 mutations. Heart Rhythm 1: 235–241. Cohen T (1959). Hypokalemic muscle paralysis associated with administration of chlorothiazide. J Am Med Assoc 170: 2083–2085. Cone AM, Sansome AJ (1992). Propofol in hyperkalaemic periodic paralysis. Anaesthesia 47: 1097. Conn JW, Knopf RF, Nesbit RM (1964). Clinical characteristics of primary aldosteronism from an analysis of 145 cases. Am J Surg 107: 159–172. Conway MJ, Seibel JA, Eaton P (1974). Thyrotoxicosis and periodic paralysis: improvement with beta blockade. Ann Intern Med 81: 332–336. Crafts LM (1900). A fifth case of family periodic paralysis. Am J Med Sci 146: 651.
99
Cruz-Martinez A, Arpa J (1997). Muscle fiber conduction velocity in situ in hypokalemic periodic paralyses. Acta Neurol Scand 96: 229–235. Cumberbatch GL, Hampton TJ (1999). Hyperkalaemic paralysis — a bizarre presentation of renal failure. J Accid Emerg Med 16: 230–232. Cumming AM, Boddy K, Brown JJ, et al. (1980). Severe hypokalaemia with paralysis induced by small doses of liquorice. Postgrad Med J 56: 526–529. Cummins TR, Zhou J, Sigworth FJ, et al. (1993). Functional consequences of a Naþ channel mutation causing hyperkalemic periodic paralysis. Neuron 10: 667–678. Dalakas MC, Engel WK (1983). Treatment of “permanent” muscle weakness in familial hypokalemic periodic paralysis. Muscle Nerve 6: 182–186. Danowski TS, Fisher ER, Vidalon C, et al. (1975). Clinical and ultrastructural observations in a kindred with normohyperkalaemic periodic paralysis. J Med Genet 12: 20–28. Daughaday WH, Rendleman D (1967). Severe symptomatic hyperkalemia in an adrenalectomized woman due to enhanced mineralocorticoid requirement. Ann Intern Med 66: 1197–1203. Davies NP, Eunson LH, Samuel M, et al. (2001). Sodium channel gene mutations in hypokalemic periodic paralysis: an uncommon cause in the UK. Neurology 57: 1323–1325. Davies NP, Imbrici PD, Herd C, et al. (2005). Andersen-Tawil syndrome — new potassium channel mutations and possible phenotypic variation. Neurology 11: 1083–1089. De Keyser J, Smitz J, Malfait R, et al. (1987). Rhabdomyolysis in hypokalaemic periodic paralysis: a clue to the mechanism that terminates the paralytic attack? J Neurol 234: 119–121. De Silva SM, Kuncl RW, Griffin JW, et al. (1990). Paramyotonia congenita or hyperkalemic periodic paralysis? Clinical and electrophysiological features of each entity in one family. Muscle Nerve 13: 21–26. Dias da Silva MR, Cerutti JM, Tengan CH, et al. (2002a). Mutations linked to familial hypokalaemic periodic paralysis in the calcium channel alpha1 subunit gene (Cav1.1) are not associated with thyrotoxic hypokalaemic periodic paralysis. Clin Endocrinol (Oxf) 56: 367–375. Dias da Silva MR, Cerutti JM, Arnaldi LA, et al. (2002b). A mutation in the KCNE3 potassium channel gene is associated with susceptibility to thyrotoxic hypokalemic periodic paralysis. J Clin Endocrinol Metab 87: 4881–4884. Djurhuus MS, Klitgaard NA, Jensen BM, et al. (1998). Multiple anomalies, hypokalaemic paralysis and partial symptomatic relief by terbutaline. Acta Paediatr 87: 475–477. Donaldson MR, Jensen JL, Tristani-Firouzi M, et al. (2003). PIP2 binding residues of Kir2.1 are common targets of mutations causing Andersen syndrome. Neurology 60: 1811–1816. Drouet B, Garcia L, Simon-Chazottes D, et al. (1993). The gene coding for the alpha 1 subunit of the skeletal dihydropyridine receptor (Cchl1a3 ¼ mdg) maps to mouse chromosome 1 and human 1q32. Mamm Genome 4: 499–503.
100
D. FIALHO AND M. G. HANNA
Dutta D, Fischler M, McClung A (2001). Angiotensin converting enzyme inhibitor induced hyperkalaemic paralysis. Postgrad Med J 77: 114–115. Ebers GC, George AL, Barchi RL, et al. (1991). Paramyotonia congenita and hyperkalemic periodic paralysis are linked to the adult muscle sodium channel gene. Ann Neurol 30: 810–816. Elbaz A, Vale-Santos J, Jurkat-Rott K, et al. (1995). Hypokalemic periodic paralysis and the dihydropyridine receptor (CACNL1A3): genotype/phenotype correlations for two predominant mutations and evidence for the absence of a founder effect in 16 caucasian families. Am J Hum Genet 56: 374–380. Engel AG (1970). Evolution and content of vacuoles in primary hypokalemic periodic paralysis. Mayo Clin Proc 45: 774–814. Engel AG, Lambert EH, Rosevear JW, et al. (1965). Clinical and electromyographic studies in a patient with primary hypokalaemic periodic paralysis. Am J Med 38: 626–640. Evers S, Engelien A, Karsch V, et al. (1998). Secondary hyperkalaemic paralysis. J Neurol Neurosurg Psychiatry 64: 249–252. Farina D, Zagari D, Gazzoni M, et al. (2004). Reproducibility of muscle-fiber conduction velocity estimates using multichannel surface EMG techniques. Muscle Nerve 29: 282–291. Feely J (1981). Potassium shift in thyrotoxic periodic paralysis. Postgrad Med J 57: 238–239. Fisher J (1982). Thyrotoxic periodic paralysis with ventricular fibrillation. Arch Intern Med 142: 1362–1364. Fleischhauer R, Mitrovic N, Deymeer F, et al. (1998). Effects of temperature and mexiletine on the F1473S Naþ channel mutation causing paramyotonia congenita. Pflu¨gers Archiv European Journal of Physiology 436: 757–765. Fodstad H, Swan H, Auberson M, et al. (2004). Lossof-function mutations of the Kþ channel gene KCNJ2 constitute a rare cause of long QT syndrome. J Mol Cell Cardiol 37: 593–602. Fontaine B (1994). Primary periodic paralysis and muscle sodium channel. Adv Nephrol Necker Hosp 23: 191–197. Fontaine B, Khurana TS, Hoffman EP, et al. (1990). Hyperkalemic periodic paralysis and the adult muscle sodium channel alpha-subunit gene. Science 250: 1000–1002. Fontaine B, Vale-Santos J, Jurkat-Rott K, et al. (1994). Mapping of the hypokalaemic periodic paralysis (HypoPP) locus to chromosome 1q31–32 in three European families. Nat Genet 6: 267–272. Fouad G, Dalakas M, Servidei S, et al. (1997). Genotype– phenotype correlations of DHP receptor alpha 1-subunit gene mutations causing hypokalemic periodic paralysis. Neuromuscul Disord 7: 33–38. Fournier E, Arzel M, Sternberg D, et al. (2004). Electromyography guides toward subgroups of mutations in muscle channelopathies. Ann Neurol 56: 650–661. Fujimoto T, Shiiki H, Takahi Y, et al. (2001). Primary Sjogren’s syndrome presenting as hypokalaemic periodic paralysis and respiratory arrest. Clin Rheumatol 20: 365–368.
Gallant EM (1983). Barium-treated mammalian skeletal muscle: similarities to hypokalaemic periodic paralysis. J Physiol 335: 577–590. Gamstorp I (1956). Adynamia episodica hereditaria. Acta Paediatr Scand 45: 1–126. Garcia-Ferreiro RE, Kerschensteiner D, Major F, et al. (2004). Mechanism of block of hEag1 Kþ channels by imipramine and astemizole. J Gen Physiol 124: 301–317. George AL Jr, Ledbetter DH, Kallen RG, et al. (1991). Assignment of a human skeletal muscle sodium channel alphasubunit gene (SCN4A) to 17q23.1–25.3. Genomics 9: 555–556. George AL Jr, Komisarof J, Kallen RG, et al. (1992). Primary structure of the adult human skeletal muscle voltagedependent sodium channel. Ann Neurol 31: 131–137. George AL Jr, Iyer GS, Kleinfield R, et al. (1993). Genomic organization of the human skeletal muscle sodium channel gene. Genomics 15: 598–606. Ghose R, Quail G, King R, et al. (1996). Hypokalaemic paralysis in remote aboriginal communities. Aust Fam Physician 25: 1172–1173. ¨ ber eine eigentu¨mliche Form von periGoldflam S (1890). U odischer familia¨rer, wahrscheinlich auto-intoxicatorischer Paralyse. Wien Med Presse 31: 1418. Goldflam S (1895). Weitere Mitteilung u¨ber die paroxysmale, familia¨re La¨hmung. Dtsch Z Nervenheilkd 7: 1–31. Goldflam S (1897). Dritte Mitteilung u¨ber die paroxysmale, familia¨re La¨hmung. Dtsch Z Nervenheilkd 11: 242–260. Gould RJ, Steeg CN, Eastwood AB, et al. (1985). Potentially fatal cardiac dysrhythmia and hyperkalemic periodic paralysis. Neurology 35: 1208–1212. Grafe P, Quasthoff S, Strupp M, et al. (1990). Enhancement of Kþ conductance improves in vitro the contraction force of skeletal muscle in hypokalemic periodic paralysis. Muscle Nerve 13: 451–457. Green DS, Hayward LJ, George AL Jr, et al. (1997). A proposed utation, Val781Ile, associated with hyperkalemic periodic paralysis and cardiac dysrhythmia is a benign polymorphism. Ann Neurol 42: 253–256. Green DS, George ALJ, Cannon SC (1998). Human sodium channel gating defects caused by missense mutations in S6 segments associated with myotonia: S804F and V12931. The Journal of Physiology Online 510: 685–694. Griggs RC, Engel WK, Resnick JS (1970). Acetazolamide treatment of hypokalemic periodic paralysis. Prevention of attacks and improvement of persistent weakness. Ann Intern Med 73: 39–48. Grosson CL, Esteban J, McKenna-Yasek D, et al. (1996). Hypokalemic periodic paralysis mutations: confirmation of mutation and analysis of founder effect. Neuromuscul Disord 6: 27–31. Haddad S, Arabi Y, Shimemeri AA (2004). Hypokalemic paralysis mimicking Guillain-Barre syndrome and causing acute respiratory failure. Middle East J Anesthesiol 17: 891–897. Hanna MG, Stewart J, Schapira AH, et al. (1998). Salbutamol treatment in a patient with hyperkalaemic periodic para-
PERIODIC PARALYSIS lysis due to a mutation in the skeletal muscle sodium channel gene (SCN4A). J Neurol Neurosurg Psychiatry 65: 248–250. ¨ ber einen Fall von intermittierender Hartwig H (1874). U Paralysis spinalis. Inaug Diss Halle. Haufe V, Camacho JA, Dumaine R, et al. (2005). Expression pattern of neuronal and skeletal muscle voltage-gated Naþ channels in the developing mouse heart. J Physiol 564: 683–696. Hawkins BR, Ma JT, Lam KS, et al. (1985). Association of HLA antigens with thyrotoxic Graves’ disease and periodic paralysis in Hong Kong Chinese. Clin Endocrinol (Oxf) 23: 245–252. Hayward LJ, Sandoval GM, Cannon SC (1999). Defective slow inactivation of sodium channels contributes to familial periodic paralysis. Neurology 52: 1447–1453. Heine R, Pika U, Lehmann-Horn F (1993). A novel SCN4A mutation causing myotonia aggravated by cold and potassium. Hum Mol Genet 2: 1349–1353. Holtzapple GE (1905). Periodic paralysis. JAMA 45: 1224. Hosaka Y, Hanawa H, Washizuka T, et al. (2003). Function, subcellular localization and assembly of a novel mutation of KCNJ2 in Andersen’s syndrome. J Mol Cell Cardiol 35: 409–415. Huang CL, Feng S, Hilgemann DW (1998). Direct activation of inward rectifier potassium channels by PIP2 and its stabilization by Gbetagamma. Nature 391: 803–806. Huppertz HJ, Disselhorst-Klug C, Silny J, et al. (1997). Diagnostic yield of noninvasive high spatial resolution electromyography in neuromuscular diseases. Muscle Nerve 20: 1360–1370. Ishikawa S, Saito T, Okada K, et al. (1985). Hypokalemic myopathy associated with primary aldosteronism and glycyrrhizine-induced pseudoaldosteronism. Endocrinol Jpn 32: 793–802. Jackson CE, Barohn RJ (1992). Improvement of the exercise test after therapy in thyrotoxic periodic paralysis. Muscle Nerve 15: 1069–1071. Jackson CE, Barohn RJ, Ptacek LJ (1994). Paramyotonia congenita: abnormal short exercise test, and improvment after mexiletine therapy. Muscle Nerve 17: 763–768. Jiang Y, Lee A, Chen J, et al. (2003). X-ray structure of a voltage-dependent Kþ channel. Nature 423: 33–41. Johnsen T (1977). Trial of the prophylactic effect of diazoxide in the treatment of familial periodic hypokalemia. Acta Neurol Scand 56: 525–532. Johnson CH, VanTassell VJ (1991). Acute barium poisoning with respiratory failure and rhabdomyolysis. Ann Emerg Med 20: 1138–1142. Junker J, Haverkamp W, Schulze-Bahr E, et al. (2002). Amiodarone and acetazolamide for the treatment of genetically confirmed severe Andersen syndrome. Neurology 59: 466. Jurkat-Rott K, Lehmann-Horn F (2004). Periodic paralysis mutation MiRP2–R83H in controls: interpretations and general recommendation. Neurology 62: 1012–1015.
101
Jurkat-Rott K, Lehmann-Horn F, Elbaz A, et al. (1994). A calcium channel mutation causing hypokalemic periodic paralysis. Hum Mol Genet 3: 1415–1419. Jurkat-Rott K, Uetz U, Pika-Hartlaub U, et al. (1998). Calcium currents and transients of native and heterologously expressed mutant skeletal muscle DHP receptor alpha1 subunits (R528H). FEBS Lett 423: 198–204. Jurkat-Rott K, McCarthy T, Lehmann-Horn F (2000a). Genetics and pathogenesis of malignant hyperthermia. Muscle Nerve 23: 4–17. Jurkat-Rott K, Mitrovic N, Hang C, et al. (2000b). Voltagesensor sodium channel mutations cause hypokalemic periodic paralysis type 2 by enhanced inactivation and reduced current. Proc Natl Acad Sci U S A 97: 9549–9554. Kannankeril PJ, Roden DM, Fish FA (2004). Suppression of bidirectional ventricular tachycardia and unmasking of prolonged QT interval with verapamil in Andersen’s syndrome. J Cardiovasc Electrophysiol 15: 119. Kantola IM, Tarssanen LT (1992). Familial hypokalaemic periodic paralysis in Finland. J Neurol Neurosurg Psychiatry 55: 322–324. Karschin C, Karschin A (1997). Ontogeny of gene expression of Kir channel subunits in the rat. Mol Cell Neurosci 10: 131–148. Kelley DE, Gharib H, Kennedy FP, et al. (1989). Thyrotoxic periodic paralysis. Report of 10 cases and review of electromyographic findings. Arch Intern Med 149: 2597–2600. Keyloun VE, Grace WJ (1967). Villous adenoma of the rectum associated with severe electrolyte imbalance. Report of a case. Am J Dig Dis 12: 104–106. Kilpatrick RE, Seiler-Smith S, Levine SN (1994). Thyrotoxic hypokalemic periodic paralysis: report of four cases in black American males. Thyroid 4: 441–445. Kim J, Hahn Y, Sohn EH, et al. (2001). Phenotypic variation of a Thr704Met mutation in skeletal sodium channel gene in a family with paralysis periodica paramyotonica. J Neurol Neurosurg Psychiatry 70: 618–623. Kim MK, Lee SH, Park MS, et al. (2004). Mutation screening in Korean hypokalemic periodic paralysis patients: a novel SCN4A Arg672Cys mutation. Neuromuscul Disord 14: 727–731. Kim TY, Song JY, Kim WB, et al. (2005). Arg16Gly polymorphism in beta2-adrenergic receptor gene is not associated with thyrotoxic periodic paralysis in Korean male patients with Graves’ disease. Clin Endocrinol (Oxf) 62: 585–589. Kobayashi T, Washiyama K, Ikeda K (2004). Inhibition of G protein-activated inwardly rectifying Kþ channels by various antidepressant drugs. Neuropsychopharmacology 29: 1841–1851. Koch MC, Ricker K, Otto M, et al. (1991a). Confirmation of linkage of hyperkalaemic periodic paralysis to chromosome 17. J Med Genet 28: 583–586. Koch MC, Ricker K, Otto M, et al. (1991b). Linkage data suggesting allelic heterogeneity for paramyotonia congenita and hyperkalemic periodic paralysis on chromosome 17. Hum Genet 88: 71–74.
102
D. FIALHO AND M. G. HANNA
Koch MC, Baumbach K, George AL, et al. (1995). Paramyotonia congenita without paralysis on exposure to cold: a novel mutation in the SCN4A gene (Val1293Ile). Neuroreport 6: 2001–2004. Koul PA, Saleem SM, Bhat D (1993). Sporadic distal renal tubular acidosis and periodic hypokalaemic paralysis in Kashmir. J Intern Med 233: 463–466. Kubo Y, Baldwin TJ, Jan YN, et al. (1993). Primary structure and functional expression of a mouse inward rectifier potassium channel. Nature 362: 127–133. Kufs WM, McBiles M, Jurney T (1989). Familial thyrotoxic periodic paralysis. West J Med 150: 461–463. Kung AW, Lau KS, Fong GC, et al. (2004). Association of novel single nucleotide polymorphisms in the calcium channel alpha 1 subunit gene (Ca(v)1.1) and thyrotoxic periodic paralysis. J Clin Endocrinol Metab 89: 1340–1345. Kuntzer T, Flocard F, Vial C, et al. (2000). Exercise test in muscle channelopathies and other muscle disorders. Muscle Nerve 23: 1089–1094. Kuo A, Gulbis JM, Antcliff JF, et al. (2003). Crystal structure of the potassium channel KirBac1.1 in the closed state. Science 300: 1922–1926. Kuzmenkin A, Muncan V, Jurkat-Rott K, et al. (2002). Enhanced inactivation and pH sensitivity of Na(þ) channel mutations causing hypokalaemic periodic paralysis type II. Brain 125: 835–843. Lajara-Nanson WA (2002). Cocaine induced hypokalaemic periodic paralysis. J Neurol Neurosurg Psychiatry 73: 92. Lambert C, Blanloeil Y, Horber RK, et al. (1994). Malignant hyperthermia in a patient with hypokalemic periodic paralysis. Anesth Analg 79: 1012–1014. Lange PS, Er F, Gassanov N, et al. (2003). Andersen mutations of KCNJ2 suppress the native inward rectifier current IK1 in a dominant-negative fashion. Cardiovasc Res 59: 321–327. Lapie P, Goudet C, Nargeot J, et al. (1996). Electrophysiological properties of the hypokalaemic periodic paralysis mutation (R528H) of the skeletal muscle alpha 1s subunit as expressed in mouse L cells. FEBS Lett 382: 244–248. Layzer RB (1982). Periodic paralysis and the sodium–potassium pump. Ann Neurol 11: 547–552. Layzer RB, Lovelace RE, Rowland LP (1967). Hyperkalemic periodic paralysis. Arch Neurol 16: 455–472. Lehmann-Horn F, Rudel R, Dengler R, et al. (1981). Membrane defects in paramyotonia congenita with and without myotonia in a warm environment. Muscle Nerve 4: 396–406. Lehmann-Horn F, Rudel R, Ricker K, et al. (1983). Two cases of adynamia episodica hereditaria: in vitro investigation of muscle cell membrane and contraction parameters. Muscle Nerve 6: 113–121. Lehmann-Horn F, Rudel R, Ricker K (1993). Non-dystrophic myotonias and periodic paralyses. A European Neuromuscular Center Workshop held 4–6 October 1992, Ulm, Germany. Neuromuscul. Disord 3: 161–168. Lerche H, Heine R, Pika U, et al. (1993). Human sodium channel myotonia: slowed channel inactivation due to substitutions for a glycine within the III–IV linker. J Physiol 470: 13–22.
Lewi Z, Bar-Khayim Y (1964). Food poisoning from barium carbonate. Lancet 2: 342–343. Leyburn P, Walton JN (1960). The effect of changes in serum potassium upon myotonia. J Neurol Neurosurg Psychiatry 23: 119–126. Ligtenberg JJ, Van Haeften TW, Van Der Kolk LE, et al. (1996). Normal insulin release during sustained hyperglycaemia in hypokalaemic periodic paralysis: role of the potassium channel opener pinacidil in impaired muscle strength. Clin Sci (Lond) 91: 583–589. Lin SH, Lin YF (2001). Propranolol rapidly reverses paralysis, hypokalemia, and hypophosphatemia in thyrotoxic periodic paralysis. Am J Kidney Dis 37: 620–623. Lin SH, Chiu JS, Hsu CW, et al. (2003). A simple and rapid approach to hypokalemic paralysis. Am J Emerg Med 21: 487–491. Linder MA (1955). Periodic paralysis associated with hyperthyroidism: report of three cases. Ann Intern Med 43: 241–254. Links TP, Zwarts MJ, Wilmink JT, et al. (1990). Permanent muscle weakness in familial hypokalaemic periodic paralysis. Clinical, radiological and pathological aspects. Brain 113 (6): 1873–1889. Links TP, Smit AJ, Molenaar WM, et al. (1994). Familial hypokalemic periodic paralysis. Clinical, diagnostic and therapeutic aspects. J Neurol Sci 122: 33–43. Lipicky RJ, Bryant SH (1966). Sodium, potassium, and chloride fluxes in intercostal muscle from normal goats and goats with hereditary myotonia. J Gen Physiol 50: 89–111. Lipicky RJ, Bryant SH (1973). A biophysical study of human myotonias. In: JE Desmedt (Ed.), New Developments in Electromyography and Clinical Neurophysiology. Karger AG, Basel pp. 451–463. Lopatin AN, Nichols CG (2001). Inward rectifiers in the heart: an update on IK1. J Mol Cell Cardiol 33: 625–638. Lopes CM, Zhang H, Rohacs T, et al. (2002). Alterations in conserved Kir channel-PIP2 interactions underlie channelopathies. Neuron 34: 933–944. Lu KC, Hsu YJ, Chiu JS, et al. (2004). Effects of potassium supplementation on the recovery of thyrotoxic periodic paralysis. Am J Emerg Med 22: 544–547. Ma JT, Wang C, Lam KS, et al. (1986). Fifty cases of primary hyperaldosteronism in Hong Kong Chinese with a high frequency of periodic paralysis. Evaluation of techniques for tumour localisation. Q J Med 61: 1021–1037. ¨ ber die paroxysmale Paralyse. Mankowsky BN (1929). U Arch F Psychiatr 87: 280. Mannuzzu LM, Moronne MM, Isacoff EY (1996). Direct physical measure of conformational rearrangement underlying potassium channel gating. Science 271: 213–216. Marchant CL, Ellis FR, Halsall PJ, et al. (2004). Mutation analysis of two patients with hypokalemic periodic paralysis and suspected malignant hyperthermia. Muscle Nerve 30: 114–117. McArdle B (1962). Adynamia epdisodica hereditaria and its treatment. Brain 85: 121–148.
PERIODIC PARALYSIS McChesney JA, Marquardt JF (1964). Hypokalemic paralysis induced by Amphotericin B. JAMA 189: 1029–1031. McClatchey AI, McKenna-Yasek D, Cros D, et al. (1992a). Novel mutations in families with unusual and variable disorders of the skeletal muscle sodium channel. Nat Genet 2: 148–152. McClatchey AI, Van den BP, Pericak-Vance MA, et al. (1992b). Temperature-sensitive mutations in the III–IV cytoplasmic loop region of the skeletal muscle sodium channel gene in paramyotonia congenita. Cell 68: 769–774. McFadzean AJ, Yeung R (1967). Periodic paralysis complicating thyrotoxicosis in Chinese. BMJ 1: 451–455. McManis PG, Lambert EH, Daube JR (1986). The exercise test in periodic paralysis. Muscle Nerve 9: 704–710. Mehta SR, Verma A, Malhotra H, et al. (1990). Normokalaemic periodic paralysis as the presenting manifestation of hyperthyroidism. J Assoc Physicians India 38: 296–297. Meyers KR, Gilden DH, Rinaldi CF, et al. (1972). Periodic muscle weakness, normokalemia, and tubular aggregates. Neurology 22: 269–279. Miller TM, Dias Da Silva MR, Miller HA, et al. (2004). Correlating phenotype and genotype in the periodic paralyses. Neurology 63: 1647–1655. Minaker KL, Meneilly GS, Flier JS, et al. (1988). Insulinmediated hypokalemia and paralysis in familial hypokalemic periodic paralysis. Am J Med 84: 1001–1006. Mitrovic N, George AL, Jr, Heine R, et al. (1994). K(þ)aggravated myotonia: destabilization of the inactivated state of the human muscle Naþ channel by the V1589M mutation. J Physiol 478 (Pt 3): 395–402. Mitrovic N, George AL, Jr, Lerche H, et al. (1995). Different effects on gating of three myotonia-causing mutations in the inactivation gate of the human muscle sodium channel. Physiol Online 487: 107–114. Mitrovic N, George AL, Jr, Rudel R, et al. (1999). Mutant channels contribute <50% to Naþ current in paramyotonia congenita muscle. Brain 122 (Pt 6): 1085–1092. Monnier N, Procaccio V, Stieglitz P, et al. (1997). Malignanthyperthermia susceptibility is associated with a mutation of the alpha 1-subunit of the human dihydropyridine-sensitive L-type voltage-dependent calcium-channel receptor in skeletal muscle. Am J Hum Genet 60: 1316–1325. Morgan-Hughes JA (1998). Tubular aggregates in skeletal muscle: their functional significance and mechanisms of pathogenesis. Curr Opin Neurol 11: 439–442. Morrill JA, Cannon SC (1999). Effects of mutations causing hypokalaemic periodic paralysis on the skeletal muscle L-type Ca2þ channel expressed in Xenopus laevis oocytes. J Physiol 520 (2): 321–336. Mu¨nsterer OJ (2003). Hyperkalaemic paralysis. Age Ageing 32: 114–115. Musgrave W (1727). A periodic palsy. Philos Trans R Soc Lond B Biol Sci 3: 33–34. Nalluri P, Venkatesh S, Rao A (2000). Cocaine-induced hypokalemic paralysis. Muscle Nerve 23: 1773. Norris FH Jr, Clark EC, Biglieri EG (1971). Studies in thyrotoxic periodic paralysis. J Neurol Sci 13: 431–442.
103
Ober KP (1992). Thyrotoxic periodic paralysis in the United States. Report of 7 cases and review of the literature. Medicine (Baltimore) 71: 109–120. Odor DL, Patel AN, Pearce LA (1967). Familial hypokalemic periodic paralysis with permanent myopathy. A clinical and ultrastructural study. J Neuropathol Exp Neurol 26: 98–114. Oh VM, Taylor EA, Yeo SH, et al. (1990). Cation transport across lymphocyte plasma membranes in euthyroid and thyrotoxic men with and without hypokalaemic periodic paralysis. Clin Sci (Lond) 78: 199–206. Okinaka S, Shizume K, Iino S, et al. (1957). The association of periodic paralysis and hyperthyroidism in Japan. J Clin Endocrinol Metab 17: 1454–1459. Okuda S, Kanda F, Nishimoto K, et al. (2001). Hyperkalemic periodic paralysis and paramyotonia congenita–a novel sodium channel mutation. J Neurol 248: 1003–1004. Ortuno AF, Cabello CN, de Diego GR, et al. (2002). [Hypokalemia-induced paraplegia secondary to acute diarrhea]. An Med Interna 19: 76–78. Owen EE, Verner JV Jr (1960). Renal tubular disease with muscle paralysis and hypokalemia. Am J Med 28: 8–21. Paasuke RT, Brownell AK (1986). Serum creatine kinase level as a screening test for susceptibility to malignant hyperthermia. JAMA 255: 769–771. Pasman JW, Gabreels FJ, Semmekrot B, et al. (1989). Hyperkalemic periodic paralysis in Gordon’s syndrome: a possible defect in atrial natriuretic peptide function. Ann Neurol 26: 392–395. Payne MW, Watters LC, Bailey CE, et al. (1979). Periodic paralysis with thyrotoxicosis — treatment with propranolol. J Med Assoc Ga 68: 701–703. Pereon Y, Lande G, Demolombe S, et al. (2003). Paramyotonia congenita with an SCN4A mutation affecting cardiac repolarization. Neurology 60: 340–342. Plassart E, Reboul J, Rime CS, et al. (1994). Mutations in the muscle sodium channel gene (SCN4A) in 13 French families with hyperkalemic periodic paralysis and paramyotonia congenita: phenotype to genotype correlations and demonstration of the predominance of two mutations. Eur J Hum Genet 2: 110–124. Plassart E, Eymard B, Maurs L, et al. (1996). Paramyotonia congenita: genotype to phenotype correlations in two families and report of a new mutation in the sodium channel gene. J Neurol Sci 142: 126–133. Plaster NM, Tawil R, Tristani-Firouzi M, et al. (2001). Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen’s syndrome. Cell 105: 511–519. Pollen RH, Williams RH (1960). Hyperkalemic neuromyopathy in Addison’s disease. N Engl J Med 263: 273–278. Poskanzer DC, Kerr DN (1961). A third type of periodic paralysis, with normokalemia and favourable response to sodium chloride. Am J Med 31: 328–342. Poux JM, Peyronnet P, Le Meur Y, et al. (1992). Hypokalemic quadriplegia and respiratory arrest revealing primary Sjogren’s syndrome. Clin Nephrol 37: 189–191.
104
D. FIALHO AND M. G. HANNA
Preisig-Muller R, Schlichthorl G, Goerge T, et al. (2002). Heteromerization of Kir2.x potassium channels contributes to the phenotype of Andersen’s syndrome. Proc Natl Acad Sci U S A 99: 7774–7779. Priori SG, Pandit SV, Rivolta I, et al. (2005). A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene. Circ Res 96: 800–807. Ptacek LJ, George AL Jr, Griggs RC, et al. (1991a). Identification of a mutation in the gene causing hyperkalemic periodic paralysis. Cell 67: 1021–1027. Ptacek LJ, Tyler F, Trimmer JS, et al. (1991b). Analysis in a large hyperkalemic periodic paralysis pedigree supports tight linkage to a sodium channel locus. Am J Hum Genet 49: 378–382. Ptacek LJ, Trimmer JS, Agnew WS, et al. (1991c). Paramyotonia congenita and hyperkalemic periodic paralysis map to the same sodium-channel gene locus. Am J Hum Genet 49: 851–854. Ptacek LJ, George AL, Jr, Barchi RL, et al. (1992). Mutations in an S4 segment of the adult skeletal muscle sodium channel cause paramyotonia congenita. Neuron 8: 891–897. Ptacek LJ, Gouw L, Kwiecinski H, et al. (1993). Sodium channel mutations in paramyotonia congenita and hyperkalemic periodic paralysis. Ann Neurol 33: 300–307. Ptacek LJ, Tawil R, Griggs RC, et al. (1994). Dihydropyridine receptor mutations cause hypokalemic periodic paralysis. Cell 77: 863–868. Raab-Graham KF, Radeke CM, Vandenberg CA (1994). Molecular cloning and expression of a human heart inward rectifier potassium channel. Neuroreport 5: 2501–2505. Rainoldi A, Bullock-Saxton JE, Cavarretta F, et al. (2001). Repeatability of maximal voluntary force and of surface EMG variables during voluntary isometric contraction of quadriceps muscles in healthy subjects. J Electromyogr Kinesiol 11: 425–438. Rajabally YA, El Lahawi M (2002). Hypokalemic periodic paralysis associated with malignant hyperthermia. Muscle Nerve 25: 453–455. Raskin RJ, Tesar JT, Lawless OJ (1981). Hypokalemic periodic paralysis in Sjogren’s syndrome. Arch Intern Med 141: 1671–1673. Resnick JS, Engel WK (1967). Myotonic lid lag in hypokalaemic periodic paralysis. J Neurol Neurosurg Psychiatry 30: 47–51. Resnick JS, Engel WK, Griggs RC, et al. (1968). Acetazolamide prophylaxis in hypokalemic periodic paralysis. N Engl J Med 278: 582–586. Richmond JE, Featherstone DE, Ruben PC (1997a). Human Naþ channel fast and slow inactivation in paramyotonia congenita mutants expressed in Xenopus laevis oocytes. J Physiol 499 (Pt 3): 589–600. Richmond JE, VanDeCarr D, Featherstone DE, et al. (1997b). Defective fast inactivation recovery and deactivation account for sodium channel myotonia in the I1160V mutant. Biophys J 73: 1896–1903. Rojas CV, Wang JZ, Schwartz LS, et al. (1991). A Met-toVal mutation in the skeletal muscle Naþ channel alpha-
subunit in hyperkalaemic periodic paralysis. Nature 354: 387–389. Rosenfeld M (1902). Akute aufsteigende La¨hmung bei Morbus Basedow. Berl klin Wchenschr 39: 538. Rosenfeld J, Sloan-Brown K, George AL, Jr (1997). A novel muscle sodium channel mutation causes painful congenital myotonia. Ann Neurol 42: 811–814. Rowley PT, Kliman B (1960). The effect of sodium loading and depletion on muscular strength and aldosterone excretion in familial periodic paralysis. Am J Med 28: 376–385. Rudel R, Lehmann-Horn F, Ricker K, et al. (1984). Hypokalemic periodic paralysis: in vitro investigation of muscle fiber membrane parameters. Muscle Nerve 7: 110–120. Ruff RL (1994). Slow Naþ channel inactivation must be disrupted to evoke prolonged depolarization-induced paralysis. Biophys J 66: 542–545. Ruff RL (1999). Insulin acts in hypokalemic periodic paralysis by reducing inward rectifier Kþ current. Neurology 53: 1556–1563. Ruff RL, Al-Mudallal A (2000). Reduced skeletal muscle membrane excitability in hypokalemic periodic paralysis (hypoPP) is due to reduced expression of Na channels. Neurology 54: A270. Ryan MM, Taylor P, Donald JA, et al. (1999). A novel syndrome of episodic muscle weakness maps to xp22.3. Am J Hum Genet 65: 1104–1113. Sansone V, Griggs RC, Meola G, et al. (1997). Andersen’s syndrome: a distinct periodic paralysis. Ann Neurol 42: 305–312. Sasaki R, Takano H, Kamakura K, et al. (1999). A novel mutation in the gene for the adult skeletal muscle sodium channel alpha-subunit (SCN4A) that causes paramyotonia congenita of von Eulenburg. Arch Neurol 56: 692–696. Sataline LR, Simonelli JM (1961). Potassium paresis following ureterosigmoidostomy. J Urol 85: 559–563. Saunders M, Ashworth B, Emery AE, et al. (1968). Familial myotonic periodic paralysis with muscle wasting. Brain 91: 295–304. Schipperheyn JJ, Buruma OJ, Voogd PJ (1978). Hypokalaemic periodic paralysis and cardiomyopathy. Acta Neurol Scand 58: 374–378. Schmidt AKE (1919). Die paroxysmale La¨hmung. Monographien aus dem Gesamtgebiete der Neurolologie und Psychiatrie Heft 1: 8. Schram G, Pourrier M, Wang Z, et al. (2003). Barium block of Kir2 and human cardiac inward rectifier currents: evidence for subunit-heteromeric contribution to native currents. Cardiovasc Res 59: 328–338. Shakhnowitsch (1882). Ein selterner Fall von intermittierender Paraplegie. Russ Uratsh 32: 537. Shankle R, Keane JR (1988). Acute paralysis from inhaled barium carbonate. Arch Neurol 45: 579–580. Shayne P, Hart A (1994). Thyrotoxic periodic paralysis terminated with intravenous propranolol. Ann Emerg Med 24: 736–740. Shiah CJ, Tsai DM, Liao ST, et al. (1994). Acute muscular paralysis in an adult with subclinical Bartter’s syndrome
PERIODIC PARALYSIS associated with gentamicin administration. Am J Kidney Dis 24: 932–935. Singer HD, Goodbody FW (1901). A case of family periodic paralysis with a critical digest of the literature. Together with a report and digest of the literature on the pathological examination of the excreta. Brain 24: 257. Soom M, Schonherr R, Kubo Y, et al. (2001). Multiple PIP2 binding sites in Kir2.1 inwardly rectifying potassium channels. FEBS Lett 490: 49–53. Soy M, Pamuk ON, Gerenli M, et al. (2005). A primary Sjogren’s syndrome patient with distal renal tubular acidosis, who presented with symptoms of hypokalemic periodic paralysis. Report of a case study and review of the literature. Rheumatol Int 26: 86–89. Sperelakis N, Schneider MF, Harris EJ (1967). Decreased Kþ conductance produced by Baþþ in frog sartorius fibers. J Gen Physiol 50: 1565–1583. Sternberg D, Maisonobe T, Jurkat-Rott K, et al. (2001). Hypokalaemic periodic paralysis type 2 caused by mutations at codon 672 in the muscle sodium channel gene SCN4A. Brain 124: 1091–1099. Sternberg D, Tabti N, Fournier E, et al. (2003). Lack of association of the potassium channel-associated peptide MiRP2R83H variant with periodic paralysis. Neurology 61: 857–859. Streib EW, Sun SF, Yarkowsky T (1982). Transient paresis in myotonic syndromes: a simplified electrophysiologic approach. Muscle Nerve 5: 719–723. Streib EW, Sun SF, Hanson M (1983). Paramyotonia congenita: clinical and electrophysiologic studies. Electromyogr Clin Neurophysiol 23: 315–325. Struyk AF, Scoggan KA, Bulman DE, et al. (2000). The human skeletal muscle Na channel mutation R669H associated with hypokalemic periodic paralysis enhances slow inactivation. J Neurosci 20: 8610–8617. Subramony SH, Wee AS (1986). Exercise and rest in hyperkalemic periodic paralysis. Neurology 36: 173–177. Sugiura Y, Aoki T, Sugiyama Y, et al. (2000). Temperaturesensitive sodium channelopathy with heat-induced myotonia and cold-induced paralysis. Neurology 54: 2179–2181. Sugiura Y, Makita N, Li L, et al. (2003). Cold induces shifts of voltage dependence in mutant SCN4A, causing hypokalemic periodic paralysis. Neurology 61: 914–918. Takahashi MP, Cannon SC (1999). Enhanced slow inactivation by V445M: a sodium channel mutation associated with myotonia. Biophys J 76: 861–868. Talbott JH (1941). Periodic paralysis, a clinical syndrome. Medicine (Baltimore) 20: 85–143. Tamai H, Tanaka K, Komaki G, et al. (1987). HLA and thyrotoxic periodic paralysis in Japanese patients. J Clin Endocrinol Metab 64: 1075–1078. Tawil R, Moxley RTIII, Griggs RC (1993). Acetazolamideinduced nephrolithiasis: implications for treatment of neuromuscular disorders. Neurology 43: 1105–1106. Tawil R, Ptacek LJ, Pavlakis SG, et al. (1994). Andersen’s syndrome: potassium-sensitive periodic paralysis, ventricular ectopy, and dysmorphic features. Ann Neurol 35: 326–330.
105
Tawil R, McDermott MP, Brown RJr, et al. (2000). Randomized trials of dichlorphenamide in the periodic paralyses. Working Group on Periodic Paralysis. Ann Neurol 47: 46–53. Tengan CH, Antunes AC, Gabbai AA, et al. (2004). The exercise test as a monitor of disease status in hypokalaemic periodic paralysis. J Neurol NeurosurgPsychiatry 75: 497–499. Tomimitsu H, Ishikawa K, Shimizu J, et al. (2002). Distal myopathy with rimmed vacuoles: novel mutations in the GNE gene. Neurology 59: 451–454. Tricarico D, Servidei S, Tonali P, et al. (1999). Impairment of skeletal muscle adenosine triphosphate-sensitive Kþ channels in patients with hypokalemic periodic paralysis. J Clin Invest 103: 675–682. Tricarico D, Barbieri M, Camerino DC (2000). Acetazolamide opens the muscular KCa2þ channel: a novel mechanism of action that may explain the therapeutic effect of the drug in hypokalemic periodic paralysis. Ann Neurol 48: 304–312. Tricarico D, Barbieri M, Mele A, et al. (2004). Carbonic anhydrase inhibitors are specific openers of skeletal muscle BK channel of Kþ-deficient rats. FASEB J 18: 760–761. Trimmer JS, Cooperman SS, Tomiko SA, et al. (1989). Primary structure and functional expression of a mammalian skeletal muscle sodium channel. Neuron 3: 33–49. Tristani-Firouzi M, Jensen JL, Donaldson MR, et al. (2002). Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome). J Clin Invest 110: 381–388. Troni W, Doriguzzi C, Mongini T (1983). Interictal conduction slowing in muscle fibers in hypokalemic periodic paralysis. Neurology 33: 1522–1525. Tsujino A, Maertens C, Ohno K, et al. (2003). Myasthenic syndrome caused by mutation of the SCN4A sodium channel. Proc Natl Acad Sci U S A 100: 7377–7382. Udezue EO, Harrold BP (1980). Hyperkalaemic paralysis due to spironolactone. Postgrad Med J 56: 254–255. Umeki S, Ohga R, Ono S, et al. (1986). Angiotensin I level and sporadic hypokalemic periodic paralysis. Arch Intern Med 146: 1956–1960. van der Hoeven JH, Zwarts MJ, van Weerden TW (1993). Muscle fiber conduction velocity in amyotrophic lateral sclerosis and traumatic lesions of the plexus brachialis. Electroencephalogr Clin Neurophysiol 89: 304–310. Vicart S, Sternberg D, Fournier E, et al. (2004). New mutations of SCN4A cause a potassium-sensitive normokalemic periodic paralysis. Neurology 63: 2120–2127. Waites GM, Wang C, Griffin PD (1998). Gossypol: reasons for its failure to be accepted as a safe, reversible male antifertility drug. Int J Androl 21: 8–12. Walker MB (1935). Potassium chloride in myasthenia gravis. Lancet 2: 47. Wallace RH, Wang DW, Singh R, et al. (1998). Febrile seizures and generalized epilepsy associated with a mutation in the Naþ-channel beta1 subunit gene SCN1B. Nat Genet 19: 366–370. Wagner S, Lerche H, Mitrovic N, et al. (1997). A novel sodium channel mutation causing a hyperkalemic paralytic and paramyotonic syndrome with variable clinical expressivity. Neurology 49: 1018–1025.
106
D. FIALHO AND M. G. HANNA
Wang YX, Chen ZX (1991). [A possible mechanism of gossypol-induced hypokalemia and its relation to gossypol dose]. Shengzhi Yu Biyun 11: 34–38. Wang P, Clausen T (1976). Treatment of attacks in hyperkalaemic familial periodic paralysis by inhalation of salbutamol. Lancet 1: 221–223. Wang J, Dubowitz V, Lehmann-Horn F, et al. (1995). In vivo sodium channel structure/function studies: consecutive Arg1448 changes to Cys, His, and Pro at the extracellular surface of IVS4. Soc. Gen Physiol Ser 50: 77–88. Wang Q, Liu M, Xu C, et al. (2005). Novel CACNA1S mutation causes autosomal dominant hypokalemic periodic paralysis in a Chinese family. J Mol Med 83: 203–208. Weiss-Guillet EM, Takala J, Jakob SM (2003). Diagnosis and management of electrolyte emergencies. Best Pract Res Clin Endocrinol Metab 17: 623–651. Weller JF, Elliott RA, Pronovost PJ (2002). Spinal anesthesia for a patient with familial hyperkalemic periodic paralysis. Anesthesiology 97: 259–260. ¨ ber einen merkwu¨rdigen Fall von periWestphal C (1885). U odischer La¨hmung aller vier Extremita¨ten mit gleichzeitigem Erlo¨schen der elektrischen Erregbarkeit wa¨hrend der La¨hmung. Berl klinWchenschr 22: 489–511. Wild E (2004). Thyrotoxic periodic paralysis in a Maori patient. N Z Med J 117: U1204. Wu FF, Takahashi MP, Pegoraro E, et al. (2001). A new mutation in a family with cold-aggravated myotonia disrupts Na(þ) channel inactivation. Neurology 56: 878–884. Wu FF, Gordon E, Hoffman EP, et al. (2005). A C-terminal skeletal muscle sodium channel mutation associated with myotonia disrupts fast inactivation. J Physiol 565: 371–380. Xia M, Jin Q, Bendahhou S, et al. (2005). A Kir2.1 gain-offunction mutation underlies familial atrial fibrillation. Biochem Biophys Res Commun 332: 1012–1019.
Yang N, Ji S, Zhou M, et al. (1994). Sodium channel mutations in paramyotonia congenita exhibit similar biophysical phenotypes in vitro. Proc Natl Acad Sci U.S.A 91: 12785–12789. Yang J, Jan YN, Jan LY (1995). Determination of the subunit stoichiometry of an inwardly rectifying potassium channel. Neuron 15: 1441–1447. Yang N, George AL Jr, Horn R (1996). Molecular basis of charge movement in voltage-gated sodium channels. Neuron 16: 113–122. Yazaki K, Kuribayashi T, Yamamura Y, et al. (1982). Hypokalemic myopathy associated with 17 alpha-hydroxylase deficiency: a case report. Neurology 32: 94–97. Yeo PP, Chan SH, Lui KF, et al. (1978). HLA and thyrotoxic periodic paralysis. BMJ 2: 930. Yeung RT, Tse TF (1974). Thyrotoxic periodic paralysis. Effect of propranolol. Am J Med 57: 584–590. Zaritsky JJ, Eckman DM, Wellman GC, et al. (2000). Targeted disruption of Kir2.1 and Kir2.2 genes reveals the essential role of the inwardly rectifying K(þ) current in K(þ)-mediated vasodilation. Circ Res 87: 160–166. Zhang L, Benson DW, Tristani-Firouzi M, et al. (2005). Electrocardiographic features in Andersen–Tawil syndrome patients with KCNJ2 mutations: characteristic T-U-wave patterns predict the KCNJ2 genotype. Circulation 111: 2720–2726. Ziegler MR, McQuarrie I (1952). Hereditary periodic paralysis. I. Effects of various induced changes in physiological state on paralytic attacks. Metabolism 1: 116–128. Zimmer T, Bollensdorff C, Haufe V, et al. (2002). Mouse heart Naþ channels: primary structure and function of two isoforms and alternatively spliced variants. Am J Physiol Heart Circ Physiol 282: H1007–H1017. Zwarts MJ, van Weerden TW, Links TP, et al. (1988). The muscle fiber conduction velocity and power spectra in familial hypokalemic periodic paralysis. Muscle Nerve 11: 166–173.
Handbook of Clinical Neurology, Vol. 86 (3rd series) Myopathies F. L. Mastaglia, D. Hilton-Jones, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 5
Malignant hyperthermia and associated conditions P. J. HALSALL* AND R. L. ROBINSON Leeds MH Investigation Unit, Leeds, UK
Malignant hyperthermia (MH) was first recognized in Australia in 1960 when a young man presented with a fractured leg giving a history of 11 relatives dying in relation to anesthesia. He subsequently experienced a life-threatening clinical reaction to anesthesia, in which the most startling event was a “raging temperature”. The family tree indicated an autosomal-dominant pattern of inheritance (Denborough and Lovell 1960). Malignant hyperthermia has presumably always been one cause of anesthetic-related deaths, e.g., “ether deaths”, but went undetected at a time when anesthesia and surgery carried a high mortality rate, until the serendipitous event described above. Malignant hyperthermia is a pharmacogenetic disease triggered by the depolarizing muscle relaxant suxamethonium and all the anesthetic vapors, although some are more potent triggers than others.
5.1. Epidemiology The original mortality from MH was 70–80%, and was one of the highest causes of morbidity and mortality in otherwise fit young patients. Following the introduction of much better standards of monitoring during anesthesia and the availability of the specific drug therapy dantrolene, the mortality rate dropped to 2–3%. In countries with poor monitoring facilities or unavailability of dantrolene, as is the case in some areas of Eastern Europe, the mortality rate remains much higher. This is also true for Taiwan where the mortality rate has been quoted as 28.6% (Wang-Hin et al., 2004). The actual incidence of MH is difficult to estimate and ranges from 1 in 8000 to 1 in 15 000. In the UK the number of new confirmed MH-positive cases has fallen from 25–30 per year to 10–15 per year over the last 10 years. This is
probably a result of changes in anesthetic practice. There has been a marked reduction in the routine use of suxamethonium, an increased use of less potent MHtriggering volatile agents, e.g., sevoflurane, whereas the use of total intravenous anesthesia (TIVA) and local anesthesia has increased. Despite these changes the referral rate for new suspected cases has increased, reflecting an increased index of suspicion by anesthetists. MH has been described in all races and more commonly occurs in the younger age groups (10–30 years) with males predominating slightly (Table 5.1). This is possibly related to lifestyle differences and the resulting type of surgery and anesthesia used rather than a true gender difference. However, when the MH status of parents of a proband is assessed there is a slight preponderance of MH-positive fathers compared to MH-positive mothers. A high incidence of minor musculoskeletal abnormalities, e.g., ptosis and hernia were also thought to be associated with MH (Britt and Kalow, 1970). However, MH-triggering types of anesthesia are more likely to be used during surgery for these conditions, e.g., ear–nose–throat (ENT), eye, dental, minor surgery and trauma. The higher incidence of MH in this patient group is consequently thought to be a spurious association. A history of previous uneventful anesthesia does not exclude MH (Halsall et al., 1979). A Danish report indicates that 37% of MH-susceptible patients have had previous anesthesia (Bendixen et al., 1997) and in the UK around 75% of MH-susceptible probands have had at least one apparently normal anesthetic (unpublished data). This is one observation that has lead to the suggestion of reduced penetrance in MH; the MH phenotype being a product of the genotype, environmental factors, e.g., duration of exposure to anesthesia, and their interaction (Falconer, 1993).
*Correspondence to: Dr P. J. Halsall MB ChB, Associate Specialist in Anaesthesia, The Leeds MH Investigation Unit, Clinical Sciences Building, St James’s University Hospital, Leeds, LS9 7TF UK.
108
P. J. HALSALL AND R. L. ROBINSON
Table 5.1
on the T-tubule, encoded by the CACNA1S gene on chromosome 1, and the tetramer ryanodine receptor located on the SR encoded by the RYR1 gene on chromosome 19 (Fig. 5.1; Jurkatt-Rott et al., 2000). Early research relied heavily on studies on pigs and biochemical studies using caffeine which stimulates the release of Ca2þ from the SR (Mickelson and Louis, 1996). In 1966 Hall et al. reported that suxamethonium and halothane precipitated a characteristic MH reaction in certain breeds of pigs, generally lean and well-muscled, e.g., Pietrain, Poland China and Landrace. However, in contrast to humans, the mode of inheritance is autosomal recessive and can be triggered by stress, for instance prior to slaughter, leading to the term porcine stress syndrome (PSS). Supportive evidence that a loss of Ca2þ homeostasis caused MH was finally described in 1985 (Lopez et al.) and 1988 (Iaizzo et al.); studies that showed the presence of increased sarcoplasmic Ca2þ during an MH reaction but not at rest. An MH reaction could be seen as the final common pathway of a defect anywhere along the E-C coupling process which ultimately results in increased sarcoplasmic Ca2þ inducing glycogenolysis and cell metabolism, resulting in heat production, excess lactate and adenosine trisphosphate (ATP) depletion, resulting in the clinical signs of MH. ATP is utilized to restore homeostasis, so leading to irreversible changes and ultimately death. Thus early recognition and treatment of MH is vital; dantrolene given too late is ineffective.
Male/female ratio (probands) (1995–2004) Malignant hyperthermia status
Malesa
Females
MHS/E MHN
94 149
54 109
a
57% of all MH susceptible probands are male; 67% of all referred probands are male.
5.2. Etiology 5.2.1. Muscle function Malignant hyperthermia has always been recognized as a skeletal muscle disease, involving the excitationcontraction (E-C) coupling mechanism, the means by which nervous activity is transferred to skeletal muscle activity at the neuromuscular junction. E-C coupling is a complex dynamic process in which Ca2þ plays a crucial role (Lyfenko et al., 2004). Deep membrane projections (the T-tubules) into the sarcoplasm ensure rapid and even distribution of the impulse. At specialized regions of the T-tubule, known as triads, the signal is transferred to the sarcoplasmic reticulum (SR), causing the release of Ca2þ into the sarcoplasm activating the contractile apparatus. Two Ca2þ channels are involved in this final stage, the voltage-gated dihydropyridine receptor (Rios and Brum, 1987) located
Diagram of structures involved in excitation-contraction coupling in skeletal muscles Sarcolemma
Terminal cisternae of SR
Ca2+ stores
DHPR Ca2+
Sarcoplasmic reticulum ATP
RYRI
ADP Ca2+
Actin Sarcomere Myosin
Fig. 5.1. Schematic diagram showing the potential sites involved in the etiology of malignant hyperthermia. DHPR: dihydropyridine receptor: a voltage sensor located on the T-tubule of the muscle membrane; RYR1: ryanodine receptor: a calcium efflux channel.
MALIGNANT HYPERTHERMIA AND ASSOCIATED CONDITIONS Recent studies using skinned muscle fibers from MHsusceptible patients suggests that reduced Mg2þ concentrations may influence the effect of halothane on Ca2þ release and so have a clinical role in the development of an MH reaction (Duke et al., 2002; 2004). Another study suggests that volatile anesthetic agents decrease the surface membrane Ca2þ currents in porcine skeletal muscle by reducing the number of functional DHPR Ca2þ channels, rather than there being a defect in the protein itself (Louis et al., 1994). Although the primary cause of MH is thought to be a SR defect, other sites along the E-C pathway, such as the sarcolemma, remain possibilities (Gallant et al., 1979; Halsall and Ellis, 1983). It may be that MH is caused by different defects or a combination of defects in different families.
5.3. Genetics of MH The ryanodine receptor, encoded by the RYR1 gene, a calcium-release channel located on the SR, appears to be crucial to the pathogenesis of MH. The first clues to its involvement originated from the discovery of the Hal locus in pigs from the investigation of PSS.The Hal locus was mapped to pig chromosome 6p11–q21 (Harbitz et al., 1990) which shows conservation with human chromosome 19q13.1 where the RYR1 gene is located. RYR1 was mapped and cloned in 1990 (MacKenzie et al., 1990; McCarthy et al., 1990; MacLennan et al., 1990). The gene contains 106 exons, two of which, exons 70 and 83, may be alternatively spliced (Phillips et al., 1996). The cDNA is 15 Kb and encodes a protein monomer of 5038 amino acids with a mass of 563 584 kDa. Ryanodine receptors comprise four monomers and function with an array of accessory proteins. The tetrameric channel has a mass of 2 250 000 Da and represents one of the largest known proteins. Each monomer is predicted to consist of a cytoplasmic N-terminal region which forms the majority of the protein, multiple membrane-spanning domains (6–10 have been predicted) and a small cytoplasmic C-terminus (Du et al., 2002). Sequence analysis of cDNA isolated from normal and susceptible pigs identified a single nucleotide change in the porcine RYR1 gene which generated an arginine to cysteine amino-acid substitution at residue 615 in the PSS swine. The same substitution was detected in six breeds with PSS (Fujii et al., 1991). In humans genetic studies were founded on the basis of the clinical reactions and deaths described in Denborough’s original family (Denborough and Lovell, 1960), and later using phenotypes generated in families from the results of the in-vitro investigations (in-vitro contracture test (IVCT) muscle biopsy test data; Ellis et al., 1986; McCarthy et al., 1990). In many families the MH susceptibility is linked
109
to the RYR1 gene on chromosome 19q12–q13.2 (Robinson et al., 1998). The mutation responsible for PSS has been shown to account for up to 4% of human cases of MH from the analysis of European families (Gillard et al., 1991). Since that initial report at least 178 RYR1 mutations have been identified in association with MH worldwide (Robinson et al., 2006). There are several different classes of mutation that may predispose to disease, e.g., deletions, insertions, single base substitutions (e.g., missense mutations, nonsense mutations) and dynamic mutations. For some mutations the pathogenic effect may be easy to predict, i.e., loss/ reduced production of protein. In the cases of certain single base substitutions, i.e., missense mutations, the functional significance and the disease causing role can be difficult to determine. Missense mutations are most commonly described in MH families and represent 96% of reported mutations detected to date. To assess the significance of these changes on normal protein function, several criteria have been adopted: 1. Does the mutation segregate with disease in independent affected families? 2. Is the mutation absent from at least 100 normal control individuals? This would exclude variants with a frequency of higher than 1% in the population under study. 3. Does the mutation occur at an evolutionary conserved site when the homologous position in genes from other species are compared? 4. Does the mutation change the chemical properties of the amino acid residue? 5. Ultimately, does functional analysis of the mutation in an experimental system demonstrate a difference in function of the mutated protein? If all criteria are met, then evidence is in favor of the mutation being disease causing. However, it is not always possible to investigate practically the functional effects of all mutations identified in vitro. Early reports investigating functional effects of RYR1 mutations included analysis of RYR1 channels isolated from pig skeletal muscle preparations in lipid bilayers. MH-susceptible, p.R615C mutation-positive specimens demonstrated higher specific ryanodine binding, indicative of a higher channel open probability and increased sensitivity to activation by micromolar calcium and caffeine compared to wildtype preparations (Ohta et al., 1989; Mickelson and Louis, 1996). Other methods, using tissue prepared from MH-susceptible individuals (MHS; diagnosed by the in-vitro muscle biopsy contracture test, IVCT) or MHS individuals where a specific mutation had been identified, have allowed the effects of specific agents on channel function to be assessed, but do not allow independent assessment of RYR1
110
P. J. HALSALL AND R. L. ROBINSON
genotype on a controlled background (Richter et al., 1997; Struk et al., 1998; Brinkmeier et al., 1999; Girard et al., 2001; Tilgen et al., 2001; Duke et al., 2002; Wehner et al., 2002; Ducreux et al., 2004; Duke et al., 2004). In contrast in-vitro recombinant methods do allow genetic background effects to be controlled and have included analysis of recombinant RYR1 (rabbit) channels expressed in HEK-293/CHO cells lacking endogenous RYR1. The drawback of this system is that it lacks muscle-specific accessory proteins which may also play a central role in the functioning of the channel (Tong et al., 1997; Lynch et al., 1999; Tong et al., 1999; Sambuughin et al., 2001). However, expression of recombinant RYR1 (rabbit) channels in RYR1 knockout myotubes (mouse) provides all relevant muscle-specific accessory proteins (Avila and Dirksen, 2001; Avila et al., 2001a; 2001b; Yang et al., 2003; Dirksen and Avila, 2004). Although these in-vitro methods show that certain RYR1 mutant channels are functionally different from the wildtype, the first murine model of MH perhaps best represents the situation in vivo (Chelu et al., 2006). Mice homozygous for mutation p.Y522S, which was originally reported in association with MH and central core disease (CCD; see below, section 5.8.2; Quane et al., 1994), die during embryonic development or soon after birth. Heterozygous mutation carriers exhibit whole-body contractions and elevated core temperatures in response to isoflurane exposure or heat stress. Unlike the phenotype observed in human p.Y522S carriers, the mutation was not associated with central cores in heterozygous mice, suggesting that other factors are required for core formation. Phenotypic IVCT data from MH patients have also been used in the attempt to differentiate the phenotypic effects of certain mutations in genotype–phenotype correlation studies (Manning et al., 1998; Girard et al., 2001; Fiege et al., 2002; Robinson et al., 2002). We
previously described the retrospective analysis of phenotypic data from 297 IVCT-tested UK MH families in relation to eight different mutations (p.R163C, p.G248R, p.G341R, p.R614C, p.R2163C, p.R2163H, p.G2434R, p.R2435H; Robinson et al., 2002). The most prevalent UK RYR1 mutation, p.G2434R, was associated with a “mild” phenotype, as were mutations p.R614C and p.R2163C. Mutations p.R163C, p.R2163H and p.R2435H, all of which have been detected in patients with both MH and/or CCD, were associated with a more “severe” phenotype. Such studies have demonstrated that phenotypic response can be correlated to genotype, although it is difficult to draw conclusions when comparing independent studies due to variation in the range of mutations and number of mutation carriers investigated in each report. Heterogeneity at the allelic level is predominant in MH, with numerous independent RYR1 mutations being reported in association with the condition. Approximately 60% of these are private to independent families (Robinson et al., 2006). Linkage studies have also demonstrated heterogeneity at the locus level, with six additional MH susceptibility loci reported (Table 5.2; Levitt et al., 1992; Iles et al., 1994; Sudbrak et al., 1995; Robinson et al., 1997). However, only two represent characterized candidate genes, CACNA2D1, CACNA1S (Iles et al., 1994; Robinson et al., 1997) and in only one have mutations been identified (CACNA1S; Monnier et al., 1997). It would appear that RYR1 is the major MH gene and also plays a significant role in CCD (Schwemmle et al., 1993).
5.4. Clinical presentation Malignant hyperthermia-susceptible patients only manifest when exposed to trigger agents, so appear outwardly normal and therefore cannot be identified preoperatively
Table 5.2 Malignant hyperthermia susceptibility loci Locus symbol
Chromosome
Gene
Protein
No. pedigrees
Comment
MHS1 MHS2
19q13.1 17q11-q24
RYR1 ?
RYR ?
>60 ?
MHS3 MHS4 MHS5
7q22-q24 3q13.1 1q32
CACNA2D1 ? CACNA1S
a2d subunit DHPR ? a1 subunit DHPR
1 1 3
MHS6
5p
?
?
1
70% UK pedigrees Putative evidence in NorthAmerican pedigrees German pedigree German pedigree French, Italian, North-American pedigree Putative evidence in Belgian pedigree
MALIGNANT HYPERTHERMIA AND ASSOCIATED CONDITIONS unless there is a personal/family history of anesthetic problems suggestive of MH. The only exception to this is CCD, which is known to be associated with MH in some families (see below, section 5.8.2). The clinical presentation of a MH crisis can be very variable and no one sign is unique to MH, making clinical diagnosis sometimes difficult. MH can develop insidiously over several hours, especially when small concentrations of a vapor are used during artificial ventilation, or it can develop into a dramatic full-blown life-threatening event within half an hour. With current monitoring standards it is apparent that the increase in temperature after which it is named is a comparatively late sign of MH. When suxamethonium is used, masseter muscle spasm (MMS) can be the first warning sign. About a third of patients in whom MMS is the only apparent sign of MH, even when anesthesia has continued, prove to be MH susceptible (Table 5.3). However, MMS is difficult to define as it is subjective and known to occur in normal patients (Leary and Ellis, 1990). MMS occurring at induction of anesthesia in the presence of an anesthetic vapor only is far too quick a response to be due to MH. In the absence of suxamethonium, the two most important early signs, as indicators of metabolic stimulation, are an unexplained, unexpected, increasing end-tidal CO2 (ETCO2) with a
Table 5.3 Clinical presentation of malignant hyperthermia (1995–2004) Classification
MHS/E
MHN
Incidence
Fulminanta Moderateb Mildc MMS with muscle signsd MMS with metabolic signse MMS alonef Cardiac arrest/deathg Miscellaneoush
15 59 14 17 8 15 2 13
0 3 75 10 9 38 7 116
100 95 16 63 47 28 22 10
111
concomitant unexplained, unexpected, increasing heart rate. Indeed, MH is often referred to as a “metabolic storm”, although it is useful to group the clinical signs into metabolic effects and muscle effects (Table 5.4). MH does not start to develop after removal of the triggering agents, so does not commence postoperatively. A postoperative pyrexia occurring after normal anesthesia and the immediate recovery period is therefore not indicative of MH (Halsall and Ellis, 1992). However, muscle damage caused during a MH reaction takes time to develop and associated signs, e.g., rhabdomyolysis/ renal failure will occur up to 2–3 days after the event and may be the only apparent signs of MH. Two attempts at classifying the severity of the clinical presentation of MH and thus the likelihood that the reaction was due to MH, have been made; the clinical grading scale (CGS; Larach et al., 1994) and clinical classification (Ellis et al., 1990). The former is based on the Delphi system of awarding points to each type of clinical sign. It is an objective system but its use is limited when signs are not recorded, as is often the case in clinical practice. The total number of points then indicates the likelihood of MH. Another drawback is that signs cannot be graded, e.g., a creatine kinase (CK) of 20 000 iu/L, when suxamethonium has been used, is awarded 15 points, whereas a CK of 19 000 iu/L is awarded no points when clearly it is a significant increase above normal. Clinical classification has been criticized because it is subjective and depends on the MH expert interpreting the anesthetic, surgical and other intraoperative interventions. Originally developed to determine the reliability of the MH in-vitro contracture testing procedure for discrimination between positive and negative patients, it is now used to give the incidence/likelihood of MH based on the mode of clinical presentation (Table 5.3).
Table 5.4 Clinical signs of malignant hyperthermia
a
Fulminant: a classical life-threatening MH crisis; b moderate: most signs of MH but not life-threatening; c mild: mild signs such as slight increases in heart rate, end-tidal CO2 production, temperature, etc.; d MMS þ muscle signs: MMS is the predominant feature with signs of muscle damage i.e., high creatinine kinase or myoglobinuria; e MMS þ metabolic signs: MMS is the predominant feature with some signs of metabolic disturbance, e.g., tachycardia; f MMS alone: no other recorded signs; g cardiac arrest/death: family history of unexplained anesthetic related death/arrest; h miscellaneous: any other presentation, e.g., postoperative pyrexia, rhabdomyolysis.
Muscle signs masseter muscle spasm (MMS) generalized muscle rigidity hyperkalemia high creatine kinase myoglobinuria renal failure
Metabolic signs
tachycardia, arrhythmias tachypnea, increasing end-tidal CO2 increasing core temperature metabolic acidosis disseminated intravascular coagulation (DIC)
112
P. J. HALSALL AND R. L. ROBINSON
5.5. Treatment of a MH crisis As already stated successful treatment depends on early diagnosis and includes the following. 5.5.1. Early management 1. Removal of all triggering agents, change to clean anesthetic circuits, etc. 2. The administration of dantrolene (see below). 3. Abandon surgery if feasible or proceed with an MH-safe anesthetic technique. 4. Measure core temperature and if necessary surface cool without causing vasoconstriction, which prevents cooling. 5. Take blood samples for measurements of serum Kþ and arterial blood gases and correct in the usual way. 6. Monitor and treat any arrhythmias in the usual way. 5.5.2. Intermediate management 1. Take first voided urine sample for myoglobin, observe renal output and treat accordingly, e.g., promote with fluids or diuretics, and provide dialysis if renal failure develops. 2. Take blood samples for initial and 24-hour CK. 5.5.3. Later management 1. Consider any differential diagnoses and perform the appropriate investigations, e.g., thyroid crisis, pheochromocytoma, infection, muscle disease particularly myotonias, recreational drugs, e.g., ecstasy. 2. Refer to a MH center for advice regarding further investigation/follow-up. 3. Inform the patient/family of the possible diagnosis of MH and its implications. Most MH centers have published guidelines for the treatment of MH. In the UK, a poster can be obtained from the Association of Anaesthetists, and is required to be displayed in all anesthetic rooms. 5.5.4. Dantrolene Synthesized in 1967 (Synder et al.), it was initially used to improve muscle spasticity, but was found to be effective in treating pigs (Harrison, 1975). It is a hydantoin derivative and highly lipophilic so an intravenous formulation was not available until the 1980s. It is presented in 20-mg vials that are made up in water prior to administration and contains 3 mg mannitol with a pH of 9.5. It is metabolized in the liver and excreted
in both bile and urine. Its precise mechanism of action and binding site(s) have not been resolved, one study suggesting it may work at a sarcolemmal level (Halsall and Ellis, 1983), while another study has shown that dantrolene inhibits the release of Ca2þ from the SR by a direct and specific action on RYR1 (Fruen et al., 1997). There is also slightly conflicting evidence of a binding site closely associated with RYR1 on the SR (Parness and Palnitkar, 1996; Krause et al., 2004). The initial dose is 1 mg/kg repeated up to 10 mg/kg. The effect of dantrolene is often described as dramatic, “like turning on the fire hose”, and it is unusual for patients to require more than 1–2 doses providing that MH is recognized early. However a response to dantrolene is not pathognomonic of MH. The prophylactic use of dantrolene for known MH-susceptible cases is no longer recommended, although it should be readily available in theatre. Side effects include muscle weakness, prolongation of muscle relaxants, dizziness, local phlebitis and drowsiness. It has a role to play in the treatment of neuroleptic malignant syndrome and ecstasy intoxication, but its role in heatstroke is uncertain.
5.6. Screening for MH Following the first description of MH many differing tests were proposed, such as CK levels, (Britt et al., 1976), studies on calcium uptake (Allen et al., 1986; Nagarajan et al., 1987) and spin-labeling of red blood cells (Ohnishi et al., 1988; Halsall et al., 1992), all of which proved unreliable for diagnostic purposes. Although CK levels tend to be higher (although not necessarily raised) in MH-susceptible individuals there is too much overlap with negative patients for diagnostic use (Britt et al., 1976). It was not until 1971 that the in-vitro screening of muscle biopsy samples was described using caffeine (Kalow et al., 1970) and halothane (Ellis et al., 1971). These tests have stood the test of time and IVCT is the gold-standard screening method. The European MH group (EMHG), now including many countries outside Europe, e.g., Australia and New Zealand, formally standardized the IVCT in 1983 (European Malignant Hyperthermia Group, 1984). It offers a 99% sensitivity and 93.6% specificity (Ording et al., 1997). Members of the North-American group (MHAUS) follow a similar but not identical protocol (Larach, 1989), with 98% sensitivity and 78% specificity (Allen et al., 1998). The two methods have been compared and are concordant in 87% of cases; divergence occurring when contractures were close to cutoff limits (Islander and Twetman, 1999). There are two further optional IVCT tests; ryanodine (Hopkins et al., 1993) and 4-chloro-m-cresol (4CmC; Baur et al., 2000), both tending to reflect the caffeine
MALIGNANT HYPERTHERMIA AND ASSOCIATED CONDITIONS results. Neither test is specific for MH but in conjunction with the standard tests may aid diagnosis. 4CmC has a high affinity for the RYR1 receptor and is used as a preservative in many drugs including suxamethonium. IVCT contractures caused by suxamethonium have been shown to be due to 4CmC, rather than suxamethonium itself (Galloway and Denborough, 1986). Other volatile agents such as sevoflurane have been shown to produce in-vitro contractures but to a lesser extent than halothane (Snoeck et al., 2000). This concords with the clinical observation that sevoflurane is a less potent but well-recognized trigger of MH. Histological examination of muscle samples is routinely performed in some MH centers, because of reports of specific MH myopathies (Harriman, 1988; Isaacs, 1978). Patient age and fiber type have been shown to have no effect on the IVCT results (Ording et al., 1988). A study on 83 patients (Mezin et al., 1997) could not identify any specific pathology in MHS patients but described an increased incidence of four non-specific abnormalities; fiber hypertrophy, atrophy, internal nuclei and myofibrillar necrosis. Ultrastructural examination was also performed which suggested an increased incidence of atypical triads showing dilatation of the SR cisternae in MHS patients. However, a larger, more recent, study of 440 patients using the same four abnormalities could not distinguish between MHS, MHE or MHN patients. This study concluded that histology was unhelpful in MH diagnosis but was useful in probands to exclude a previously unrecognized myopathy which may have accounted for the anesthetic difficulties (Breunig et al., 2004). Since 2001 (Urwyler et al.), DNA testing also has a role to play in conjunction with, rather than completely replacing, muscle biopsy.
5.6.1. Muscle biopsy (IVCT) This is an open surgical procedure in which several strips of muscle bundles are carefully dissected from the surface of the vastus medialis muscle via a 5 cm incision under either a femoral nerve block or occasionally a “MH-safe” general anesthetic. Each muscle sample weighs around 100 mg, measuring 2–3 cm in length and less than 0.5 cm in width and is kept in carbogenated Krebs solution at room temperature for storage and transport to the laboratory. A muscle sample is placed in a tissue bath perfused with carbogenated Krebs solution at 37 C and attached to an isometric strain gauge to measure muscle tension onto a recording device. The sample is electrically stimulated to ensure viability. After initially stretching the sample to 150% of its original length, it is exposed to increasing concentrations of halo-
113
thane (0.5, 1.0 and 2.0% vaporizer settings equivalent to 0.11, 0.22 and 0.44 mM). This is known as the static halothane test. For the static caffeine test a separate sample is exposed to increasing concentrations of caffeine in a similar manner (0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 32.0 mM). Some centers also perform a dynamic halothane test when the muscle is alternatively stretched and relaxed in the presence of increasing halothane concentrations, after obtaining three control stretch/relaxation curves. The tests are duplicated and are performed according to the EMHG protocol (European Malignant Hyperthermia Group, 1984). An example of the muscle responses to halothane for MH susceptible and normal individuals is shown in Fig. 5.2. A positive result is defined as a sustained muscle contracture of 0. 2 g, or more, on exposure to concentrations of either 2% halothane or 2 mM caffeine, or less. These threshold values are set deliberately low to avoid potentially dangerous false-negative diagnoses, with the consequent incidence of false-positive diagnoses. The laboratory results are designated MHS (susceptible) when both the halothane and caffeine tests are positive, MHE(h) when only the halothane test is positive, MHE (c) when only caffeine is positive and MHN(normal) when both tests are negative. MHE(h) results occur frequently but MHE(c) results are rare. Both MHS and MHE results are classified clinically as MH positive, so the patient is told that they are either MH susceptible or MH negative/normal. MH-susceptible patients are provided with information about MH, warning cards and discs and many centers also have a patient support group, e.g., in the UK this is the British MH Association (BMHA) (www.bmha.co.uk). Muscle biopsy screening is not performed on children less than 10–12 years largely because of the length of specimen required (2–3 cm). Nor is it performed on pregnant patients or those on long-term steroid therapy, as steroids have been shown to attenuate the in-vitro muscle contractures (Cain and Ellis, 1977), with the potential risk of a false-negative diagnosis. In these situations the closest most appropriate relative is tested, e.g., the parents of young children. Once the index case (proband) has been confirmed as MH susceptible then family screening is offered in a formalized manner, based on an autosomal-dominant pattern of inheritance, commencing with first-degree relatives. Family studies are valuable because although a large number of family members need to be warned about the potential risk of MH only a small proportion of the family need to be tested to identify the smaller number of individuals who would be MH susceptible, the remainder of the family simply carrying the general population risk.
114
P. J. HALSALL AND R. L. ROBINSON Static Halothane Test
MHS
Scale = 1 gm 0.5%
1.0% 2.0%
4.0%
= 1 min MHN
0.5%
1.0%
2.0%
Fig. 5.2. Traces of the static halothane test demonstrating the contractures obtained on exposure to increasing concentrations of halothane (0.5, 1.0, 2.0, 4.0%) in susceptible (MHS; upper trace) compared to normal (MHN; lower trace) muscle.
Malignant hyperthermia centers maintain a register of all MH patients and their families and this is a focal point for enquiries for both the patients and medical attendants, especially anesthetists. It is also essential for co-ordinating appropriate family studies in particular with regard to the suitability of muscle biopsy and/ or DNA screening. 5.6.2. DNA diagnosis in MH Guidelines for use of mutation data in DNA diagnosis of MH were proposed by the EMHG in 2001 (Urwyler et al., 2001). These outline certain RYR1 mutations (Table 5.5 and www.emhg.org) which fulfill the criteria used for assessment of the potential pathogenicity of missense changes already described. Crucially, all the mutations included have been shown by analysis in vitro to give a higher amplitude of calcium release
in response to low concentrations of caffeine and halothane compared to wildtype RYR channel controls (Otsu et al., 1994; Treves et al., 1994; Tong et al., 1997; Censier et al., 1998; Lynch et al., 1999). It is vital that a patient is not falsely labeled as MH negative, because of potentially dangerous consequences during anesthesia. Muscle biopsy test results are interpreted in such a way that false-negative diagnoses are avoided at the cost of some false positives. DNA screening for MH has been introduced cautiously as retrospective genetic analysis of MH families screened by the IVCT has detected discordance between IVCT phenotype and RYR1 genotypes (Deufel et al., 1995; Robinson et al., 2003). Discordance could be explained by false þve/ve IVCT results, variable penetrance of the mutation detected or additional genetic mutations being involved in determination of phenotype in a discordant individual (Monnier et al., 2002). This
MALIGNANT HYPERTHERMIA AND ASSOCIATED CONDITIONS
115
Table 5.5 Mutations currently used for DNA diagnosis of malignant hyperthermia susceptibility and their frequency in the UK population Exon
Nucleotide
Amino acid
Phenotype
UK frequency (n¼460 families)
2 6 9 11 12 14 15 17 17 39 39 39 40 44 44 45 45 46 46 100 101 101 102
103 T>C 487 C>T 742 G>A 1021 G>A 1209 C>G 1565 A>C 1654 C>T 1840 C>T 1841 G>T 6487 C>T 6488 G>A 6502 G>A 6617 C>T 7048 G>A 7124 G>C 7300 G>A 7304 G>A 7372 C>T 7373 G>A 14387 A>G 14512 C>G 14582 G>A 14693 T>C
Cys-35-Arg Arg-163-Cys Gly-248-Arg Gly-341-Arg Ile-403-Met Tyr-522-Ser Arg-552-Trp Arg-614-Cys Arg-614-Leu Arg-2163-Cys Arg-2163-His Val-2168-Met Thr-2206-Met Ala-2350-Thr Gly-2375-Ala Gly-2434-Arg Arg-2435-His Arg-2458-Cys Arg-2458-His Tyr-4796-Cys Leu-4838-Val Arg-4861-His Ile-4898-Thr
MHS MHS and/or CCD MHS MHS CCD MHS and/or CCD MHS MHS MHS MHS MHS and/or CCD MHS MHS MHS MHS MHS MHS and/or CCD MHS MHS CCD and nemaline rods MHS CCD MHS / CCD
Not 13 3 17 Not Not 1 6 Not 1 8 6 22 3 Not 90 7 Not 11 Not 1 1 Not
finding raised concern as to how genetic data should be used in MH diagnosis, as on the basis of genetic data alone a patient may be given potentially false negative diagnosis imposing a clinical risk. The EMHG guidelines are structured to avoid this scenario, as in the absence of a familial mutation it is recommended that an individual be referred for an IVC-test to confirm their status. Therefore, it is essential that genetic testing for MH is conducted in conjunction with a recognized IVCT center. As approximately 80% of MH families worldwide are linked to RYR1, with 40% carrying one of the mutations described in the EMHG guidelines; remaining families rely solely on muscle biopsy for their diagnosis. Much work is still needed before all families can be offered DNA screening. For these reasons, MH diagnosis relies on the combination of both DNA and muscle biopsy and therefore MH centers are best placed to co-ordinate family investigations. At the Leeds MH Investigation Unit the first stage in screening is referral for assessment of the clinical reaction. If MH cannot be excluded on clinical grounds the proband (index patient), or the most appropriate relative if the proband cannot be tested, has the clinical
detected
detected detected
detected
detected
detected detected
detected
diagnosis confirmed by muscle biopsy. If this indicates susceptibility to MH a blood sample, obtained with consent at the time of the biopsy, is then screened for all UK prevalent “diagnostic” RYR1 mutations (Table 5.5; www.emhg.org). If a mutation is found, family members can then be offered a preliminary DNA blood test looking only for the same familial mutation identified in the proband. If the individual is mutation-positive he/she can be designated MH susceptible without the need for a muscle biopsy. However, if mutation-negative a confirmatory muscle biopsy will be required before an MH-negative diagnosis can be made for safety reasons as previously described. If no mutations are identified in the proband the family is screened in the usual way by muscle biopsy, but the proband’s DNA sample is stored and screened for new mutations as and when they become recognized for use in diagnosis.
5.7. Anesthesia for MH-susceptible patients Malignant hyperthermia susceptible patients should not be denied essential surgery on the grounds of MH alone. In the majority of situations a “MH-safe” technique should not pose difficulty especially as TIVA is
116
P. J. HALSALL AND R. L. ROBINSON
now widely used and local anesthesia more acceptable to patients. However, in certain situations difficulties can occur, for example when inhalational anesthesia or a rapid sequence induction are the methods of choice for induction of anesthesia. Table 5.6 lists agents that are safe to use. When a vapor-free anesthetic machine is unavailable, the vaporizers and circuits should be removed and both the machine and ventilator blown through with a high flow of oxygen for 20–30 mins. Standard monitoring for the surgical procedure is acceptable and as already stated prophylactic dantrolene is not required. Patients with a family history of MH do not necessarily need to be tested prior to surgery. The chosen approach to their management will depend on the urgency of the surgery and also whether treating a patient for non-elective surgery with a “MH-safe” technique poses any additional risk, so is at the discretion of the anesthetist directly involved. When general anesthesia is required in obstetrics for a normal mother and an MHsusceptible father the mother should not be given MHtriggering agents that cross the placenta to a significant degree until after delivery of the baby, who carries a 50% risk, e.g., all the anesthetic vapors, although suxamethonium can be used. There have been no reports of patients reacting to normal anesthesia following a negative muscle biopsy (Islander and Twetman, 1995, unpublished data)
5.8. Associated conditions 5.8.1. Muscle diseases Malignant hyperthermia-like crises have been reported in patients with a variety of myopathies including Duchenne and Becker dystrophies, myotonia congenita and myotonic dystrophy and periodic paralysis. It seems unlikely that the molecular mechanisms for these disorders are the same as MH. Histological examination of
Table 5.6 Malignant-hyperthermia-safe agents used in anesthesia All induction agents All non-depolarizing muscle relaxants and reversal agents All analgesics All local anesthetic agents with or without adrenaline All antiemetics Nitrous oxide Sedative agents, e.g., benzodiazepines Ephedrine Atropine/glycopyrronium bromide Ketamine
MH muscle rarely shows evidence of muscle disease other than CCD. An early review of patients with neuromuscular disorders (NMD; Brownell 1988) suggested that only CCD was truly associated (see below). However, positive IVCT results have been found in some NMD patients usually consisting of small contractures. The lack of specificity of the IVCT is thought to account for this rather than reflecting true MH (Lehmann-Horn and Iaizzo, 1990; Heytens et al., 1992) In the myotonic conditions the disturbed excitability of the sarcolemma leading to electrical overactivity is thought to interfere with the IVCT. Other diseases may also involve disturbed Ca2þ movements so affecting the IVCT result. It should be emphasized that NMD patients do carry significant, sometimes life-threatening risks with anesthesia, particularly with suxamethonium, for many other reasons and should always be treated with caution. Anesthesia for arthrogryphosis multiplex congenital (AMC) patients is sparsely documented but there have been several reports of pyrexial responses, none of which have been fully investigated. One report described two AMC children who developed possible MH reactions but concluded that these children can develop a hypermetabolic response to anesthesia which is unrelated to MH and is responsive to simple cooling measures (Hopkins et al., 1991). There are several reports of positive IVCT results in unrelated patients presenting with exercise-induced rhabdomyolysis (Hopkins et al., 1991; Wappler et al., 2001; Davis et al., 2004). Following neurological examination these patients should be offered muscle biopsy for both histological examination and IVCT for MH. 5.8.2. Central core disease (CCD) Association of MH with central core disease was first reported by Denborough, Dennett and Anderson in 1973. CCD is a rare congenital myopathy in which type I skeletal muscle fibers exhibit cores that run the length of the myofiber, which lack mitochondria and oxidative enzyme activity. Common clinical symptoms include muscle atrophy, lower limb skeletal weakness, floppy infant syndrome and skeletal deformities, e.g., hip displacement and scoliosis. Patients have variable clinical features. Patients with classic central core disease may suffer severe disability as a result of muscle weakness (Quinlivan et al., 2003). In contrast, patients with “core myopathy” on histological examination may be asymptomatic; in fact it has been proposed that 40% of patients exhibiting cores may be clinically normal (Shuaib et al., 1987). Both autosomal-dominant and -recessive modes of inheritance have been documented and a sporadic, or neomutation rate of 10% has been estimated (Monnier et al., 2001).
MALIGNANT HYPERTHERMIA AND ASSOCIATED CONDITIONS Phenotypic variability with respect to MH status has been observed within CCD families (Curran et al., 1999; Monnier et al., 2001; Shepherd et al., 2004). Explanations for such variability include the independent segregation of mutations predisposing to CCD and MH within the same family, or could reflect the patient’s age at the time of histological examination of muscle biopsy preparations and the mildly progressive nature of CCD documented in some individuals. Molecular analysis suggests that certain mutations in the RYR1 gene produce both MH and CCD, whereas others result in an MH phenotype only, a CCD phenotype only, or in rare cases a multi-minicore disease (MmD) phenotype. Multi-minicore disease, also referred to as minicore or multicore disease, is one of two diseases related to CCD. It and nemaline myopathy (NEM) may be distinguished from CCD on histological examination of muscle specimens and by certain clinical features in some cases. However, all three conditions exhibit some degree of overlap (Monnier et al., 2000; Scacheri et al., 2000). Classic MmD has been described as an earlyonset autosomal-recessive congenital myopathy where axial muscle weakness may lead to development of severe, life-threatening respiratory insufficiency and scoliosis in two-thirds of patients. Histologically, type I and type II muscle fibers are characterized by multiple cores which do not fully extend throughout the length of the fiber, unlike in CCD, and short areas of sarcomere disorganization lacking mitochondria. Three other subgroups include a moderate form characterized by generalized muscle weakness which predominantly affects the pelvic girdle and hands with amyotrophy and hyperlaxity, and two classic forms, one including the additional feature of ophthalmoplegia, the other with antenatal onset in addition to arthrogryposis (Ferreiro et al., 2002a; 2002b; Guis et al. 2004). Typical nemaline myopathy is described as autosomal recessive with onset from birth to infancy, and where patients suffer from the danger of nocturnal hypoxia or hypercarbia but otherwise have no respiratory problems. Severe, intermediate, mild adult and Amish subtypes have also been reported. Histological features include sarcoplasmic rods in type I muscle fibers, which can vary from less than 1% to virtually all fibers (Clarkson 2004). Mutations in RYR1 have been reported in association with both CCD and MmD, the involvement of RYR1 in NEM being less clear. The majority of mutations reported in association with CCD cluster to the C-terminal region of the RYR1 gene which encodes the ion channel pore, with specific mutations predisposing to MH susceptibility and/or CCD. It has been shown that patients with mutations in RYR1 have a recognizable
117
pattern on muscle MRI, suggesting that clinical assessment by MRI may supplement diagnosis of these congenital myopathies and aid in the direction of possible genetic testing (Jungbluth et al., 2004a; 2004b). For the purposes of molecular characterization of CCD patients, with a wide spectrum of RYR1 mutations now reported in individual families, the C-terminal region of the gene remains the primary site for initial investigation and mutation screening (Monnier et al., 2001; Shepherd et al., 2004). RYR1 mutations have also been shown to account for certain variants of CCD. A homozygous RYR1 mutation p.P3527S was detected in three patients in an Algerian family where the myopathy was characterized by the presence of cores and rods, characteristic of NEM (Ferreiro et al., 2002a). Mutation p.V4849I was detected in a family with a recessively inherited congenital myopathy characterized by cores (Jungbluth et al., 2002). RYR1 mutations have also been detected in cases of CCD presenting with fetal akinesia syndrome (Romero et al., 2003). Two families were reported with recessive inheritance and were compound heterozygotes for mutations p.R614C/p.G215E and p.L4650P/ p.K4724Q. A third family was reported with autosomal-dominant inheritance where mutation p.G4899E was detected. Finally, a substitution in intron 101, c.14646þ2.99kbA>G was described in a North-African patient with a recessive form of multi-minicore disease and ophthalmoplegia (Monnier et al., 2003). The mutation was shown to generate a cryptic splice site which resulted in a premature termination of the protein product. Two further mutations, p.Gln4837fsX4838 and c.14869–1G>C (IVS 103–1G>C), which potentially diminish the level of normal RYR1 transcript have also been reported in association with CCD or MmD and muscle weakness (Robinson et al., 2006) rather than MH susceptibility alone. This supports the observation that patients susceptible to MH are asymptomatic, rarely exhibiting abnormal muscle pathology and that reduced transcript levels may be responsible for the abnormal pathology observed.
5.8.3. Periodic paralyses Familial periodic paralyses (PP) are characterized by recurring episodic muscle weakness. They form a rare group of autosomal-dominant ion channelopathies. Hypo- (hypoPP) and hyper-kalemic forms (hyperPP) may be distinguished by serum potassium (Kþ) levels during an attack. HypoPP may also be subdivided into types I and II, which may be distinguished on the basis of genotype (reviewed by Kullmann and Hanna, 2002; Jurkat-Rott and Lehmann-Horn, 2005).
118
P. J. HALSALL AND R. L. ROBINSON
HypoPP generally presents with paralysis triggered by carbohydrate ingestion and is ameliorated by Kþ intake, paralytic attacks typically lasting 12–24 hours. Kþ disturbance can be so severe that cardiac complications arise. During an attack death can also occur due to respiratory insufficiency. The condition is associated with loss-of-function mutations occurring in two different ion channel types, i.e., hypoPP type I with mutations in CACNA1S which encodes the a-subunit of the voltage-dependent calcium channel Cav1.1, also known as the dihydropyridine receptor and hypoPP type II with mutations in SCNA4 which encodes the a-subunit of the voltage-dependent skeletal muscle sodium channel Nav1.4. Mutations in CACNA1S (PR528H, PR1239H) and SCN4A (PR672H, PR672G, PR672S) have been reported to account for mutations in up to 78% of patients (n¼58) presenting with type I/type II hypoPP in the sporadic or familial form (Sternberg et al., 2001; Davies et al., 2001). Potassium channel mutations have also been associated with PP, i.e., in the inwardly rectifying potassium channel Kir2.1, or in the accessory subunit MiRP2. However, the involvement of MiRP2 and mutation p. R83H is likely to be spurious following its detection in three out of 321 unrelated healthy controls and five unaffected relatives from families with PP (Jurkatt-Rott and Lehmann-Horn, 2004). HyperPP generally presents in childhood with attacks of limb muscle weakness lasting minutes to hours and which are often precipitated by rest after exercise. With age, the frequency and severity of attacks diminish. In contrast to hypoPP, hyperPP may be triggered by Kþ, and administration of glucose is a remedy. Mutations in SCN4A account for the majority of cases. Although there are reports of the association of hypoPP and MH at the clinical level, and the two disorders share a common candidate susceptibility locus, CACNA1S, predisposition to MH has never been correlated with a specific hypoPP mutation (Rajabally and El Lahawi, 2002; Marchant et al., 2004). It is therefore currently not possible to verify the association of hypoPP and MH at the molecular level. 5.8.4. King–Denborough syndrome (KDS) Described in 1973 (King and Denborough, 1973) its presence in four boys out of 19 probands lead to the suggestion that KDS affected 25% of probands. Each had experienced an undescribed anesthetic problem attributed to MH. Three of the four died, presumably due to the anesthetic reaction, although this is not clear. Although only one case was examined critically, the four boys were said to have a similar phenotypic appearance; delayed milestones, short stature, slowly progressive
myopathy, thoracic kyphosis, lumber lordosis, undescended testes, pectus carinatum and an unusual facial appearance characterized by a small chin, low set ears and antimongoloid obliquity of the palpebral fissure. Poorly described muscle pathology reported in the only surviving child was suggestive of muscular dystrophy, a disease which poses significant problems with anesthesia. No formal testing for MH was carried out within the families. Unfortunately there are no laboratory features available to distinguish these children with certainty. Consequently it is difficult to know if KDS is a true entity, which in turn poses difficulties in interpreting other publications claiming an association between KDS and MH based on abnormal IVCT findings (Heiman-Patterson et al., 1986; Isaacs and Badenhorst, 1992).
5.8.5. Neuroleptic malignant syndrome (NMS) First described in France in 1960, over 1000 cases were recorded in the 1990s despite no accepted diagnostic criteria. This may explain some contradictory findings, such as an incidence ranging from 0.07 to 2.2% and the association with other disorders, such as MH. NMS develops over 24–72 hours of administration of neuroleptic drugs and can develop 10–20 days after discontinuation. The mortality rate has dropped from reports of 76% in 1970 to 11% in 1984, renal failure being a high mortality indicator. Three major symptoms indicate a high probability of NMS; hyperthermia, muscle rigidity and raised CK levels reflecting rhabdomyolysis. Treatment is with a dopamine agonist, e.g., bromocriptine and/or dantrolene and the avoidance of dehydration. There are two major theories to explain NMS; a neuroleptic-induced alteration of central neuroregulatory mechanisms or an abnormal reaction of predisposed skeletal muscle. Neuroleptic drugs block hypothalamic dopamine receptor sites which leads to abnormal central thermoregulation. The latter theory is based on the close similarities with the clinical signs of MH, the effectiveness of dantrolene and abnormal IVCT results from some patients, although a direct toxic effect is possible. The reported IVCT findings may be explained because patients with NMS form a heterogeneous group because of the lack of diagnostic criteria, variable clinical presentation and response to treatment in addition to differing laboratory procedures for IVCT. Adnet and colleagues (2000) reported 33 patients and found a <10% association with MH and suggested that patients with NMS should be considered at risk from MH. However, they then recommended that suxamethonium can be given safely for electroconvulsive therapy (ECT), contradicting the usual
MALIGNANT HYPERTHERMIA AND ASSOCIATED CONDITIONS management of MH. In the UK, at least, NMS is no longer considered to be an indication for MH screening. 5.8.6. Ecstasy 3,4-Methylenedioxymethamphetamine (MDMA), commonly known as ecstasy, can cause effects such as hyperthermia, metabolic acidosis and muscle rigidity in certain individuals. Because of the close similarities with features of a MH crisis an association was postulated. A study in pigs given MDMA showed that all pigs developed MH-like signs but these were more severe in MH-susceptible compared to MH-normal pigs, the signs only being partly relieved by dantrolene. The study recommended that patients developing toxic effects from MDMA should be screened for MH (Fiege et al., 2003). However, a later study demonstrated that MDMA enhanced the sensitivity of human skeletal muscle to caffeine but did not cause contractures on its own. This effect was greater in normal muscle than in MH-susceptible muscle. The same study demonstrated that the neuromuscular junction is the target of MDMA and that activation of the nicotinic acetylcholine receptor contributes to the muscle-related signs (Klinger et al., 2005). 5.8.7. Sudden infant death syndrome (SIDS) Sudden infant death syndrome was first accepted as a registered cause of death in England and Wales in 1971. Prior to this deaths were usually recorded as respiratory tract diseases. It is a diagnosis made by exclusion of other rigorously sought causes, including extensive microbiological investigations. This, together with increased awareness of the condition, has reduced the incidence of SIDS. All the reported studies in MH and SIDS were done prior to this more rigorous approach to diagnosis. The first report of a possible association with MH was by Denborough et al. in 1982, based on the finding that three of nine MH families had lost a child due to SIDS. As there was no control group and families with a history of anesthetic problems were encouraged to come forward, the study was biased. Another similar study supported this theory but no attempt was made to verify any of the reported anesthetic incidents and the SIDS diagnosis was accepted uncritically (Peterson and Davis, 1986). A later prospective study recruited 195 MH families and 106 SIDS parents. There was no greater incidence of SIDS in the MH families than the general population. Of the 278 anesthetics given to the SIDS parents there were no anesthetic deaths and only five incidents reported, none of which could be attributed
119
to MH. Fourteen of these SIDS parents agreed to undergo IVCT, all of whom were MHN according to the EMHG protocol (Ellis et al., 1988). It is now accepted that SIDS families carry a no greater risk of MH than the general population risk.
5.8.8. Heatstroke Heatstroke is a medical emergency and is characterized by increased body temperature, altered mental state and in classic heatstroke, hot and dry skin, with a rectal tem perature of 40.6 C, although as cooling has often been initiated prior to the temperature reading this figure can be misleading. It can lead to multiorgan failure and death. This may be related to endotoxic-induced cytochrome release from the gut (Muldoon et al., 2004). The mortality rate has been variously reported as 10–50% over the past 50 years. There are several related illnesses; heat syncope, heat cramp, heat exhaustion as well as heatstroke, the latter being divided into exertional, occurring in fit young men exercizing in hot humid conditions and non-exertional (classic), occurring in extremes of heat usually in the elderly. An important predisposing factor is the environmental temperature/humidity and its effect on heat loss due to sweating, although cases have been reported in more temperate climates. It occurs particularly in soldiers who exercise with heavy loads, fun/club runners and some occupational groups, e.g., firemen. Other predisposing factors include concurrent illness and lack of sleep, water or food. It rarely occurs in women, although it is unclear whether this is a sex-related or muscle-mass phenomenon. An association with MH was proposed because of the similarity in clinical signs and there have been several reports of patients with exertional heat stroke having positive IVCT results (Hackl et al., 1991; Kochling et al., 1998; Grogan and Hopkins 2002). 31P magnetic spectroscopy studies in these patients have demonstrated several metabolic abnormalities including effects on Ca2þ and the SR (Bendahan et al., 2001). Exercise studies on MH patients have been inconclusive, although there is some evidence of reduced heat dissipation (Campbell et al., 1983; Green et al., 1987). Until the relationship between the two conditions is more clearly resolved, heatstroke patients will continue to be offered MH screening. Conversely, MH patients are not generally advised to limit exercise any differently to normal individuals, but there has been one report of a heatstroke death in a young boy who had had a previous possible MH anesthetic reaction (Tobin et al., 2001).
120
P. J. HALSALL AND R. L. ROBINSON
References Adnet P, Lestavel P, Krisovic-Horber R (2000). Neurolept malignant syndrome. Br J Anaesth 85: 129–135. Allen PD, Ryan JF, Jones DE, et al. (1986). Sarcoplasmic reticulum calcium uptake in cryostat sections of skeletal muscle for malignant hyperthermia patients and controls. Muscle Nerve 9: 474–475. Allen GC, Larach MG, Kunselman AR (1998). The sensitivity and specificity of the caffeine-halothane contracture test: a report from the North American MH Registry. The North American MH Registry of MHAUS. Anesthesiology 88: 578–588. Avila G, Dirksen RT (2001). Functional effects of central core disease mutations in the cytoplasmic region of the skeletal muscle ryanodine receptor. J Gen Physiol 118: 277–290. Avila G, O’Brien JJ, Dirksen RT (2001). Excitation-contraction uncoupling by a human central core disease mutation in the ryanodine receptor. Proc Natl Acad Sci U S A 98: 4215–4220. Baur C, Bellon L, Felleiter P, et al. (2000). A multicentre study of chlorocresol for the diagnosis of malignany hyperthermia susceptibility. Anesth Analg 90: 200–205. Bendahan D, Kozak-Ribbens G, Confort-Gouny S, et al. (2001). A non-invasive investigation of muscle energetics supports similarities between exertional heat stroke and malignant hyperthermia. Anesth Analg 93: 683–689. Bendixen D, Skovgaard LT, Ording H (1997). Analysis of anesthesia in patients suspected to be susceptible to malignant hyperthermia before diagnostic in-vitro contracture test. Acta Anaesthesiol Scand 41: 480–484. Breunig F, Wappler F, Hagel C, et al. (2004). Histomorphological examination of skeletal muscle preparations does not differentiate between malignant hyperthermia susceptible and normal patients. Anesthesiology 100: 789–794. Brinkmeier H, Kramer J, Kramer R, et al. (1999). Malignant hyperthermia causing Gly2435Arg mutation of the ryanodine receptor facilitates ryanodine-induced calcium release in myotubes. Br J Anaesth 83: 855–861. Britt BA, Kalow W (1970). Malignant hyperthermia: a statistical review. Can Anaesth Soc J 17: 293–315. Britt BA, Endrenyi L, Peters PL, et al. (1976). Screening of malignant hyperthermia susceptible families by creatine phosphokinase measurement and other clinical investigations. Can Anaesth Soc J 23: 263–284. Brownell AKW (1988). Malignant hyperthermia: relationship to other diseases. Br J Anaesth 60: 303–308. Cain PA, Ellis FR (1977). Anaesthesia for patients susceptible to malignant hyperpyrexia. A study of pancuronium and methypredisolone. Br J Anaesth 49: 941–944. Campbell IT, Ellis FR, Evans RT, et al. (1983). Studies of body temperature, blood lactate, cortisol and free fatty acid levels during exercise in human subjects susceptible to malignant hyperpyrexia. Acta Anaesth Scand 27: 349–355. Censier K, Urwyler A, Zorzato F, et al. (1998). Intracellular calcium homeostasis in human primary muscle cells from malignant hyperthermia-susceptible and normal individuals. Effect of overexpression of recombinant wild-type
and Arg163Cys mutated ryanodine receptors. J Clin Invest 101: 1233–1242. Chelu MG, Goonasekera SA, Durham WJ, et al. (2006). Heatand anesthesia-induced malignant hyperthermia in an RyR1 knock-in mouse. FASEB 20: 329–330. Clarkson E, Costa CF, Machesky LM (2004). Congenital myopathies: diseases of the actin cytoskeleton. J Pathol 204: 407–417. Curran JL, Hall WJ, Halsall PJ, et al. (1999). Segregation of malignant hyperthermia, central core disease and chromosome 19 markers. Br J Anaesth 83: 217–222. Davies NP, Eunson LH, Samuel M, et al. (2001). Sodium channel gene mutations in hypokalemic periodic paralysis: an uncommon cause in the UK. Neurology 57 (7): 1323–1325. Davis M, Brown R, Dickson A, et al. (2004). Malignant hyperthermia associated with exercise-induced rhabdomyolysis or congenital abnormalities and a novel RYR1 mutation in New Zealand and Australian pedigrees. Br J Anaesth 88: 508–515. Denborough MA, Lovell RRH (1960). Anaesthetic deaths in a family. Lancet ii: 45. Denborough MA, Dennett X, Anderson R (1973). Central core disease and malignant hyperpyrexia. BMJ 1: 272–273. Denborough MA, Galloway GJ, Hopkinson KC (1982). Malignant hyperpyrexia and sudden infant death. Lancet ii: 1068. Deufel T, Sudbrak R, Feist Y, et al. (1995). Discordance in a malignant hypethermia pedigree between in vitro contracture test phenotypes and haplotypes for the MHS1 region on chromosome 19q12–13.2 comprising the C1840T transition in the RYR1 gene. Am J Hum Genet 56: 1334–1342. Dirksen RT, Avila G (2004). Distinct effects on Ca2þ handling caused by malignant hyperthermia and central core disease mutations in RYR1. Biophys J 87: 3193–3204. Du GG, Sandhu B, Khanna VK, et al. (2002). Toplogy of the Ca2þ release channel of skeletal muscle sarcoplasmic reticulum (RYR1). Proc Natl Acad Sci U S A 99: 16725–16730. Ducreux S, Zorzato F, Mueller C, et al. (2004). Effect of ryanodine receptor mutations on IL-6 release and intracellular calcium homeostasis in human myotubes from malignant hyperthermia susceptible individuals and patients affected by central core disease. J Biol Chem 279: 43838–43846. Duke AM, Hopkins PM, Steele DS (2002). Effects of Mg2þ and SR luminal Ca2þ on caffeine-induced Ca2þ release in skeletal muscle from humans susceptible to malignant hyperthermia. J Physiol 544: 85–95. Duke AM, Hopkins PM, Halsall PJ, et al. (2004). Mg2þ-dependence of halothane-induced Ca2þ release from the sarcoplasmic reticulum in skeletal muscle from humans susceptible to malignant hyperthermia. Anesthesiology 101: 1339–1346. Ellis FR, Harriman DGF, Keaney NP, et al. (1971). Halothaneinduced muscle contracture as a cause of hyperpyrexia. Br J Anaesth 43: 721–722. Ellis FR, Halsall PJ, Harriman DG (1986). The work of the Leeds Malignant Hyperpyrexia Unit, 1971–84. Anaesthesia 41: 809–815. Ellis FR, Halsall PJ, Harriman DGF (1988). Malignant hyperpyrexia and sudden infant death syndrome. Br J Anaesth 60: 28–30.
MALIGNANT HYPERTHERMIA AND ASSOCIATED CONDITIONS Ellis FR, Halsall PJ, Christian AS (1990). Clinical presentation of suspected malignant hyperthermia during anesthesia in 402 probands. Anaesthesia 45: 838–841. European Malignant Hyperthermia Group (1984). A protocol for the investigation of malignant hyperthermia (MH) susceptibility. Br J Anaesth 56: 1267–1269. Falconer DS. (1993). Values and means. In: DS Falconer (Ed.), Introduction to Quantitative Genetics, 3rd edn. Longman Scientific and Technical, Harlow, pp. 111–124. Ferreiro A, Monnier N, Romero NB, et al. (2002a). A recessive form of central core disease, transiently presenting as multi-minicore disease, is associated with a homozygous mutation in the ryanodine receptor type 1 gene. Ann Neurol 51: 750–759. Ferreiro A, Quijano-Roy S, Pichereau C, et al. (2002b). Mutations in the Selenoprotein N gene, which is implcated in rigid spine and muscular dystrophy, cause the classical phenotype of multiminicore disease: reassessing the nosology of earlyonset myopathies. Am J Hum Genet 71: 739–749. Fiege M, Wappler F, Weisshorn R, et al. (2002). Results of contracture tests with halothane, caffeine and ryanodine depend on different malignant hyperthermia associated ryanodine receptor gene mutations. Anesthesiology 97: 345–350. Fiege M, Wappler F, Weisshorn R, et al. (2003). Induction of malignant hyperthermia in susceptible swine by 3,4methylenedioxymethamphetamine (“Ecstasy”). Anaesthesiology 99: 1132–1136. Fruen BR, Mickelson JR, Louis CF (1997). Dantrolene inhibition of sarcoplasmic reticulum Ca2þ release by direct and specific action at skeletal muscle ryanodine receptors. J Biol Chem 272: 26965–26971. Fujii J, Otsu K, Zorzato F, De Leon S, et al. (1991). Identification of a mutation in porcine ryanodine receptor associated with malignant hyperthermia. Science 253: 448–451. Gallant EM, Godt RE, Gronert GA (1979). Role of plasma membrane defect of skeletal muscle in malignant hyperthermia. Muscle Nerve 2: 491–494. Galloway GJ, Denborough MA (1986). Suxamethonium chloride and malignant hyperthermia. Br J Anaesth 58: 447–450. Gillard EF, Otsu H, Fujii J, et al. (1991). A substitution of cysteine for argentine 614 in the ryanodine receptor is potentially causative of human malignant hyperthermia. Genomics 11: 751–755. Girard T, Urwyler A, Censier K, et al. (2001). Genotype– henotype comparison of the Swiss malignant hyperthermia population. Hum Mutat 18: 357–358. Green JH, Ellis FR, Halsall PJ, et al. (1987). Thermoregulation, plasma catecholamines and metabolic levels during submaximal work in individuals susceptible to malignant hyperthermia. Acta Anaesthesiol Scand 31: 122–126. Grogan H, Hopkins PM (2002). Heat stroke: implications for critical care and anaesthesia. Br J Anaesth 88: 700–707. Guis S, Figarella-Branger D, Monnier N, et al. (2004). Multiminicore disease in a family susceptible to malignant hyperthermia: histology, in vitro contracture tests, and genetic characterisation. Arch Neurol 61: 106–113.
121
Hackl W, Winkler M, Mauritz W, et al. (1991). Muscle biopsy for diagnosis of malignant hyperthermia susceptibility in 2 patients with severe exercised-induced myolysis. Br J Anaesth 66: 138–140. Hall LW, Woolf N, Bradley JW, et al. (1966). Unusual reaction to suxamethonium chloride. BMJ 2: 1305. Halsall PJ, Ellis FR (1983). The control of muscle contracture by the action of dantrolene on the sarcolemma. Acta Anaesthesiol Scand 27: 229–232. Halsall PJ, Ellis FR (1992). Does post-operative pyrexia indicate malignant hyperthermia susceptibility. Br J Anaesth 68: 209–210. Halsall PJ, Cain PA, Ellis FR (1979). Retrospective analysis of anaesthethics received by patients before malignant hyperthermia was recognised. Br J Anaesth 51: 949–954. Halsall PJ, Ellis FR, Knowles PF (1992). Evaluation of spin resonance spectroscopy of red blood cell membranes to detect malignant hyperthermia susceptibility. Br J Anaesth 69: 471–473. Halsall J, Robinson R (2004). Genetic testing for malignant hyperthermia. Curr Anaesth Crit Care 15: 11–21. Harbitz I, Chowdhary B, Thomsen PD, et al. (1990). Assignment of the porcine calcium release channel gene, a candidate for the malignant hyperthermia locus, to the 6p11–q21 segment of chromosome 6. Genomics 8: 243–248. Harrison GG (1975). Control of the malignant hyperpyrexia syndrome in MHS swine by dantrolene sodium. Br J Anaesth 47: 62–65. Harriman DGF (1988). Malignant hyperthermia myopathy — a critical review. Br J Anaesth 60: 309–316. Heiman-Patterson TD, Rosenberg HR, Binning CP, et al. (1986). King–Denborough syndrome: contracture testing and literature review. Pediatr Neurol 2 (3): 175–177. Heytens L, Martin JJ, Van de Kelft E, et al. (1992). In-vitro contracture tests in patients with various muscle diseases. Br J Anaesth 68: 72–75. Hopkins PM, Ellis FR, Halsall PJ (1991). Hypermetabolism in arthrogryposis multiplex congenital. Anaesthesia 46: 374–375. Hopkins PM, Ellis FE, Halsall PJ (1993). Comparison of invitro contracture testing with ryanodine, halothane and caffeine in malignant hyperthermia and other neuromuscular disorders. Br J Anaesth 70: 397–401. Iaizzo PA, Klein W, Lehmann-Horn F (1988). Fura-2 detected myoplasmic calcium and its correlation with contracture force in skeletal muscle from normal and malignant hyperthermia susceptible pigs. Pflugers Arch 411: 648–653. Iles DE, Lehmann-Horn F, Scherer SW, et al. (1994). Localization of the gene encoding the alpha 2/delta-subunits of the L-type voltage-dependent calcium channel to chromosome 7q and analysis of the segregation of flanking markers in malignant hyperthermia susceptible families. Hum Mol Genet 3: 969–975. Isaacs H (1978). Myopathy and malignant hyperthermia. In: JA Aldrete, BA Britt (Eds.), Proceedings of the Second International Symposium on Malignant Hyperthermia. Grune and Stratton, New York, pp. 89–101.
122
P. J. HALSALL AND R. L. ROBINSON
Isaacs H, Badenhorst ME (1992). Dominantly inherited malignant hyperthermia (MH) in the King–Denborough syndrome. Muscle Nerve 15: 740–742. Islander G, Twetman ER (1995). Evaluation of anaesthesia in malignant hyperthermia negative patients. Acta Anaesthesiol Scand 39: 819–821. Islander G, Twetman ER (1999). Anaesth Analg 88: 1155–1160. Jungbluth H, Muller CR, Halliger-Keller B, et al. (2002). Autosomal recessive inheritance of RYR1 mutations in congenital myopathy with cores. Neurology 59: 284–287. Jungbluth H, Sewry C, Counsell S, et al. (2004a). Magnetic resonance of muscle in nemaline myopathy. Neuromuscul Disord 14: 779–784. Jungbluth H, Davis M, Mueller C, et al. (2004b). Magnetic resonance imaging of muscle in congenital myopathies associated with RYR1 mutations. Neuromuscul Disord 14: 785–790. Jurkat-Rott K, McCarthy T, Lehmann-Horn F (2000). Genetics and pathogenesis of malignant hyperthermia. Muscle Nerve 23: 4–17. Jurkat-Rott K, Lehmann-Horn F (2004). Periodic paralysis mutation MiRP2-R83H in controls. Neurology 62: 1012–1015. Jurkat-Rott K, Lehmann-Horn F (2005). Muscle channelopathies and critical points in functional and genetic studies. J Clin Invest 115: 2000–2009. Kalow W, Britt BA, Terreau ME, et al. (1970). Metabolic error of muscle metabolism after recovery from malignant hyperthermia. Lancet 2: 895–898. King JO, Denborough MA (1973). Anaesthetic induced malignant hyperpyrexia in children. J Pediatr 83: 37–40. Klinger W, Heffron JJA, Jurkat-Rott K, et al. (2005). 3,4-methylenedioxymethamphetamine (Ecstasy) activates skeletal muscle nicotinic acetylcholine receptors. J Pharmacol Exp Ther 314: 1267–1273. Kochling A, Wappler F, Winkler G, et al. (1998). Rhabdomyolysis following severe physical exercise in a patient with predisposition to malignant hyperthermia. Anaesth Intensive Care 26: 315–318. Krause T, Gerbershagen MU, Fiege M, et al. (2004). Dantrolene — a review of its pharmacology, therapeutic use and new developments. Anaesthesia 59: 364–373. Kullmann DM, Hanna MG (2002). Neurological disorders caused by inherited ion-channel mutations. Lancet Neurol 1: 157–166. Larach MG (1989). Standardisation of the caffeine–halothane muscle contracture test. North American MH Group. Anesth Analg 69: 511–515. Larach MG, Localio AR, Allen GC, et al. (1994). A clinical grading scale to predict malignant hyperthermia susceptibility. Anesthesiology 80: 771–779. Leary NP, Ellis FR (1990). Masseteric spasm as a normal response to suxamethonium. Br J Anaesth 64: 488–492. Lehmann-Horn F, Iaizzo PA (1990). Are myotonias and periodic paralyses associated with susceptibility to malignant hyperthermia. Br J Anaesth 65: 692–697. Levitt RC, Olckers A, Meyers S, et al. (1992). Evidence for the localization of a malignant hyperthermia susceptibility
locus (MHS2) to human chromosome 17q. Genomics 14: 562–566. Lopez JR, Alamo L, Caputo C, et al. (1985). Intracellular ionised calcium concentration in muscles from humans with malignant hyperthermia. Muscle Nerve 8: 355–358. Louis CF, Roghair T, Mickelson JR (1994). Volatile anaesthetics inhibit dihydropyridine binding to malignant hyperthermia susceptible and normal pig skeletal muscle membrane. Anesthesiology 80: 618–624. Lyfenko AD, Goonasekera SA, Dirksen RT (2004). Dynamic alterations in myoplasmic Ca2þ in malignant hyperthermia and central core disease. Biochem Biophys Res Commun 322: 1256–1266. Lynch PJ, Krivosic-Horber R, Reyford H, et al. (1997). Identification of heterozygous and homozygous individuals with the novel RYR1 mutation Cys35Arg in a large kindred. Anesthesiology 86: 620–626. Lynch PJ, Tong J, Lehane M, et al. (1999). A mutation in the transmembrane/luminal domain of the ryanodine receptor is associated with abnormal calcium release channel function and severe central core disease. Proc Natl Acad Sci U S A 96: 4164–4169. MacKenzie AE, Korneluk RG, Zorzato F, et al. (1990). The human ryanodine receptor gene: its mapping to 19q13.1, placement in a chromosome 19 linkage group, and exclusion as the gene causing myotonic dystrophy. Am J Hum Genet 46: 1082–1089. MacLennan DH, Duff C, Zorzato F, et al. (1990). Ryanodine receptor gene is a candidate for predisposition to malignant hyperthermia. Nature 343: 559–561. Manning B, Quane K, Ording H, et al. (1998). Identification of novel mutations in the ryanodine receptor gene (RYR1) in malignant hyperthermia: genotype–phenotype Correlation. Am J Hum Genet 62: 599–609. Marchant C, Ellis F, Halsall J, et al. (2004). Mutation analysis of two patients with hypokalemic periodic paralysis and suspected malignant hyperthermia. Muscle Nerve 30: 114–117. McCarthy TV, Healy JM, Heffron JJ, et al. (1990). Localization of the malignant hyperthermia susceptibility locus to human chromosome 19q12–13.2. Nature 342: 562–564. Mezin P, Payen J-F, Bosson J-L, et al. (1997). Histological support for the difference between malignant hyperthermia susceptible (MHS), equivocal (MHE) and negative (MHN) muscle biopsies. Br J Anaesth 79: 327–331. Mickelson JR, Louis CF (1996). Malignant hyperthermia: excitation-contraction coupling, Ca2þ release channel, and cell Ca2þ regulation defects. Physiol Rev 76: 537–592. Monnier N, Procaccio V, Stieglitz P, et al. (1997). Malignanthyperthermia susceptibility is associated with a mutation of the alpha1-subunit of the human dihydropyridine-sensitive L-type voltage-dependent calcium-channel receptor in skeletal muscle. Am J Hum Genet 60: 1316–1325. Monnier N, Romero N, Lerale J, et al. (2000). An autosomal dominant congenital myopathy with cores and rods is associated with a neomutation in the RYR1 gene encoding the skeletal\muscle ryanodine receptor. Hum Mol Genet 9: 2599–2608.
MALIGNANT HYPERTHERMIA AND ASSOCIATED CONDITIONS Monnier N, Romero NB, Lerale J, et al. (2001). Familial and sporadic forms of central core disease are associated with mutations in the C-terminal domain of the skeletal muscle ryanodine receptor. Hum Mol Genet 22: 2581–2592. Monnier N, Krivosic-Horber R, Payen JF, et al. (2002). Presence of two different genetic traits in malignant hyperthermia families: implication for genetic analysis, diagnosis, and incidence of malignant hyperthermia susceptibility. Anesthesiology 97: 1067–1074. Monnier N, Ferreiro A, Marty I, et al. (2003). A homozygous splicing mutation causing a depletion of skeletal muscle RYR1 is associated with multi-minicore disease congenital myopathy with opthalmoplegia. Hum Mol Genet 12: 1171–1178. Muldoon SM, Deuster P, Brandom B, et al. (2004). Is there a link between malignant hyperthermia and exertional heat illness? Exerc Sport Sci Rev 32: 174–179. Nagarajan K, Fishbein WN, Muldoon SM, et al. (1987). Calcium uptake in frozen muscle biopsy sections compared with other predictors of malignant hyperthermia susceptibility. Anesthesiology 66: 680–685. Ohnishi ST, Katagi H, Ohnishi T, et al. (1988). Detection of malignant hyperthermia susceptibility using a spinlabel technique in red blood cells. Br J Anaesth 61: 565–568. Ohta T, Endo M, Nakano T, et al. (1989). Ca2þ-inducedCa2þ release in malignant hyperthermia-susceptible pig skeletal muscle. Am J Physiol 256: C358–367. Ording H, for the European MH Group (1997). In-vitro contracture test for diagnosis of malignant hyperthermia following the protocol of the EMHG: results of testing patients surviving fulminant MH and low-risk subjects. Acta Anaesthesiol Scand 41: 955–966. Ording H, Heinsen U, Skovgaard LT (1988). Age, fibre type composition and in-vitro contracture responses in human malignant hyperthermia. Acta Anaesthesiol Scand 32: 121–124. Otsu K, Nishida K, Kimura Y, et al. (1994). The point mutation Arg615–>Cys in the Ca2þ release channel of skeletal sarcoplasmic reticulum is responsible for hypersensitivity to caffeine and halothane in malignant hyperthermia. J Biol Chem 269: 9413–9415. Parness J, Palnitkar SS (1996). Identification of dantrolene binding site in porcine skeletal muscle sarcoplasmic reticulum. J Biol Chem 1270: 18465–18472. Peterson DR, Davis N (1986). Sudden infant death syndrome and malignant hyperthermia diathesis. Aust Paediatr J 22 (Suppl 1): 33–35. Phillips MS, Fujii J, Khanna VK, et al. (1996). The structural organisation of the ryanodine receptor (RYR1) gene. Genomics 34: 24–41. Quane K, Keating K, Healy S, et al. (1994). Mutation screening of the RYR1 gene in malignant hyperthermia: detection of a novel Tyr to Ser mutation in a pedigree with associated central cores. Genomics 23: 236–239.
123
Quinlivan RM, Mueller CR, Davis M, et al. (2003). Central core disease: clinical, pathological, and genetic features. Arch Dis Child 88: 1051–1055. Rajabally YA, El Lahawi M (2002). Hypokalemic periodic paralysis associated with malignant hyperthermia. Muscle Nerve 25: 453–455. Richter M, Schleithoff L, Deufel T, et al. (1997). Functional characterisation of distinct ryanodine receptor mutation in human malignant hyperthermia susceptible muscle. J Biol Chem 272: 5256–5260. Rios E, Brum G (1987). Involvement of the dihydropyridine receptors in excitation-contraction coupling in skeletal muscle. Nature 325: 717–720. Robinson RL, Monnier N, Wolz W, et al. (1997). A genomewide search for susceptibility loci in two European malignant hyperthermia pedigrees. Hum Mol Genet 6: 953–961. Robinson RL, Curran JL, Hall WJ, et al. (1998). Genetic heterogeneity and HOMOG analysis in British malignant hyperthermia families. J Med Genet 35: 196–201. Robinson RL, Brooks C, Brown SL, et al. (2002). RYR1 mutations causing central core disease are associated with more severe malignant hyperthermia in vitro contracture test phenotypes. Hum Mutat 20: 88–97. Robinson RL, Anetseder MJ, Brancadoro V, et al. (2003). Recent advance in the diagnosis of malignant hyperthermia susceptibility: how confident can we be of genetic testing? Eur J Hum Genet 11: 342–348. Robinson RL, Carpenter D, Shaw M-A, et al. (2006). Mutations in RYR1 in malignant hyperthermia and central core disease. Hum Mutat 27: 977–989. Romero NB, Monnier N, Viollet L, et al. (2003). Dominant and recessive central core disease associated with RYR1 mutations and fetal akinesia. Brain 126: 2341–2349. Sambuughin N, Nelson T, Jankovic J, et al. (2001). Identification and functional characterisation of a novel ryanodine receptor mutation causing malignant hypethermia in North American and South American families. Neuromuscul Disord 11: 530–537. Scacheri P, Hoffman E, Fratkin J, et al. (2000). A novel ryanodine receptor gene mutation causing both cores and rods in congenital myopathy. Neurology 55: 1689–1696. Schwemmle S, Wolff K, Palmucci LM, et al. (1993). Multipoint mapping of the central core disease locus. Genomics 17: 205–207. Shepherd S, Ellis F, Halsall J, et al. (2004). RYR1 mutations in UK central core disease patients: more than just the Cterminal transmembrane region of the RYR1 gene. J Med Genet 41: e33. Shuaib A, Paasuke RT, Brownell AKW (1987). Central core disease: clinical features in 13 patients. Medicine 66: 389–396. Snoeck MM, Gielen MJ, Tangerman A, et al. (2000). Contracture in skeletal muscle of malignant hyperthermia susceptible patients after in-vitro exposure to sevoflurane. Acta Anaesthesiol Scand 44: 334–337. Sternberg D, Maisonobe T, Jurkat-Rott K, et al. (2001). Hypokalemic periodic paralysis type 2 caused by
124
P. J. HALSALL AND R. L. ROBINSON
mutations at codon 672 in the muscle sodium channel gene SCN4A. Brain 124: 1091–1099. Struk A, Lehmann-Horn F, Melzer W (1998). Voltagedependent calcium release in human malignant hyperthermia muscle fibers. Biophys J 75: 2402–2410. Sudbrak R, Procaccio V, Klausnitzer M, et al. (1995). Mapping of a further malignant hyperthermia susceptibility locus to chromosome 3q13.1. Am J Hum Genet 3: 684–691. Synder HRJr, Davis CS, Bickerton RK, et al. (1967). 1-[(5arylfurfurylidene) amino]-hydantoins. A new class of muscle relaxants. J Med Chem 10: 807–810. Tilgen N, Zorzato F, Halliger-Keller B, et al. (2001). Identification of four novel mutations in the C-terminal membrane spanning domain of the ryanodine receptor 1: association with central core disease and alteration of calcium homeostasis. Hum Mol Genet 10: 2879–2887. Tobin JR, Jason DR, Challa VR, et al. (2001). Malignant hyperthermia and apparent heat stroke. JAMA 286: 168–169. Tong J, Oyamada H, Demaurex N, et al. (1997). Caffeine and halothane sensitivity of intracellular Ca2þ release is altered by 15 calcium release channel (ryanodine receptor) mutations associated with malignant hyperthermia and/or central core disease. J Biol Chem 272: 26332–26339. Tong J, McCarthy TV, MacLennan DH (1999). Measurement of resting cytosolic Ca2þ concentrations and Ca2þ store size in HEK-293 cells transfected with malignant hyper-
thermia or central core disease mutant Ca2þ release channels. J Biol Chem 274: 693–702. Treves S, Larini F, Menegazzi P, et al. (1994). Alteration of intracellular Ca2þ transients in COS-7 cells transfected with the cDNA encoding skeletal-muscle ryanodine receptor carrying a mutation associated with malignant hyperthermia. Biochem J 301: 661–665. Urwyler A, Deufel T, McCarthy T, et al. (2001). Guidelines for the molecular detection of susceptibility to malignant hyperthermia. Br J Anaesth 86: 283–287. Wang-Hin Y, Mingi C-L, Seng-Jin O, et al. (2004). A survey for prevention and treatment of malignant hyperthermia in Taiwan. Acta Anaesthesiol Taiwanb 42: 147–151. Wappler F, Fiege M, Steinforth M, et al. (2001). Evidence for susceptibility to malignant hyperthermia in patients with exercise-induced rhabdomyolysis. Anesthesiology 94: 95–100. Wehner M, Rueffert H, Koenig F, et al. (2002). Increased sensitivity to 4-chloro-m-cresol and caffeine in primary myotubes from malignant hyperthermia susceptible individuals carrying the ryanodine receptor 1 Thr2206Met (C6617T) mutation. Clin Genet 62: 135–146. Yang T, Ta TA, Pessah IN, et al. (2003). Functional defects in six ryanodine receptor isoform-1 (RyR1) mutations associated with malignant hyperthermia and their impact on skeletal excitation-contraction coupling. J Biol Chem 278: 25722–25730.
Handbook of Clinical Neurology, Vol. 86 (3rd series) Myopathies F. L. Mastaglia, D. Hilton-Jones, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 6
Mitochondrial encephalomyopathies ´ R TULINIUS ANDERS OLDFORS* AND MA Sahlgrenska University Hospital, Go¨teborg, Sweden
6.1. Introduction The earliest reports on intracellular structures that probably represented mitochondria go back to 1841, only a few years after the discovery of the cell nucleus. The first to recognize the ubiquitous occurrence of these structures was Altmann in 1890. He called them bioblasts and concluded that they were elementary organs living inside cells and carrying out vital functions. The name mitochondrion was introduced in 1898 by Benda and originates from the Greek “mitos” (thread) and “chondros” (granule), referring to the appearance of these structures during spermatogenesis. Mitochondria are thought to have originated from the fusion of a eukaryotic cell with a prokaryotic cell capable of oxidative phosphorylation some 1.5 billion years ago (endosymbiotic hypothesis). Relics of this endosymbiotic event are the double membrane structure, the circular genome with specific transcription, translation and protein assembly systems, the presence of mitochondrial proteins enabling organelle dynamics and movement, the presence of specific transmembrane carrier systems for ions, metabolites, and proteins and the numerous and diverse degradative and biosynthetic reactions carried out in addition to oxidative phosphorylation (OXPHOS). OXPHOS is a main function of mitochondria, i.e., the oxidation of substrates, mainly pyruvate and fatty acids, to H2O and CO2, generating the bulk of ATP produced by the cell. The OXPHOS system, which is built up of five enzyme complexes, is embedded in the inner membrane of the mitochondrion (Figs 6.1 and 6.2). The components of the OXPHOS system are encoded by two separate genetic systems, the nuclear and the mitochondrial genomes (Figs 6.1 and 6.2). The nuclear genome encodes most of the subunits of the enzyme complexes, assembly proteins and most of the factors necessary for
mitochondrial DNA (mtDNA) replication and expression, whereas the mitochondrial genome encodes 13 subunits of the OXPHOS system, as well as the ribosomal and transfer RNA components of the mitochondrial translational apparatus (Fig. 6.3). Complex I (NADH: ubiquinone oxidoreductase) accepts electrons donated from NADH-linked substrates and donates them to ubiquinone, or coenzyme Q10. It is composed of at least 43 subunits, seven of which are encoded by mtDNA (Smeitink et al., 2001; Carroll et al., 2002). Complex II (succinate: ubiquinone oxidoreductase, succinate dehydrogenase) catalyses the oxidation of succinate to fumarate and feeds electrons from FADHlinked substrates to the respiratory chain ubiquinone pool (Cecchini, 2003). It is composed of four subunits, all encoded by nuclear genes. Complex III (ubiquinone: cytochrome c oxidoreductase) catalyses the transfer of electrons from ubiquinone to cytochrome c. It is composed of 11 polypeptide subunits of which all but one (cytochrome b) are encoded by nuclear DNA. Complex IV (cytochrome c oxidase, COX), which is the terminal component of the respiratory chain, catalyses the reduction of molecular oxygen by reduced cytochrome c. It is composed of 13 subunits, 10 of which are encoded by nuclear genes. The three mtDNA-encoded subunits form the catalytic core of the enzyme and are similar to those from prokaryotic cells in which a fully functional enzyme complex generally requires only four subunits. Complex V (ATP synthase), is composed of 16 subunits, two of which are encoded by mtDNA. The complex consists of the membrane-spanning F0 segment, responsible for proton translocation, and the F1 stalk which extends into the matrix and contains the catalytic center.
*Correspondence to: Anders Oldfors, MD, PhD, Department of Pathology, Sahlgrenska University Hospital, SE-413-45 Go¨teborg, Sweden. E-mail:
[email protected], Tel: þ46-31-342-2084, Mobile: þ46-707-338-116, Fax: þ46-31-417283.
126
A. OLDFORS AND M. TULINIUS in 1988 of the first disease caused by a mitochondrial DNA mutation was a major breakthrough. During the last decade there has been an immense development in the field of mitochondrial diseases and hundreds of different pathogenic human mtDNA mutations have been identified. In spite of this development exact knowledge concerning the pathophysiological events that lead to disease is still lacking (James and Murphy, 2002; McKenzie et al., 2004). Development of animal models are important tools for such studies (Silva and Larsson, 2002; Wallace, 2002; Hansson et al., 2004).
6.2. Genetics of mitochondrial diseases
Fig. 6.1. Schematic illustration of the influence of mitochondrial and nuclear genes on the oxidative phosphorylation (OXPHOS) system, which is located in the inner mitochondrial membrane. Mitochondrial DNA (mtDNA) encodes for 13 of the polypeptides of the oxidative phosphorylation (OXPHOS) system, which is composed of five enzyme complexes (I–V). The mtDNA-encoded subunits constitute parts of complex I, III, IV, and V. All subunits of complex II (succinate dehydrogenase) are nuclear DNAencoded. The 13 polypeptides encoded by mtDNA are synthesized within the mitochondria. tRNA and rRNA genes necessary for this synthesis are encoded by mtDNA. Nuclear genes encode for approximately 76 of the subunits of OXPHOS as well as proteins that are important for assembly of the complexes of OXPHOS. These are synthesized in the cytoplasm and imported into the mitochondria. Nuclear genes are also encoding proteins that are important for mtDNA replication and transcription.
Mitochondrial disorders are due to a defective OXPHOS system. The history goes back 40 years, when a patient with defective coupling of OXPHOS was first described (Luft’s disease). During the 1960s several patients with multisystem disorders and morphologically abnormal mitochondria were identified. By means of biochemical and enzyme histochemical techniques developed in the 1970s mitochondrial diseases could be more accurately characterized. Several syndromes such as Leigh syndrome and Kearns–Sayre syndrome were demonstrated to be mitochondrial disorders. The finding
Since the OXPHOS system is built up of proteins that are encoded from either the mitochondrial DNA (mtDNA, Figs 6.2 and 6.3) or the nuclear DNA (nDNA) the genetics of OXPHOS diseases involve both genomes. In addition, mtDNA transcription and replication are under nuclear control. Therefore OXPHOS diseases that are caused by reduced copy number or multiple mutations of mtDNA may be primarily due to nuclear gene mutations and such diseases show Mendelian inheritance. A summary of the various mitochondrial and nuclear gene defects that have been shown to cause OXPHOS diseases are presented in Fig. 6.4. 6.2.1. Primary mtDNA mutations associated with OXPHOS diseases Only 13 of some 87 proteins, which build up the OXPHOS system, are encoded by mtDNA (Fig. 6.2), and it has been estimated that mtDNA mutations are responsible for approximately 20% of the OXPHOS diseases. However, the majority of mitochondrial disorders, in which the etiology has been established, are due to primary mtDNA defects. Since mtDNA is maternally inherited, mutations will only be transmitted from mother to child, although there are rare exceptions to this rule (Schwartz and Vissing, 2002; Filosto et al., 2003; Taylor et al., 2003a). mtDNA with pathogenic mutations usually coexists with wildtype mtDNA, socalled heteroplasmy. Neutral polymorphisms are homoplasmic with few exceptions. It has not been clarified whether pathogenic mtDNA mutations are always functionally recessive (Shoubridge et al., 1990; Moraes et al., 1992), but the proportion of mutant mtDNA copies is essential for the phenotypic expression of a mutation. When the mutant load exceeds a threshold level, the cell will be affected by a biochemical defect of the OXPHOS system (Petruzzella et al., 1994; Sciacco et al., 1994; Moslemi et al., 1998). The threshold level for expression of mtDNA mutations is usually high (85–95%), but varies with different mutations. When a
MITOCHONDRIAL ENCEPHALOMYOPATHIES
127
Fig. 6.2. Schematic drawing of the mitochondrial oxidative phosphorylation system. Protons (Hþ) are pumped from the matrix to the inter-membranous space through complex I, III and IV and then flow back into the matrix through complex V to produce ATP. mtDNA encoded subunits in complex I, III, IV and V are marked with white letters. Coenzyme Q10 (CoQ) and cytochrome c (Cyt c) are electron transfer carriers encoded by nDNA. Illustration by Yvonne Heijl.
Fig. 6.3. Schematic drawing of mtDNA (16568 bp) with the heavy (outer circle) and light strands (inner circle). Protein coding genes: ND1–6: NADH-dehydrogenase (complex I) subunits 1–6; Cyt b: cytochrome b (complex III); COI–III: cytochrome c oxidase (complex IV) subunit I–III; ATPase 6 and 8: ATP synthase (complex V) subunit 6 and 8. Transfer RNA genes: short gray bars with corresponding amino acid letter. Ribosomal RNA genes: 12S rRNA and 16S rRNA. D-loop: Displacement loop. OH: origin of heavy chain replication OL: origin of light chain replication. Illustration by Yvonne Heijl.
pathogenic mtDNA mutation segregates in a family the maternal inheritance may be obvious from pedigree analysis. However, the level of heteroplasmy may be below the threshold in many family members carrying
the mutation (Larsson et al., 1992). In such families there may be only one or a few affected individuals. Many de-novo mutations have also been reported causing sporadic cases of mitochondrial encephalomyopathies.
128
A. OLDFORS AND M. TULINIUS Major clinical phenotyes MELAS, MERRF, PEO, KSS, Pearson, LS, Myopathy, Encephalopathy, Cardiomyopathy, Diabetes, Sensorineural hearing loss, Retinitis pigmentosa, Optic atrophy, Endocrinopathy, Hepatopathy, Tubulopathy
tRNA/rRNA point mutations or large-scale deletions
Mitochondrial DNA
Complex I
Mutations in polypeptide subunits of OXPHOS
ND1, ND2, ND3, ND4, ND5, ND6
Complex III
Exercise intolerance, Myoglobinuria, Encephalopathy
Complex IV
COXI, COXII, COXIII
LS, Encephalopathy, Exercise intolerance, Myoglobinuria
Complex V
ATP6
LS, NARP
Complex I Mutations in polypeptide subunits of OXPHOS Complex II
NDUFS1, NDUFS2, NDUFS3 NDUFS4, NDUFS6, NDUFS7 NDUFS8, NDUFV1, NDUFV2 SDHA SDHB, SDHC, SDHD
Complex III
Complex IV
Nuclear DNA Mutations in proteins involved in mitochondrial DNA translation
Mutations in proteins involved in mtDNA maintenance and associated with multiple mtDNA deletions
Mutations in proteins involved in mtDNA maintenance and associated with reduced mtDNA copy number
LS, Encephalopathy Paraganglioma, Pheochromocytoma Encephalopathy, tubulopathy and liver failure
SURF1
LS, Villus atrophy and hypertrichosis
SCO2
Encephalopathy and liver failure Encephalopathy and cardiomyopathy
COX10
Encephalopathy and tubulopathy, Ls, Sensorineural hearing loss and cardiomyopathy
COX15
Cardiomyopathy, LS
LRPPRC Complex V
LS, Encephalopathy, Cardiomyopathy
BCSIL
SCO1 Mutations in proteins important for assembly of OXPHOS subunits
LHON, MELAS, LS, Myopathy
Cytochrome b
LS
ATP12
Cerebral dysgenesis and atrophy, dysmorphism
EFG1
Encephalopathy and hepatopathy
MRPS16
Cerebral dysgenesis, dysmorphism
PUS1
Mitochondrial myopathy and sideroblastic anemia
ANT1
adPEO
C10orf2 (Twinkle)
adPEO
POLG1
adPEO, arPEO, SANDO, Alpers, Parkinsonism Sensory ataxic neuropathy with multiorgan disease
ECGF1 (TP)
MNGIE
TK2 DGUOK (dGK)
Myopathy Encephalopathy and liver failure
SUCLA2
Encephalopathy and muscle hypotonia
MPV17
Encephalopathy and liver failure
Fig. 6.4. Summary of the genes known to be involved in OXPHOS diseases by affecting one or several of the five enzyme complexes of the respiratory chain. Abbreviations: OXPHOS: oxidative phosphorylation; tRNA: transfer RNA; rRNA: ribosomal RNA; ND1–6: NADH-dehydrogenase subunits 1–6; COX I–III: cytochrome c oxidase subunit I–III; ATP6: ATP synthase subunit 6: TP: thymidine phosphorylase; MELAS: mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes; MERRF: myoclonus epilepsy with ragged red fibres; PEO: progressive external ophthalmoplegia; KSS: Kearns–Sayre syndrome; Pearson: Pearson marrow– pancreas syndrome; LS: Leigh syndrome; LHON: Leber’s hereditary optic neuropathy; NARP: neurogenic muscle weakness, ataxia, and retinitis pigmentosa; ad(ar)PEO: autosomal-dominant (autosomal-recessive) progressive external ophthalmoplegia; MNGIE: mitochondrial neurogastrointestinal encephalomyopathy; SANDO: sensory ataxic neuropathy, dysarthria and ophthalmoparesis; Alpers: Alpers syndrome.
The mutant load often varies between tissues and between cells within a tissue. mtDNA mutations may be restricted to one or few tissues and mtDNA analysis of blood samples may show no mutation in such cases. For diagnostic purposes it is therefore important to analyze affected tissues. For two common mutations (A2343G and A8344G) there is a relationship between mutant load in muscle (but not in blood) and the presence of specific clinical symptoms (Chinnery et al., 1997). For another common mutation at position 8993 there appears to be little tissue- and age-related variation (White et al., 1999a). The segregation of mutant mtDNA can occur at cell division (mitotic segregation), which may result in
changes of mutant load after cell division. Since mtDNA replication is not directly linked to cell division the mutant load may also change with time in a single cell. This is especially important in cells that do not divide and are not replaced during adult life, including nerve cells, muscle fibers and cardiomyocytes. The mutant load may show progressive increase (Larsson et al., 1990; Weber et al., 1997) or decrease (Horvath et al., 2004) in such tissues. Point mutations of tRNA and rRNA genes as well as large-scale deletions of mtDNA cause impaired protein synthesis that affects all of the 13 mtDNA encoded polypeptides and lead to more or less pronounced deficiency
MITOCHONDRIAL ENCEPHALOMYOPATHIES of complex I, III, IV and V. Mutations of any of the protein-encoding genes of mtDNA typically cause deficiency restricted to the corresponding complex, but combined deficiencies may be observed (Lamantea et al., 2002a). 6.2.1.1. Point mutations of tRNA and rRNA genes Although nearly 80% of the coding part of the mitochondrial genome is allocated to protein-coding genes and approximately 10% to tRNA genes, the majority of the pathogenic point mutations so far described affect tRNA genes (approximately 100 point mutations). Most cases are maternally inherited but de-novo mutations occur. Pathogenic mutations have been identified in most of the 22 tRNA genes, but some tRNA genes are more frequently affected than others. Among these are the tRNALeu(UUR), tRNAIle and tRNALys. The most common tRNA mutation is tRNALeu(UUR) A3243G, which is typically associated with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS). However, several other phenotypes have been described with this mutation including myoclonius epilepsy and ragged red fibers (MERRF) and progressive external ophthalmoplegia (PEO; Folgero et al., 1995; Hammans et al., 1995). Maternally inherited diabetes mellitus is also frequently associated with this mutation (Reardon et al., 1992; Maassen, 2002). However the MELAS syndrome can also be caused by various other mtDNA mutations and has been described in association with 13 different point mutations in addition to large-scale deletions of mtDNA. Another common mutation, tRNALys A8344G, is typically associated with the MERRF syndrome (Shoffner et al., 1990; Zeviani et al., 1991; Silvestri et al., 1993). The A8344G mutation has also been reported in other syndromes, such as PEO, Leigh syndrome (LS) and multiple symmetric lipomatosis (Fukuhara, 1995) and in a sporadic case of infantile histiocytoid cardiomyopathy (Vallance et al., 2004). There are thus no specific phenotypes linked to each tRNA mutation. Although tRNA mutations are frequently expressed as multisystem disorders, some mutations are more or less organ specific. For example the tRNAIle A4300G mutation appears to be associated with isolated cardiomyopathy (Casali et al., 1995; Taylor et al., 2003b). tRNA gene mutations often disrupt conserved base pairing in the tRNA molecule, and thereby cause conformational changes of the tRNA. Mutations may also change the amino acid acceptor region or the anticodon site. Why each tRNA mutation frequently is associated with a certain phenotype is not known, but abnormal mitochondrial RNA processing in a tissueand mutation-specific way can explain some of the variability (Bindoff et al., 1991; Schon et al., 1992).
129
Although tRNA mutations affect the translation of all mitochondrial encoded polypeptides, some mutations are typically associated with complex I deficiency such as the tRNALeu(UUR) A3243G and A3302G mutations (Bindoff et al., 1993; Mariotti et al., 1995), whereas others are associated with deficiency of complex III (Pulkes et al., 2000) or complex IV (Silvestri et al., 1998). As a rule pathogenic tRNA point mutations are heteroplasmic, but there are a few exceptions (Taylor et al., 2003b; McFarland et al., 2004a). Mitochondrial myopathy is usually, but not always, present in OXPHOS diseases caused by tRNA mutations. Point mutations of ribosomal RNA genes are a rare cause of mitochondrial disease but have been described in association with deafness. Patients with homoplasmic point mutations at position 1555 in the 12S rRNA gene can develop rapidly progressive hearing impairment during treatment with aminoglycosides (Prezant et al., 1993; Estivill et al., 1998; Malik et al., 2003). Hearing impairment and deafness may also occur independent of such antibiotic treatment (Prezant et al., 1993; Thyagarajan et al., 2000; Malik et al., 2003). A point mutation at position 1095 in the 12S rRNA gene has been associated with maternally inherited sensorineural deafness, levodopa-responsive parkinsonism, and neuropathy (Thyagarajan et al., 2000). 6.2.1.2. Point mutations of polypeptide genes of mtDNA Point mutations in protein coding genes of mtDNA are a less frequent cause of mitochondrial diseases than tRNA mutations. Seven genes of mtDNA encode for subunits of complex I (ND1–6 and ND4L). Several of the pathogenic mutations in mtDNA encoded subunits of complex I are missense mutations associated with Leber hereditary optic neuropathy (LHON; Singh et al., 1989; Man et al., 2002), the most common being G3460A, G11778A and T14484C. Other phenotypes associated with mutations in mtDNA encoded ND subunits include encephalopathies such as MELAS and Leigh syndrome or overlap of these syndromes. Infantile encephalopathies including LS have been described in association with mutations in genes encoding the ND3, ND4, ND5, and ND6 subunits (Kirby et al., 2000; Komaki et al., 2002; Taylor et al., 2002; Chol et al., 2003; Deschauer et al., 2003a; Kirby et al., 2003; McFarland et al., 2004b). The ND5 subunit appears to be a hot spot region associated with MELAS/Leigh syndromes (Corona et al., 2001; Taylor et al., 2002; Chol et al., 2003; Crimi et al., 2003; Liolitsa et al., 2003). The majority of mutations in mtDNA encoded subunits of complex I are maternally inherited. They are usually not associated with mitochondrial
130
A. OLDFORS AND M. TULINIUS
myopathy with ragged red fibers but there are exceptions. For example the G13513A mutation has been demonstrated to be associated with clinical and muscle biopsy findings typical of MELAS (Pulkes et al., 1999). One subunit of complex III is encoded by mtDNA (cytochrome b). Numerous mutations have been described in the cytochrome b gene, which is the only subunit of complex III so far associated with pathogenic mutations. The majority of these mutations have presented with severe and progressive exercise intolerance, occasionally associated with myoglobinuria and lactic acidosis (Andreu et al., 1999a; Lamantea et al., 2002a; Bruno et al., 2003; Mancuso et al., 2003a). Typically there is mitochondrial myopathy with cytochrome c oxidase (COX) positive ragged red fibers (Andreu et al., 1999b). Interestingly all such cases have been sporadic and in most instances the mutations have been restricted to muscle indicating that they are somatic and not affecting the germ line. This pattern has been described also for mutations in other protein-encoding genes of mtDNA and rarely in association with mutations in tRNA genes. However, mutations in the cytochrome b gene have also been described in multisytem disorders (De Coo et al., 1999; Rana et al., 2000; Wibrand et al., 2001; Schuelke et al., 2002). Mutations in genes encoding subunits of complex IV have only been described in the three subunits encoded by mtDNA, which form the catalytic core of COX. These mutations have shown great phenotypic variability including recurrent myoglobinuria (Keightley et al., 1996; Karadimas et al., 2000; McFarland et al., 2004c; Kollberg et al., 2005), a LS-like disease (Tiranti et al., 2000), motor neuron disease (Comi et al., 1998), and multisystem disease (Bruno et al., 1999; Campos et al., 2001; Uusimaa et al., 2003). Muscle biopsies show COX deficiency by biochemical and enzyme histochemical analyses and in most cases also ragged red fibers. Cases with isolated myopathy are in most instances sporadic. Mutations in the subunits of complex V have only been described in the mtDNA-encoded ATPase subunit 6. This subunit is one of the 10 subunits comprising the F0 domain, which is embedded in the mitochondrial inner membrane and conducts protons from the intermembrane space to the matrix. Maternal inheritance is a consistent finding. These mutations are typically associated with LS or NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa; Holt et al., 1990; De Vries et al., 1993). The phenotypic expression is related to the mutant load with LS occurring in children with very high levels of mutant mtDNA. Most cases are due to either T8993G or T8993C (White et al., 1999b) mutations but other mutations have also been described (Thyagarajan et al., 1995).
6.2.1.3. Single large-scale deletions of mtDNA Single large-scale deletions of mtDNA, occasionally with coexisting duplications, are usually associated with progressive external ophthalmoplegia (PEO; Holt et al., 1988; Zeviani et al., 1988). PEO is often seen as part of the multisystem disorder Kearns–Sayre syndrome (KSS). In cases with a mixture of deletion and duplication of mtDNA there is evidence that only the deletions are pathogenic and cause COX deficiency (Manfredi et al., 1997; Houshmand et al., 2004). However, the duplications may play a pathogenic role in the determination of clinical expression of mitochondrial diseases associated with single mtDNA deletions (Odoardi et al., 2003). The early onset syndrome of sideroblastic anemia and exocrine pancreas dysfunction (Pearson’s syndrome) is associated with large scale mtDNA deletions (Ro¨tig et al., 1990). Pearson’s syndrome can later in life develop into KSS (Larsson et al., 1990; McShane et al., 1991). Large-scale mtDNA deletions are usually located in the major arc between the origins of replication of the light and heavy strands of mtDNA. The deleted parts include protein encoding genes as well as tRNA genes. More than one hundred different mtDNA deletions have been identified. The 4977-bp “common deletion” is present in about one-third of the cases (Schon et al., 1989). The deleted part is flanked by a 13-bp nucleotide repeat. Most large-scale deletions show such repeats in the breakpoint regions. This finding has formed the basis for the hypothesis that the sequences flanking the deletion breakpoints are important for the formation of these deletions (Shoffner et al., 1989; Mita et al., 1990). A study on the distribution of 263 different human deletions of mtDNA and the distribution of direct repeats indicated that the two 13-bp repeats that are associated with the “common deletion” are involved in the formation of most deletions and that the process is related to mtDNA replication (Samuels et al., 2004). Diseases caused by single large-scale deletions of mtDNA usually appear as sporadic cases. However, maternal transmission of the mutation may occur (Bernes et al., 1993; Shanske et al., 2002), the risk being approximately 4% (Chinnery et al., 2004). Mitochondrial myopathy with COX-negative muscle fibers is usually present in OXPHOS diseases caused by large-scale mtDNA deletions. 6.2.2. Nuclear gene mutations causing OXPHOS diseases Several nuclear gene mutations causing OXPHOS deficiency have recently been identified. These may be divided into mutations of subunits of the respiratory chain
MITOCHONDRIAL ENCEPHALOMYOPATHIES enzyme complexes, mutations of proteins involved in assembly or translation of subunits of the respiratory chain, and mutations of proteins that affect mtDNA stability and maintenance. 6.2.2.1. Mutations in structural proteins of the OXPHOS system encoded by nuclear DNA Mutations in nuclear genes encoding subunits of the OXPHOS system enzyme complexes have so far been identified only in complex I and II. Complex I deficiency is the most common cause of OXPHOS disease and is responsible for about one-third of the cases (Kirby et al., 1999). The identification of the gene defects underlying complex I deficiency is hampered by the large number of involved genes. The first nuclear gene mutations associated with complex I deficiency were described 1998 in patients with LS (Loeffen et al., 1998; Van den Heuvel et al., 1998). Since then several recessive mutations have been described in the NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS6, NDUFS7, NDUFS 8, NDUFV1 and NDUFV2 subunits (Schuelke et al., 1999; Petruzzella et al., 2001; Smeitink et al., 2001; Triepels et al., 2001; Petruzzella and Papa, 2002; Benit et al., 2004; Kirby et al., 2004; Procaccio and Wallace, 2004; Ugalde et al., 2004). These subunits are evolutionary conserved and most of them play a major role in the catalytic activity (Benit et al., 2001). The clinical picture is variable but the majority of patients have presented with early onset neurological disorders including hypotonia, ataxia, psychomotor retardation or LS. Cardiomyopathy has also been reported in patients with mutations in the genes encoding NDUFS2 and NDUFV2 (Loeffen et al., 2001; Benit et al., 2003). In most cases there is an isolated complex I deficiency but a combined deficiency of complex I and III has been described in NDUFS4 gene mutation (Budde et al., 2000). A possible explanation could be that abnormalities of one complex may have deleterious effects on the structural integrity of the entire OXPHOS system (Scha¨gger and Pfeiffer, 2000). Although complex I deficiency may be demonstrated in muscle tissue, mitochondrial myopathy with ragged red fibers have usually not been described in patients with mutations in nuclear genes encoding subunits of complex I. The first report on a nuclear OXPHOS gene mutation was in a patient with LS and complex II deficiency (Bourgeron et al., 1995). Complex II deficiency is an infrequent cause of mitochondrial disease and represents less than 1% of the cases with respiratory chain deficiency (Parfait et al., 2000). Complex II is composed of four nuclear encoded subunits. The flavoprotein (SDHA) and iron-sulfur (SDHB) protein subunits are anchored to the inner mitochondrial membrane by two
131
smaller subunits (SDHC and SDHD). Mutations in SDHA have been associated with LS (Bourgeron et al., 1995; Parfait et al., 2000). One additional patient showed hypotonia and respiratory insufficiency and died at 5 months of age of cardiorespiratory failure (Van Coster et al., 2003). Two sisters with only one heterozygous mutation in SDHA showed partial complex II deficiency and a late-onset neurodegenerative disease (BirchMachin et al., 2000). Mutations in SDHB, SDHC and SDHD have been associated with pheochromocytoma and with hereditary paraganglioma, a usually benign tumor in the head and neck region (Ackrell, 2002; Astuti et al., 2003; Neumann et al., 2004). 6.2.2.2. Mutations of nuclear-encoded proteins involved in assembly of the respiratory chain subunits Pathogenic mutations of the 10 nuclear-DNA-encoded subunits of complex III have not yet been described. However, six patients from four unrelated Turkish families with complex III deficiency showed mutations in BCS1L, which encodes a respiratory chain assembly protein (De Lonlay et al., 2001). The patients presented with severe encephalopathy, liver failure, tubulopathy, and lactic acidosis. Two Spanish siblings with congenital lactic acidosis, hypoglycemia, failure to thrive, hepatopathy, encephalopathy and renal tubulopathy had complex III deficiency and mutations in BCS1L (De Meirleir et al., 2003). Mutations in BCS1L were associated with the GRACILE (growth retardation, aminoaciduria, cholestasis, iron overload, lactacidosis and early death) syndrome in Finnish patients (Visapaa et al., 2002). The Finnish patients had no neurological problems and no clearly decreased complex III activity. Although no mutations of nuclear genes encoding for complex IV subunits have been identified, LS with COX deficiency is frequently suspected to be inherited as an autosomal-recessive trait. Mutations in the SURF1 gene, which is of importance for the assembly of COX (Barrientos et al., 2002) was demonstrated to cause of LS with COX deficiency (Tiranti et al., 1998; Zhu et al., 1998), and is probably the most frequent cause of LS with COX deficiency (Pequignot et al., 2001). The majority of the patients have null alleles with some exceptions (Moslemi et al., 2003) but there is always some residual COX activity indicating that SURF1 is not obligatory for COX assembly. Pathogenic mutations in SURF1 are not always associated with typical LS (Rahman et al., 2001a; Salviati et al., 2004), and a case with villus atrophy, hypertrichosis and only mild neurological involvement has been reported (Von Kleist-Retzow et al., 2001). SCO2 mutations have been associated with a fatal infantile COX deficiency disorder presenting with
132
A. OLDFORS AND M. TULINIUS
hypertrophic cardiomyopathy, hypotonia and encephalopathy or spinal cord disease mimicking Werdnig–Hoffmann disease (Papadopoulou et al., 1999; Salviati et al., 2002a; Tarnopolsky et al., 2004), and also early spontaneous abortions (Tay et al., 2004). SCO2 encodes a copper chaperone, which transports copper to complex IV. COX activity in cultured cells from patients with SCO2 mutations could be improved by adding copper to the culture medium (Jaksch et al., 2001; Salviati et al., 2002b). SCO1, another gene involved in copper import to complex IV, has been associated with early onset hepatic failure and encephalopathy associated with COX deficiency (Valnot et al., 2000a). Mutations in COX10, which is involved in mitochondrial heme A biosynthesis, were first described in association with COX deficiency, tubulopathy and encephalopathy (Valnot et al., 2000b). More recently, COX10 mutations were associated with other clinical phenotypes including LS, and a patient with anemia, sensorineural deafness and fatal infantile hypertrophic cardiomyopathy (Antonicka et al., 2003a; Coenen et al., 2004a). Mutations in COX15, which encodes another protein involved in mitochondrial heme biosynthesis, have been shown to be associated with COX deficiency and hypertrophic cardiomyopathy (Antonicka et al., 2003b) or LS (Oquendo et al., 2004; Bugiani et al., 2005). The French-Canadian type of LS (LSFC; OMIM 220111; Morin et al., 1993) has been demonstrated to be caused by mutations in the leucine-rich pentatricopeptide repeat cassette (LRPPRC) gene (Mootha et al., 2003). LRPPRC mutations are associated with reduced translation of COX subunits (Xu et al., 2004). The only pathogenic mutation in a complex V assembly gene so far identified (ATP12) was described in a child with hyperlactatemia, dysmorphic features, hypoplasia of the white matter, cortical and subcortical atrophy and dysgenesis of corpus callosum (De Meirleir et al., 2004). 6.2.2.3. Mutations of nuclear-encoded proteins involved in mitochondrial translation A group of OXPHOS diseases are caused by nuclear gene mutations affecting proteins involved in the translation machinery of the mitochondria. Reduced activity of all mtDNA-encoded complexes of the respiratory chain was present in two siblings with prenatal onset of encephalopathy and hepatopathy leading to liver failure and early death (Coenen et al., 2004b). A defect in mitochondrial translation was identified and shown to be associated with a mutation
in the elongation factor G1 gene (EFG1), which is a mitochondrial translation factor. A child with facial dysmorphic features, limb edema, agenesis of the corpus callosum, increased liver transaminases, lactic acidosis and death at 3 days of age was demonstrated to have reduced activities of complex I and IV and a mitochondrial translation defect (Miller et al., 2004). Reduction in the level of mitochondrial 12S rRNA transcripts and a homozygous mutation in the gene encoding ribosomal protein S16 (MRPS16) were identified. Mitochondrial myopathy and sideroblastic anemia (MLASA) is a rare, autosomal-recessive disease affecting children and adolescents expressed as muscle weakness with exercise intolerance and anemia (Casas and Fischel-Ghodsian, 2004). A mutation in the pseudouridine synthase 1 gene (PUS1) has been identified as the cause of the disease (Bykhovskaya et al., 2004). Loss of tRNA pseudouridylation was demonstrated, implying that compromised structure and function of tRNAs may lead to impaired translation (Patton et al., 2005). 6.2.2.4. Mutations in nuclear genes affecting mtDNA maintenance Diseases associated with multiple large-scale mtDNA deletions, and diseases associated with quantitative loss of mtDNA, so-called depletion, show Mendelian inheritance indicating that these mtDNA defects are secondary to nuclear gene mutations. The first description of a disease with autosomaldominant inheritance and multiple mtDNA deletions goes back to 1989 (Zeviani et al., 1989). Multiple mtDNA deletions have been associated with several clinical manifestations, which in most cases present after the first decade of life. The most common, albeit not constant, symptom is progressive external ophthalmoplegia (PEO) with the variable addition of exercise intolerance, recurrent myoglobinuria, ataxia, parkinsonism, major depression, peripheral neuropathy, hypogonadism and cardiomyopathy (Zeviani et al., 1990; Cormier et al., 1991; Ohno et al., 1991; Servidei et al., 1991; Haltia et al., 1992; Suomalainen et al., 1992a; Prelle et al., 1993; Checcarelli et al., 1994; Kawashima et al., 1994; Takei et al., 1995; Ville-Ferlin et al., 1995; Bohlega et al., 1996; Campos et al., 1996a; Chalmers et al., 1996; Fabrizi et al., 1996; Melberg et al., 1996a; Suomalainen et al., 1997; Carrozzo et al., 1998; Federico et al., 1998; Melberg et al., 1998; Nishizuka et al., 1998). As in disorders due to single large-scale deletions, mitochondrial myopathy with COX-deficient RRF is usually, but not always, present in autosomal-recessive or -dominant PEO with multiple mtDNA deletions. Biochemical analysis typically shows reduction in the partially
MITOCHONDRIAL ENCEPHALOMYOPATHIES mtDNA-encoded respiratory chain complexes I, III and IV (Suomalainen et al., 1992a). A variable proportion of mtDNA with deletions are found in postmitotic tissues such as skeletal muscle, myocardium and CNS (Suomalainen et al., 1992a; Moslemi et al., 1999). The cerebellum usually shows a lower proportion of mtDNA with deletions than other brain regions. Multiple deletions are not found in cultured myoblasts and they are considered somatic mutations. In muscle tissue the deletions are clonally expanded in muscle fiber segments, with one unique deletion in each fiber segment (Moslemi et al., 1996). The genes, which are associated with multiple mtDNA deletions or mtDNA depletion are either involved in mtDNA replication and/or play a role in mitochondrial nucleotide metabolism. Several different nuclear gene mutations have been identified in adPEO with multiple mtDNA deletions. The first identified gene associated with this syndrome is encoding the muscle-heart specific mitochondrial adenine nucleotide translocator 1 (ANT1; Kaukonen et al., 2000; Agostino et al., 2003). How the defective ANT1 causes mtDNA deletions is not known, but various mechanisms have been proposed (Chen, 2002; Fontanesi et al., 2004). The second gene that was demonstrated to be associated with adPEO is C10orf2, encoding a mitochondrial protein similar to phage T7 primase/helicase (gp4) named Twinkle (Spelbrink et al., 2001; Agostino et al., 2003; Deschauer et al., 2003b). In-vitro experiments have demonstrated that Twinkle is the helicase at the mitochondrial DNA replication fork and that it is essential for mtDNA replication (Korhonen et al., 2004). Studies in mice have shown that Twinkle is essential for mtDNA maintenance, and may be a key regulator of mtDNA copy number (Tyynismaa et al., 2004). The third gene associated with PEO and multiple mtDNA deletions is encoding mtDNA polymerase g (POLG1), which is the only mtDNA polymerase in mitochondria (Van Goethem et al., 2001). POLG1 mutations may be either dominant or recessive, and have emerged as the major cause of PEO with multiple mtDNA deletions, frequently in combination with manifestations from CNS and other organs (Van Goethem et al., 2001; Lamantea et al., 2002b; Van Goethem et al., 2002; Di Fonzo et al., 2003; Van Goethem et al., 2003a; Lamantea and Zeviani, 2004; Mancuso et al., 2004a; Gonzalez-Vioque et al., 2006; Pagnamenta et al., 2006). Polymerase g exhibits a polymerase region and an exonuclease (proof-reading) region. Most dominant mutations are located in the polymerase region while recessive mutations have been identified mainly in the exonuclease and linker regions. In several families with adPEO, parkinsonism was shown to segregate with the POLG1
133
mutation (Luoma et al., 2004). Recently POLG1 mutations have been proposed to be associated with various neurological diseases also without PEO. These include Alpers syndrome (Naviaux and Nguyen, 2004; Ferrari et al., 2005; Kollberg et al., 2006), sensory ataxic neuropathy, combined with variable features of CNS involvement (Van Goethem et al., 2004) and parkinsonism (Davidzon et al., 2006). In these conditions mitochondrial myopathy was not always found and multiple mtDNA deletions were not always present in muscle. However, mtDNA depletion was demonstrated in some cases (Kollberg et al., 2006). A mutation in mtDNA polymerase g (PolgA) in the mouse results in multiple somatic mtDNA mutations and a premature-aging phenotype (Trifunovic et al., 2004). This finding indicates that somatic mtDNA mutations are one important cause of aging. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is caused by mutations in the thymidine phosphorylase (TP) gene (ECGF1; Nishino et al., 1999; 2000). TP deficiency alters the metabolism of the nucleosides thymidine and deoxyuridine, which, in turn, produces abnormalities of mtDNA including depletion, deletions, and point mutations (Marti et al., 2003; Nishigaki et al., 2003a; Marti et al., 2004). Severe mtDNA depletion syndromes (MDDS) usually present in infancy but may appear later in childhood (Barthelemy et al., 2001). Several genes have been identified: the deoxyguanosine kinase gene (DGUOK), which is associated with hepatic failure and encephalopathy (Mandel et al., 2001b; Taanman et al., 2002; Mancuso et al., 2005; Tadiboyina et al., 2005; Wang et al., 2005) and the thymidine kinase-2 gene (TK2) associated with severe myopathy (Saada et al., 2001; Carrozzo et al., 2003; Mancuso et al., 2003b; Tulinius et al., 2005; Wang et al., 2005). In one report the mtDNA depletion associated with TK2 mutations was reversible (Vila et al., 2003). Two additional genes associated with severe infantile mtDNA depletion have been identified. A homozygous mutation in SUCLA2, which encodes the beta subunit of the ADP-forming succinyl-CoA synthetase ligase, was associated with mtDNA depletion, encephalopathy, muscle hypotonia and hearing loss (Elpeleg et al., 2005). Mutations in MPV17, which encodes an inner mitochondrial membrane protein, were associated with mtDNA depletion, encephalopathy and liver failure (Spinazzola et al., 2006). Mutations in POLG1 (see above) are associated with mtDNA depletion as well as multiple mtDNA deletions. In this context it is also of interest that depletion/multiple deletions of mtDNA and mitochondrial myopathy may also be induced by treatment with the nucleoside reverse transcriptase inhibitors (Chariot et al., 1999; Maagaard et al., 2006).
134
A. OLDFORS AND M. TULINIUS
In Amish microcephaly (MCPHA) the mitochondrial deoxynucleotide carrier (SLC25A19) is mutated (Rosenberg et al., 2002). It was proposed that insufficient transport of dNTPs into mitochondria may interfere with synthesis of mtDNA and cause abnormal brain growth. 6.2.2.5. Defects of other nuclear encoded proteins with effects on the respiratory chain Friedreich ataxia and hereditary spastic paraplegia (HSP) may be considered as mitochondrial diseases with secondary effects on the OXPHOS system. In Friedreich ataxia, which is due to a trinucleotide expansion in the frataxin gene, complex I-III and aconitase deficiency have been demonstrated (Ro¨tig et al., 1997a). The pathogenesis has been proposed to involve oxidative damage to iron-sulfur clusters, resulting from hampered superoxide dismutase signaling (Chantrel-Groussard et al., 2001). In autosomal-recessive HSP, which is due to mutations in the mitochondrial protein paraplegin, there are signs of OXPHOS deficiency and mitochondrial myopathy with RRF (Casari et al., 1998). Primary CoQ10 deficiency is associated with heterogeneous clinical presentations. The first described form was an encephalomyopathy with exercise intolerance, episodic myolglobinuria, ataxia and seizures (Ogasahara et al., 1989; Sobreira et al., 1997; Boitier et al., 1998). The others include a predominantly cerebellar form with ataxia and cerebellar atrophy (Musumeci et al., 2001; Lamperti et al., 2003), a fatal infantile encephalomyopathy with renal failure (Ro¨tig et al., 2000; Rahman et al., 2001b; Salviati et al., 2005), Leigh syndrome (Van Maldergem et al., 2002) and a form characterized by isolated myopathy with (Lalani et al., 2005) or without recurrent myoglobinuria (Horvath et al., 2006). Mitochondrial myopathy with ragged red fibers, occasional cytochrome c oxidase deficient fibers and lipid accumulation is observed in some cases, but this is not a consistent finding. Correct diagnosis is important since treatment with CoQ10 is often beneficial. The genetic defect in two siblings with severe, primary CoQ10 deficiency has recently been demonstrated to be a homozygous missense mutation in CoQ2 (Quinzii et al., 2006). The gene encodes para-hydroxybenzoate-polyprenyl transferase, which is an enzyme in the biosynthetic pathway of CoQ10.
6.3. Epidemiology A number of epidemiological studies of mitochondrial disease have been carried out over the last decade, clearly demonstrating that mitochondrial disorders are far more common than previously anticipated (Schaefer et al., 2004). The first population-based study of a single
pathogenic mtDNA mutation, the A3243G mutation, which is typically associated with MELAS, was carried out in northern Finland (Majamaa et al., 1998). The authors examined medical records and identified a cohort of adults with clinical features suggestive of a mitochondrial disease. Molecular genetic testing of the probands followed by careful family tracing allowed the authors to estimate the minimum point prevalence of the A3243G mutation to be 16.3 of 100 000 adults. The first population-based study of all mitochondrial disorders in adults was carried out in the north-east of England (Chinnery et al., 2000) and was based on referrals to one single center in Newcastle-upon-Tyne. It was found that 1 in 15 217 adults had a disease due to a pathogenic mtDNA mutation. Further, by studying family members, it was estimated that 1 in 13 175 individuals were at risk of developing a mitochondrial disease, giving a minimum prevalence of 1 in 8070 carrying some type of pathogenic mtDNA mutation. The most common mtDNA disease found in the adult population of north-east England was Leber hereditary optic neuropathy (LHON), constituting half of the cases in the study, followed by progressive external ophthalmoplegia (PEO) and Kearns–Sayre syndrome (KSS; 19%) and MELAS syndrome (15%). A study from western Sweden described the preschool incidence, point prevalence and mortality of mitochondrial encephalomyopathies in children (Darin et al., 2001). The incidence of mitochondrial encephalomyopathies in preschool children (<6 years of age) was 1 in 11 000. The point prevalence in children under 16 years of age was lower (1 in 21 000), due to the high mortality of the children in the study. The median survival for patients with infantile onset was until 12 years of age, many dying 1–2 years after onset of disease. The most common mitochondrial encephalomyopathy was Leigh syndrome, followed by Alpers syndrome and infantile mitochondrial myopathy. In this study 16% of the patients had a pathogenic mtDNA mutation. A similar study was carried out in Australia based upon referrals to the Melbourne Children’s Hospital over a 10-year period (Skladal et al., 2003). Using clinical, biochemical and molecular genetic criteria the minimum birth prevalence of mitochondrial disease was estimated to be 1 in 20 000 with the proportion of mtDNA mutations of 15%. These two concordant studies suggest that the prevalence figure of 1 in 20 000 is probably accurate, making respiratory chain disorders amongst the most common inherited metabolic diseases.
6.4. Clinical phenotypes The clinical presentations of mitochondrial diseases are highly variable and the symptoms are often initially
MITOCHONDRIAL ENCEPHALOMYOPATHIES vague and non-specific. This clinical heterogeneity reflects in part the complex genetics underlying these disorders. In addition organs with high energy demands are more susceptible to defects in the OXPHOS system. Striated muscle and the nervous system are especially vulnerable. Patients with mitochondrial disease may present their first signs and symptoms at any age, and mitochondrial disease should be considered in patients with apparently unexplained combinations of symptoms and signs, especially if there are neurological features. The clinical course is in general progressive, although there may be long periods without bouts of progression. Infections, other physical stress or psychic stress may provoke relapses of the disease. Multiorgan involvement is common, sometimes presenting as defined syndromes. A frequent feature is an increasing number of organs involved in the course of the disease (Munnich and Rustin, 2001). Lactate is the product of anaerobic glucose metabolism and accumulates in the body fluids when the aerobic metabolism in the mitochondria is impaired. Hyperlactatemia is therefore a marker of mitochondrial disease. Hyperlactatemia also accompanies several other metabolic disorders, e.g., glycogen storage disease and disorders of the fatty acid and amino acid metabolism, or may be the consequence of for example impaired circulation, hypoxia or hepatic or renal failure. Below follows descriptions of the well-defined clinical phenotypes of mitochondrial disease, with emphasis on mitochondrial encephalomyopathies (also summarized in Table 6.1). The clinical phenotypes are described in order of age at presentation, beginning with infantile and childhood forms. However, many patients, especially those with diseases caused by mtDNA mutations, present with overlap features of the more typical mitochondrial syndromes, and many patients present with other forms of encephalopathies and/or myopathies. 6.4.1. Prenatal onset of mitochondrial disease OXPHOS disease seems to be a rare cause of cerebral developmental abnormalities and other congenital malformations (Samson et al., 1994; Cormier-Daire et al., 1996; Damian et al., 1996; Lincke et al., 1996; De Koning et al., 1999; De Meirleir et al., 2004). Pontocerebellar hypoplasia, intracerebral calcifications, porencephaly and dysgenesis of the corpus callosum have all been associated with OXPHOS disease (Von Kleist-Retzow et al., 2003). However, many of these cases may be missed because the patients are so severely affected at birth that they die early, and because the findings suggest infectious or other prenatal causes rather than a metabolic disease. Recently a patient with a mutation in the complex V assembly gene ATP12 was described (De Meirleir et al.,
135
2004). This girl was hypertonic and had dysmorphic features at birth, including micrognathia, rocker-bottom feet and flexion contractures of the limbs associated with camptodactylia. The patient had increased concentrations of lactate in blood, cerebrospinal fluid (CSF) and urine. Urinary fumarate, methylglutaconic acid and amino acids were also increased. Two siblings with a mutation in the mitochondrial elongation factor G1 (EFG1) and combined deficiency of mtDNA encoded OXPHOS complexes presented with microcephaly and hypoplasia of corpus callosum (Coenen et al., 2004b). One of them also had cystic lesions in the region of the basal ganglia. Both had liver failure and died at early infancy. One child who died at 3 days of age had agenesis of the corpus callosum, dysmorphic features and lactic acidosis. She was demonstrated to have a mitochondrial translation defect due to a mutation in the mitochondrial ribosomal protein S16 (MRPS16) (Miller et al., 2004). 6.4.2. Leigh syndrome Subacute necrotizing encephalomyelopathy, Leigh syndrome (LS), was described in 1951 as a distinctive neuropathological entity characterized by symmetric areas of spongy degeneration of the neuropil, preferentially affecting the periventricular areas of the brainstem, diencephalon and basal ganglia (Leigh, 1951). Although LS is a neuropathological entity, diagnosis is now possible premortem by computed tomography (CT) or magnetic resonance imaging (MRI) of the brain (Valanne et al., 1998; Farina et al., 2002). LS is genetically a heterogeneous disorder. It may be associated with deficiency of the pyruvate dehydrogenase complex (PDHc) and of enzymes of the oxidative phosphorylation, especially complex I, IV and V. Mutations of mitochondrial DNA (mtDNA) associated with LS include the ATPase6 T8993G/C mutations (White et al., 1999b), the tRNALys A8344G mutation (Sweeney et al., 1994; Santorelli et al., 1998) and several others. Mutations of nuclear genes encoding subunits of complex I (Smeitink et al., 2001) and complex II (Bourgeron et al., 1995; Parfait et al., 2000) have been demonstrated to be associated with LS and mutations in the COX assembly gene, SURF1, have been shown to be a frequent cause of LS with COX deficiency (Pequignot et al., 2001). The preschool incidence of LS has been estimated to be 1 per 32 000 births (Darin et al., 2001). In that and other series LS was the most common form of mitochondrial disorder among children (Zeviani et al., 1996; Darin et al., 2001; Skladal et al., 2003) Patients who develop LS are usually normal at birth and show normal early psychomotor development. Onset of disease is usually during the first year of life. In infants the first symptoms are often failure to thrive
136
Table 6.1 Clinical syndromes Lactic acidodsis; OXPHOS deficiency
Syndrome
Major clinical features
Age at presentation
Major neuroradiologic features
Leigh
Failure to thrive, hypotonus, psychomotor regression, brainstem dysfunction, ataxia, dystonia, optic atrophy
Pearson
Failure to thrive, sideroblastic anemia, pancytopenia, exocrine pancreas dysfunction, liver failure, renal tubulopathy Failure to thrive, complex refractory seizures, psychomotor deterioration, tetraparesis, acquired microcephalus, liver dysfunction Muscle weakness, hypotonus, respiratory and feeding difficulties
Usually before 1 year of age, sometimes during childhood, occasionally later Before 1 year of age
MRI: increased signal intensity in basal ganglia, brainstem and white matter (T2-weighted images) CT and MRI normal or unspecific
Lactic acidemia; complex I or complex IV or complex II or complex V in decreasing frequency Lactic acidemia; variable defects of OXPHOS
Before 1 year of age
Lactic acidemia (rare); deficiency mainly of complex I or IV
Before 1 year of age
CT and MRI: atrophy of cerebral cortex, especially occipital lobes, later microcephaly CT and MRI: normal
Childhood, adolescence or adulthood
CT: focal parieto-occipital lesions, basal ganglia calcifications
Childhood, adolescence or adulthood
CT and MRI: normal or unspecific
Childhood, adolescence or adulthood
Young adulthood
MRI: increased signal intensity in basal ganglia, white matter, and cerebellum (T2-weighted images) CT and MRI: normal or unspecific
20–40 years of age
CT and MRI: normal or unspecific
Alpers
Infantile myopathy MELAS
MERRF
Short stature, migraine-like headache, generalized seizures, stroke-like episodes, dementia, ataxia, sensorineural hearing loss, muscle weakness, diabetes mellitus Myoclonic and generalized seizures, ataxia, muscle weakness, sensorineural hearing loss
Lactic acidosis; combined deficiency of OXPHOS, mainly complex IV Lactic acidosis; mainly complex I deficiency
Lactic acidemia; mainly combined deficiency of complex I and IV Lactic acidemia; variable defects of OXPHOS, which may even be normal
ad/ar PEO
PEO, retinitis pigmentosa, cardiac conduction defects, short stature, sensorineural hearing loss, cerebellar ataxia, dementia, diabetes mellitus Muscle weakness, sensory neuropathy, ataxia, retinitis pigmentosa, dementia Muscle weakness and exercise intolerance, PEO
LHON
Rapid loss of central vision, optic atrophy
Usually adulthood, occasionally in childhood
CT and MRI: usually normal
Variable defects of OXPHOS, which may even be normal Complex I deficiency
Myopathy of adults
Muscle weakness and wasting Exercise intolerance Myoglobinuria
Adulthood
CT and MRI: normal
Variable defects of OXPHOS
KSS
NARP
Mainly normal
Leigh: Leigh syndrome; Pearson: Pearson syndrome; Alpers: Alpers syndrome; MELAS: mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes; MERRF: myoclonus epilepsy and ragged red fibers; KSS: Kearns–Sayre syndrome; NARP: neurogeric muscle weakness, ataxia and retinitis pigmentosa; ad/arPEO: autosomal-dominant or -recessive progressive external ophthalmoplegia; LHON: Leber hereditary optic neuropathy; CT: computed tomography; MRI: magnetic resonance imaging; OXPHOS: oxidative phosphorylation.
MITOCHONDRIAL ENCEPHALOMYOPATHIES with increasing feeding difficulties. Common symptoms and signs are progressive, often episodic, psychomotor deterioration with hypotonia and muscle weakness, ataxia, dystonia, choreoathetosis, nystagmus, ophthalmoplegia, swallowing difficulties, growth retardation and hypertrichosis. Severe respiratory insufficiency and rapid multisystem deterioration may lead to death during the first years of life. Childhood, juvenile and adult onset is commonly associated with episodes of ataxia, muscle weakness and hypotonia, followed by respiratory and feeding difficulties. In most patients the disease has a progressive course and eventually leads to death. However, the clinical picture in patients with LS varies considerably and depends somewhat on the causative mutation. For example, the clinical course in patients with LS associated with the mtDNA ATPase6 T8993G mutation is more severe than in patients with the T8993C mutation (White et al., 1999b). LS with COX deficiency and SURF1 mutations is characterized by early normal development with onset of disease characteristically between 6 and 12 months. Failure to thrive, vomiting and feeding difficulties are very common early symptoms, followed by rapid neurological deterioration. Death usually occurs during the first years of life although exceptions to this have been reported in a few cases (Farina et al., 2002; Moslemi et al., 2003). Seizures and involuntary movements were less common in patients with LS caused by SURF1 mutations than in other LS patients (Sue et al., 2000; Farina et al., 2002). Characteristic neuroradiological features of LS are lesions of the basal ganglia (Fig. 6.5), but lesions are also commonly seen in the medulla oblongata, pons, midbrain, cerebellum, the subthalamic nuclei and thalami (Valanne et al., 1998; Munoz et al., 1999; Farina et al., 2002). MR imaging is superior to computed tomography in detecting lesions in the brainstem and cerebellum. With brain computed tomography hypodense areas in basal ganglia have been the most common finding. However, with MR imaging high T2 signal intensity is commonly seen in the putamen as well as in the other locations described above (Valanne et al., 1998; Farina et al., 2002; Ogawa et al., 2002; Moslemi et al., 2003). LS is usually not associated with mitochondrial myopathy. 6.4.3. Pearson syndrome In 1979 four children were described with a syndrome of refractory sideroblastic anemia with vacuolization of marrow precursors and exocrine pancreatic dysfunction with onset in infancy (Pearson et al., 1979). There was a variable degree of neutropenia and thrombocytopenia, and of exocrine pancreatic dysfunction. All infants
137
Fig. 6.5. Magnetic resonance scan of the brain showing hyperintense signals in the dorsal parts of putamen in a 18-month-old girl with Leigh syndrome, cytochrome c oxidase deficiency and SURF1 mutations. Illustration courtesy of Lars-Martin Wiklund.
required regular blood transfusions. Two children died, but two recovered. They needed regular blood transfusions until 11 and 20 months, respectively. Bone marrows from all the children had normal cellularity but were characterized by remarkable vacuolization of erythroid and myeloid precursors, hemosiderosis and ringed sideroblasts. Pearson syndrome is associated with large-scale deletions in mtDNA (Ro¨tig et al., 1989). It is usually fatal during early life, but children who survive may later develop Kearns–Sayre syndrome (KSS; Larsson et al., 1990). In a series of 21 children Ro¨tig et al. found that 12 of 21 had died before the age of 3 years (Ro¨tig et al., 1995). Three of the children died of hepatic failure. Nine of 21 had renal tubulopathy. All of the nine children, who survived, later developed various multiorgan diseases. Although the majority of patients with mtDNA deletions are sporadic, there is a small risk of recurrence in women with PEO due to large-scale single deletions. Two women with PEO gave birth to children who developed Pearson syndrome (Shanske et al., 2002; Chinnery et al., 2004). Pearson syndrome is very rare. In a large multicenter study only 11 of a total of 226 patients with large-scale mtDNA deletions had Pearson syndrome (Chinnery et al., 2004).
138
A. OLDFORS AND M. TULINIUS
6.4.4. Alpers syndrome Alpers syndrome (AS; Alpers, 1931; 1960) is a progressive infantile poliodystrophy, characterized by early onset, rapid and pronounced psychomotor deterioration parallel to acquired microcephaly, complex refractory seizures and liver dysfunction. Although AS is a neuropathological entity, diagnosis is now possible premortem by CT or MRI of the brain (Kendall et al., 1987; Harding, 1990; Barkovich et al., 1993; Smith et al., 1996) in combination with clinical and laboratory findings (Fig. 6.6). AS is a genetically heterogeneous disorder. It has in most instances been associated with deficiency of the enzymes of the respiratory chain, especially complex I and complex IV. Mutations of mitochondrial DNA (mtDNA) associated with AS include one case with a mutation in the COX II gene (Uusimaa et al., 2003). Mutations in the polymerase ggene, POLG1, have also been shown to be associated with AS and mitochondrial DNA depletion and/or multiple mtDNA deletions (Naviaux and Nguyen, 2004; Ferrari et al., 2005; Kollberg et al., 2006). AS is a rare disorder. In a study of the incidence of mitochondrial encephalomyopathies in childhood the preschool incidence of AS was found to be 1 in 51 000, compared to 1 in 32 000 for LS (Darin et al., 2001). CT of the brain may show atrophy and areas of low density involving the cortex and white matter, especially in
A
the occipital region (Kendall et al., 1987). Brain MR imaging of two cases showed atrophy of the occipital lobes in one case and diffuse atrophy in the other (Smith et al., 1996). The neuropathology of AS is characterized by cortical neuronal loss, parenchymal vacuolation and astrocytosis associated with a prominent capillary proliferation. Neuronal loss, spongy change and astrocytosis may also involve subcortical gray matter (Alpers, 1931; 1960; Harding et al., 1986; 1990; Kollberg et al., 2006). Mitochondrial myopathy is usually not present but may be seen. Children with AS are usually normal at birth and show normal early psychomotor development. Onset of disease is usually during the first year of life, but there are also many cases described with childhood or juvenile onset, and a few cases with adult onset (Harding et al., 1995a). The first symptoms in infants are irritability and failure to thrive, followed by development of severe, refractory seizures, psychomotor retardation and spastic quadriplegia. Myoclonic jerks occur often independent of epileptic seizures. Electroencephalography (EEG) shows a characteristic pattern with highamplitude slow activity together with smaller polyspikes (Boyd et al., 1986), and hypsarrhythmia is frequent (Tulinius and Hagne, 1991). In some patients liver involvement is marked and can lead to death in liver failure (Huttenlocher et al., 1976; Harding et al., 1986; 1990). AS in combination with liver failure is
B
Fig. 6.6. Magnetic resonance scans of the brain of a girl with Alpers–Huttenlocher syndrome and mutations in POLG at three and four years of age showing on T2 FLAIR, (A) initial signal abnormalities in the cortex of the left occipital lobe, and (B) one year later progressive atrophy of both occipital lobes. Illustrations courtesy of Lars-Martin Wiklund.
MITOCHONDRIAL ENCEPHALOMYOPATHIES frequently due to POLG1 mutations (Ferrari et al., 2005; Kollberg et al., 2006). 6.4.5. Isolated mitochondrial myopathy in infants Isolated mitochondrial myopathy in infants has mainly been associated with COX deficiency (DiMauro et al., 1980; 1983; Oldfors et al., 1989). A fatal (DiMauro et al., 1980) and a benign reversible form (DiMauro et al., 1983) have been described. Both infantile myopathies begin soon after birth and are associated with severe generalized weakness, breathing and feeding difficulties and lactic acidosis. In the reversible form the children improve spontaneously after 5 months of age, and the lactic acid level gradually decreases, paralleling the patient’s clinical improvement. Some of these patients have residual muscle weakness later in life although there are no signs of mitochondrial myopathy. The fatal myopathic form has been associated with mitochondrial depletion syndrome (MDS; MIM 251880) and mutations in the thymidine kinase-2 gene (TK2; Saada et al., 2001; Mancuso et al., 2002; Carrozzo et al., 2003; Vila et al., 2003; Tulinius et al., 2005). The clinical course is severe with increasing muscle weakness and wasting with early death in almost all cases. The fatal variant may also be associated with cardiomyopathy (Rimoldi et al., 1982; Tulinius et al., 1991; Darin et al., 2003; Holmgren et al., 2003) or nephropathy (DiMauro et al., 1980). MDS has also been associated with a multiorgan disorder affecting mainly the brain and liver with mutations in the deoxyguanosine kinase gene (DGUOK; Mandel et al., 2001a). Although an increasing number of genetic defects resulting in COX deficiency have been described, the molecular basis of the majority of cases remains unidentified (Darin et al., 2003). 6.4.6. MELAS syndrome Pavlakis et al. (1984) described two of their own patients and reviewed nine other patients from the literature with normal early development, short stature, seizures and alternating hemiparesis, hemianopia or cortical blindness. They concluded that patients with mitochondrial myopathy, encephalopathy, lactic acidosis and strokelike episodes (MELAS) syndrome represented a distinct clinical entity that should be differentiated from Kearns–Sayre and MERRF syndromes. The first mutation associated with MELAS, tRNALeu(UUR)A3243G, was identified in 1990 (Goto et al., 1990). As many as 80% of patients fulfilling the clinical criteria for MELAS syndrome harbor this mutation (Goto et al., 1992a). However, there are at least 12 other distinct pathogenic mtDNA gene mutations associated with the MELAS phe-
139
notype (Iizuka et al., 2002). These include mutations at position 3271 (Goto et al., 1991) and 3291 (Goto et al., 1994) in the tRNALeu gene, the T3308C mutation in the ND1 gene (Campos et al., 1997), various ND5 gene mutations (Liolitsa et al., 2003), the T9957C point mutation in the CO III gene (Manfredi et al., 1995) and large-scale deletions (Campos et al., 1995). MELAS syndrome is one of the most frequently occurring mitochondrial diseases. In a population-based study from Finland the A3243G mutation was estimated to occur in 16 of 100 000 adults (Majamaa et al., 1998). In that study the frequency of the A3243G mutation was particularly high in certain disease groups including those with deafness and a family history of hearing loss (7.4%), occipital stroke (6.9%), ophthalmoplegia (13%) and hypertrophic cardiomyopathy (14%). Patients with MELAS syndrome are usually normal at birth and develop normally during the first years of life. The patients are often of short stature and have episodes of vomiting with severe headache leading to somnolence and coma. Some of these episodes lead to severe generalized seizures with stroke-like episodes of hemiparesis, cortical blindness and hemianopia. The stroke-like episodes are characteristically parietooccipital at first. Dementia, ataxia, sensorineural deafness, muscle weakness, exercise intolerance and diabetes mellitus are frequently seen and cardiomyopathy may also develop in the late stages of the disease. Phenotypic heterogeneity has, however, also been well documented in patients with the A3243G mutation. These clinical variations include a pure myopathy with PEO, diabetes and deafness, cardiomyopathy, Wolff– Parkinson–White syndrome, LS, MERRF/MELAS and other overlap syndromes. Infarct-like, often transient lesions not confined to vascular territories are the imaging hallmark of MELAS syndrome (Valanne et al., 1998; Abe et al., 2004). The first lesions are typically localized parieto-occipitally, and they often affect the cortex more than the white matter (Fig. 6.7). CT abnormalities include focal low density, cortical atrophy and calcification in the basal ganglia (Fig. 6.8; Goto et al., 1992a). The neuropathology of MELAS syndrome is variable and includes calcification of basal ganglia, small and large necrotic foci, in addition to laminar necrosis, spongy degeneration, capillary proliferation and gliosis in the neocortex (Hirano and Pavlakis, 1994; Prayson and Wang, 1998). The necrotic lesions resemble infarctions, in acute as well as in late stages, but do not respect vascular territories. Mitochondrial myopathy is usually present. A typical finding in muscle biopsies of MELAS patients with the A3243G mutation is cytochrome c oxidase positive ragged red fibers (Petruzzella et al., 1994).
140
A. OLDFORS AND M. TULINIUS
Fig. 6.7. Magnetic resonance (MR) scan of the brain showing an infarct-like lesion with swelling and hyperintensive cortical and subcortical parenchyma in the right parieto-occipital lobe of a ten-year old girl with MELAS syndrome and the A3243G mutation. The MR scan was performed 5 days after a strokelike episode. Illustration courtesy of Lars-Martin Wiklund.
Fig. 6.8. Computed tomography scan of the brain of a 13year-old girl with MELAS syndrome and the A3243G mutation showing typical calcifications in the globus pallidus. Illustration courtesy of Lars-Martin Wiklund.
6.4.7. MERRF syndrome Myoclonus epilepsy and ragged red fibers (MERRF) syndrome was fully described in 1980 (Fukuhara et al., 1980). The first mutation to be associated with MERRF syndrome was tRNALys A8344G (Shoffner et al., 1990). More than 90% of patients with MERRF syndrome have this mutation (Shoffner et al., 1990; Huang et al., 2002). Two more rare mutations in the same gene have been associated with the MERRF phenotype, the T8356C and G8363C mutations (Silvestri et al., 1992; Ozawa et al., 1997). MERRF syndrome has also been associated with other mutations in the tRNALeu(UUR), tRNASer and tRNAPhe genes (Nakamura et al., 1995; Nishigaki et al., 2003b; Mancuso et al., 2004b). MERRF syndrome does not seem to be as common as MELAS syndrome. The frequency of the A3243G mutation was found to be four times that of the A8344G mutation in north-east England (Chinnery et al., 2000). In two epidemiological studies no patients with MERRF were identified (Darin et al., 2001; Remes et al., 2003). The main clinical features of patients with MERRF syndrome are myoclonus, epileptic seizures, ataxia and muscle weakness (Fukuhara, 1995). Onset of disease is usually in childhood, but onset in adult life occurs. The course can be slowly progressive or rapidly deteriorating.
Myoclonus is usually stimulus sensitive. Seizures are tonic–clonic, often with photosensitivity. Other common features are short stature, sensorineural hearing loss, optic atrophy, dementia, peripheral neuropathy and spastic paraparesis. In a review of 62 patients with MERRF syndrome and the A8344G mutation, one-third had cardiomyopathy presenting either in adolescence or adulthood (Hirano and DiMauro, 1996). A few patients have multiple neck and truncal lipomas. Clinical features of affected relatives vary in pattern and severity of symptoms. Age of onset differs among family members. Many relatives are asymptomatic with low levels of mutated mtDNA (Larsson et al., 1992). The results from neuroradiologic imaging in patients with MERRF syndrome are non-specific. Cerebral and cerebellar atrophy is typical and there is often patchy white matter abnormality of these regions (Fukuhara, 1995). The neuropathology of patients with MERRF syndrome is typically a systemic degeneration involving the globus pallidus, substantia nigra, red, dentate, and inferior olivary nuclei, cerebellar cortex, spinocerebellar tracts, dorsal columns and Clarke’s column, which show degeneration and gliosis (Oldfors et al., 1995a;
MITOCHONDRIAL ENCEPHALOMYOPATHIES Sparaco et al., 1995). Muscle biopsy usually shows mitochondrial myopathy with COX- negative fibers. 6.4.8. Kearns–Sayre syndrome Kearns–Sayre syndrome (KSS) was first recognized as a distinct clinical entity in 1958 (Kearns and Sayre, 1958). It is defined by the triad of PEO, pigmentary retinopathy and onset before age 20 years, with at least one of the following additional features: cerebellar syndrome, cardiac conduction block or cerebrospinal fluid protein greater than 100 mg/dl (Berenberg et al., 1977, Rowland et al., 1983). It is the most common clinical phenotype associated with single largescale deletions of mtDNA (Holt et al., 1988; Zeviani et al., 1988). Other, less common phenotypes of single large-scale mtDNA deletions are PEO without other hallmarks of KSS (Moraes et al., 1989), and Pearson syndrome (Ro¨tig et al., 1990; 1995). Sporadic cases presenting with non-autoimmune Addison disease (Boles et al., 1998), intestinal pseudo-obstruction associated with encephalopathy and cardiomyopathy (Campos et al., 2000), childhood-onset neuropathy and cirrhosis (McDonald et al., 2002), hypoparathyroidism and renal tubular nephropathy (Tulinius et al., 1995) have also been described. In an epidemiological study, PEO and KSS, together, were the second most common type of mtDNA disease in adults, constituting 19% of the cases (Chinnery et al., 2000). The majority of patients with mtDNA deletions are sporadic (Chinnery et al., 2004). The onset of disease is most often during childhood or adolescence. The first symptoms are partial ptosis and PEO, with pigmentary degeneration of the retina, followed by cerebellar ataxia and dementia, sensorineural hearing loss, growth failure, endocrinologic disturbances such as diabetes mellitus and hypoparthyroidism. Seizures are infrequent and usually associated with hypoparathyroidism. Progressive cardiac conduction defects may develop, often leading to complete A-V block with sudden death or need of pacemaker implantation. Cardiomyopathy with cardiac failure occurs in some cases (Moslemi et al., 2000) and a few patients with KSS have undergone cardiac transplantation (Tranchant et al., 1993). Patients with later onset usually have a milder and more slowly progressive disease. Imaging studies in KSS show involvement of the white matter and of the deep gray matter nuclei, particularly the globus pallidus, the thalamus and the cerebellar dentate nucleus (Fig. 6.9). CT scans show cortical and white matter atrophy, hypodensity of the cerebral and cerebellar white matter and variable hypodensity or calcification of the basal nuclei (Barkovich et al., 1993).
141
In KSS the most typical and consistent pathological change is spongiform vacuolation of the white matter (Oldfors et al., 1990; Sparaco et al., 1993). The distribution and extent of the spongiosis varies and may affect the cerebrum, cerebellum, brainstem and spinal cord. In addition there is often degeneration and mineral deposition in the basal ganglia. 6.4.9. Neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP) The first mutation in the neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP) syndrome was identified in the ATPase-6 gene (T8993G; Holt et al., 1990). Variable combinations of retinitis pigmentosa, ataxia, developmental delay, dementia, seizures, proximal muscle weakness and sensory neuropathy characterize NARP. Onset is usually in young adulthood and the clinical course is slowly progressive. Another mutation (T8993C) at the same position was described several years later (De Vries et al., 1993) and it was recognized that when the mutation load was very high, these mutations caused Leigh syndrome. It was also found that the clinical course in patients with NARP associated with the T8993G mutation was more severe than in patients with the T8993C mutation (White et al., 1999b). 6.4.10. Autosomal-dominant/-recessive PEO with multiple mtDNA deletions Autosomal-dominant/-recessive progressive external ophthalmoplegia (ad/ar PEO) usually refers to an adultonset condition with PEO plus various additional clinical manifestations and multiple mtDNA deletions in muscle (Suomalainen and Kaukonen, 2001; Van Goethem et al., 2003b). A special entity, which usually is included in this group of disorders, is the mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) syndrome (Hirano et al., 1994; Nishino et al., 2001; Hirano et al., 2004). In ad/ar PEO, muscle weakness and exercise intolerance are the most common symptoms. Additional manifestations, which sometimes may be the presenting symptoms, include peripheral neuropathy, ataxia, tremor, parkinsonism, mental depression, cataracts, pigmentary retinopathy, dysphagia, hypoacusia, episodic rhabdomyolysis and hypogonadism (Zeviani et al., 1990; Servidei et al., 1991; Kaukonen et al., 1996; Melberg et al., 1996a; 1996b; Suomalainen et al., 1997; Melberg et al., 1998; Kaukonen et al., 1999). The MNGIE syndrome includes gastrointestinal manifestations, cachexia, leukoencephalopathy, peripheral neuropathy and mitochondrial myopathy (Nishino et al., 2001).
142
A. OLDFORS AND M. TULINIUS
A
B
Fig. 6.9. Magnetic resonance scan of the brain of a nine-year-old girl with a multisystem disorder with a single large-scale deletion of mtDNA showing hyperintensive signals in the (A) the globus pallidus and thalamus and (B) subcornical white matter on T2-weighted images. Illustration courtesy of Lars-Martin Wiklund.
Nuclear gene mutations associated with adPEO include the muscle-heart specific mitochondrial adenine nucleotide translocator 1 (ANT1; Kaukonen et al., 2000), C10orf2, encoding a mitochondrial protein similar to phage T7 primase/helicase (gp4) called Twinkle (Spelbrink et al., 2001) and mtDNA polymerase g (POLG1), which is the only mtDNA polymerase in mitochondria (Van Goethem et al., 2001). arPEO and sporadic cases of PEO have been associated with mutations in POLG1 (Van Goethem et al., 2002; Di Fonzo et al., 2003). The sensory ataxic neuropathy, dysarthria and ophthalmoparesis (SANDO) syndrome has also been associated with recessive POLG1 mutations (Van Goethem et al., 2003a). MNGIE, which is a recessively inherited disease, is associated with mutations in the thymidine phosphorylase (TP) gene (ECGF1; Nishino et al., 1999; 2000). Most patients with ad/arPEO and MNGIE show mitochondrial myopathy with COX-deficient, and occasionally COX-positive, ragged red fibers. Biochemical analysis typically shows reduction in the partially mtDNA-encoded respiratory chain complexes I, III and IV (Suomalainen et al., 1992a). However, mitochondrial myopathy and multiple mtDNA deletions in muscle are not a consistent finding (Van Goethem et al., 2003a), and the clinical manifestations evolve gradually probably as a consequence of the gradual accumulation of somatic mtDNA mutations.
6.4.11. Leber hereditary optic neuropathy (LHON) Leber hereditary optic neuropathy (LHON) is the most frequent mtDNA disease with a prevalence of 1 in 50 000 in Finland (Huoponen, 2001) and approximately 1 in 25 000 in north-east England (Man et al., 2003). It is characterized by acute or subacute visual loss with an age at onset between 15 and 35 years, but the range is from young children to individuals older than 60 and there is a marked male predominance (Newman et al., 1991; Johns et al., 1992a; Harding et al., 1995b; Nikoskelainen et al., 1996; Macmillan et al., 1998; Sadun et al., 2003). The loss of vision usually starts in one eye followed by affection of the other eye within weeks or months. The typical field defect is a centrocaecal scotoma and early impairment of color perception is common. There is usually no pain. The maximal loss of vision is within a month in acute forms but the course may be protracted over months or even years. Ophthalmoscopic findings are characteristic during the acute phase with early peripapillary telangiectatic microangiopathy followed by hyperemia, swelling of the optic disc and arteriolar dilatation (Huoponen, 2001; Man et al., 2002). In the chronic stage there is optic atrophy. The final outcome is severely reduced visual acuity, although many patients experience some recovery (Riordan-Eva et al., 1995).
MITOCHONDRIAL ENCEPHALOMYOPATHIES Some patients show in addition to loss of vision other neurological manifestations. These include tremor, polyneuropathy, ataxia, dystonia, migraine-like disorder, deafness and skeletal deformities (Newman, 1993; Jun et al., 1994; Nikoskelainen et al., 1995; Huoponen, 2001; Cupini et al., 2003). In addition, a group of patients develop clinical and neuroimaging features, which cannot be distinguished from multiple sclerosis (Harding et al., 1992; Kellar-Wood et al., 1994; Olsen et al., 1995; Jansen et al., 1996). This may be especially associated with the G11778A mutation (Riordan-Eva et al., 1995). Leber hereditary optic neuropathy is a maternally inherited disease. There are three mtDNA mutations accounting for more than 95% of the cases: G3460A (ND1 gene; Howell et al., 1991; Huoponen et al., 1991), G11778A (ND4 gene; Wallace et al., 1988), and T14484C (ND6 gene; Johns et al., 1992b). The G11778A mutation is the most frequent and is also associated with the worst prognosis. In addition there are several rare mutations in the ND5 and ND6 genes that are also considered as primary LHON mutations (Jun et al., 1994; Wissinger et al., 1997; Howell et al., 1998; Chinnery et al., 2001a). In the majority of LHON families there is homoplasmy, which is unusual for pathogenic mtDNA mutations. Heteroplasmy has been demonstrated in only 15% (Smith et al., 1993). There appears not to be any difference between patients that are homoplasmic compared to those that are heteroplasmic (Smith et al., 1993). In addition to the primary LHON mutations, there are several other mtDNA mutations that increase the risk for LHON and these are considered as secondary. Some of these are clustered on a specific mtDNA background, haplotype J. The risk of visual loss in carriers with the G11778A and T14484C mutations is increased by haplotype J (Man et al., 2004). Biochemical investigation of mitochondrial function has demonstrated no or modest reduction of complex I activity in various cells and tissues (Man et al., 2002). These results have raised questions about the pathophysiology of LHON. Studies on hybrids have indicated that there is reduced activity of the EAAT1 glutamate transporter in LHON, which may increase the susceptibility of retinal ganglion cells to exitotoxic damage (Beretta et al., 2004).
6.4.12. Isolated mitochondrial myopathy in adolescents and adults Mitochondrial diseases may occasionally present as isolated skeletal myopathy, which are sometimes but not consistently accompanied by ptosis and/or external
143
ophthalmoplegia. The disease manifestations are variable. The patients may experience exercise intolerance with fatigue, muscle pain and stiffness and occasionally muscle cramps. Proximal muscle weakness is also common. A rare manifestation is episodic rhabdomyolysis with myoglobinuria. Onset of disease manifestations may be in childhood or more frequently in adulthood. Most patients show a progressive course, but spontaneous recovery has been reported. Isolated mitochondrial myopathy has been described in association with various mtDNA mutations, including single or multiple large-scale deletions (Laforet et al., 1995; Di Fonzo et al., 2003) as well as point mutations in the genes encoding tRNAs (Goto et al., 1992b; Ionasescu et al., 1994; Ogle et al., 1997; Kleinle et al., 1998; Silvestri et al., 1998; Hadjigeorgiou et al., 1999; Pulkes et al., 2000; Sternberg et al., 2001), cytochrome b (Andreu et al., 1998; 1999a; 1999b; Legros et al., 2001), COX I, II and III (Keightley et al., 1996; Rahman et al., 1999; Karadimas et al., 2000; McFarland et al., 2004c; Kollberg et al., 2005), and ND4 (Andreu et al., 1999c). In most instances the isolated myopathy is explained by the occurrence of a mtDNA mutation only in muscle. Such cases are usually sporadic, and probably the result of de-novo mutations. In other patients the mutation exceeds the threshold level for manifestation only in muscle. In one case the expression of the disease only in muscle was explained by a mitochondrial RNA processing error that was restricted to muscle tissue (Bindoff et al., 1993). In cases with multiple mtDNA deletions the mtDNA mutations are usually somatic and secondary to nuclear gene mutations (Suomalainen and Kaukonen, 2001). In isolated mitochondrial myopathies with clinical manifestations from muscle, the histochemical analysis shows muscle fibers with abnormal proliferation and ultrastructural alterations of the mitochondria, which may give the clue to correct diagnosis. COX-positive ragged red fibers will indicate a mutation in the genes encoding cytochrome b, tRNALeu or NADH-dehydrogenase (ND genes), whereas COX-deficient fibers indicate a mutation in a COX gene, a tRNA gene, mtDNA depletion or large-scale deletion(s). Isolated mitochondrial myopathy with ragged red fibers and occasional COXdeficient fibers may also be due to muscle coenzyme Q10 deficiency (Lalani et al., 2005). In myopathy with deficiency of succinate dehydrogenase and aconitase there is mitochondrial myopathy with ragged red fibers (Hall et al., 1993; Drugge et al., 1995). The patients experience exercise intolerance with early exhaustion and dyspnea, muscle pain and cramps and in some instances myoglobinuria. The succcinate dehydrogenase deficiency is evident by enzyme-histochemical as well as biochemical analyses. The underlying genetic defect has not yet been identified.
144
A. OLDFORS AND M. TULINIUS
6.5. Organ manifestations A summary of the organ manifestations is presented in Fig. 6.10. 6.5.1. Nervous system and ocular manifestations The central nervous system (CNS), peripheral nervous system (PNS) and skeletal muscle are affected in the
majority of mitochondrial disorders. The signs and symptoms from the nervous system may include mental retardation, autistic features, mental depression, apnea attacks, myoclonic seizures, epilepsy, ataxia, migrainelike headache, stroke-like episodes, sensorineural hearing loss, reduced vision and blindness, hemianopsia, peripheral neuropathy, muscle weakness and fatigue, muscle hypotonia and hypertonia, ptosis and ophthalmoparesis, autonomic disturbances and others. The CNS
Fig. 6.10. Summary of organ and tissue manifestations in mitochondrial diseases. Illustration by Yvonne Heijl.
MITOCHONDRIAL ENCEPHALOMYOPATHIES involvement may be selective or generalized. White matter changes or leukodystrophy are common and especially prominent in KSS (Bordarier et al., 1990; Oldfors et al., 1990; Bonilla et al., 1992; Sparaco et al., 1993). There is spongiosis of the white matter at the light-microscopic level due to splitting of the myelin sheath. Gray matter degeneration may predominate in some conditions. Cortical changes include diffuse loss of nerve cells and gliosis, spongiotic changes, widespread or focal laminar necrosis and infarct-like lesions. Cortical changes are especially prominent in MELAS and Alpers syndrome (Fujii et al., 1990; Harding, 1990; Kim et al., 1996; Iizuka et al., 2003; Kollberg et al., 2006). Subcortical gray matter degeneration, spongiosis and capillary proliferation can be seen in various mitochondrial diseases but is especially prominent in Leigh syndrome (Leigh, 1951; Gogus et al., 1994; Agapitos et al., 1997). Calcification of the basal ganglia is an unspecific change that can be seen in various mitochondrial disorders (Robertson et al., 1979; Legido et al., 1988; Verma et al., 1996; Prayson and Wang, 1998). System degeneration without focal lesions is a typical feature of MERRF syndrome and often involves the globus pallidus, substantia nigra, red nuclei, dentate nuclei, inferior olivary nuclei, cerebellar cortex, spinocerebellar tracts, dorsal columns and Clarke’s column (Berkovic et al., 1989; Lombes et al., 1989; Fukuhara, 1991; Oldfors et al., 1995a). Prenatal onset of mitochondrial disorders may lead to various brain malformations. Dysgenesis or agenesis of corpus callosum has been described in several reports (Von Kleist-Retzow et al., 2003; Coenen et al., 2004b; Miller et al., 2004). Optic atrophy with visual impairment is found in different mitochondrial diseases but is especially associated with Leber hereditary optic neuropathy (LHON) and Leigh syndrome (Leuzzi et al., 1992; Makelabengs et al., 1995; Birch-Machin et al., 2000; Carelli et al., 2002; Hwang et al., 2002; Man et al., 2002; Benit et al., 2004). Retinal pigmentary degeneration is common in mitochondrial diseases especially in diseases due to mtDNA mutations, and the changes are often subclinical (Sue et al., 1997; Isashiki et al., 1998; Mojon, 2001). Cataract is an additional ocular manifestation in mitochondrial disorders that can occur in diseases due to single mtDNA deletions and point mutations as well as in disorders due to multiple mtDNA deletions (Servidei et al., 1991; Melberg et al., 1996b; Pitkanen et al., 1996; Cursiefen et al., 1998; Wibrand et al., 2001; Sacconi et al., 2002; Bene et al., 2003). The progressive external ophthalmoplegia (PEO), which is a typical sign of OXPHOS diseases is probably of myogenic origin (Carlow et al., 1998) and may be due to the special properties of these muscles that make them more vulnerable (Yu Wai Man et al., 2005).
145
Sensorineural hearing impairment is common in mitochondrial diseases (Lehtonen et al., 2000; Zwirner and Wilichowski, 2001; Edmonds et al., 2002). It can occur as part of a multisytem disorder (Keats, 2002), such as MELAS (Karkos et al., 2004a), MERRF (Calabresi et al., 1994) and KSS (Wilichowski et al., 1997) or combined with diabetes mellitus (Remes et al., 1993). Nonsyndromic sensorineural hearing impairment has been described in association with different mutations in the aminoacyl acceptor stem of tRNASer(UCN) gene (Reid et al., 1994; Sue et al., 1999; Hutchin et al., 2000). Mutations at position 1555 in the 12S rRNA gene are associated with hearing impairment especially after treatment with aminoglycosides (Prezant et al., 1993; Estivill et al., 1998; Malik et al., 2003). Peripheral neuropathy is commonly encountered in mitochondrial diseases. Axonal degeneration is the most frequent pathological change but primary myelin damage may occur (Schro¨der, 1993; Bouillot et al., 2002). Motor neuron disease and spinal muscular atrophy have been described in association with OXPHOS diseases (Comi et al., 1998; Kirches et al., 1999; Berger et al., 2003; Tarnopolsky et al., 2004). 6.5.2. Skeletal muscle Mitochondrial disorders are usually, but not consistently, associated with myopathy, which may lead to moderate muscle wasting, exercise intolerance, muscle pain, cramps, fatigue and episodic rhabdomyolysis. Myopathy may be the only manifestation of a mitochondrial disease but usually it is part of a multisystem disorder. In diseases due to mtDNA rearrangements or tRNA point mutations, mitochondrial myopathy with ragged red fibers (RRF) is a typical finding (Fig. 6.11). The RRF usually show enzyme histochemical COX deficiency and accumulation of abnormal mitochondria. The number of COX-deficient fibers and/or RRF does not reflect the proportion of mutant mtDNA but rather the distribution of mutant and wild-type mtDNA (Oldfors et al., 1992). The fibers are COX deficient when there is accumulation of mutant mtDNA and the threshold for expression of the mutation is exceeded (Boulet et al., 1992; Moslemi et al., 1998). tRNA point mutations are occasionally associated with COX-positive RRF. The most well-known example is the A3243G MELAS mutation (Petruzzella et al., 1994). Only some of the mutations of protein-encoding genes of mtDNA are associated with mitochondrial myopathy. For example the T8993G/C mutation in the ATPase6 gene, which is associated with the NARP/LS, and the different mutations in complex I (ND) genes associated with LHON, do not present with typical mitochondrial
146
A. OLDFORS AND M. TULINIUS
C
B
A
D
E
Fig. 6.11. (A) Light microscopy of mitochondrial myopathy with several muscle fibers showing accumulation of mitochondria (arrows). Enzyme-histochemical staining of succinate dehydrogenase, which specifically stains mitochondria. (B–E) Electron microscopy of mitochondria in mitochondrial myopathy showing various alterations such as paracrystalline inclusions (B: arrow), electron-dense inclusions (C: arrow), circular arrangements of cristae (D: arrow) and giant mitochondria with inclusions (E: arrow).
myopathy. However mutations in the genes encoding cytochrome b, COX I-III and some ND subunits show mitochondrial myopathy with RRF (Andreu et al., 1999b; 1999c; Kollberg et al., 2005). There are usually no major degenerative changes or interstitial fibrosis in muscle tissue, although mtDNA mutations may rarely cause recurrent rhabdomyolysis (Andreu et al., 1999a; Karadimas et al., 2000; McFarland et al., 2004c; Kollberg et al., 2005) and occasionally changes suggestive of muscular dystrophy (Vissing et al., 1998). Mutations of nuclear genes causing OXPHOS deficiency are in some instances associated with mitochondrial myopathy with RRF, as seen in adPEO and mtDNA depletion disorders. In contrast, mutations in nuclear-encoded complex I and II subunits, which are in most instances associated with LS, usually do not show typical mitochondrial myopathy. SURF1 mutations are associated with generalized COX deficiency in muscle but no RRF (Zhu et al., 1998; Pequignot et al., 2001; Moslemi et al., 2003). An obstacle in the diagnostic work on mitochondrial myopathies is the frequent presence of age-related mitochondrial changes (Fayet et al., 2002) and mitochondrial alterations that occur secondary to other disease
processes, e.g., in inclusion body myositis (Oldfors et al., 1995b; Oldfors et al., 2006). A special disease entity called “Late-onset mitochondrial myopathy” has emerged as a differential diagnosis in these cases (Johnston et al., 1995). These aging-associated mitochondrial changes are due to somatic mutations of mtDNA. Premature aging can be induced in mice by creating a mutation in mtDNA polymerase g, which results in multiple somatic mtDNA mutations (Trifunovic et al., 2004). 6.5.3. Heart Cardiac disease is one of the most frequent manifestations of mitochondrial disorders. It has been estimated to occur in about 20% of the cases of pediatric mitochondrial diseases (Darin et al., 2001; Holmgren et al., 2003). In a study on 17 children with mitochondrial cardiomyopathy all had hypertrophic non-obstructive cardiomyopathy (Holmgren et al., 2003). Dilated cardiomyopathy (DCM) has been reported less frequently (Hu¨bner et al., 1986; Suomalainen et al., 1992b; Anan et al., 1995; Antozzi and Zeviani, 1997; Moslemi et al., 2000), but the delineation between hypertrophic and dilated cardiomyopathy depends on definitions (Holmgren et al.,
MITOCHONDRIAL ENCEPHALOMYOPATHIES 2003). The cardiomyopathy may evolve from hypertrophic cardiomyopathy to severe dilated cardiomyopathy (Terasaki et al., 2001). Other expressions of mitochondrial disease in the heart include conduction block and ventricular dysrythmias (Antozzi and Zeviani, 1997). KSS and PEO patients with large-scale mtDNA deletions frequently develop conduction blocks, which may necessitate pacemaker treatment. Patients with large-scale mtDNA deletions may occasionally develop severe cardiac failure (Tranchant et al., 1993; Moslemi et al., 2000). The underlying genetic defects of mitochondrial cardiomyopathies include mtDNA mutations as well as nuclear gene mutations (Antozzi and Zeviani, 1997; Marin-Garcia and Goldenthal, 1997; Loeffen et al., 2001; Benit et al., 2003; Holmgren et al., 2003). Mutations in mtDNA tRNA genes associated with cardiomyopathy commonly affect either tRNALeu(UUR), tRNALys or tRNAIle (Antozzi and Zeviani, 1997). Patients with cardiomyopathy associated with mutations in tRNALeu (UUR) or tRNALys are usually also affected by encephalomyopathy. However, when there is a mutation in the tRNAIle gene, cardiomyopathy is frequently the main clinical manifestation (Taniike et al., 1992; Casali et al., 1995; Santorelli et al., 1995). Leigh syndrome caused by mutations in the mtDNA encoded ATPase6 gene or the nuclear-encoded COX assembly SURF1 gene may be associated with cardiomyopathy (Pastores et al., 1994; Holmgren et al., 2003). Mutations in other COX assembly genes such as COX10, COX15 and SCO2 have also been associated with cardiomyopathy (Papadopoulou et al., 1999; Antonicka et al., 2003a; 2003b).
6.5.4. Liver The liver is frequently affected in mitochondrial diseases and liver failure may be the major manifestation of some diseases such as mitochondrial DNA depletion syndromes associated with mutations in the deoxyguanosine kinase gene (DGUOK; Mandel et al., 2001a; Taanman et al., 2002; Wang et al., 2005), and in some cases of Alpers syndrome, which has been associated with mutations in mtDNA polymerase gamma (POLG1; Naviaux and Nguyen, 2004; Ferrari et al., 2005). It can also be observed in association with mtDNA rearrangements such as in Pearson syndrome and other conditions (Ro¨tig et al., 1990; Gurakan et al., 1999; McDonald et al., 2002). The hepatic pathology may range from steatosis to necrosis and cirrhosis (Mandel et al., 2001b; Ferrari et al., 2005; Kollberg et al., 2006). One important aspect of liver disease in mitochondrial disorders is the risk for valproate-induced acute liver failure (Bicknese et al., 1992; Krahenbuhl et al., 2000; Gauthier-Villars et al., 2001; Kollberg et al., 2006).
147
6.5.5. Kidney The most frequent renal manifestation in mitochondrial cytopathies is de Toni–Fanconi–Debre syndrome in infants due to proximal renal tubular dysfunction (Ro¨tig et al., 1997b). Other manifestations include tubulointerstitial nephropathy, renal tubular acidosis, focal segmental glomerulosclerosis with nephrotic syndrome and in some cases renal failure (Buemi et al., 1997; Ro¨tig et al., 1997b; Hirano et al., 2002; Dinour et al., 2004). The kidney disease is usually part of a multisystem OXPHOS disease but may be the predominant or initial manifestation in some cases (Tulinius et al., 1995; Ro¨tig et al., 1997b; Kurogouchi et al., 1998; Tzen et al., 2001; Ueda et al., 2004). Various tRNA point mutations as well as large-scale deletions of mtDNA have been associated with kidney disease (Ro¨tig, 2003). Nuclear gene mutations causing mitochondrial disease with renal involvement include mutations in COX10 associated with complex IV deficiency and proximal tubulopathy (Valnot et al., 2000b), mutations in BCCS1L associated with complex III deficiency and proximal tubulopathy (De Lonlay et al., 2001) and mutations in COQ2 associated with primary CoQ10 and segmental glomerulosclerosis (Quinzii et al., 2006). 6.5.6. Endocrine organs Endocrine disturbances are common manifestations of mitochondrial diseases (Harvey and Barnett, 1992; Quade et al., 1992; Nissenkorn et al., 1999). These involve the hypothalamic-pituitary gland system, the thyroid and parathyroid glands, the adrenals, the b cells of the pancreas islets and the gonads. Reported disturbances include growth hormone deficiency, adrenocorticotropic hormone (ACTH) deficiency, hypothalamopituitary hypothyroidism, gonadotropin deficiency, diabetes insipidus, hypothyroidism, hypoparathyroidism, Addison disease, hyperaldosteronism, hypoglycaemia, diabetes mellitus (insulin and non-insulin dependent) and hypogonadism (Harvey and Barnett, 1992; Quade et al., 1992; Chen and Huang, 1995; Tulinius et al., 1995; Papadimitriou et al., 1996; Nicolino et al., 1997; Wilichowski et al., 1997; Boles et al., 1998; Nissenkorn et al., 1999; Balestri and Grosso, 2000). The mitochondrial diseases associated with endocrine dysfunction may be caused by mtDNA large-scale deletions as well as mtDNA point mutations, especially those affecting the tRNALeu(UUR) gene (Harvey and Barnett, 1992; Quade et al., 1992; Balestri and Grosso, 2000; DiMauro et al., 2004a). A common cause of diabetes mellitus in 7mitochondrial diseases is mutations in the tRNALeu (UUR) gene (Reardon et al., 1992; Van den Ouweland et al., 1992), and it has been estimated that the tRNALeu
148
A. OLDFORS AND M. TULINIUS
(UUR)
A3243G accounts for approximately 0.5–1.5% of non-insulin dependent diabetes mellitus (Gerbitz et al., 1995; Maassen and Kadowaki, 1996; Newkirk et al., 1997). In addition to the endocrine dysfunction of the pancreatic islets, exocrine dysfunction of pancreas is typically associated with large-scale mtDNA rearrangements in the Pearson bone marrow–pancreas syndrome (Pearson et al., 1979; Ro¨tig et al., 1990; 1995; Van den Ouweland et al., 2000; Krauch et al., 2002). 6.5.7. Skin
Skin manifestations are not uncommon in mitochondrial disorders (Birch-Machin, 2000). One study, which included a review of 274 patients, reported skin manifestations in 16 patients (Flynn et al., 1998), whereas another study reported 14 patients in a cohort of 140 patients (Bodemer et al., 1999). The major skin manifestations have been hair shaft alterations frequently combined with alopecia, pigmentation abnormalities with hyper- and hypo-pigmentation, hypertrichosis and acrocyanosis (Bodemer et al., 1999; Birch-Machin, 2000; Von Kleist-Retzow et al., 2001). The underlying molecular defect is frequently a mtDNA rearrangement, but other mtDNA or nuclear DNA mutations have also been reported (Bodemer et al., 1999; Von Kleist-Retzow et al., 2001). Multiple symmetrical lipomas is an additional cutaneous expression of mitochondrial disease, which has usually been associated with the tRNALys A8344G mutation (Holme et al., 1993; Calabresi et al., 1994; Larsson et al., 1995; Tra¨ff et al., 1995) but other mtDNA mutations have also been reported (Campos et al., 1996b; Klopstock et al., 1997; Suzuki et al., 1997; Mancuso et al., 1999). 6.5.8. Gastrointestinal tract Symptoms from the gastrointestinal tract are frequent in patients with mitochondrial disorders (Chinnery and Turnbull, 1997). Common symptoms are dysphagia and constipation. Gut dysmotility is especially associated with the mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) syndrome (Hirano et al., 1994; 2004), but may occur also in other mitochondrial disorders (Hammans et al., 1995; Verma et al., 1997; Haftel et al., 2000; Chang et al., 2004). Malabsorption associated with villus atrophy has been described (Cormier-Daire et al., 1994), and gastrointestinal symptoms may also be explained by exocrine pancreas dysfunction in some cases. Although abnormal mitochondria may be observed in smooth muscle and ganglion cells of the intestine in MNGIE (PerezAtayde et al., 1998) the underlying mechanism in
mitochondrial enteropathy may not be primarily within the gastrointestinal tract (Chinnery et al., 2001b). 6.5.9. Bone marrow Sideroblastic anemia is the cardinal feature of Pearson bone marrow–pancreas syndrome (Pearson et al., 1979), which is caused by single large-scale mtDNA deletions (Ro¨tig et al., 1990). Pancytopenia is sometimes present and the bone marrow shows vacuolization of myeloid precursors and ringed sideroblasts. Sideroblastic anemia has also been reported in association with multiple mtDNA deletions (Casademont et al., 1994) and mtDNA point mutations (Gattermann et al., 1997).
6.6. Treatment Patients with OXPHOS deficiency are difficult to evaluate as to the benefits of any therapeutic trial, due to the variability of clinical manifestations and the fluctuating course of the disease. In the majority of patients the clinical course is progressive. There is currently no cure available (Chinnery et al., 2006). However, symptomatic therapy can be very helpful (DiMauro et al., 2004b). OXPHOS deficiency limits energy metabolism and disrupts the balance between energy supply and demand. Therefore adequate caloric intake is of utmost importance, especially in infants and young children, in whom feeding problems may also necessitate percutaneous endoscopic gastrostomy. Seizures are a major problem in MELAS, MERRF and AS, but are less common in KSS, PS and LS. Seizures can be treated with conventional antiepileptic drugs. However, valproic acid should be avoided in patients with OXPHOS disease because of inhibition of carnitine uptake (Tein et al., 1993). Further, it may enhance liver toxicity commonly reported in children with AS. Patients with diabetes mellitus, hypoparathyroidism and other endocrinologic disturbances respond to conventional therapy. The use of growth hormone for children with growth retardation is controversial because the increased metabolic demand may be ill tolerated. This is also true for thyroxine substitution. High-dose corticosteroids have improved symptoms in patients with MELAS and in other cases of mitochondrial encephalomyopathy (Shapira et al., 1977; Montagna et al., 1988). Pacemaker implantation may be life-saving in patients with KSS who develop complete A-V block. Heart transplantation has been offered to patients with cardiac failure, especially when the cardiac symptoms
MITOCHONDRIAL ENCEPHALOMYOPATHIES are the predominant problem (Tranchant et al., 1993; Santorelli et al., 2002; Holmgren et al., 2003). A few patients with liver failure have been treated with liver transplantation (Sokal et al., 1999; Rake et al., 2000; Dubern et al., 2001; Salviati et al., 2002c). Severe ptosis and congenital cataracts may be treated by surgery. Treatment of the sensorineural hearing loss in mitochondrial diseases by cochlear implantation may be successful (Yamaguchi et al., 1997; Sue et al., 1998; Sinnathuray et al., 2003; Karkos et al., 2004b). Dichloroacetate, an inhibitor of pyruvate dehydrogenase kinase, decreases lactate concentration effectively in most patients with lactic acidosis (Stacpoole et al., 1997). However, there is little evidence of associated clinical benefit, except in a few patients with MELAS and LS (Saijo et al., 1991; Taivassalo et al., 1996; Kuroda et al., 1997; Takanashi et al., 1997; Saitoh et al., 1998; Fujii et al., 2002; Mori et al., 2004). A common side effect of dichloroacetate treatment is that it may aggravate or cause a peripheral neuropathy (Stacpoole et al., 1997; Spruijt et al., 2001; Kaufmann et al., 2006). The neuropathy is considered to be a result of secondary thiamine deficiency caused by an increased demand for this vitamin associated with dichloroacetate therapy. Co-administration of thiamine may therefore decrease the risk for dichloroacetateassociated neuropathy (Stacpoole et al., 1997; Fujii et al., 2002). A mild liver dysfunction has also been noted in patients with MELAS on long-term treatment with dichloroacetate (Mori et al., 2004). Since hepatocarcinogenicity of dichloroacetate has been noticed in rodents (DeAngelo et al., 1996), regular follow-up of patients on treatment with dichloroacetate with liver function tests and ultrasound studies of the liver have been recommended (Mori et al., 2004). Treatment with coenzyme Q10 (ubidecarenone) and other cofactors and vitamins is given with the aim to improve ATP production. Coenzyme Q10 functions as an electron shuttle from complex I and II to complex III. It is also a scavenger of oxygen free radicals protecting mitochondrial inner membrane proteins and lipids and mitochondrial DNA against oxidative damage (Walker and Byrne, 1995). Patients with coenzyme Q10 deficiency benefit from coenzyme Q10 supplementation (Ogasahara et al., 1989; Sobreira et al., 1997; Boitier et al., 1998; Di Giovanni et al., 2001). Coenzyme Q10 has also been shown to improve cerebral metabolism in patients with mitochondrial disease (Nishikawa et al., 1989; Gold et al., 1996). However, improvement has not always been documented (Bresolin et al., 1990; Matthews et al., 1993). In a recent review of children with mitochondrial disease treated with any or all of thiamine, riboflavin, coenzyme Q10, vitamin C and a high-fat diet, it was
149
concluded that high-dose vitamin and cofactor treatment was well tolerated and possibly effective in the short term, but ineffective in the long term (Panetta et al., 2004). They described that a pattern emerged, in which initial improvement, usually up to 12 months, was followed by a period of stability, which in turn was followed by deterioration and death. They also pointed out that in most previous reports, in which clinical improvement following treatment was documented, the follow-up period was less than 12 months (Panetta et al., 2004). They concluded that high-dose vitamin and cofactor treatment of patients with mitochondrial disorders is safe and does not seem to cause adverse effects. However, patients and families should be counseled that the effect of this therapy is very limited. It seems to improve energy level and quality of life in the short term but is ineffective in the long term (Panetta et al., 2004). Taken together, these findings support the conclusion that the outcome and morbidity are related more to the biochemical and molecular diagnosis than to the treatment (Artuch et al., 1998). Creatine is the substrate for the synthesis of phosphocreatine, which is the most abundant energy storage compound in muscle, heart and brain. Both open and randomized clinical trials have shown improvement in muscle strength, physical exercise and aerobic oxidative function in patients with mitochondrial disease who have been treated with creatine (Hagenfeldt et al., 1994; Tarnopolsky et al., 1997; Komura et al., 2003). Creatine is virtually free of side effects so its administration may be warranted. Caution has been adverted for exercise training of patients with mitochondrial disease because of fear of increasing muscle damage. However, several recent studies have shown that patients benefit from aerobic training with increased work and oxidative capacity (Taivassalo et al., 1996; Taivassalo et al., 2001; Trenell et al., 2006). Gene therapy for mitochondrial disorders is not yet available. However, gene shifting has been discussed as a method to reduce the relative amount of mutant mtDNA, and it can in some instances be accomplished by induction of muscle fiber damage and regeneration, if the satellite cells do not harbor the mtDNA mutation (Clark et al., 1997; Taivassalo et al., 1999).
6.7. Genetic counseling Genetic counseling aims to provide accurate information on prognosis of affected individuals, the recurrence risk, and options on avoiding further pregnancies with affected children. Increasing numbers of nuclear genes are being found that cause Leigh syndrome, Alpers syndrome, mtDNA depletion syndrome and other severe
150
A. OLDFORS AND M. TULINIUS
multiorgan mitochondrial diseases with early onset. In these autosomal recessive disorders genetic counseling is possible and prenatal diagnosis is an option in future pregnancies when the genetic defect has been identified in an older affected sibling. Although the majority of patients with mtDNA deletions are sporadic, there is a small risk of recurrence in women with PEO or KSS due to large-scale single deletions (Chinnery et al., 2004). Two women with PEO gave birth to children who developed Pearson syndrome (Bernes et al., 1993; Shanske et al., 2002) and identical deletions have been found in a mother and son, both with KSS (Puoti et al., 2003). Most adults and older children with OXPHOS disease have a disease caused by point mutations of mtDNA. Genetic counseling is difficult although our understanding of the effects of different mutant loads of the most common mutations on the offspring of mothers carrying these point mutations is constantly increasing (Larsson et al., 1992; Harding et al., 1995b; Chinnery et al., 1998; White et al., 1999b). Prenatal diagnosis of point mutations of mtDNA such as in MELAS and MERRF is, however, still very difficult because the mutant load in amniocytes or chorionic villi does not necessarily correspond to that of other fetal tissues and the mutant load measured in prenatal samples may shift during later stages of pregnancy or after birth due to mitotic segregation (White et al., 1999b; DiMauro et al., 2004b). There is evidence that the G8993T and G8993C mutations causing NARP/LS show less tissueand age-related variations, thus making prenatal diagnosis possible in these families (White et al., 1999b; 1999c; Leshinsky-Silver et al., 2003).
References Abe K, Yoshimura H, Tanaka H, et al. (2004). Comparison of conventional and diffusion-weighted MRI and proton MR spectroscopy in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like events. Neuroradiology 46: 113–117. Ackrell B (2002). Cytopathies involving mitochondrial complex II. Mol Aspects Med 23: 369. Agapitos E, Pavlopoulos PM, Patsouris E, et al. (1997). Subacute necrotizing encephalomyelopathy (Leigh’s disease): a clinicopathologic study of ten cases. Gen Diagn Pathol 142: 335–341. Agostino A, Valletta L, Chinnery PF, et al. (2003). Mutations of ANT1, Twinkle, and POLG1 in sporadic progressive external ophthalmoplegia (PEO). Neurology 60: 1354–1356. Alpers BJ (1931). Diffuse progressive degeneration of the grey matter of the cerebrum. Arch Neurol Psychiatry 25: 469–505. Alpers BJ (1960). Progessive cerebral degeneration of infancy. J Nerv Ment Dis 130: 442–448.
Anan R, Nakagawa M, Miyata M, et al. (1995). Cardiac involvement in mitochondrial diseases: a study on 17 patients with documented mitochondrial DNA defects. Circulation 91: 955–961. Andreu AL, Bruno C, Shanske S, et al. (1998). Missense mutation in the mtDNA cytochrome b gene in a patient with myopathy. Neurology 51: 1444–1447. Andreu AL, Bruno C, Dunne TC, et al. (1999a). A nonsense mutation (G15059A) in the cytochrome b gene in a patient with exercise intolerance and myoglobinuria. Ann Neurol 45: 127–130. Andreu AL, Hanna MG, Reichmann H, et al. (1999b). Exercise intolerance due to mutations in the cytochrome b gene of mitochondrial DNA. N Engl J Med 341: 1037–1044. Andreu AL, Tanji K, Bruno C, et al. (1999c). Exercise intolerance due to a nonsense mutation in the mtDNA ND4 gene. Ann Neurol 45: 820–823. Antonicka H, Leary SC, Guercin GH, et al. (2003a). Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency. Hum Mol Genet 12: 2693–2702. Antonicka H, Mattman A, Carlson CG, et al. (2003b). Mutations in COX15 produce a defect in the mitochondrial heme biosynthetic pathway, causing early-onset fatal hypertrophic cardiomyopathy. Am J Hum Genet 72: 101–114. Antozzi C, Zeviani M (1997). Cardiomyopathies in disorders of oxidative metabolism. Cardiovasc Res 35: 184–199. Artuch R, Vilaseca MA, Pineda M (1998). Biochemical monitoring of the treatment in paediatric patients with mitochondrial disease. J Inherit Metab Dis 21: 837–845. Astuti D, Hart-Holden N, Latif F, et al. (2003b). Genetic analysis of mitochondrial complex II subunits SDHD, SDHB and SDHC in paraganglioma and phaeochromocytoma susceptibility. Clin Endocrinol (Oxf) 59: 728–733. Balestri P, Grosso S (2000). Endocrine disorders in two sisters affected by MELAS syndrome. J Child Neurol 15: 755–758. Barkovich AJ, Good WV, Koch TK, et al. (1993). Mitochondrial disorders — analysis of their clinical and imaging characteristics. Am J Neuroradiol 14: 1119–1137. Barrientos A, Korr D, Tzagoloff A (2002). Shy1p is necessary for full expression of mitochondrial COX1 in the yeast model of Leigh’s syndrome. EMBO J 21: 43–52. Barthelemy C, Ogier de Baulny H, Diaz J, et al. (2001). Lateonset mitochondrial DNA depletion: DNA copy number, multiple deletions, and compensation. Ann Neurol 49: 607–617. Bene J, Nadasi E, Kosztolanyi G, et al. (2003). Congenital cataract as the first symptom of a neuromuscular disease caused by a novel single large-scale mitochondrial DNA deletion. Eur J Hum Genet 11: 375–379. Benit P, Chretien D, Kadhom N, et al. (2001). Large-scale deletion and point mutations of the nuclear NDUFV1 and NDUFS1 genes in mitochondrial complex I deficiency. Am J Hum Genet 68: 1344–1352. Benit P, Beugnot R, Chretien D, et al. (2003). Mutant NDUFV2 subunit of mitochondrial complex I causes early
MITOCHONDRIAL ENCEPHALOMYOPATHIES onset hypertrophic cardiomyopathy and encephalopathy. Hum Mutat 21: 582–586. Benit P, Slama A, Cartault F, et al. (2004). Mutant NDUFS3 subunit of mitochondrial complex I causes Leigh syndrome. J Med Genet 41: 14–17. Berenberg RA, Pellock JM, et al. (1977). Lumping or splitting? “Ophthalmoplegia plus” or Kearns–Sayre syndrome? Ann Neurol 1: 37–54. Beretta S, Mattavelli L, Sala G, et al. (2004). Leber hereditary optic neuropathy mtDNA mutations disrupt glutamate transport in cybrid cell lines. Brain 127: 2183–2192. Berger A, Mayr JA, Meierhofer D, et al. (2003). Severe depletion of mitochondrial DNA in spinal muscular atrophy. Acta Neuropathol (Berl) 105: 245–251. Berkovic F, Carpenter S, Evans A, et al. (1989). Myoclonus epilepsy and ragged-red fibres (MERRF) 1. A clinical, pathological, biochemichal, magnetic resonance spectrographic and positron emission tomographic study. Brain 112: 1231–1260. Bernes SM, Bacino C, Prezant TR, et al. (1993). Identical mitochondrial DNA deletion in mother with progressive external ophthalmoplegia and son with Pearson Marrow– Pancreas syndrome. J Pediatr 123: 598–602. Bicknese AR, May W, Hickey WF, et al. (1992). Early childhood hepatocerebral degeneration misdiagnosed as valproate hepatotoxicity. Ann Neurol 32: 767–775. Bindoff LA, Birchmachin MA, Cartlidge NEF, et al. (1991). Respiratory chain abnormalities in skeletal muscle from patients with Parkinson’s disease. J Neurol Sci 104: 203–208. Bindoff LA, Howell N, Poulton J, et al. (1993). Abnormal RNA processing associated with a novel tRNA mutation in mitochondrial DNA. A potential disease mechanism. J Biol Chem 268: 19559–19564. Birch-Machin MA (2000). Mitochondria and skin disease. Clin Exp Dermatol 25: 141–146. Birch-Machin MA, Taylor RW, Cochran B, et al. (2000). Late-onset optic atrophy, ataxia, and myopathy associated with a mutation of a complex II gene. Ann Neurol 48: 330–335. Bodemer C, Ro¨tig A, Rustin P, et al. (1999). Hair and skin disorders as signs of mitochondrial disease. Pediatrics 103: 428–433. Bohlega S, Tanji K, Santorelli FM, et al. (1996). Multiple mitochondrial DNA deletions associated with autosomal recessive ophthalmoplegia and severe cardiomyopathy. Neurology 46: 1329–1334. Boitier E, Degoul F, Desguerre I, et al. (1998). A case of mitochondrial encephalomyopathy associated with a muscle coenzyme Q(10) deficiency. J Neurol Sci 156: 41–46. Boles RG, Roe T, Senadheera D, et al. (1998). Mitochondrial DNA deletion with Kearns Sayre syndrome in a child with Addison disease. Eur J Pediatr 157: 643–647. Bonilla E, Sciacco M, Tanji K, et al. (1992). New morphological approaches to the study of mitochondrial encephalomyopathies. Brain Pathol 2: 113–119. Bordarier C, Duyckaerts C, Robain O, et al. (1990). Kearns– sayre syndrome. Two clinico-pathological cases. Neuropediatrics 21: 106–109.
151
Bouillot S, Martin-Negrier ML, Vital A, et al. (2002). Peripheral neuropathy associated with mitochondrial disorders: 8 cases and review of the literature. J Peripher Nerv Syst 7: 213–220. Boulet L, Karpati G, Shoubridge EA (1992). Distribution and threshold expression of the tRNA(Lys) mutation in skeletal muscle of patients with myoclonic epilepsy and ragged-red fibers (MERRF). Am J Hum Genet 51: 1187–1200. Bourgeron T, Rustin P, Chretien D, et al. (1995). Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency. Nature Genetics 11: 144–149. Boyd SG, Harden A, Egger J, et al. (1986). Progressive neuronal degeneration of childhood with liver disease (“Alpers’ disease”): characteristic neurophysiological features. Neuropediatrics 17: 75–80. Bresolin N, Doriguzzi C, Ponzetto C, et al. (1990). Ubidecarenone in the treatment of mitochondrial myopathies: a multi-center double-blind trial. J Neurol Sci 100: 70–78. Bruno C, Martinuzzi A, Tang Y, et al. (1999). A stop-codon mutation in the human mtDNA cytochrome c oxidase I gene disrupts the functional structure of complex IV. Am J Hum Genet 65: 611–620. Bruno C, Santorelli FM, Assereto S, et al. (2003). Progressive exercise intolerance associated with a new muscle-restricted nonsense mutation (G142X) in the mitochondrial cytochrome b gene. Muscle Nerve 28: 508–511. Budde SM, van den Heuvel LP, Janssen AJ, et al. (2000). Combined enzymatic complex I and III deficiency associated with mutations in the nuclear encoded NDUFS4 gene. Biochem Biophys Res Commun 275: 63–68. Buemi M, Allegra A, Ro¨tig A, et al. (1997). Renal failure from mitochondrial cytopathies. Nephron 76: 249–253. Bugiani M, Tiranti V, Farina L, et al. (2005). Novel mutations in COX15 in a long surviving Leigh syndrome patient with cytochrome c oxidase deficiency. J Med Genet 42: e28. Bykhovskaya Y, Casas K, Mengesha E, et al. (2004). Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial myopathy and sideroblastic anemia (MLASA). Am J Hum Genet 74: 1303–1308. Calabresi PA, Silvestri G, DiMauro S, et al. (1994). Ekbom’s syndrome: lipomas, ataxia, and neuropathy with MERRF. Muscle Nerve 17: 943–945. Campos Y, Garciasilva T, Barrionuevo CR, et al. (1995). Mitochondrial DNA deletion in a patient with mitochondrial myopathy, lactic acidosis, and stroke-like episodes (MELAS) and fanconi’s syndrome. Pediatric Neurology 13: 69–72. Campos Y, Martin MA, Rubio JC, et al. (1996a). Multiple deletions of mitochondrial DNA in muscle from a patient with benign progressive external ophthalmoplegia. J Inherited Metab Dis 19: 366–367. Campos Y, Martin MA, Navarro C, et al. (1996b). Single large-scale mitochondrial DNA deletion in a patient with mitochondrial myopathy associated with multiple symmetric lipomatosis. Neurology 47: 1012–1014. Campos Y, Martin MA, Rubio JC, et al. (1997). Bilateral striatal necrosis and MELAS associated with a new T3308C
152
A. OLDFORS AND M. TULINIUS
mutation in the mitochondrial ND1 gene. Biochem Biophys Res Commun 238: 323–325. Campos Y, Martin MA, Caballero C, et al. (2000). Single large-scale mitochondrial DNA deletion in a patient with encephalopathy, cardiomyopathy, and prominent intestinal pseudo- obstruction. Neuromuscul Disord 10: 56–58. Campos Y, Garcia-Redondo A, Fernandez-Moreno MA, et al. (2001). Early-onset multisystem mitochondrial disorder caused by a nonsense mutation in the mitochondrial DNA cytochrome c oxidase II gene. Ann Neurol 50: 409–413. Carelli V, Ross-Cisneros FN, Sadun AA (2002). Optic nerve degeneration and mitochondrial dysfunction: genetic and acquired optic neuropathies. Neurochem Int 40: 573–584. Carlow TJ, Depper MH, Orrison WW (1998). MR of extraocular muscles in chronic progressive external ophthalmoplegia. Am J Neuroradiol 19: 95–99. Carroll J, Shannon RJ, Fearnley IM, et al. (2002). Definition of the nuclear encoded protein composition of bovine heart mitochondrial complex I: Identification of two new subunits. J Biol Chem 277: 50311–50317. Carrozzo R, Hirano M, Fromenty B, et al. (1998). Multiple mtDNA deletions features in autosomal dominant and recessive diseases suggest distinct pathogeneses. Neurology 50: 99–106. Carrozzo R, Bornstein B, Lucioli S, et al. (2003). Mutation analysis in 16 patients with mtDNA depletion. Hum Mutat 21: 453–454. Casademont J, Barrientos A, Cardellach F, et al. (1994). Multiple deletions of mtDNA in two brothers with sideroblastic anemia and mitochondrial myopathy and in their asymptomatic mother. Hum Mol Genet 3: 1945–1949. Casali C, Santorelli FM, Damati G, et al. (1995). A novel mtDNA point mutation in maternally inherited cardiomyopathy. Biochem Biophys Res Commun 213: 588–593. Casari G, De Fusco M, Ciarmatori S, et al. (1998). Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease. Cell 93: 973–983. Casas KA, Fischel-Ghodsian N (2004). Mitochondrial myopathy and sideroblastic anemia. Am J Med Genet A 125: 201–204. Cecchini G (2003). Function and structure of complex II of the respiratory chain. Ann Rev Biochem 72: 77–109. Chalmers RM, Brockington M, Howard RS, et al. (1996). Mitochondrial encephalopathy with multiple mitochondrial DNA deletions: a report of two families and two sporadic cases with unusual clinical and neuropathological features. J Neurol Sci 143: 41–45. Chang TM, Chi CS, Tsai CR, et al. (2004). Paralytic ileus in MELAS with phenotypic features of MNGIE. Pediatr Neurol 31: 374–377. Chantrel-Groussard K, Geromel V, Puccio H, et al. (2001). Disabled early recruitment of antioxidant defenses in Friedreich’s ataxia. Hum Mol Genet 10: 2061–2067. Chariot P, Drogou I, de Lacroix-Szmania I, et al. (1999). Zidovudine-induced mitochondrial disorder with massive liver steatosis, myopathy, lactic acidosis, and mitochondrial DNA depletion. J Hepatol 30: 156–160.
Checcarelli N, Prelle A, Moggio M, et al. (1994). Multiple deletions of mitochondrial DNA in sporadic and atypical cases of encephalomyopathy. J Neurol Sci 123: 74–79. Chen XJ (2002). Induction of an unregulated channel by mutations in adenine nucleotide translocase suggests an explanation for human ophthalmoplegia. Hum Mol Genet 11: 1835–1843. Chen CM, Huang CC (1995). Gonadal dysfunction in mitochondrial encephalomyopathies. Eur Neurol 35: 281–286. Chinnery PF, Turnbull DM (1997). Mitochondrial medicine. Q J Med 90: 657–667. Chinnery PF, Howell N, Lightowlers RN, et al. (1997). Molecular pathology of MELAS and MERRF: the relationship between mutation load and clinical phenotypes. Brain 120: 1713–1721. Chinnery PF, Howell N, Lightowlers RN, et al. (1998). MELAS and MERRF. The relationship between maternal mutation load and the frequency of clinically affected offspring. Brain 121: 1889–1894. Chinnery PF, Johnson MA, Wardell TM, et al. (2000). The epidemiology of pathogenic mitochondrial DNA mutations. Ann Neurol 48: 188–193. Chinnery PF, Brown DT, Andrews RM, et al. (2001a). The mitochondrial ND6 gene is a hot spot for mutations that cause Leber’s hereditary optic neuropathy. Brain 124: 209–218. Chinnery PF, Jones S, Sviland L, et al. (2001b). Mitochondrial enteropathy: the primary pathology may not be within the gastrointestinal tract. Gut 48: 121–124. Chinnery PF, DiMauro S, Shanske S, et al. (2004). Risk of developing a mitochondrial DNA deletion disorder. Lancet 364: 592–596. Chinnery P, Majamaa K, Turnbull D, et al. (2006). Treatment for mitochondrial disorders. Cochrane Database Syst Rev CD004426.. Chol M, Lebon S, Benit P, et al. (2003). The mitochondrial DNA G13513A MELAS mutation in the NADH dehydrogenase 5 gene is a frequent cause of Leigh-like syndrome with isolated complex I deficiency. J Med Genet 40: 188–191. Clark KM, Bindoff LA, Lightowlers RN, et al. (1997). Reversal of a mitochondrial DNA defect in human skeletal muscle. Nat Genet 16: 222–224. Coenen MJ, van den Heuvel LP, Ugalde C, et al. (2004a). Cytochrome c oxidase biogenesis in a patient with a mutation in COX10 gene. Ann Neurol 56: 560–564. Coenen MJ, Antonicka H, Ugalde C, et al. (2004b). Mutant mitochondrial elongation factor G1 and combined oxidative phosphorylation deficiency. N Engl J Med 351: 2080–2086. Comi GP, Bordoni A, Salani S, et al. (1998). Cytochrome c oxidase subunit I microdeletion in a patient with motor neuron disease. Ann Neurol 43: 110–116. Cormier V, Ro¨tig A, Tardieu M, et al. (1991). Autosomal dominant deletions of the mitochondrial genome in a case of progressive encephalomyopathy. Am J Hum Genet 48: 643–648.
MITOCHONDRIAL ENCEPHALOMYOPATHIES Cormier-Daire V, Bonnefont JP, Rustin P, et al. (1994). Mitochondrial DNA rearrangements with onset as chronic diarrhea with villous atrophy. J Pediatr 124: 63–70. Cormier-Daire V, Rustin P, Ro¨tig A, et al. (1996). Craniofacial anomalies and malformations in respiratory chain deficiency. Am J Med Genet 66: 457–463. Corona P, Antozzi C, Carrara F, et al. (2001). A novel mtDNA mutation in the ND5 subunit of complex I in two MELAS patients. Ann Neurol 49: 106–110. Crimi M, Galbiati S, Moroni I, et al. (2003). A missense mutation in the mitochondrial ND5 gene associated with a LeighMELAS overlap syndrome. Neurology 60: 1857–1861. Cupini LM, Massa R, Floris R, et al. (2003). Migraine-like disorder segregating with mtDNA 14484 Leber hereditary optic neuropathy mutation. Neurology 60: 717–719. Cursiefen C, Kuchle M, Scheurlen W, et al. (1998). Bilateral zonular cataract associated with the mitochondrial cytopathy of Pearson syndrome. Am J Ophthalmol 125: 260–261. Damian MS, Seibel P, Schachenmayr W, et al. (1996). VACTERL with the mitochondrial NP 3243 point mutation. Am J Med Genet 62: 398–403. Darin N, Oldfors A, Moslemi AR, et al. (2001). The incidence of mitochondrial encephalomyopathies in childhood: clinical features and morphological, biochemical, and DNA anbormalities. Ann Neurol 49: 377–383. Darin N, Moslemi AR, Lebon S, et al. (2003). Genotypes and clinical phenotypes in children with cytochrome-c oxidase deficiency. Neuropediatrics 34: 311–317. Davidzon G, Greene P, Mancuso M, et al. (2006). Earlyonset familial parkinsonism due to POLG mutations. Ann Neurol 59: 859–862. De Coo IF, Renier WO, Ruitenbeek W, et al. (1999). A 4-base pair deletion in the mitochondrial cytochrome b gene associated with parkinsonism/MELAS overlap syndrome. Ann Neurol 45: 130–133. De Koning TJ, de Vries LS, Groenendaal F, et al. (1999). Pontocerebellar hypoplasia associated with respiratory-chain defects. Neuropediatrics 30: 93–95. De Lonlay P, Valnot I, Barrientos A, et al. (2001). A mutant mitochondrial respiratory chain assembly protein causes complex III deficiency in patients with tubulopathy, encephalopathy and liver failure. Nat Genet 29: 57–60. De Meirleir L, Seneca S, Damis E, et al. (2003). Clinical and diagnostic characteristics of complex III deficiency due to mutations in the BCS1L gene. Am J Med Genet A 121: 126–131. De Meirleir L, Seneca S, Lissens W, et al. (2004). Respiratory chain complex V deficiency due to a mutation in the assembly gene ATP12. J Med Genet 41: 120–124. De Vries DD, van Engelen BG, Gabreels FJ, et al. (1993). A 2nd missense mutation in the mitochondrial ATPase-6 gene in Leigh’s syndrome. Ann Neurol 34: 410–412. DeAngelo AB, Daniel FB, Most BM, et al. (1996). The carcinogenicity of dichloroacetic acid in the male Fischer 344 rat. Toxicology 114: 207–221. Deschauer M, Bamberg C, Claus D, et al. (2003a). Lateonset encephalopathy associated with a C11777A mutation of mitochondrial DNA. Neurology 60: 1357–1359.
153
Deschauer M, Kiefer R, Blakely EL, et al. (2003b). A novel Twinkle gene mutation in autosomal dominant progressive external ophthalmoplegia. Neuromuscul Disord 13: 568–572. Di Fonzo A, Bordoni A, Crimi M, et al. (2003). POLG mutations in sporadic mitochondrial disorders with multiple mtDNA deletions. Hum Mutat 22: 498–499. Di Giovanni S, Mirabella M, Spinazzola A, et al. (2001). Coenzyme Q10 reverses pathological phenotype and reduces apoptosis in familial CoQ10 deficiency. Neurology 57: 515–518. DiMauro S, Mendell JR, Sahenk Z, et al. (1980). Fatal infantile mitochondrial myopathy and renal dysfunction due to cytochrome-c-oxidase deficiency. Neurology 30: 795–804. DiMauro S, Nicholson JF, Hays AP, et al. (1983). Benign infantile mitochondrial myopathy due to reversible cytochrome c oxidase deficiency. Ann Neurol 14: 226–234. DiMauro S, Tay S, Mancuso M (2004a). Mitochondrial encephalomyopathies: diagnostic approach. Ann N Y Acad Sci 1011: 217–231. DiMauro S, Mancuso M, Naini A (2004b). Mitochondrial encephalomyopathies: therapeutic approach. Ann N Y Acad Sci 1011: 232–245. Dinour D, Mini S, Polak-Charcon S, et al. (2004). Progressive nephropathy associated with mitochondrial tRNA gene mutation. Clin Nephrol 62: 149–154. Drugge U, Holmberg M, Holmgren G, et al. (1995). Hereditary myopathy with lactic acidosis, succinate dehydrogenase and aconitase deficiency in northern Sweden: a genealogical study. J Med Genet 32: 344–347. Dubern B, Broue P, Dubuisson C, et al. (2001). Orthotopic liver transplantation for mitochondrial respiratory chain disorders: a study of 5 children. Transplantation 71: 633–637. Edmonds JL, Kirse DJ, Kearns D, et al. (2002). The otolaryngological manifestations of mitochondrial disease and the risk of neurodegeneration with infection. Arch Otolaryngol Head Neck Surg 128: 355–362. Elpeleg O, Miller C, Hershkovitz E, et al. (2005). Deficiency of the ADP-forming succinyl-CoA synthase activity is associated with encephalomyopathy and mitochondrial DNA depletion. Am J Hum Genet 76: 1081–1086. Estivill X, Govea N, Barcelo E, et al. (1998). Familial progressive sensorineural deafness is mainly due to the mtDNA A1555G mutation and is enhanced by treatment of aminoglycosides. Am J Hum Genet 62: 27–35. Fabrizi GM, Lodi R, Dettorre M, et al. (1996). Autosomal dominant limb girdle myopathy with ragged-red fibers and cardiomyopathy — a pedigree study by in vivo P-31-MR spectroscopy indicating a multisystem mitochondrial defect. J Neurol Sci 137: 20–27. Farina L, Chiapparini L, Uziel G, et al. (2002). MR findings in Leigh syndrome with COX deficiency and SURF-1 mutations. AJNR Am J Neuroradiol 23: 1095–1100. Fayet G, Jansson M, Sternberg D, et al. (2002). Ageing muscle: clonal expansions of mitochondrial DNA point mutations and deletions cause focal impairment of mitochondrial function. Neuromuscul Disord 12: 484–493. Federico A, Dotti MT, Cardaioli E, et al. (1998). Association in the same patient of autosomal dominant progressive
154
A. OLDFORS AND M. TULINIUS
external ophthalmoplegia with multiple mtDNA deletions and X-linked ichthyosis: clinical, biochemical, histological, submicroscopic and molecular genetic study. J Submicrosc Cytol Pathol 30: 521–526. Ferrari G, Lamantea E, Donati A, et al. (2005). Infantile hepatocerebral syndromes associated with mutations in the mitochondrial DNA polymerase-gammaA. Brain 128: 723–731. Filosto M, Mancuso M, Vives-Bauza C, et al. (2003). Lack of paternal inheritance of muscle mitochondrial DNA in sporadic mitochondrial myopathies. Ann Neurol 54: 524–526. Flynn MK, Wee SA, Lane AT (1998). Skin manifestations of mitochondrial DNA syndromes: case report and review. J Am Acad Dermatol 39: 819–823. Folgero T, Torbergsen T, Oian P (1995). The 3243 MELAS mutation in a pedigree with MERRF. Eur Neurol 35: 168–171. Fontanesi F, Palmieri L, Scarcia P, et al. (2004). Mutations in AAC2, equivalent to human adPEO-associated ANT1 mutations, lead to defective oxidative phosphorylation in saccharomyces cerevisiae and affect mitochondrial DNA stability. Hum Mol Genet 13: 923–934. Fujii T, Okuno T, Ito M, et al. (1990). CT, MRI, and autopsy findings in brain of a patient with MELAS. Pediatr Neurol 6: 253–256. Fujii T, Ito M, Miyajima T, et al. (2002). Dichloroacetate therapy in Leigh syndrome with a mitochondrial T8993C mutation. Pediatr Neurol 27: 58–61. Fukuhara N (1991). MERRF — a clinicopathological study — relationships between myoclonus epilepsies and mitochondrial myopathies. Rev Neurol 147: 476–479. Fukuhara N (1995). Clinicopathological features of MERRF. Muscle Nerve S90–S94. Fukuhara N, Tokiguchi S, Shirakawa K, et al. (1980). Myoclonus epilepsy associated with ragged-red fibres (mitochondrial abnormalities): disease entity or a syndrome? J Neurol Sci 47: 117–133. Gattermann N, Retzlaff S, Wang YL, et al. (1997). Heteroplasmic point mutations of mitochondrial DNA affecting subunit I of cytochrome c oxidase in two patients with acquired idiopathic sideroblastic anemia. Blood 90: 4961–4972. Gauthier-Villars M, Landrieu P, Cormier-Daire V, Jacquemin V, et al. (2001). Respiratory chain deficiency in Alpers syndrome. Neuropediatrics 32: 150–152. Gerbitz KD, van den Ouweland JMW, Maassen JA, et al. (1995). Mitochondrial diabetes mellitus: a review. Biochim Biophys Acta 1271: 253–260. Gogus S, Yalaz K, Gucsavas M, et al. (1994). Subacute necrotizing encephalopathy (Leigh syndrome): report of two juvenile cases with fatal outcome. Turk J Pediatr 36: 57–65. Gold R, Seibel P, Reinelt G, et al. (1996). Phosphorus magnetic resonance spectroscopy in the evaluation of mitochondrial myopathies: results of a 6-month therapy study with coenzyme Q. Eur Neurol 36: 191–196. Gonzalez-Vioque E, Blazquez A, Fernandez-Moreira D, et al. (2006). Association of novel POLG mutations and multiple mitochondrial DNA deletions with variable clinical phenotypes in a Spanish population. Arch Neurol 63: 107–111.
Goto Y, Nonaka I, Horai S (1990). A mutation in the tRNA (Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 348: 651–653. Goto Y, Nonaka I, Horai S (1991). A new mtDNA mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). Biochim Biophys Acta 1097: 238–240. Goto Y, Horai S, Matsuoka T, et al. (1992a). Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) — a correlative study of the clinical features and mitochondrial DNA mutation. Neurology 42: 545–550. Goto Y, Tojo M, Tohyama J, Horai S, et al. (1992b). A novel point mutation in the mitochondrial transfer-RNA Leu (UUR) gene in a family with mitochondrial myopathy. Ann Neurol 31: 672–675. Goto YI, Tsugane K, Tanabe Y, et al. (1994). A new point mutation at nucleotide pair 3291 of the mitochondrial tRNA(Leu (UUR)) gene in a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Biochem Biophys Res Commun 202: 1624–1630. Gurakan B, Ozbek N, Varan B, et al. (1999). Fatal acidosis in a neonate with Pearson syndrome. Turk J Pediatr 41: 361–364. Hadjigeorgiou GM, Kim SH, Fischbeck KH, et al. (1999). A new mitochondrial DNA mutation (A3288G) in the tRNA (Leu(UUR)) gene associated with familial myopathy. J Neurol Sci 164: 153–157. Haftel LT, Lev D, Barash V, et al. (2000). Familial mitochondrial intestinal pseudo-obstruction and neurogenic bladder. J Child Neurol 15: 386–389. Hagenfeldt L, Vondobeln U, Solders G, et al. (1994). Creatine treatment in MELAS. Muscle Nerve 17: 1236–1237. Hall RE, Henriksson KG, Lewis SF, et al. (1993). Mitochondrial myopathy with succinate dehydrogenase and aconitase deficiency — abnormalities of several Iron-Sulfur proteins. J Clin Invest 92: 2660–2666. Haltia M, Suomalainen A, Majander A, et al. (1992). Disorders associated with multiple deletions of mitochondrial DNA. Brain Pathol 2: 133–139. Hammans SR, Sweeney MG, Hanna MG, et al. (1995). The mitochondrial DNA transfer RNA(Leu(UUR)) A->G ((3243)) mutation — a clinical and genetic study. Brain 118: 721–734. Hansson A, Hance N, Dufour E, et al. (2004). A switch in metabolism precedes increased mitochondrial biogenesis in respiratory chain-deficient mouse hearts. Proc Natl Acad Sci U S A 101: 3136–3141. Harding BN (1990). Progressive neuronal degeneration of childhood with liver disease (Alpers–Huttenlocher syndrome): a personal review. J Child Neurol 5: 273–287. Harding BN, Egger J, Portmann B, et al. (1986). Progressive neuronal degeneration of childhood with liver disease. A pathological study. Brain 109: 181–206. Harding AE, Sweeney MG, Miller DH, et al. (1992). Occurrence of a multiple sclerosis-like illness in women who have a Leber’s hereditary optic neuropathy mitochondrial DNA mutation. Brain 115: 979–989.
MITOCHONDRIAL ENCEPHALOMYOPATHIES Harding BN, Alsanjari N, Smith SJM, et al. (1995a). Progressive neuronal degeneration of childhood with liver disease (Alpers’ disease) presenting in young adults. J Neurol Neurosurg Psychiatry 58: 320–325. Harding AE, Sweeney MG, Govan GG, et al. (1995b). Pedigree analysis in Leber hereditary optic neuropathy families with a pathogenic mtDNA mutation. Am J Hum Genet 57: 77–86. Harvey JN, Barnett D (1992). Endocrine dysfunction in Kearns–Sayre syndrome — case report and review. Clin Endocrinol 37: 97–104. Hirano M, Pavlakis SG (1994). Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) — current concepts. J Child Neurol 9: 4–13. Hirano M, Silvestri G, Blake DM, et al. (1994). Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) — clinical, biochemical, and genetic features of an autosomal recessive mitochondrial disorder. Neurology 44: 721–727. Hirano M, DiMauro S (1996). Cinical features of mitochondrial myopathies and encephalomyopathies In: Handbook of muscle disease. Ed. Lane RJN. Dekker. New York pp. 479–504. Hirano M, Konishi K, Arata N, et al. (2002). Renal complications in a patient with A-to-G mutation of mitochondrial DNA at the 3243 position of leucine tRNA. Intern Med 41: 113–118. Hirano M, Nishigaki Y, Marti R (2004). Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): a disease of two genomes. Neurologist 10: 8–17. Holme E, Larsson NG, Oldfors A, et al. (1993). Multiple symmetric lipomas with high levels of mtDNA with the tRNA (Lys) A->G(8344) mutation as the only manifestation of disease in a carrier of myoclonus epilepsy and ragged-red fibers (MERRF) syndrome. Am J Hum Genet 52: 551–556. Holmgren D, Wahlander H, Eriksson BO, et al. (2003). Cardiomyopathy in children with mitochondrial disease. Clinical course and cardiological findings. Eur Heart J 24: 280–288. Holt IJ, Harding AE, Morgan-Hughes JA (1988). Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 331: 717–719. Holt IJ, Harding AE, Petty RK, et al. (1990). A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. Am J Hum Genet 46: 428–433. Horvath R, Lochmu¨ller H, Hoeltzenbein M, et al. (2004). Spontaneous recovery of a childhood onset mitochondrial myopathy caused by a stop mutation in the mitochondrial cytochrome c oxidase III gene. J Med Genet 41: e75. Horvath R, Schneiderat P, Schoser BG, et al. (2006). Coenzyme Q10 deficiency and isolated myopathy. Neurology 66: 253–255. Houshmand M, Gardner A, Hallstro¨m T, et al. (2004). Different tissue distribution of a mitochondrial DNA duplication and the corresponding deletion in a patient with a mild mitochondrial encephalomyopathy: deletion in muscle, duplication in blood. Neuromuscul Disord 14: 195–201. Howell N, Bindoff LA, McCullough DA, et al. (1991). Leber hereditary optic neuropathy. Identification of the same
155
mitochondrial NDI mutation in sx pedigrees. Am J Hum Genet 49: 939–950. Howell N, Bogolin C, Jamieson R, et al. (1998). mtDNA mutations that cause optic neuropathy: how do we know? Am J Hum Genet 62: 196–202. Huang CC, Kuo HC, Chu CC, et al. (2002). Clinical phenotype, prognosis and mitochondrial DNA mutation load in mitochondrial encephalomyopathies. J Biomed Sci 9: 527–533. Huoponen K (2001). Leber hereditary optic neuropathy: clinical and molecular genetic findings. Neurogenetics 3: 119–125. Huoponen K, Vilkki J, Aula P, et al. (1991). A New mtDNA mutation associated with Leber hereditary optic neuroretinopathy. Am J Hum Genet 48: 1147–1153. Hutchin TP, Parker MJ, Young ID, et al. (2000). A novel mutation in the mitochondrial tRNA(Ser(UCN)) gene in a family with non-syndromic sensorineural hearing impairment. J Med Genet 37: 692–694. Huttenlocher PR, Solitare GB, Adams G (1976). Infantile diffuse cerebral degeneration with hepatic cirrhosis. Arch Neurol 33: 186–192. Hu¨bner G, Gokel JM, Pongratz D, et al. (1986). Fatal mitochondrial cardiomyopathy in Kearns–Sayre syndrome. Virchows Arch A 408: 611–621. Hwang JM, Chang BL, Koh HJ, et al. (2002). Leber’s hereditary optic neuropathy with 3460 mitochondrial DNA mutation. J Korean Med Sci 17: 283–286. Iizuka T, Sakai F, Suzuki N, et al. (2002). Neuronal hyperexcitability in stroke-like episodes of MELAS syndrome. Neurology 59: 816–824. Iizuka T, Sakai F, Kan S, et al. (2003). Slowly progressive spread of the stroke-like lesions in MELAS. Neurology 61: 1238–1244. Ionasescu VV, Hart M, Dimauro S, et al. (1994). Clinical and morphologic features of a myopathy associated with a point mutation in the mitochondrial tRNA(Pro) gene. Neurology 44: 975–977. Isashiki Y, Nakagawa M, Ohba N, Kamimura N, et al. (1998). Retinal manifestations in mitochondrial diseases associated with mitochondrial DNA mutation. Acta Ophthalmol Scand 76: 6–13. Jaksch M, Paret C, Stucka R, et al. (2001). Cytochrome c oxidase deficiency due to mutations in SCO2, encoding a mitochondrial copper-binding protein, is rescued by copper in human myoblasts. Hum Mol Genet 10: 3025–3035. James AM, Murphy MP (2002). How mitochondrial damage affects cell function. J Biomed Sci 9: 475–487. Jansen PHP, Vanderknaap MS, Decoo IFM (1996). Leber’s hereditary optic neuropathy with the 11778 mtDNA mutation and white matter disease resembling multiple sclerosis: clinical, MRI and MRS findings. J Neurol Sci 135: 176–180. Johns DR, Smith KH, Miller NR (1992a). Leber’s hereditary optic neuropathy — clinical manifestations of the 3460 mutation. Arch Ophthalmol 110: 1577–1581.
156
A. OLDFORS AND M. TULINIUS
Johns DR, Neufeld MJ, Park RD (1992b). An ND-6 mitochondrial DNA mutation associated with Leber hereditary optic neuropathy. Biochem Biophys Res Commun 187: 1551–1557. Johnston W, Karpati G, Carpenter S, et al. (1995). Late-onset mitochondrial myopathy. Ann Neurol 37: 16–23. Jun AS, Brown MD, Wallace DC (1994). A mitochondrial DNA mutation at nucleotide pair 14459 of the NADH dehydrogenase subunit 6 gene associated with maternally inherited leber hereditary optic neuropathy and dystonia. Proc Natl Acad Sci U S A 91: 6206–6210. Karadimas CL, Greenstein P, Sue CM, et al. (2000). Recurrent myoglobinuria due to a nonsense mutation in the COX I gene of mitochondrial DNA. Neurology 55: 644–649. Karkos PD, Waldron M, Johnson IJ (2004a). The MELAS syndrome. Review of the literature: the role of the otologist. Clin Otolaryngol 29: 1–4. Karkos PD, Anari S, Johnson IJ (2004b). Cochlear implantation in patients with MELAS syndrome. Eur Arch Otorhinolaryngol 262: 322–324. Kaufmann P, Engelstad K, Wei Y, et al. (2006). Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial. Neurology 66: 324–330. Kaukonen JA, Amati P, Suomalainen A, et al. (1996). An autosomal locus predisposing to multiple deletions of mtDNA on chromosome 3p. Am J Hum Genet 58: 763–769. Kaukonen J, Zeviani M, Comi GP, et al. (1999). A third locus predisposing to multiple deletions of mtDNA in autosomal dominant progressive external ophthalmoplegia [letter]. Am J Hum Genet 65: 256–261. Kaukonen J, Juselius JK, Tiranti V, et al. (2000). Role of adenine nucleotide translocator 1 in mtDNA maintenance. Science 289: 782–785. Kawashima S, Ohta S, Kagawa Y, et al. (1994). Widespread tissue distribution of multiple mitochondrial DNA deletions in familial mitochondrial myopathy. Muscle Nerve 17: 741–746. Kearns TP, Sayre GP (1958). Retinitis pigmentosa, external ophthalmoplegia, and complete heart block. Arch Ophthalmol 60: 280–289. Keats BJ (2002). Genes and syndromic hearing loss. J Commun Disord 35: 355–366. Keightley JA, Hoffbuhr KC, Burton MD, et al. (1996). A microdeletion in cytochrome c oxidase (COX) subunit III associated with COX deficiency and recurrent myoglobinuria. Nat Genet 12: 410–416. Kellar-Wood H, Robertson N, Govan GG, et al. (1994). Leber’s hereditary optic neuropathy mitochondrial DNA mutations in multiple sclerosis. Ann Neurol 36: 109–112. Kendall BE, Boyd SG, Egger J, et al. (1987). Progressive neuronal degeneration of childhood with liver disease. Computed tomographic features. Neuroradiology 29: 174–180. Kim IO, Kim JH, Kim WS, et al. (1996). Mitochondrial myopathy-encephalopathy-lactic acidosis- and strokelike episodes (MELAS) syndrome: CT and MR findings in seven children. Am J Roentgenol 166: 641–645. Kirby DM, Crawford M, Cleary MA, et al. (1999). Respiratory chain complex I deficiency: an underdiagnosed energy generation disorder. Neurology 52: 1255–1264.
Kirby DM, Kahler SG, Freckmann ML, et al. (2000). Leigh disease caused by the mitochondrial DNA G14459A mutation in unrelated families. Ann Neurol 48: 102–104. Kirby DM, Boneh A, Chow CW, et al. (2003). Low mutant load of mitochondrial DNA G13513A mutation can cause Leigh’s disease. Ann Neurol 54: 473–478. Kirby DM, Salemi R, Sugiana C, et al. (2004). NDUFS6 mutations are a novel cause of lethal neonatal mitochondrial complex I deficiency. J Clin Invest 114: 837–845. Kirches E, Winkler K, Vielhaber S, et al. (1999). Mitochondrial tRNA(Cys) mutation A5823G in a patient with motor neuron disease and temporal lobe epilepsy. Pathobiology 67: 214–218. Kleinle S, Schneider V, Moosmann P, et al. (1998). A novel mitochondrial tRNA(Phe) mutation inhibiting anticodon stem formation associated with a muscle disease. Biochem Biophys Res Commun 247: 112–115. Klopstock T, Naumann M, Seibel P, et al. (1997). Mitochondrial DNA mutations in multiple symmetric lipomatosis. Mol Cell Biochem 174: 271–275. Kollberg G, Moslemi AR, Lindberg C, et al. (2005). Mitochondrial myopathy and rhabdomyolysis associated with a novel nonsense mutation in the gene encoding cytochrome c oxidase subunit I. J Neuropathol Exp Neurol 64: 123–128. Kollberg G, Moslemi AR, Darin N, et al. (2006). POLG1 mutations associated with progressive encephalopathy in childhood. J Neuropathol Exp Neurol 65: 758–768. Komaki H, Fukazawa T, Houzen H, et al. (2002). A novel D104G mutation in the adenine nucleotide translocator 1 gene in autosomal dominant progressive external ophthalmoplegia patients with mitochondrial DNA with multiple deletions. Ann Neurol 51: 645–648. Komura K, Hobbiebrunken E, Wilichowski EK, et al. (2003). Effectiveness of creatine monohydrate in mitochondrial encephalomyopathies. Pediatr Neurol 28: 53–58. Korhonen JA, Pham XH, Pellegrini M, et al. (2004). Reconstitution of a minimal mtDNA replisome in vitro. EMBO J 23: 2423–2429. Krahenbuhl S, Brandner S, Kleinle S, et al. (2000). Mitochondrial diseases represent a risk factor for valproateinduced fulminant liver failure. Liver 20: 346–348. Krauch G, Wilichowski E, Schmidt KG, et al. (2002). Pearson marrow-pancreas syndrome with worsening cardiac function caused by pleiotropic rearrangement of mitochondrial DNA. Am J Med Genet 110: 57–61. Kuroda Y, Ito M, Naito E, et al. (1997). Concomitant administration of sodium dichloroacetate and vitamin B1 for lactic acidemia in children with MELAS syndrome. J Pediatr 131: 450–452. Kurogouchi F, Oguchi T, Mawatari E, et al. (1998). A case of mitochondrial cytopathy with a typical point mutation for MELAS, presenting with severe focal-segmental glomerulosclerosis as main clinical manifestation. Am J Nephrol 18: 551–556. Laforet P, Lombes A, Eymard B, et al. (1995). Chronic progressive external ophthalmoplegia with ragged-red fibers: clinical, morphological and genetic investigations in 43 patients. Neuromuscul Disord 5: 399–413.
MITOCHONDRIAL ENCEPHALOMYOPATHIES Lalani SR, Vladutiu GD, Plunkett K, et al. (2005). Isolated mitochondrial myopathy associated with muscle coenzyme Q10 deficiency. Arch Neurol 62: 317–320. Lamantea E, Carrara F, Mariotti C, et al. (2002a). A novel nonsense mutation (Q352X) in the mitochondrial cytochrome b gene associated with a combined deficiency of complexes I and III. Neuromuscul Disord 12: 49–52. Lamantea E, Tiranti V, Bordoni A, et al. (2002b). Mutations of mitochondrial DNA polymerase gammaA are a frequent cause of autosomal dominant or recessive progressive external ophthalmoplegia. Ann Neurol 52: 211–219. Lamantea E, Zeviani M (2004). Sequence analysis of familial PEO shows additional mutations associated with the 752C–>T and 3527C–>T changes in the POLG1 gene. Ann Neurol 56: 454–455. Lamperti C, Naini A, Hirano M, et al. (2003). Cerebellar ataxia and coenzyme Q10 deficiency. Neurology 60: 1206–1208. Larsson NG, Holme E, Kristiansson B, et al. (1990). Progressive increase of the mutated mitochondrial DNA fraction in Kearns–Sayre syndrome. Pediatr Res 28: 131–136. Larsson NG, Tulinius MH, Holme E, et al. (1992). Segregation and manifestations of the mtDNA tRNA(Lys) A->G (8344) mutation of myoclonus epilepsy and ragged-red fibers (MERRF) syndrome. Am J Hum Genet 51: 1201–1212. Larsson NG, Tulinius MH, Holme E, et al. (1995). Pathogenetic aspects of the A8344G mutation of mitochondrial DNA associated with MERRF syndrome and multiple symmetric lipomas. Muscle Nerve S102–S106. Legido A, Zimmerman RA, Packer RJ, et al. (1988). Significance of basal ganglia calcification on computed tomography in children. Pediatr Neurosci 14: 64–70. Legros F, Chatzoglou E, Frachon P, et al. (2001). Functional characterization of novel mutations in the human cytochrome b gene. Eur J Hum Genet 9: 510–518. Lehtonen MS, Uimonen S, Hassinen IE, et al. (2000). Frequency of mitochondrial DNA point mutations among patients with familial sensorineural hearing impairment. Eur J Hum Genet 8: 315–318. Leigh D (1951). Subacute necrotizing encephalomyelopathy in an infant. J Neurochem 14: 216–221. Leshinsky-Silver E, Perach M, Basilevsky E, et al. (2003). Prenatal exclusion of Leigh syndrome due to T8993C mutation in the mitochondrial DNA. Prenat Diagn 23: 31–33. Leuzzi V, Bertini E, Denegri AM, et al. (1992). Bilateral striatal necrosis, dystonia and optic atrophy in two siblings. J Neurol Neurosurg Psychiatry 55: 16–19. Lincke CR, van den Bogert C, Nijtmans LG, et al. (1996). Cerebellar hypoplasia in respiratory chain dysfunction. Neuropediatrics 27: 216–218. Liolitsa D, Rahman S, Benton S, et al. (2003). Is the mitochondrial complex I ND5 gene a hot-spot for MELAS causing mutations? Ann Neurol 53: 128–132. Loeffen J, Smeitink J, Triepels R, et al. (1998). The first nuclear-encoded complex I mutation in a patient with Leigh syndrome. Am J Hum Genet 63: 1598–1608. Loeffen J, Elpeleg O, Smeitink J, et al. (2001). Mutations in the complex I NDUFS2 gene of patients with
157
cardiomyopathy and encephalomyopathy. Ann Neurol 49: 195–201. Lombes A, Mendell JR, Nakase H, et al. (1989). Myoclonic epilepsy and ragged-red fibers with cytochrome oxidase deficiency: neuropathology, biochemistry, and molecular genetics. Ann Neurol 26: 20–33. Luoma P, Melberg A, Rinne JO, et al. (2004). Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma mutations: clinical and molecular genetic study. Lancet 364: 875–882. Maagaard A, Holberg-Petersen M, Kollberg G, et al. (2006). Mitochondrial DNA in peripheral blood may not reflect the mitochondrial status in skeletal muscle in HIV-infected patients. Antivir Ther 11: 601–608. Maassen JA (2002). Mitochondrial diabetes: pathophysiology, clinical presentation, and genetic analysis. Am J Med Genet 115: 66–70. Maassen JA, Kadowaki T (1996). Maternally inherited diabetes and deafness: a new diabetes subtype. Diabetologia 39: 375–382. Macmillan C, Kirkham T, Fu K, et al. (1998). Pedigree analysis of French Canadian families with T14484C Leber’s hereditary optic neuropathy. Neurology 50: 417–422. Majamaa K, Moilanen JS, Uimonen S, et al. (1998). Epidemiology of A3243G, the mutation for mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes: prevalence of the mutation in an adult population. Am J Hum Genet 63: 447–454. Makelabengs P, Suomalainen A, Majander A, et al. (1995). Correlation between the clinical symptoms and the proportion of mitochondrial DNA carrying the 8993 point mutation in the NARP syndrome. Pediatric Res 37: 634–639. Malik SG, Pieter N, Sudoyo H, et al. (2003). Prevalence of the mitochondrial DNA A1555G mutation in sensorineural deafness patients in island Southeast Asia. J Hum Genet 48: 480–483. Man PY, Turnbull DM, Chinnery PF (2002). Leber hereditary optic neuropathy. J Med Genet 39: 162–169. Man PY, Griffiths PG, Brown DT, et al. (2003). The epidemiology of Leber hereditary optic neuropathy in the North East of England. Am J Hum Genet 72: 333–339. Man PY, Howell N, Mackey DA, et al. (2004). Mitochondrial DNA haplogroup distribution within Leber hereditary optic neuropathy pedigrees. J Med Genet 41: e41. Mancuso M, Bianchi MC, Santorelli FM, et al. (1999). Encephalomyopathy with multiple mitochondrial DNA deletions and multiple symmetric lipomatosis: further evidence of a possible association. J Neurol 246: 1197–1198. Mancuso M, Salviati L, Sacconi S, et al. (2002). Mitochondrial DNA depletion: mutations in thymidine kinase gene with myopathy and SMA. Neurology 59: 1197–1202. Mancuso M, Filosto M, Stevens JC, et al. (2003a). Mitochondrial myopathy and complex III deficiency in a patient with a new stop-codon mutation (G339X) in the cytochrome b gene. J Neurol Sci 209: 61–63. Mancuso M, Filosto M, Bonilla E, et al. (2003b). Mitochondrial myopathy of childhood associated with mitochondri-
158
A. OLDFORS AND M. TULINIUS
al DNA depletion and a homozygous mutation (T77M) in the TK2 gene. Arch Neurol 60: 1007–1009. Mancuso M, Filosto M, Bellan M, et al. (2004a). POLG mutations causing ophthalmoplegia, sensorimotor polyneuropathy, ataxia, and deafness. Neurology 62: 316–318. Mancuso M, Filosto M, Mootha VK, et al. (2004b). A novel mitochondrial tRNAPhe mutation causes MERRF syndrome. Neurology 62: 2119–2121. Mancuso M, Ferraris S, Pancrudo J, et al. (2005). New DGK gene mutations in the hepatocerebral form of mitochondrial DNA depletion syndrome. Arch Neurol 62: 745–747. Mandel H, Szargel R, Labay V, et al. (2001a). The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA. Nat Genet 29: 337–341. Mandel H, Hartman C, Berkowitz D, et al. (2001b). The hepatic mitochondrial DNA depletion syndrome: ultrastructural changes in liver biopsies. Hepatology 34: 776–784. Manfredi G, Schon EA, Moraes CT, et al. (1995). A new mutation associated with MELAS is located in a mitochondrial DNA polypeptide-coding gene. Neuromuscul Disord 5: 391–398. Manfredi G, Vu T, Bonilla E, et al. (1997). Association of myopathy with large-scale mitochondrial DNA duplications and deletions: which is pathogenic? Ann Neurol 42: 180–188. Marin-Garcia J, Goldenthal MJ (1997). Mitochondrial cardiomyopathy: molecular and biochemical analysis. Pediatr Cardiol 18: 251–260. Mariotti C, Savarese N, Suomalainen A, et al. (1995). Genotype to phonotype correlations in mitochondrial encephalomyopathies associated with the A3243G mutation of mitochondrial DNA. J Neurol 242: 304–312. Marti R, Nishigaki Y, Vila MR, et al. (2003). Alteration of nucleotide metabolism: a new mechanism for mitochondrial disorders. Clin Chem Lab Med 41: 845–851. Marti R, Spinazzola A, Tadesse S, et al. (2004). Definitive diagnosis of mitochondrial neurogastrointestinal encephalomyopathy by biochemical assays. Clin Chem 50: 120–124. Matthews PM, Ford B, Dandurand RJ, et al. (1993). Coenzyme-Q(10) with multiple vitamins is generally ineffective in treatment of mitochondrial disease. Neurology 43: 884–890. McDonald DG, McMenamin JB, Farrell MA, et al. (2002). Familial childhood onset neuropathy and cirrhosis with the 4977bp mitochondrial DNA deletion. Am J Med Genet 111: 191–194. McFarland R, Schaefer AM, Gardner JL, et al. (2004a). Familial myopathy: new insights into the T14709C mitochondrial tRNA mutation. Ann Neurol 55: 478–484. McFarland R, Kirby DM, Fowler KJ, et al. (2004b). De novo mutations in the mitochondrial ND3 gene as a cause of infantile mitochondrial encephalopathy and complex I deficiency. Ann Neurol 55: 58–64. McFarland R, Taylor RW, Chinnery PF, et al. (2004c). A novel sporadic mutation in cytochrome c oxidase subunit II as a cause of rhabdomyolysis. Neuromuscul Disord 14: 162–166. McKenzie M, Liolitsa D, Hanna MG (2004). Mitochondrial disease: mutations and mechanisms. Neurochem Res 29: 589–600.
McShane MA, Hammans SR, Sweeney M, et al. (1991). Pearson syndrome and mitochondrial encephalomyopathy in a patient with a deletion of mtDNA. Am J Hum Genet 48: 39–42. Melberg A, Lundberg PO, Henriksson KG, et al. (1996a). Muscle–nerve involvement in autosomal dominant progressive external ophthalmoplegia with hypogonadism. Muscle Nerve 19: 751–757. Melberg A, Arnell H, Dahl N, et al. (1996b). Anticipation of autosomal dominant progressive external ophthalmoplegia with hypogonadism. Muscle Nerve 19: 1561–1569. Melberg A, Holme E, Oldfors A, et al. (1998). Rhabdomyolysis in autosomal dominant progressive external ophthalmoplegia. Neurology 50: 299–300. Miller C, Saada A, Shaul N, et al. (2004). Defective mitochondrial translation caused by a ribosomal protein (MRPS16) mutation. Ann Neurol 56: 734–738. Mita S, Rizzuto R, Moraes CT, et al. (1990). Recombination via flanking direct repeats is a major cause of large-scale deletions of human mitochondrial DNA. Nucleic Acids Res 18: 561–567. Mojon D (2001). Eye diseases in mitochondrial encephalomyopathies. Ther Umsch 58: 49–55. Montagna P, Gallassi R, Medori R, et al. (1988). MELAS syndrome: characteristic migrainous and epileptic features and maternal transmission. Neurology 38: 751–754. Mootha VK, Lepage P, Miller K, et al. (2003). Identification of a gene causing human cytochrome c oxidase deficiency by integrative genomics. Proc Natl Acad Sci U S A 100: 605–610. Moraes CT, DiMauro S, Zeviani M, et al. (1989). Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns–Sayre syndrome. N Engl J Med 320: 1293–1299. Moraes CT, Ricci E, Petruzzella V, et al. (1992). Molecular analysis of the muscle pathology associated with mitochondrial DNA deletions. Nat Genet 1: 359–367. Mori M, Yamagata T, Goto T, et al. (2004). Dichloroacetate treatment for mitochondrial cytopathy: long-term effects in MELAS. Brain Dev 26: 453–458. Morin C, Mitchell G, Larochelle J, et al. (1993). Clinical, metabolic, and genetic aspects of Cytochrome-C oxidase deficiency in Saguenay-Lac-Saint-Jean. Am J Hum Genet 53: 488–496. Moslemi AR, Melberg A, Holme E, et al. (1996). Clonal expansion of mitochondrial DNA with multiple deletions in autosomal dominant progressive external ophthalmoplegia. Ann Neurol 40: 707–713. Moslemi AR, Tulinius M, Holme E, et al. (1998). Threshold expression of the tRNA(Lys) A8344G mutation in single muscle fibres. Neuromuscul Disord 8: 345–349. Moslemi AR, Melberg A, Holme E, et al. (1999). Autosomal dominant progressive external ophthalmoplegia: distribution of multiple mitochondrial DNA deletions. Neurology 53: 79–84. Moslemi AR, Selimovic N, Bergh CH, et al. (2000). Fatal dilated cardiomyopathy associated with a mitochondrial DNA deletion. Cardiology 94: 68–71.
MITOCHONDRIAL ENCEPHALOMYOPATHIES Moslemi AR, Tulinius M, Darin N, et al. (2003). SURF1 gene mutations in three cases with Leigh syndrome and cytochrome c oxidase deficiency. Neurology 61: 991–993. Munnich A, Rustin P (2001). Clinical spectrum and diagnosis of mitochondrial disorders. Am J Med Genet 106: 4–17. Mun˜oz A, Mateos F, Simon R, et al. (1999). Mitochondrial diseases in children: neuroradiological and clinical features in 17 patients. Neuroradiology 41: 920–928. Musumeci O, Naini A, Slonim AE, et al. (2001). Familial cerebellar ataxia with muscle coenzyme Q10 deficiency. Neurology 56: 849–855. Nakamura M, Nakano S, Goto Y, et al. (1995). A novel point mutation in the mitochondrial tRNA(Ser(UCN)) gene detected in a family with MERRF/MELAS overlap syndrome. Biochem Biophys Res Commun 214: 86–93. Naviaux RK, Nguyen KV (2004). POLG mutations associated with Alpers’ syndrome and mitochondrial DNA depletion. Ann Neurol 55: 706–712. Neumann HP, Pawlu C, Peczkowska M, et al. (2004). Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA 292: 943–951. Newkirk JE, Taylor RW, Howell N, et al. (1997). Maternally inherited diabetes and deafness: prevalence in a hospital diabetic population. Diabet Med 14: 457–460. Newman NJ (1993). Leber’s hereditary optic neuropathy. New genetic considerations. Arch Neurol 50: 540–548. Newman NJ, Lott MT, Wallace DC (1991). The clinical characteristics of pedigrees of Leber’s hereditary optic neuropathy with the 11778 mutation. Am J Ophthalmol 111: 750–762. Nicolino M, Ferlin T, Forest M, et al. (1997). Identification of a large-scale mitochondrial deoxyribonucleic acid deletion in endocrinopathies and deafness: report of two unrelated cases with diabetes mellitus and adrenal insufficiency, respectively. J Clin Endocrinol Metab 82: 3063–3067. Nikoskelainen EK, Marttila RJ, Huoponen K, et al. (1995). Leber’s ‘’plus’’: neurological abnormalities in patients with Leber’s hereditary optic neuropathy. J Neurol Neurosurg Psychiatry 59: 160–164. Nikoskelainen EK, Huoponen K, Juvonen V, et al. (1996). Ophthalmologic findings in Leber hereditary optic neuropathy, with special reference to mtDNA mutations. Ophthalmology 103: 504–514. Nishigaki Y, Marti R, Copeland WC, et al. (2003a). Sitespecific somatic mitochondrial DNA point mutations in patients with thymidine phosphorylase deficiency. J Clin Invest 111: 1913–1921. Nishigaki Y, Tadesse S, Bonilla E, et al. (2003b). A novel mitochondrial tRNA(Leu(UUR)) mutation in a patient with features of MERRF and Kearns–Sayre syndrome. Neuromuscul Disord 13: 334–340. Nishikawa Y, Takahashi M, Yorifuji S, et al. (1989). Longterm coenzyme Q10 therapy for a mitochondrial encephalomyopathy with cytochrome c oxidase deficiency: a 31P NMR study. Neurology 39: 399–403.
159
Nishino I, Spinazzola A, Hirano M (1999). Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder. Science 283: 689–692. Nishino I, Spinazzola A, Papadimitriou A, et al. (2000). Mitochondrial neurogastrointestinal encephalomyopathy: an autosomal recessive disorder due to thymidine phosphorylase mutations. Ann Neurol 47: 792–800. Nishino I, Spinazzola A, Hirano M (2001). MNGIE: from nuclear DNA to mitochondrial DNA. Neuromuscul Disord 11: 7–10. Nishizuka S, Tamura G, Goto Y, et al. (1998). Tissue-specific involvement of multiple mitochondrial DNA deletions in familial mitochondrial myopathy. Biochem Biophys Res Commun 247: 24–27. Nissenkorn A, Zeharia A, Lev D, et al. (1999). Multiple presentation of mitochondrial disorders. Arch Dis Child 81: 209–214. Odoardi F, Rana M, Broccolini A, et al. (2003). Pathogenic role of mtDNA duplications in mitochondrial diseases associated with mtDNA deletions. Am J Med Genet 118A: 247–254. Ogasahara S, Engel AG, Frens D, et al. (1989). Muscle coenzyme Q deficiency in familial mitochondrial encephalomyopathy. Proc Natl Acad Sci U S A 86: 2379–2382. Ogawa Y, Naito E, Ito M, et al. (2002). Three novel SURF-1 mutations in Japanese patients with Leigh syndrome. Pediatr Neurol 26: 196–200. Ogle RF, Christodoulou J, Fagan E, et al. (1997). Mitochondrial myopathy with tRNA(Leu(UUR)) mutation and complex I deficiency responsive to riboflavin. J Pediatr 130: 138–145. Ohno K, Tanaka M, Sahashi K, et al. (1991). Mitochondrial DNA deletions in inherited recurrent myoglobinuria. Ann Neurol 29: 364–369. Oldfors A, Sommerland H, Holme E, et al. (1989). Cytochrome-c oxidase deficiency in infancy. Acta Neuropathol 77: 267–275. Oldfors A, Fyhr IM, Holme E, et al. (1990). Neuropathology in Kearns–Sayre syndrome. Acta Neuropathol (Berl) 80: 541–546. Oldfors A, Larsson NG, Holme E, et al. (1992). Mitochondrial DNA deletions and cytochrome-c oxidase deficiency in muscle fibres. J Neurol Sci 110: 169–177. Oldfors A, Holme E, Tulinius M, et al. (1995a). Tissue distribution and disease manifestations of the tRNA(Lys) A>G(8344) mitochondrial DNA mutation in a case of myoclonus epilepsy and ragged red fibres. Acta Neuropathol 90: 328–333. Oldfors A, Moslemi AR, Fyhr IM, et al. (1995b). Mitochondrial DNA deletions in muscle fibers in inclusion body myositis. J Neuropathol Exp Neurol 54: 581–587. Oldfors A, Moslemi AR, Jonasson L, et al. (2006). Mitochondrial abnormalities in inclusion-body myositis. Neurology 66: S49–S55. Olsen NK, Hansen AW, Norby S, et al. (1995). Leber’s hereditary optic neuropathy associated with a disorder indistinguishable from multiple sclerosis in a male harbouring the mitochondrial DNA 11778 mutation. Acta Neurol Scand 91: 326–329.
160
A. OLDFORS AND M. TULINIUS
Oquendo CE, Antonicka H, Shoubridge EA, et al. (2004). Functional and genetic studies demonstrate that mutation in the COX15 gene can cause Leigh syndrome. J Med Genet 41: 540–544. Ozawa M, Nishino I, Horai S, et al. (1997). Myoclonus epilepsy associated with ragged-red fibers: a G-to-A mutation at nucleotide pair 8363 in mitochondrial tRNA(Lys) in two families. Muscle Nerve 20: 271–278. Pagnamenta AT, Taanman JW, Wilson CJ, et al. (2006). Dominant inheritance of premature ovarian failure associated with mutant mitochondrial DNA polymerase gamma. Hum Reprod 21: 2467–2473. Panetta J, Smith LJ, Boneh A (2004). Effect of high-dose vitamins, coenzyme Q and high-fat diet in paediatric patients with mitochondrial diseases. J Inherit Metab Dis 27: 487–498. Papadimitriou A, Hadjigeorgiou GM, Divari R, et al. (1996). The influence of coenzyme Q(10) on total serum calcium concentration in two patients with Kearns–Sayre syndrome and hypoparathyroidism. Neuromuscul Disord 6: 49–53. Papadopoulou LC, Sue CM, Davidson MM, et al. (1999). Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene. Nat Genet 23: 333–337. Parfait B, Chretien D, Ro¨tig A, et al. (2000). Compound heterozygous mutations in the flavoprotein gene of the respiratory chain complex II in a patient with Leigh syndrome. Hum Genet 106: 236–243. Pastores GM, Santorelli FM, et al. (1994). Leigh-syndrome and hypertrophic cardiomyopathy in an infant with a mitochondrial DNA point mutation (T8993G). Am J Med Genet 50: 265–271. Patton JR, Bykhovskaya Y, Mengesha E, et al. (2005). Mitochondrial myopathy and sideroblastic anemia (MLASA): Missense mutation in the pseudouridine synthase 1 (PUS1) gene is associated with the loss of tRNA psedouridylation. J Biol Chem 280: 19823–19828. Pavlakis SG, Phillips PC, DiMauro S, et al. (1984). Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes: a distinctive clinical syndrome. Ann Neurol 16: 481–488. Pearson HA, Lobel JS, Kocoshis SA, et al. (1979). A new syndrome of refractory sideroblastic anemia with vacuolization of marrow precursors and exocrine pancreatic dysfunction. J Pediatr 95: 976–984. Pequignot MO, Dey R, Zeviani M, et al. (2001). Mutations in the SURF1 gene associated with Leigh syndrome and cytochrome C oxidase deficiency. Hum Mutat 17: 374–381. Perez-Atayde AR, Fox V, Teitelbaum JE, et al. (1998). Mitochondrial neurogastrointestinal encephalomyopathy: diagnosis by rectal biopsy. Am J Surg Pathol 22: 1141–1147. Petruzzella V, Papa S (2002). Mutations in human nuclear genes encoding for subunits of mitochondrial respiratory complex I: the NDUFS4 gene. Gene 286: 149–154. Petruzzella V, Moraes CT, Sano MC, et al. (1994). Extremely high levels of mutant mtDNAs co-localize with cytochrome c oxidase-negative ragged-red fibers in patients
harboring a point mutation at nt 3243. Hum Mol Genet 3: 449–454. Petruzzella V, Vergari R, Puzziferri I, et al. (2001). A nonsense mutation in the NDUFS4 gene encoding the 18 kDa (AQDQ) subunit of complex I abolishes assembly and activity of the complex in a patient with Leigh-like syndrome. Hum Mol Genet 10: 529–535. Pitkanen S, Merante F, Mcleod DR, et al. (1996). Familial cardiomyopathy with cataracts and lactic acidosis: a defect in complex i (NADH-dehydrogenase) of the mitochondria respiratory chain. Pediatr Res 39: 513–521. Prayson RA, Wang N (1998). Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) syndrome: an autopsy report. Arch Pathol Lab Med 122: 978–981. Prelle A, Moggio M, Checcarelli N, et al. (1993). Multiple deletions of mitochondrial DNA in a patient with periodic attacks of paralysis. J Neurol Sci 117: 24–27. Prezant TR, Agapian JV, Bohlman MC, et al. (1993). Mitochondrial ribosomal RNA mutation associated with both antibiotic-induced and non-syndromic deafness. Nat Genet 4: 289–294. Procaccio V, Wallace DC (2004). Late-onset Leigh syndrome in a patient with mitochondrial complex I NDUFS8 mutations. Neurology 62: 1899–1901. Pulkes T, Eunson L, Patterson V, et al. (1999). The mitochondrial DNA G13513A transition in ND5 is associated with a LHON/MELAS overlap syndrome and may be a frequent cause of MELAS. Ann Neurol 46: 916–919. Pulkes T, Siddiqui A, Morgan-Hughes JA, et al. (2000). A novel mutation in the mitochondrial tRNA(Tyr) gene associated with exercise intolerance. Neurology 55: 1210–1212. Puoti G, Carrara F, Sampaolo S, et al. (2003). Identical large scale rearrangement of mitochondrial DNA causes Kearns– Sayre syndrome in a mother and her son. J Med Genet 40: 858–863. Quade A, Zierz S, Klingmuller D (1992). Endocrine abnormalities in mitochondrial myopathy with external ophthalmoplegia. Clin Investig 70: 396–402. Quinzii C, Naini A, Salviati L, et al. (2006). A mutation in para-hydroxybenzoate-polyprenyl transferase (COQ2) causes primary coenzyme Q10 deficiency. Am J Hum Genet 78: 345–349. Rahman S, Taanman JW, Cooper JM, et al. (1999). A missense mutation of cytochrome oxidase subunit II causes defective assembly and myopathy. Am J Hum Genet 65: 1030–1039. Rahman S, Brown RM, Chong WK, et al. (2001a). A SURF1 gene mutation presenting as isolated leukodystrophy. Ann Neurol 49: 797–800. Rahman S, Hargreaves I, Clayton P, et al. (2001b). Neonatal presentation of coenzyme Q10 deficiency. J Pediatr 139: 456–458. Rake JP, van Spronsen FJ, Visser G, et al. (2000). End-stage liver disease as the only consequence of a mitochondrial respiratory chain deficiency: no contra-indication for liver transplantation. Eur J Pediatr 159: 523–526. Rana M, de Coo I, Diaz F, et al. (2000). An out-of-frame cytochrome b gene deletion from a patient with parkinsonism is
MITOCHONDRIAL ENCEPHALOMYOPATHIES associated with impaired complex III assembly and an increase in free radical production. Ann Neurol 48: 774–781. Reardon W, Ross RJM, Sweeney MG, et al. (1992). Diabetes-mellitus associated with a pathogenic point mutation in mitochondrial DNA. Lancet 340: 1376–1379. Reid FM, Vernham GA, Jacobs HT (1994). A novel mitochondrial point mutation in a maternal pedigree with sensorineural deafness. Hum Mutat 3: 243–247. Remes AM, Majamaa K, Herva R, et al. (1993). Adult-onset diabetes-mellitus and neurosensory hearing loss in maternal relatives of MELAS patients in a family with the Transfer-RNA(Leu)(UUR) mutation. Neurology 43: 1015–1020. Remes AM, Karppa M, Moilanen JS, et al. (2003). Epidemiology of the mitochondrial DNA 8344A>G mutation for the myoclonus epilepsy and ragged red fibres (MERRF) syndrome. J Neurol Neurosurg Psychiatry 74: 1158–1159. Rimoldi M, Bottacchi E, Rossi L, et al. (1982). CytochromeC-oxidase deficiency in muscles of a floppy infant without mitochondrial myopathy. J Neurol 227: 201–207. Riordan–Eva P, Sanders MD, Govan GG, et al. (1995). The clinical features of Leber’s hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation. Brain 118: 319–337. Robertson WC, Viseskul C, Lee YE, et al. (1979). Basal ganglia calcification in Kearns–Sayre syndrome. Arch Neurol 36: 711–713. Rosenberg MJ, Agarwala R, Bouffard G, et al. (2002). Mutant deoxynucleotide carrier is associated with congenital microcephaly. Nat Genet 32: 175–179. Rowland LP, Hays AP, DiMauro S, et al. (1983). Diverse clinical disorders associated with morphological abnormalities of mitochondria. In: Mitochondrial pathology in muscle disease. Ed. Scarlato G and Cerri C. Piccin Medical Books. Padua pp 141–158. Ro¨tig A (2003). Renal disease and mitochondrial genetics. J Nephrol 16: 286–292. Ro¨tig A, Colonna M, Bonnefont JP, et al. (1989). Mitochondrial DNA deletion in Pearson’s marrow/pancreas syndrome. Lancet 1: 902–903. Ro¨tig A, Cormier V, Blanche S, et al. (1990). Pearson’s marrow-pancreas syndrome. A multisystem mitochondrial disorder in infancy. J Clin Invest 86: 1601–1608. Ro¨tig A, Bourgeron T, Chretien D, et al. (1995). Spectrum of mitochondrial DNA rearrangements in the Pearson marrow-pancreas syndrome. Hum Mol Genet 4: 1327–1330. Ro¨tig A, deLonlay P, Chretien D, et al. (1997a). Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia. Nat Genet 17: 215–217. Ro¨tig A, Lehnert A, Chretien D, et al. (1997b). Kidney involvement in mitochondrial disorders. Med Sci 13: 18–27. Ro¨tig A, Appelkvist EL, Geromel V, et al. (2000). Quinoneresponsive multiple respiratory-chain dysfunction due to widespread coenzyme Q10 deficiency. Lancet 356: 391–395. Saada A, Shaag A, Mandel H, et al. (2001). Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy. Nat Genet 29: 342–344.
161
Sacconi S, Salviati L, Gooch C, et al. (2002). Complex neurologic syndrome associated with the G1606A mutation of mitochondrial DNA. Arch Neurol 59: 1013–1015. Sadun AA, Carelli V, Salomao SR, et al. (2003). Extensive investigation of a large Brazilian pedigree of 11778/ haplogroup J Leber hereditary optic neuropathy. Am J Ophthalmol 136: 231–238. Saijo T, Naito E, Ito M, et al. (1991). Therapeutic effect of sodium dichloroacetate on visual and auditory hallucinations in a patient with MELAS. Neuropediatrics 22: 166–167. Saitoh S, Momoi MY, Yamagata T, et al. (1998). Effects of dichloroacetate in three patients with MELAS. Neurology 50: 531–534. Salviati L, Hernandez-Rosa E, Walker WF, et al. (2002a). Copper supplementation restores cytochrome c oxidase activity in cultured cells from patients with SCO2 mutations. Biochem J 363: 321–327. Salviati L, Sacconi S, Mancuso M, et al. (2002b). Mitochondrial DNA depletion and dGK gene mutations. Ann Neurol 52: 311–317. Salviati L, Sacconi S, Rasalan MM, et al. (2002c). Cytochrome c oxidase deficiency due to a novel SCO2 mutation mimics Werdnig–Hoffmann disease. Arch Neurol 59: 862–865. Salviati L, Freehauf C, Sacconi S, et al. (2004). Novel SURF1 mutation in a child with subacute encephalopathy and without the radiological features of Leigh Syndrome. Am J Med Genet 128A: 195–198. Salviati L, Sacconi S, Murer L, et al. (2005). Infantile encephalomyopathy and nephropathy with CoQ10 deficiency: a CoQ10-responsive condition. Neurology 65: 606–608. Samson JF, Barth PG, de Vries JI, et al. (1994). Familial mitochondrial encephalopathy with fetal ultrasonographic ventriculomegaly and intracerebral calcifications. Eur J Pediatr 153: 510–516. Samuels DC, Schon EA, Chinnery PF (2004). Two direct repeats cause most human mtDNA deletions. Trends Genet 20: 393–398. Santorelli FM, Mak SC, Vazquezacevedo M, et al. (1995). A novel mitochondrial DNA point mutation associated with mitochondrial encephalocardiomyopathy. Biochem Biophys Res Commun 216: 835–840. Santorelli FM, Tanji K, Shanske S, et al. (1998). The mitochondrial DNA A8344G mutation in Leigh syndrome revealed by analysis in paraffin-embedded sections: revisiting the past. Ann Neurol 44: 962–964. Santorelli FM, Gagliardi MG, Dionisi-Vici C, et al. (2002). Hypertrophic cardiomyopathy and mtDNA depletion. Successful treatment with heart transplantation. Neuromuscul Disord 12: 56–59. Schaefer AM, Taylor RW, Turnbull DM, et al. (2004). The epidemiology of mitochondrial disorders — past, present and future. Biochim Biophys Acta 1659: 115–120. Scha¨gger H, Pfeiffer K (2000). Supercomplexes in the respiratory chains of yeast and mammalian mitochondria. EMBO J 19: 1777–1783. Schon EA, Rizzuto R, Moraes CT, et al. (1989). A direct repeat is a hotspot for large-scale deletion of human mitochondrial DNA. Science 244: 346–349.
162
A. OLDFORS AND M. TULINIUS
Schon EA, Koga Y, Davidson M, et al. (1992). The mitochondrial transfer RNALeu(UUR) mutation in MELAS — a model for pathogenesis. Biochim Biophys Acta 1101: 206–209. Schro¨der JM (1993). Neuropathy associated with mitochondrial disorders. Brain Pathol 3: 177–190. Schuelke M, Smeitink J, Mariman E, et al. (1999). Mutant NDUFV1 subunit of mitochondrial complex I causes leukodystrophy and myoclonic epilepsy. Nat Genet 21: 260–261. Schuelke M, Krude H, Finckh B, et al. (2002). Septo-optic dysplasia associated with a new mitochondrial cytochrome b mutation. Ann Neurol 51: 388–392. Schwartz M, Vissing J (2002). Paternal inheritance of mitochondrial DNA. N Engl J Med 347: 576–580. Sciacco M, Bonilla E, Schon EA, et al. (1994). Distribution of wild-type and common deletion forms of mtDNA in normal and respiration-deficient muscle fibers from patients with mitochondrial myopathy. Hum Mol Genet 3: 13–19. Servidei S, Zeviani M, Manfredi G, et al. (1991). Dominantly inherited mitochondrial myopathy with multiple deletions of mitochondrial DNA — clinical, morphologic, and biochemical studies. Neurology 41: 1053–1059. Shanske S, Tang Y, Hirano M, et al. (2002). Identical mitochondrial DNA deletion in a woman with ocular myopathy and in her son with Pearson syndrome. Am J Hum Genet 71: 679–683. Shapira Y, Harel S, Russell A (1977). Mitochondrial encephalomyopathies: a group of neuromuscular disorders with defects in oxidative metabolism. Isr J Med Sci 13: 161–164. Shoffner JM, Lott MT, Voljavec AS, et al. (1989). Spontaneous Kearns–Sayre/chronic external ophthalmoplegia plus syndrome associated with a mitochondrial DNA deletion: a slip-replication model and metabolic therapy. Proc Natl Acad Sci U S A 86: 7952–7956. Shoffner JM, Lott MT, Lezza AM, et al. (1990). Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNA(Lys) mutation. Cell 61: 931–937. Shoubridge EA, Karpati G, Hastings KE (1990). Deletion mutants are functionally dominant over wild-type mitochondrial genomes in skeletal muscle fiber segments in mitochondrial disease. Cell 62: 43–49. Silva J, Larsson N (2002). Manipulation of mitochondrial DNA gene expression in the mouse. Biochim Biophys Acta 1555: 106. Silvestri G, Moraes CT, Shanske S, et al. (1992). A new mtDNA mutation in the trans-RNA(Lys) gene associated with myoclonic epilepsy and ragged-red fibers (MERRF). Am J Hum Genet 51: 1213–1217. Silvestri G, Ciafaloni E, Santorelli FM, et al. (1993). Clinical features associated with the A->G transition at nucleotide8344 of mtDNA (MERRF mutation). Neurology 43: 1200–1206. Silvestri G, Rana M, DiMuzio A, et al. (1998). A late-onset mitochondrial myopathy is associated with a novel mitochondrial DNA (mtDNA) point mutation in the tRNA (Trp) gene. Neuromuscul Disord 8: 291–295.
Singh G, Lott MT, Wallace DC (1989). A mitochondrial DNA mutation as a cause of Leber’s hereditary optic neuropathy. N Engl J Med 320: 1300–1305. Sinnathuray AR, Raut V, Awa A, et al. (2003). A review of cochlear implantation in mitochondrial sensorineural hearing loss. Otol Neurotol 24: 418–426. Skladal D, Halliday J, Thorburn DR (2003). Minimum birth prevalence of mitochondrial respiratory chain disorders in children. Brain 126: 1905–1912. Smeitink J, Sengers R, Trijbels F, et al. (2001). Human NADH:ubiquinone oxidoreductase. J Bioenerg Biomembr 33: 259–266. Smith KH, Johns DR, Heher KL, et al. (1993). Heteroplasmy in Leber hereditary optic neuropathy. Arch Ophthalmol 111: 1486–1490. Smith JK, Mah JK, Castillo M (1996). Brain MR imaging findings in two patients with Alpers’ syndrome. Clin Imaging 20: 235–237. Sobreira C, Hirano M, Shanske S, et al. (1997). Mitochondrial encephalomyopathy with coenzyme Q(10) deficiency. Neurology 48: 1238–1243. Sokal EM, Sokol R, Cormier V, et al. (1999). Liver transplantation in mitochondrial respiratory chain disorders. Eur J Pediatr 158 (Suppl 2): S81–S84. Sparaco M, Bonilla E, DiMauro S, et al. (1993). Neuropathology of mitochondrial encephalomyopathies due to mitochondrial DNA defects. J Neuropathol Exp Neurol 52: 1–10. Sparaco M, Schon EA, DiMauro S, et al. (1995). Myoclonic epilepsy with ragged-red fibers (MERRF): an immunohistochemical study of the brain. Brain Pathol 5: 125–133. Spelbrink JN, Li FY, Tiranti V, et al. (2001). Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene 4-like protein localized in mitochondria. Nat Genet 28: 223–231. Spinazzola A, Viscomi C, Fernandez-Vizarra E, et al. (2006). MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion. Nat Genet 38: 570–575. Spruijt L, Naviaux RK, McGowan KA, et al. (2001). Nerve conduction changes in patients with mitochondrial diseases treated with dichloroacetate. Muscle Nerve 24: 916–924. Stacpoole PW, Barnes CL, Hurbanis MD, et al. (1997). Treatment of congenital lactic acidosis with dichloroacetate. Arch Dis Child 77: 535–541. Sternberg D, Chatzoglou E, Laforet P, et al. (2001). Mitochondrial DNA transfer RNA gene sequence variations in patients with mitochondrial disorders. Brain 124: 984–994. Sue CM, Mitchell P, Crimmins DS, et al. (1997). Pigmentary retinopathy associated with the mitochondrial DNA 3243 point mutation. Neurology 49: 1013–1017. Sue CM, Lipsett LJ, Crimmins DS, et al. (1998). Cochlear origin of hearing loss in MELAS syndrome. Ann Neurol 43: 350–359. Sue CM, Tanji K, Hadjigeorgiou G, et al. (1999). Maternally inherited hearing loss in a large kindred with a novel T7511C mutation in the mitochondrial DNA tRNA(Ser (UCN)) gene. Neurology 52: 1905–1908.
MITOCHONDRIAL ENCEPHALOMYOPATHIES Sue CM, Karadimas C, Checcarelli N, et al. (2000). Differential features of patients with mutations in two COX assembly genes, SURF-1 and SCO2. Ann Neurol 47: 589–595. Suomalainen A, Kaukonen J (2001). Diseases caused by nuclear genes affecting mtDNA stability. Am J Med Genet 106: 53–61. Suomalainen A, Majander A, Haltia M, et al. (1992a). Multiple deletions of mitochondrial DNA in several tissues of a patient with severe retarded depression and familial progressive external ophthalmoplegia. J Clin Invest 90: 61–66. Suomalainen A, Paetau A, Leinonen H, et al. (1992b). Inherited idiopathic dilated cardiomyopathy with multiple deletions of mitochondrial DNA. Lancet 340: 1319–1320. Suomalainen A, Majander A, Wallin M, et al. (1997). Autosomal dominant progressive external ophthalmoplegia with multiple deletions of mtDNA: clinical, biochemical, and molecular genetic features of the 10q-linked disease. Neurology 48: 1244–1253. Suzuki Y, Suzuki S, Hinokio Y, et al. (1997). Diabetes associated with a novel 3264 mitochondrial tRNA(Leu(UUR)) mutation. Diabetes Care 20: 1138–1140. Sweeney MG, Hammans SR, Duchen LW, et al. (1994). Mitochondrial DNA mutation underlying Leigh’s syndrome: clinical, pathological, biochemical, and genetic studies of a patient presenting with progressive myoclonic epilepsy. J Neurol Sci 121: 57–65. Taanman JW, Kateeb I, Muntau AC, et al. (2002). A novel mutation in the deoxyguanosine kinase gene causing depletion of mitochondrial DNA. Ann Neurol 52: 237–239. Tadiboyina VT, Rupar A, Atkison P, et al. (2005). Novel mutation in DGUOK in hepatocerebral mitochondrial DNA depletion syndrome associated with cystathioninuria. Am J Med Genet A 135: 289–291. Taivassalo T, Matthews PM, De Stefano N, et al. (1996). Combined aerobic training and dichloroacetate improve exercise capacity and indices of aerobic metabolism in muscle cytochrome oxidase deficiency. Neurology 47: 529–534. Taivassalo T, Fu K, Johns T, et al. (1999). Gene shifting: a novel therapy for mitochondrial myopathy. Hum Mol Genet 8: 1047–1052. Taivassalo T, Shoubridge EA, Chen J, et al. (2001). Aerobic conditioning in patients with mitochondrial myopathies: physiological, biochemical, and genetic effects. Ann Neurol 50: 133–141. Takanashi J, Sugita K, Tanabe Y, et al. (1997). Dichloroacetate treatment in Leigh syndrome caused by mitochondrial DNA mutation. J Neurol Sci 145: 83–86. Takei YI, Ikeda SI, Yanagisawa N, et al. (1995). Multiple mitochondrial DNA deletions in a patient with mitochondrial myopathy and cardiomyopathy but no ophthalmoplegia. Muscle Nerve 18: 1321–1325. Taniike M, Fukushima H, Yanagihara I, et al. (1992). Mitochondrial transfer RNAIle mutation in fatal cardiomyopathy. Biochem Biophys Res Commun 186: 47–53. Tarnopolsky MA, Roy BD, MacDonald JR (1997). A randomized, controlled trial of creatine monohydrate in patients with mitochondrial cytopathies. Muscle Nerve 20: 1502–1509.
163
Tarnopolsky MA, Bourgeois JM, Fu MH, et al. (2004). Novel SCO2 mutation (G1521A) presenting as a spinal muscular atrophy type I phenotype. Am J Med Genet 125A: 310–314. Tay SK, Shanske S, Kaplan P, et al. (2004). Association of mutations in SCO2, a cytochrome c oxidase assembly gene, with early fetal lethality. Arch Neurol 61: 950–952. Taylor RW, Morris AA, Hutchinson M, et al. (2002). Leigh disease associated with a novel mitochondrial DNA ND5 mutation. Eur J Hum Genet 10: 141–144. Taylor RW, McDonnell MT, Blakely EL, et al. (2003a). Genotypes from patients indicate no paternal mitochondrial DNA contribution. Ann Neurol 54: 521–524. Taylor RW, Giordano C, Davidson MM, et al. (2003b). A homoplasmic mitochondrial transfer ribonucleic acid mutation as a cause of maternally inherited hypertrophic cardiomyopathy. J Am Coll Cardiol 41: 1786–1796. Tein I, DiMauro S, Xie ZW, et al. (1993). Valproic acid impairs carnitine uptake in cultured human skin fibroblasts. An in vitro model for the pathogenesis of valproic acidassociated carnitine deficiency. Pediatr Res 34: 281–287. Terasaki F, Tanaka M, Kawamura K, et al. (2001). A case of cardiomyopathy showing progression from the hypertrophic to the dilated form: association of Mt8348A–>G mutation in the mitochondrial tRNA(Lys) gene with severe ultrastructural alterations of mitochondria in cardiomyocytes. Jpn Circ J 65: 691–694. Thyagarajan D, Shanske S, Vazquez-Memije M, et al. (1995). A novel mitochondrial ATPase 6 point mutation in familial bilateral striatal necrosis. Ann Neurol 38: 468–472. Thyagarajan D, Bressman S, Bruno C, et al. (2000). A novel mitochondrial 12SrRNA point mutation in parkinsonism, deafness, and neuropathy. Ann Neurol 48: 730–736. Tiranti V, Hoertnagel K, Carrozzo R, et al. (1998). Mutations of SURF-1 in Leigh disease associated with cytochrome c oxidase deficiency. Am J Hum Genet 63: 1609–1621. Tiranti V, Corona P, Greco M, et al. (2000). A novel frameshift mutation of the mtDNA COIII gene leads to impaired assembly of cytochrome c oxidase in a patient affected by Leigh-like syndrome. Hum Mol Genet 9: 2733–2742. Tra¨ff J, Holme E, Ekbom K, et al. (1995). Ekbom’s syndrome of photomyoclonus, cerebellar ataxia and cervical lipoma is associated with the tRNA(Lys) A8344G mutation in mitochondrial DNA. Acta Neurol Scand 92: 394–397. Tranchant C, Mousson B, Mohr M, et al. (1993). Cardiac transplantation in an incomplete Kearns–Sayre syndrome with mitochondrial DNA deletion. Neuromuscul Disord 3: 561–566. Trenell MI, Sue CM, Kemp GJ, et al. (2006). Aerobic exercise and muscle metabolism in patients with mitochondrial myopathy. Muscle Nerve 33: 524–531. Triepels RH, Van Den Heuvel LP, Trijbels JM, et al. (2001). Respiratory chain complex I deficiency. Am J Med Genet 106: 37–45. Trifunovic A, Wredenberg A, Falkenberg M, et al. (2004). Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429: 417–423.
164
A. OLDFORS AND M. TULINIUS
Tulinius MH, Hagne I (1991). EEG findings in children and adolescents with mitochondrial encephalomyopathies — a study of 25 cases. Brain Dev 13: 167–173. Tulinius M, Holme E, Kristiansson B, et al. (1991). Mitochondrial encephalomyopathies in children. II Clinical manifestations and syndromes. J Pediatr 119: 251–259. Tulinius MH, Oldfors A, Holme E, et al. (1995). Atypical presentation of multisystem disorders in two girls with mitochondrial DNA deletions. Eur J Pediatr 154: 35–42. Tulinius M, Moslemi AR, Darin N, et al. (2005). Novel mutations in the thymidine kinase 2 gene (TK2) associated with fatal mitochondrial myopathy and mitochondrial DNA depletion. Neuromuscular Disord 15: 412–415. Tyynismaa H, Sembongi H, Bokori-Brown M, et al. (2004). Twinkle helicase is essential for mtDNA maintenance and regulates mtDNA copy number. Hum Mol Genet 13: 3219–3227. Tzen CY, Tsai JD, Wu TY, et al. (2001). Tubulointerstitial nephritis associated with a novel mitochondrial point mutation. Kidney Int 59: 846–854. Ueda Y, Ando A, Nagata T, et al. (2004). A boy with mitochondrial disease: asymptomatic proteinuria without neuromyopathy. Pediatr Nephrol 19: 107–110. Ugalde C, Vogel R, Huijbens R, et al. (2004). Human mitochondrial complex I assembles through the combination of evolutionary conserved modules: a framework to interpret complex I deficiencies. Hum Mol Genet 13: 2461–2472. Uusimaa J, Finnila S, Vainionpaa L, et al. (2003). A mutation in mitochondrial DNA-encoded cytochrome c oxidase II gene in a child with Alpers-Huttenlocher-like disease. Pediatrics 111: e262–e268. Valanne L, Ketonen L, Majander A, et al. (1998). Neuroradiologic findings in children with mitochondrial disorders. AJNR Am J Neuroradiol 19: 369–377. Vallance HD, Jeven G, Wallace DC, et al. (2004). A case of sporadic infantile histiocytoid cardiomyopathy caused by the A8344G (MERRF) mitochondrial DNA mutation. Pediatr Cardiol 25: 538–540. Valnot I, Osmond S, Gigarel N, et al. (2000a). Mutations of the SCO1 gene in mitochondrial cytochrome c oxidase deficiency with neonatal-onset hepatic failure and encephalopathy. Am J Hum Genet 67: 1104–1109. Valnot I, von Kleist-Retzow JC, Barrientos A, et al. (2000b). A mutation in the human heme A:farnesyltransferase gene (COX10 ) causes cytochrome c oxidase deficiency. Hum Mol Genet 9: 1245–1249. Van Coster R, Seneca S, Smet J, et al. (2003). Homozygous Gly555Glu mutation in the nuclear-encoded 70 kDa flavoprotein gene causes instability of the respiratory chain complex II. Am J Med Genet 120A: 13–18. Van den Heuvel L, Ruitenbeek W, Smeets R, et al. (1998). Demonstration of a new pathogenic mutation in human complex I deficiency: a 5-bp duplication in the nuclear gene encoding the 18-kD (AQDQ) subunit. Am J Hum Genet 62: 262–268. Van den Ouweland JMW, Lemkes HH PJ, Ruitenbeek W, et al. (1992). Mutation in mitochondrial transfer RNA(Leu(UUR))
gene in a large pedigree with maternally transmitted type-II diabetes-mellitus and deafness. Nat Genet 1: 368–371. Van den Ouweland JM, de Klerk JB, van de Corput MP, et al. (2000). Characterization of a novel mitochondrial DNA deletion in a patient with a variant of the Pearson marrowpancreas syndrome. Eur J Hum Genet 8: 195–203. Van Goethem G, Dermaut B, Lofgren A, et al. (2001). Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions. Nat Genet 28: 211–212. Van Goethem G, Martin JJ, Van Broeckhoven C (2002). Progressive external ophthalmoplegia and multiple mitochondrial DNA deletions. Acta Neurol Belg 102: 39–42. Van Goethem G, Martin JJ, Dermaut B, et al. (2003a). Recessive POLG mutations presenting with sensory and ataxic neuropathy in compound heterozygote patients with progressive external ophthalmoplegia. Neuromuscul Disord 13: 133–142. Van Goethem G, Martin JJ, Van Broeckhoven C (2003b). Progressive external ophthalmoplegia characterized by multiple deletions of mitochondrial DNA: unraveling the pathogenesis of human mitochondrial DNA instability and the initiation of a genetic classification. Neuromolecular Med 3: 129–146. Van Goethem G, Luoma P, Rantamaki M, et al. (2004). POLG mutations in neurodegenerative disorders with ataxia but no muscle involvement. Neurology 63: 1251–1257. Van Maldergem L, Trijbels F, DiMauro S, et al. (2002). Coenzyme Q-responsive Leigh’s encephalopathy in two sisters. Ann Neurol 52: 750–754. Verma A, Moraes CT, Shebert RT, et al. (1996). A MERRF/PEO overlap syndrome associated with the mitochondrial DNA 3243 mutation. Neurology 46: 1334–1336. Verma A, Piccoli DA, Bonilla E, et al. (1997). A novel mitochondrial G8313A mutation associated with prominent initial gastrointestinal symptoms and progressive encephaloneuropathy. Pediatr Res 42: 448–454. Vila MR, Segovia-Silvestre T, Gamez J, et al. (2003). Reversion of mtDNA depletion in a patient with TK2 deficiency. Neurology 60: 1203–1205. Ville-Ferlin T, Dumoulin R, Stepien G, et al. (1995). Fine mapping of randomly distributed multiple deletions of mitochondrial DNA in a case of chronic progressive external ophthalmoplegia. Mol Cell Probes 9: 207–214. Visapaa I, Fellman V, Vesa J, et al. (2002). GRACILE syndrome, a lethal metabolic disorder with iron overload, is caused by a point mutation in BCS1L. Am J Hum Genet 71: 863–876. Vissing J, Salamon MB, Arlien-Soborg P, et al. (1998). A new mitochondrial tRNA(Met) gene mutation in a patient with dystrophic muscle and exercise intolerance. Neurology 50: 1875–1878. Von Kleist-Retzow JC, Yao J, Taanman JW, et al. (2001). Mutations in SURF1 are not specifically associated with Leigh syndrome. J Med Genet 38: 109–113.
MITOCHONDRIAL ENCEPHALOMYOPATHIES Von Kleist-Retzow JC, Cormier-Daire V, Viot G, et al. (2003). Antenatal manifestations of mitochondrial respiratory chain deficiency. J Pediatr 143: 208–212. Walker UA, Byrne E (1995). The therapy of respiratory chain encephalomyopathy: a critical review of the past and current perspective. Acta Neurol Scand 92: 273–280. Wallace DC (2002). Animal models for mitochondrial disease. Methods Mol Biol 197: 3–54. Wallace DC, Singh G, Lott MT, et al. (1988). Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science 242: 1427–1430. Wang L, Limongelli A, Vila MR, et al. (2005). Molecular insight into mitochondrial DNA depletion syndrome in two patients with novel mutations in the deoxyguanosine kinase and thymidine kinase 2 genes. Mol Genet Metab 84: 75–82. Weber K, Wilson JN, Taylor L, et al. (1997). A new mtDNA mutation showing accumulation with time and restriction to skeletal muscle. Am J Hum Genet 60: 373–380. White SL, Shanske S, McGill JJ, et al. (1999a). Mitochondrial DNA mutations at nucleotide 8993 show a lack of tissue- or age-related variation. J Inherit Metab Dis 22: 899–914. White SL, Collins VR, Wolfe R, et al. (1999b). Genetic counseling and prenatal diagnosis for the mitochondrial DNA mutations at nucleotide 8993. Am J Hum Genet 65: 474–482. White SL, Shanske S, Biros I, et al. (1999c). Two cases of prenatal analysis for the pathogenic T to G substitution at nucleotide 8993 in mitochondrial DNA. Prenat Diagn 19: 1165–1168. Wibrand F, Ravn K, Schwartz M, et al. (2001). Multisystem disorder associated with a missense mutation in the mitochondrial cytochrome b gene. Ann Neurol 50: 540–543. Wilichowski E, Gruters A, Kruse K, et al. (1997). Hypoparathyroidism and deafness associated with pleioplasmic large scale rearrangements of the mitochondrial DNA: a clinical and molecular genetic study of four children with Kearns–Sayre syndrome. Pediatr Res 41: 193–200. Wissinger B, Besch D, Baumann B, et al. (1997). Mutation analysis of the ND6 gene in patients with Leber’s heredi-
165
tary optic neuropathy. Biochem Biophys Res Commun 234: 511–515. Xu F, Morin C, Mitchell G, et al. (2004). The role of the LRPPRC (leucine-rich pentatricopeptide repeat cassette) gene in cytochrome oxidase assembly: mutation causes lowered levels of COX (cytochrome c oxidase) I and COX III mRNA. Biochem J 382: 331–336. Yamaguchi T, Himi T, Harabuchi Y, et al. (1997). Cochlear implantation in a patient with mitochondrial disease — Kearns–Sayre syndrome: a case report. Adv Otorhinolaryngol 52: 321–323. Yu Wai Man CY, Chinnery PF, Griffiths PG (2005). Extraocular muscles have fundamentally distinct properties that make them selectively vulnerable to certain disorders. Neuromuscul Disord 15: 17–23. Zeviani M, Moraes CT, DiMauro S, et al. (1988). Deletions of mitochondrial DNA in Kearns–Sayre syndrome. Neurology 38: 1339–1346. Zeviani M, Servidei S, Gellera C, et al. (1989). An autosomal dominant disorder with multiple deletions of mitochondrial DNA starting at the D-loop region. Nature 339: 309–311. Zeviani M, Bresolin N, Gellera C, et al. (1990). Nucleusdriven multiple large-scale deletions of the human mitochondrial genome: a new autosomal dominant disease. Am J Hum Genet 47: 904–914. Zeviani M, Amati P, Bresolin N, et al. (1991). Rapid detection of the A->G(8344) mutation of mtDNA in Italian families with myoclonus epilepsy and ragged-red fibers (MERRF). Am J Hum Genet 48: 203–211. Zeviani M, Bertagnolio B, Uziel G (1996). Neurological presentations of mitochondrial diseases. J Inherit Metab Dis 19: 504–520. Zhu Z, Yao J, Johns T, et al. (1998). SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome. Nat Genet 20: 337–343. Zwirner P, Wilichowski E (2001). Progressive sensorineural hearing loss in children with mitochondrial encephalomyopathies. Laryngoscope 111: 515–521.
Handbook of Clinical Neurology, Vol. 86 (3rd series) Myopathies F. L. Mastaglia, D. Hilton-Jones, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 7
Disorders of carbohydrate metabolism SALVATORE DIMAURO*, ORHAN AKMAN AND ARTHUR P. HAYS Columbia University Medical Center, New York, NY, USA
7.1. Introduction The two major energy sources for muscle contraction are glycogen and fatty acids, whose metabolic pathways converge into acetyl-CoA for final intramitochondrial oxidation through the Krebs cycle and the respiratory chain. Defects of substrate utilization in muscle cause two main clinical presentations: (i) acute, recurrent, reversible muscle dysfunction, manifesting as exercise intolerance, myalgia with or without painful cramps (contractures), often culminating in muscle breakdown and myoglobinuria; or (ii) fixed, often axial and proximal limb weakness, sometimes simulating dystrophic or inflammatory processes. Fig. 7.1 is an updated version of a similar scheme that we first published in 1985 (DiMauro, 1985). Three new glycogenoses (aldolase deficiency, b-enolase deficiency, and deficiencies of AMP-activated protein kinase) have been discovered in the intervening 20 years, and Lafora disease has been included among the glycogenoses. There are several recent detailed descriptions of the muscle glycogen storage diseases (GSD; Chen, 2001; DiMauro et al., 2004; Engel et al., 2004). This chapter, therefore, summarizes typical clinical presentations, muscle morphology and biochemistry, focusing instead on molecular genetics and physiopathology.
7.2. Glycogen as muscle fuel The “fuel” utilized by muscle depends on several factors, most importantly the type, intensity and duration of exercise, but also diet and physical conditioning. At rest, muscle utilizes predominantly fatty acids. At the opposite end of the spectrum, the energy for extremely intense exercise (close to one’s maximal oxygen uptake, or VO2max, in dynamic exercise, or to maximal force
generation in isometric exercise) derives from anaerobic glycolysis (i.e., glycogen metabolism), especially when there is a “burst” of activity with rapid acceleration to maximal exercise. During submaximal exertion, the type of fuel utilized by muscle depends on the relative intensity of exercise. At low intensity (below 50% VO2max), the primary source of energy is represented by blood glucose and free fatty acids (FFA). At higher intensities, the proportion of energy derived from carbohydrate oxidation increases, and glycogen becomes an important fuel: at 70–80% VO2max, aerobic metabolism of glycogen is the crucial source of energy, and fatigue appears to set in when glycogen is exhausted. The type of circulating substrate utilized during mild exercise varies with time, and there is a gradual increase in the utilization of FFA over glucose until, a few hours into exercise, lipid oxidation becomes the major source of energy (Haller and Vissing, 2004a). In agreement with the concept that glycogen metabolism is crucial for anaerobic or intense aerobic exercise, the complaints of patients with muscle glycogenoses are almost invariably related to an identifiable, and usually strenuous, bout of exertion. Also, the muscles that hurt, swell, or go into contracture are those that have been engaged in that particular type of exercise. The effect of diet is interesting. Whereas fasting is a potential trigger of myoglobinuria in patients with carnitine palmitoyltransferase II (CPT II) deficiency, who cannot utilize free fatty acids, patients with myophosphorylase deficiency (McArdle disease) note a beneficial effect of fasting on their exercise ability, which is explained by the mobilization of circulating FFA, an alternative fuel to the unavailable endogenous glycogen. Patients with McArdle disease also benefit from glucose administration or from a sucrose load before exercise (Vissing and Haller, 2003a) because their metabolic block, which
*Correspondence to: Salvatore DiMauro, MD, 4–420 College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA. E-mail:
[email protected], Tel: þ1-212-305-1662, Fax: þ1-212-305-3986.
168
S. DIMAURO ET AL.
Fig. 7.1. Scheme of glycogen metabolism and glycolysis. Roman numerals denote muscle glycogenoses due to defects in the following enzymes: I, glucose-6-phosphatase; II, acid maltase; III, debrancher; IV, brancher; V, myophosphorylase; VI, liver phosphorylase; VII, muscle phosphofructokinase; VIII, phosphorylase b kinase; IX, phosphoglycerate kinase; X, phosphoglycerate mutase; XI, lactate dehydrogenase; XII, aldolase; XIII, b-enolase. Symbols in italics indicate glycogenoses causing fixed weakness; standard symbols indicate glycogenoses causing exercise intolerance, cramps and myoglobinuria. Defects of 50 AMP-activated protein kinase (AMPK) cause familial hypertrophic cardiomyopathy with Wolff–Parkinson–White syndrome (FHC/WPWS). Defects in laforin or malin cause accumulation of polyglucosan by an unknown mechanism. Reproduced in modified form from DiMauro et al. (1984) with permission from Taylor & Francis, Inc, http://www.taylorandfrancis.com.
is far upstream in carbohydrate metabolism, impairs glycogen but not glucose utilization (Fig. 7.1). In contrast, meals rich in carbohydrate exacerbate the exercise intolerance of patients with phosphofructokinase (PFK) deficiency for two reasons: (i) due to the metabolic
block downstream in glycolysis (Fig. 7.1), their muscle cannot utilize either glycogen or glucose; (ii) glucose decreases the blood concentration of the alternative fuels FFA and ketones, a situation dubbed the “out of wind” phenomenon (Haller and Lewis, 1991).
DISORDERS OF CARBOHYDRATE METABOLISM 7.2.1. Glycogenoses causing exercise intolerance and myoglobinuria Throughout this chapter, we will follow the metabolic “flow” in the glycogenolytic and glycolytic pathways rather than the historical numeration (Fig. 7.1). 7.2.1.1. Phosphorylase kinase deficiency (GSD VIII) Phosphorylase kinase (Phk) is a key regulatory enzyme in glycogen metabolism because it activates glycogen phosphorylase in response to neuronal or hormonal stimuli. Phk deficiency has been associated with four distinct clinical presentations, which are distinguished on the basis of tissue involvement (liver, muscle, heart, or liver and muscle) and mode of inheritance (autosomal or X-linked). This clinical and genetic heterogeneity is explained by the complexity of the enzyme, a decahexameric protein composed of four subunits (abgd)4. The a and b subunits are regulatory, the g subunit is catalytic, and the d subunit is identical to calmodulin and confers calcium sensitivity to the enzyme. In addition, two different isoforms of the a subunit (aM for muscle and aL for liver) are encoded by two different genes on the X chromosome (PHKA1, PHKA2), while the b subunit, two isoforms of the g subunit (gM for muscle and gTL for testis/liver), and three isoforms of calmodulin are encoded by autosomal genes (PHKB, PHKG1, PHKG2, CALM1–3). The complexity of this enzyme explains, in part at least, the clinical heterogeneity of disorders due to Phk deficiency. Thus, two X-linked forms of hepatic glycogenosis, one also involving blood cells, XLG1, the other sparing blood cells, XLG2, have been associated with different mutations in PHKA2. The autosomal-recessive and relatively benign liver and muscle variant has been associated to mutations in PHKB, whereas the more severe purely hepatopathic variant is due to mutations in PHKG2 (Burwinkel et al., 2003a). Not surprisingly, the myopathic variant of Phk deficiency presents clinically like a mild form of myophosphorylase deficiency (McArdle disease), with exercise intolerance, cramps and recurrent myoglobinuria in young adults. Less frequent presentations include infantile weakness and respiratory insufficiency or late-onset weakness. Muscle morphology shows subsarcolemmal deposits of normal-looking glycogen, and muscle biochemistry shows moderately increased glycogen concentration and markedly reduced Phk activity. The predominance of affected men suggested that the X-linked aM isoform may be involved, a concept bolstered by reports of mutations in the PHKA1 gene in two patients (Wehner et al., 1994; Bruno et al., 1998).
169
However, a thorough molecular study of six myopathic patients, five men and one woman, revealed only one novel mutation in PHKA1, whereas no pathogenic mutations were found in any of the six genes (PHKA1, PHKB, PHKG1, CALM1, CALM2, CALM3) encoding muscle subunits of Phk in the other five patients (Burwinkel et al., 2003b). This surprising result suggested that most myopathic patients with low Phk activity either harbor elusive mutations in Phk genes or mutations in other unidentified genes. A mystery concerning the fatal infantile cardiopathic variant of Phk deficiency — there are no heart-specific Phk isozymes — has been at least partially solved. In three of five reported cases, Burwinkel et al found no mutations in PHK genes, but a functionally severe mutation (R531Q) in the gene (PRKAG2) encoding the g2-subunit of AMP-activated protein kinase (AMPK complex) (Burwinkel et al., 2005). It is not clear how dysfunction of the AMPK complex causes Phk deficiency in the hearts of these infants. 7.2.1.2. AMP-activated Protein Kinase (AMPK) deficiency The AMPK complex appears to function as a sensor of the energy status of the cell through binding sites for ATP and AMP. It is a heterotrimer composed of a catalytic a subunit, and two regulatory subunits (b and g). As mentioned above, a severe mutation (R531Q) in the g2-subunit of the AMPK complex underlies many (but not all) cases of fatal infantile cardiomyopathy with glycogen storage and Phk deficiency (Burwinkel et al., 2005). Milder mutations in the same gene (PRKAG2) cause autosomal-dominant familial hypertrophic cardiomyopathy with Wolff–Parkinson–White syndrome (FHC/WPWS; Arad et al., 2002; 2005). Interestingly, much of the polysaccharide stored in this condition has the staining and ultrastructural features of polyglucosan, suggesting that AMPK deficiency somehow tips the ratio of glycogen synthetase and branching enzyme in favor of the former (see below). One patient with FHC/WPWS also had exercise intolerance, increased serum CK and morphological evidence of glycogen storage in muscle (Laforet et al., 2006), indicating that AMPK deficiency should now be included in the differential diagnosis of muscle/heart glycogenoses, which was thus far confined to Pompe disease (GSD II), debrancher deficiency (GSD III) and branching enzyme deficiency (GSD IV). In addition, mutations in PRKAG3, the gene encoding the muscle-specific g3-subunit of AMPK, cause glycogen storage in porcine skeletal muscle, making this gene a good candidate for unexplained human muscle glycogenoses (Milan et al., 2000).
170
S. DIMAURO ET AL.
7.2.1.3. Myophosphorylase deficiency (GSD V; McArdle disease) In 1951, on the basis of astute clinical observation and a few critically chosen laboratory tests, Brian McArdle gave a remarkably precise description of the metabolic problem in a young man with exercise intolerance and cramps (McArdle, 1951). He noted that ischemic exercise resulted in painful cramps of forearm muscles, and that no electrical activity was recorded from the shortened muscles, indicating that they were in a state of contracture. He also noted that oxygen consumption and ventilation were normal at rest but increased excessively with exercise. Having observed that venous lactate and pyruvate did not increase after exercise, McArdle concluded that his patient’s disorder was “characterized by a gross failure of the breakdown of glycogen to lactic acid”. Nor was the specific involvement of muscle lost on McArdle, who noted that epinephrine elicited a normal rise of blood glucose and “shed blood” in vitro accumulated lactate normally, leading him to conclude that “the disorder of carbohydrate metabolism affected chiefly if not entirely the skeletal muscles”. There are three isoforms of glycogen phosphorylase: brain/heart, liver and muscle, encoded by different genes. The gene for myophosphorylase (PYGM) is on chrosome 11q13 and McArdle disease is due to mutations in PGYM. The clinical picture is characterized by exercise intolerance, with myalgia and stiffness or weakness of exercising muscles, which is relieved by rest. Two types of exertion are more likely to cause symptoms: brief intense
A
isometric exercise, such as pushing a stalled car, or less intense but sustained dynamic exercise, such as walking in the snow. Moderate exercise, such as walking on level ground, is usually well tolerated. In contrast, strenuous exercise often results in painful cramps, which are real contractures because — as noted by McArdle — the shortened muscles are electrically silent. An interesting phenomenon almost always reported or recognized by patients with McArdle disease is the “second wind” that they experience when they rest briefly at the first appearance of exercise-induced myalgia (Haller and Vissing, 2002). Although myoglobinuria (with the attendant risk of renal shutdown) occurs in only about half the patients, McArdle disease is the second most common cause of recurrent myoglobinuria in adults, after CPT II deficiency (Tonin et al., 1990). The clinical diagnosis of McArdle disease is suggested by cramps and myalgia following strenuous exercise and affecting engaged muscles. Electromyography (EMG) can be normal or show non-specific myopathic features at rest, but it documents electrical silence in contractured muscles. As in most muscle glycogenoses, resting serum creatine kinase (CK) is elevated in patients with McArdle disease. Muscle histochemistry shows subsarcolemmal accumulation of periodic acid-Schiff (PAS)-positive material (glycogen) that is normally digested by diastase (Fig. 7.2). A specific histochemical stain for phosphorylase can be diagnostic except when the muscle specimen is taken too soon after an episode of myoglobinuria because regenerating fibers express
B
Fig. 7.2. Muscle biopsy in phosphorylase deficiency. (A) Excessive sarcoplasmic glycogen appears as darkly stained aggregates within the subsarcolemmal region of muscle fibers (arrows) of a transverse section of muscle. This pattern of glycogen accumulation is typical of deficiency of phosphorylase, debrancher enzyme, phosphofructokinase and other glycolytic enzymes. Semithin plastic section, toluidine blue–periodic acid Schiff reagent (PAS), bar ¼ 25 mm. (B) Glycolytic enzyme defects appear as accumulation of normal-appearing small glycogen particles in the subsarcolemmal zone (arrows) by electron microscopy. The surface membrane of the myofiber borders the mass of glycogen but does not surround it. This contrasts with the lysosomal disorder, acid maltase deficiency, which shows that much of the glycogen is completely surrounded by a unit membrane (see Fig. 7.4(C)). Bar ¼ 1.0 mm.
DISORDERS OF CARBOHYDRATE METABOLISM transiently the brain isoform of phosphorylase, thus masking the deficiency of myophosphorylase. Biochemical analysis of muscle provides the definitive answer, but muscle biopsy may be avoided altogether in Caucasian patients if the clinical suspicion of McArdle disease is strong enough. In these cases, it is expedient to look for the common mutation (R49X) in genomic DNA isolated from blood cells. The presence of the mutation — even in heterozygosity — establishes the diagnosis. The forearm ischemic exercise (FIE) test is informative but is being abandoned because: (i) it depends on the ability and willingness of the patient to exercise vigorously; (ii) it is not specific of McArdle disease, as lactate is not formed anaerobically in all defects of glycolysis (Fig. 7.1); (iii) it is painful and may provoke local muscle damage. Alternative diagnostic tests include a nonischemic version of the FIE (Kazemi-Esfarjani et al., 2002) and a cycle test based on the decrease in heart rate shown characteristically by patients with McArdle disease between the 7th and the 15th minute of moderate exercise and reflecting the second-wind phenomenon (Vissing and Haller, 2003b). Clinical variants of McArdle disease include the fatal infantile myopathy described in a few cases, and fixed weakness in older patients (DiMauro et al., 2004). However, some degree of fixed weakness develops with age also in patients with typical McArdle disease and is probably due to focal muscle necrosis, which occurs in these patients even with everyday activities and is reflected by their chronically elevated serum CK levels. After the first description of three mutations in PGYM (Tsujino et al., 1993a), the number of pathogenic mutations has rapidly escalated to over 40 (Martin et al., 2003; Quintans et al., 2004). As mentioned above, by far the most common mutation in Caucasian patients is the R49X (Arg49Stop) mutation, which accounts for 81% of the alleles in British patients (Bartram et al., 1993) and 63% of alleles in US patients (El-Schahawi et al., 1996). It is important to keep in mind that the frequency of different mutations varies in different ethnic groups: for example, the R49X mutation has never been described in Japan, where a single codon deletion 708/ 709 seems to prevail (Tsujino et al., 1994). The plot thickened when it was documented that an apparently innocent polymorphism in the PYGM gene impaired cDNA splicing and was, in fact, pathogenic (Fernandez-Cadenas et al., 2003). This “echo of silence” (Mankodi and Ashizawa, 2003) has to be taken into account in patients with McArdle disease not having clearly pathogenic mutations. The many different mutations are spread all over the gene (Martin et al., 2003), and it is not easy to discern any genotype–phenotype correlation. Even patients with the same genotype (e.g., homozygous for the commonest
171
mutation, R49X) may have very different clinical manifestations, varying from relatively mild exercise-related discomfort to almost crippling myalgia and recurrent myoglobinuria. Although these differences can be due in part to different lifestyles or dietary regimens, other factors must play a role. For example, rare cases of genetic “double trouble”, such as the coexistence in the same individual of homozygous mutations in PYGM and in the gene for adenylate deaminase, may explain more severe phenotypes (Tsujino et al., 1995; Martinuzzi et al., 2003). Perhaps more importantly, screening for insertion/deletion polymorphism in the angiotensinconverting enzyme (ACE) in 47 patients showed a good correlation between clinical severity and number of ACE genes harboring deletion (Martinuzzi et al., 2003). Our ignorance about genetype–phenotype correlation is best illustrated by two children, both homozygous for the R49X mutation: one had fatal infantile myopathy (Tsujino et al., 1993a), the other had sudden infant death syndrome (SIDS; El-Schahawi et al., 1997). There is no specific therapy for McArdle disease, although several pharmacological and nutritional remedies have been tried, as reviewed by Quinlivan and Beynon (2004). Probably, the most important therapy is aerobic exercise (Haller, 2000), although oral sucrose may have a prophylactic effect when taken before planned activity (Vissing and Haller, 2003a). 7.2.1.4. Phosphofructokinase (PFK) deficiency (Tarui disease; GSD VII) Phosphofructokinase is a tetrameric enzyme under the control of three autosomal genes, PFKM on chromosome 12, which encodes the muscle subunit (Nakajima et al., 2002); PFKL on chromosome 21, which encodes the liver subunit; and PFKP on chromosome 10, which encodes the platelet subunit. Mature human muscle expresses only the M subunit and contains exclusively the M homotetramer (M4), whereas erythrocytes, which contain both the M and the L subunits, contain five isozymes, the two homotetramers (M4 and L4) and three hybrid forms (M1L3, M2L2, M3L1). In patients with typical PFK deficiency, mutations in PFKM cause total lack of activity in muscle but only partial PFK deficiency in red blood cells, where the residual activity approximates 50% and is accounted for by the L4 isozyme. Clinically, PFK deficiency, first described in 1965 in a Japanese family (Tarui et al., 1965), is indistinguishable from McArdle disease, except for the absence of the second-wind phenomenon. In fact, comparative exercise studies of 29 patients with McArdle disease and 5 patients with PFK deficiency showed that a spontaneous second wind (manifested by decreased heart rate and perceived exertion) occurred in all McArdle patients
172
S. DIMAURO ET AL.
but in no PFK-deficient patient (Haller and Vissing, 2004b). Some laboratory tests help in the differential diagnosis, including increased bilirubin concentration and reticulocyte count, reflecting a compensated hemolytic trait. Thus, the diagnosis of PFK deficiency is based on the combination of muscle symptoms (exercise intolerance, cramps, and recurrent myoglobinuria) and compensated hemolytic anemia; the only other muscle glycogenosis with similar features is phosphoglycerate kinase (PGK) deficiency (see below). Of the two main clinical variants, one manifests as fixed weakness in adults (most of whom, however, recognize having suffered from exercise intolerance in their youth), while the other affects infants or young children, who have both generalized weakness and symptoms of multisystem involvement (seizures, cortical blindness, corneal opacifications or cardiopathy; DiMauro et al., 2004). The infantile variant is difficult to explain purely on the basis of muscle PFK deficiency (in fact, no mutation in the PFK-M gene has been documented in these children) and is probably genetically different from the typical adult myopathy. As mentioned earlier, patients with PFK deficiency notice worsening of their exercise intolerance after high-carbohydrate meals, which was attributed to the fact that glucose lowers the blood concentration of alternative muscle fuels, such as free fatty acids and ketone bodies (Haller and Lewis, 1991). Muscle histochemistry shows predominantly subsarcolemmal deposits of glycogen, most of which stains normally with the PAS and is normally digested by diastase. However, in addition to normal glycogen, patients with PFK deficiency also accumulate polyglucosan, which stains intensely with the PAS reaction but is resistant to diastase digestion and — in the electron microscope — appears to be composed of finely granular and filamentous material, similar to the polysaccharide in branching enzyme deficiency and in Lafora disease (Fig. 7.3). A plausible explanation for the deposition of polyglucosan in PFK-deficient muscle is a skewed activity ratio of glycogen synthetase and branching enzyme, probably due to the accumulation of glucose6-phosphate, a physiological activator of glycogen synthetase (Agamanolis et al., 1980; Hays et al., 1981). This concept is supported by experiments in transgenic mice, in which the activity of glycogen synthetase in muscle had been upregulated (Raben et al., 2001). Although the clinical diagnosis is supported by the presence of polyglucosan in the muscle biopsy and by the lack of the histochemical reaction for PFK, conclusive evidence comes from the biochemical documentation of PFK deficiency. A word of caution is needed here: the muscle specimen for biochemical analysis should be flash-frozen at the time of biopsy because
PFK is notoriously labile. As in the case of McArdle disease, muscle biopsy can be avoided if the clinical presentation is typical and a known pathogenic mutation can be documented in blood DNA; however, the task here is made more difficult by the lack of a common mutation. The first molecular defect in PFK deficiency was identified in the Japanese family originally described by Tarui and coworkers (Nakajima et al., 1990), and soon thereafter Raben and her coworkers described two mutations, which turned out to be common among Ashkenazi Jewish patients (Raben et al., 1993; Sherman et al., 1994). At least 15 mutations have been reported in the PFKM gene of patients with typical PFK deficiency (Nakajima et al., 2002; DiMauro et al., 2004). Therapeutic attempts at bypassing the metabolic block are more difficult than in McArdle disease because glucose is not an alternative substrate in PFK deficiency. In fact, the “out-of-wind” phenomenon suggests that patients should avoid high-carbohydrate meals (Haller and Lewis, 1991). A 2-year-old boy with the infantile (and usually rapidly fatal) form of PFK deficiency, including arthrogryposis multiplex congenita, respiratory insufficiency, slowed motor nerve conductions and abnormal EEG, seemed to benefit remarkably from a ketogenic diet (Swoboda et al., 1997). There was clear improvement in strength, electromyographic features, and EEG pattern. Unfortunately, the child worsened suddenly at 35 months and died of complications of pneumonia. Still, ketogenic diet might be considered, at least in children with the more severe variant of PFK deficiency. 7.2.1.5. Phosphoglycerate kinase (PGK) deficiency (GSD IX) Phosphoglycerate kinase is a single polypeptide encoded by a gene (PGK1) on Xq13 for all tissues except spermatogenic cells. Although this enzyme is virtually ubiquitous, clinical presentations depend on the isolated or associated involvement of three tissues, erythrocytes (hemolytic anemia), central nervous system (CNS, with seizures, mental retardation, stroke) and skeletal muscle (exercise intolerance, cramps, myoglobinuria). The most common clinical association, seen in 8 of 27 reported patients, is non-spherocytic hemolytic anemia and CNS dysfunction. The second most common presentation is isolated myopathy (seven patients), followed by isolated blood dyscrasia (six patients), and by myopathy with CNS dysfunction (three patients; Morimoto et al., 2003). Only one patient had myopathy and hemolytic anemia, while two patients showed involvement of all three tissues. The seven myopathic cases were clinically indistinguishable from McArdle disease, but muscle biopsies
DISORDERS OF CARBOHYDRATE METABOLISM
A
B
C
D
173
Fig. 7.3. Phosphofructokinase deficiency (PFK). (A) A defect of PFK produces an excess of glycogen that predominates along the periphery of muscle fibers as exhibited in phosphorylase deficiency. In addition, some patients with PFK deficiency demonstrate discrete PAS-positive deposits (arrow) of abnormal glycogen within a small percent of myofibers as displayed in this transverse section of muscle. The material has long peripheral glucose chains and forms compact inclusions known as polyglucosan bodies. Cryosection, PAS, bar ¼ 50 mm. Reproduced from DiMauro et al. (1984) with permission from Taylor & Francis, Inc., http://www.taylorandfrancis.com. (B) Prior digestion of the tissue section by a-amylase or diastase removes normal finely granular glycogen, but does not remove all of the polyglucosan material (arrow) indicating that it is diastase-resistant. Cryosection, PAS-diastase, bar ¼ 50 mm. Reproduced from DiMauro et al. (1984) with permission from Taylor & Francis, Inc., http://www.taylorandfrancis.com. (C) A longitudinal section of a semithin plastic section demonstrates that the polyglucosan bodies are arranged in columns in a myofiber in the lower half of the figure. The bodies consist of pale PAS-positive material but contain kernels of intense PAS staining (dark, arrows). The sarcoplasm contains no detectable normal glycogen. The upper half of the field has another myofiber that contains normal glycogen (dark). Toluidine blue–PAS, bar ¼ 15 mm. Reproduced from DiMauro et al. (1984) with permission from Taylor & Francis, Inc., http://www.taylorandfrancis.com. (D) An electron micrograph of the same myofiber demonstrates abnormal glycogen that is composed of unbranched filaments 6–8 nm wide. An inner part of the body (upper third of the figure) contains material of greater electron opacity (arrows). This part consists of finely granular material as well as filaments and corresponds to the intensely PAS-positive kernels demonstrated in Figure 7.3(C). Bar ¼ 0.5 mm. Reproduced from DiMauro et al. (1984) with permission from Taylor & Francis, Inc., http://www.taylorandfrancis.com.
174
S. DIMAURO ET AL.
showed less severe glycogen accumulation (DiMauro et al., 1983; Tonin et al., 1992; Cohen-Solal et al., 1994; Ookawara et al., 1996; Schroder et al., 1996; Aasly et al., 2000; Hamano et al., 2000). Mutations in PGK1 were identified in four of the seven myopathic patients. The various involvement of single or multiple tissues is difficult to explain and may relate to the severity of different mutations and the amount of residual PGK activity in individual tissues. 7.2.1.6. Phosphoglycerate mutase (PGAM) deficiency (GSD X) In contrast to PGK deficiency, PGAM deficiency affects only muscle, causing exercise intolerance, cramps and recurrent myoglobinuria. This is because PGAM is a dimeric enzyme composed of a muscle-specific (M) and a brain-specific (B) subunit, and normal muscle contains predominantly the MM homodimer, which accounts for 95% of the total activity. The only other tissues containing substantial amounts of the M subunit are heart and sperm, but there is no evidence of cardiopathy or male infertility in PGAM deficiency (DiMauro et al., 2004). The M subunit of PGAM is encoded by a gene (PGAMM) on chromosome 7. About a dozen patients with muscle PGAM deficiency have been described: the first six patients were AfricanAmerican (DiMauro et al., 1981, 1982; Bresolin et al., 1983; Kissel et al., 1985; Tsujino et al., 1993b) but subsequent cases have included Italians (Toscano et al., 1996), Japanese (Hadjigeorgiou et al., 1999), and Pakistani (Vissing et al., 1999) patients. The clinical picture is stereotypical: exercise intolerance and cramps after vigorous exercise, often followed by myoglobinuria. Manifesting heterozygotes have been identified in several families. The muscle biopsy shows inconsistent and mild glycogen accumulation, accompanied in one case by tubular aggregates (Vissing et al., 1999). Four different mutations in the PGAMM gene have been identified (DiMauro et al., 2004). 7.2.1.7. Aldolase deficiency (GSD XII) There are three isoforms of aldolase (A, B and C); skeletal muscle and erythrocytes contain predominantly the A isoform, which is encoded by a gene (ALDOA) on chromosome 16. The only reported patient with aldolase deficiency was a 4.5-year-old boy, who had episodes of exercise intolerance and weakness following febrile illnesses (Kreuder et al., 1996). Rhabdomyolysis was described, but there was no pigmenturia and the highest serum CK value reported was 6480 u/l (normal: <60 u/l). Muscle biopsy showed no glycogen accumulation. Biochemical analysis showed markedly decreased levels of aldolase
in both muscle and erythrocytes. A missense mutation was identified in ALDOA. 7.2.1.8. b-enolase deficiency (GSD XIII) b-enolase is a dimeric enzyme present in different isoforms, which result from various combinations of three subunits, a, b and g. Skeletal muscle contains predominantly the bb homodimer and — in lesser amount — the ab heterodimer. The b subunit is encoded by a gene (ENO3) on chromosome 17. This new glycogenosis is still represented by a single patient, a 47-year-old Italian man with adult-onset but rapidly progressive exercise intolerance and myalgia, and chronically elevated serum CK (Comi et al., 2001). The muscle biopsy was normal by light microscopy and showed subsarcolemmal deposits of glycogen by electron microscopy. Sequence analysis of ENO3 showed that the patient was a compound heterozygote for two missense mutations. 7.2.1.9. Lactate dehydrogenase (LDH) deficiency (GSD XI) Lactate dehydrogenase is a tetrameric enzyme composed of two subunits, M (or A) and H (or B) forming five isozymes, the two homotetramers M4 and H4 and three heterodimers. Skeletal muscle contains LDH isozymes composed predominantly by M subunits, whereas heart and other tissues contain isozymes composed predominantly by H subunits. The gene for LDH-M (LDHA) is encoded by a gene on chromosome 11. The discovery of this glycogenosis was due to the astute observation that a patient with myoglobinuria had predictably sky-high values of serum CK but extremely low values of LDH (Kanno et al., 1980). Several Japanese patients and two Caucasian patients with LDH-M deficiency have been reported. All have had exercise intolerance and cramps, with or without myoglobinuria. Skin lesions and dystocia have been described in Japanese patients (Kanno and Maekawa, 1995). Several mutations in LDHA have been reported.
7.3. Glycogenoses causing progressive weakness These include a defect in the glycogenosynthetic pathway (branching enzyme deficiency), one in the cytosolic glycogenolytic pathway (debranching enzyme deficiency), and another in the lysosomal glycogenolytic pathway (acid a-glucosidase, or acid maltase; Fig. 7.1). In addition, recent work on myoclonus epilepsy with Lafora bodies (Lafora disease) suggests that this is a glycogenosis, probably due to abnormal glycogen synthesis.
DISORDERS OF CARBOHYDRATE METABOLISM 7.3.1. Acid maltase deficiency (AMD, GSD II) Acid maltase (a-1,4 and a-1,6 glucosidase) is a lysosomal enzyme encoded by a gene (GAA) on chromosome 17. The predicted frequency of this disease is 1 in 40 000 (Ausems et al., 1999). The defect of this single ubiquitous protein causes three different clinical phenotypes distinguished by clinical features and age at onset (Engel et al., 2004). The first variant (infantile AMD or Pompe disease) is a generalized infantile form dominated by massive cardiomegaly and invariably fatal before 2 years of age. The second variant (juvenile AMD) starts either in infancy or in childhood, affects exclusively muscle, and causes severe proximal, truncal and respiratory muscle weakness. Calf hypertrophy is occasionally present and, in boys, can raise the suspicion of Duchenne muscular dystrophy. Death usually occurs in the second or third decade, due to respiratory failure. The third variant is also confined to muscle, but onset is in adult and even late life, simulating limb-girdle muscular dystrophy or polymyositis. However, a recent survey of 255 patients older than 2 years performed through a questionnaire showed more of a continuum for the muscular variant, where disease severity correlated best with duration of the disease rather than age at onset (Hagemans et al., 2005). Nevertheless, a subgroup of patients under 15 years of age had earlier onset and more rapid and severe clinical course, similar to the “non-typical infantile” patients described by Slonim et al. (2000). The diagnosis of Pompe disease is suggested by the association of profound weakness (floppy infant syndrome) and massive cardiomegaly, but must be confirmed by muscle biopsy, which shows severe vacuolar myopathy with accumulation of both intralysosomal and free glycogen. The diagnosis is more difficult in the myopathic forms of AMD, especially in the adult variant, where glycogen storage in muscle can be minimal in some biopsies. One useful clinical clue is the early and preferential involvement of truncal and respiratory muscles. A study on the quality of life of a large cohort of adult-onset AMD patients confirmed that this disorder causes severe physical limitations while not impairing mental health (Hagemans et al., 2004). Characteristically, the EMG shows — besides myopathic features — fibrillation potentials, positive waves, and myotonic discharges, more easily seen in paraspinal muscles (Engel et al., 2004). Muscle biopsy shows massive accumulation of glycogen in both infantile and childhood variants (Fig. 7.4), but may be unimpressive in adult cases, with variable involvement of different muscles. The histochemical stain for acid phosphatase, another lysosomal enzyme, is virtually absent in normal muscle but very prominent
175
in the lysosome-rich muscle of AMD patients. Over 80 pathogenic mutations in GAA are known (Engel et al., 2004). Some degree of genotype–phenotype correlation is becoming apparent, with “severe” mutations associated with the infantile form and “leaky” mutations associated with the myopathic variant (Engel et al., 2004). However, the biochemical bases for the different phenotypes remain largely unclear. Palliative therapy includes respiratory support, dietary regimens (e.g., high-protein diet), and aerobic exercise. Gene therapy is being actively pursued in vitro and in animal models but is not yet applicable to patients. However, great strides were achieved with enzyme-replacement therapy using recombinant human a-glucosidase, although this therapeutic modality is invasive and expensive. Four infants with Pompe disease were treated with impressive results; although one patient died of an intercurrent infection at 4 years of age (typically, patients with Pompe disease die before 1 year of age), all four patients showed remarkable clinical improvement in motor and cardiac function and parallel improvement in muscle morphology (Van den Hout et al., 2000; 2004). The same therapeutic approach was applied with success in three children with the muscular variant (Winkel et al., 2004). Before starting enzyme replacement, all three were wheelchair-bound and two were respirator-dependent. After 3 years of treatment, their pulmonary function had stabilized and their exercise tolerance had improved, and the youngest patient resumed walking independently. It is important to start enzyme replacement therapy as soon as possible.
7.3.2. Debrancher deficiency (glycogenosis type III) The debrancher is a “double-duty” enzyme, with two catalytic functions, oligo-1,4-1,4-glucantransferase and amylo-1,6-glucosidase. After the peripheral chains of glycogen have been shortened by phosphorylase to about four glycosyl units, these stumps are removed by the debrancher in two steps. First, a maltotriosyl unit is transferred from a donor to an acceptor chain (transferase activity), leaving behind a single glucosyl unit, which is then hydrolyzed by the amylo-1,6-glucosidase. The enzyme is encoded by a single-copy gene (AGL) on chromosome 1p21. There are different clinical presentations of debrancher deficiency, depending on which tissues are affected and which enzymatic function is deficient (Shen and Chen, 2002). In the most common clinical variant (IIIa), the enzyme defect is generalized but liver and muscle are predominantly affected. In the rare variant IIIb, only liver is affected. The even less frequent variants IIIc and IIId are characterized by the selective defect of the
176
S. DIMAURO ET AL.
A
B
C Fig. 7.4. Acid maltase deficiency. (A) A transverse semithin plastic sections of muscle demonstrates PAS-positive aggregates of glycogen (dark) in virtually every muscle fiber of a patient with the infantile form of acid maltase deficiency (Pompe disease). Much of the glycogen accumulates within lysosomes of the subsarcolemmal zone (arrow) as well as the intermyofibrillar spaces (arrowhead). Toluidine blue–PAS, bar ¼ 20 mm. Reproduced from DiMauro et al. (1984) with permission from Taylor & Francis, Inc., http://www.taylorandfrancis.com. (B) A histochemical stain for acid phosphatase, a lysosomal enzyme, shows greatly increased enzyme activity of lysosomes within muscle fibers of a patient with the childhood form of the disorder. Normally, myofibers contain sparse very small lysosomes. Marked activity of lysosomes in glycogen storage diseases provides a pathological clue that the disorder is caused by acid maltase deficiency. Cryosection, bar ¼ 45 mm. (C) An electron micrograph demonstrates excessive glycogen particles that are often enclosed by a lysosomal membrane (arrows). Bar ¼ 0.5 mm. Reproduced from DiMauro et al. (1984) with permission from Taylor & Francis, Inc., http://www.taylorandfrancis.com.
glucosidase activity (IIIc) or of the transferase activity (IIId). Patients with the IIIa variant typically present in childhood with hepatomegaly, growth retardation,
hypoglycemia and occasional seizures related to hypoglycemia. Symptoms tend to resolve spontaneously around puberty. Clinical myopathy may not be apparent in infants or children, although some of them show
DISORDERS OF CARBOHYDRATE METABOLISM hypotonia and delayed motor milestones. Myopathy often appears in adult life, long after liver symptoms have subsided. Adult-onset myopathies have been distinguished into two groups, distal and generalized (Kiechl et al., 1999a). Patients with distal myopathy develop atrophy of leg and intrinsic hand muscles, often suggesting the diagnosis of motor neuron disease or peripheral neuropathy (DiMauro et al., 1979). The course is slowly progressive and the myopathy is rarely crippling. Patients with generalized myopathy are more severely affected and often suffer from respiratory distress (Kiechl et al., 1999a, 1999b). Although debrancher works in parallel with myophosphorylase, the symptoms of debrancher deficiency are very different from those of McArdle disease and cramps and myoglobinuria are exceedingly rare. In agreement with the notion that the enzyme defect is generalized, peripheral neuropathy has been documented both electrophysiologically and by nerve biopsy and may contribute to the weakness and the neurogenic features of some patients. Similarly, while clinical cardiopathy is uncommon (Miller et al., 1972; Rossignol et al., 1979; Lee et al., 1997), cardiac involvement is demonstrable by laboratory tests in virtually all patients with myopathy (Moses et al., 1989). In the EMG, myopathic features are mixed with “irritative features” (fibrillations, positive sharp waves, myotonic discharges), a pattern that may reinforce the diagnosis of motor neuron disease in patients with distal muscle atrophy. As mentioned above, nerve conduction velocities are often decreased (DiMauro et al., 2004). Muscle biopsy typically shows a vacuolar myopathy. The vacuoles contain PAS-positive material and — in the electron microscope — correspond to large pools of normal-looking glycogen, most of which is free in the cytoplasm (Fig. 7.5). However, some of the glycogen is present within lysosomes. Biochemical analysis shows greatly increased concentration of glycogen, which — by iodine spectrum — has unusually short peripheral chains, as expected. Over 30 mutations in the AGL gene have been reported (Horinishi et al., 2002; Lucchiari et al., 2003; Lam et al., 2004). While there is no specific therapy, young patients should be protected from fasting hypoglycemia with frequent feedings and nocturnal gastric infusions of glucose and uncooked cornstarches. Liver transplantation should be considered in children with cirrhosis or hepatocellular carcinoma (Matern et al., 1999). 7.3.3. Branching enzyme deficiency (GSD IV) Glycogen branching enzyme (GBE) is encoded by a gene (GBE1) on chromosome 3p14, but alternative splicing
177
Fig. 7.5. Debrancher enzyme deficiency. This semithin plastic section demonstrates deposits of PAS-positive (dark) glycogen within myofibers (arrows). The glycogen predominates in the subsarcolemmal zone. This location resembles the pattern of glycogen accumulation caused by defects of phosphorylase and glycolytic enzymes but is greater in quantity. A ring fiber (arrowhead) is included in the section. Toluidine blue–PAS, bar ¼ 20 mm. Reproduced from DiMauro et al. (1984) with permission from Taylor & Francis, Inc., http://www.taylorandfrancis.com.
may generate different isozymes, some of which may be tissue-specific (Moses and Parvari, 2002). Glycogen branching enzyme deficiency can be silent or variably affect liver, heart, skeletal muscle and brain (Moses and Parvari, 2002; DiMauro et al., 2004). The presentation described as “typical” until recently includes hepatoslenomegaly in infancy, progressing to liver cirrhosis and death from liver failure or gastrointestinal bleeding, usually before 4 years of age. However, nonprogressive hepatopathy was also reported in some children (McConkie-Rosell et al., 1996), while cardiomyopathy dominated the clinical picture in a few older children (Farrans et al., 1966; Nase et al., 1995; Ewert et al., 1999). Myopathy is a common manifestation of GBE deficiency, either alone or associated with hepatopathy or cardiopathy. Recent experience suggests that congenital myopathy was probably underdiagnosed (Tang et al., 1994; Nambu et al., 2003; Bruno et al., 2004; Tay et al., 2004). Even within this group, clinical presentations vary from perinatal fetal akinesia deformation sequence (FADS), characterized by arthrogryposis multiplex congenita, hydrops fetalis, and perinatal death (Bruno et al., 2004), to isolated myopathy (Bruno et al., 2004), to congenital myopathy and cardiomyopathy (Tang et al., 1994; Nambu et al., 2003; Tay et al., 2004), to Werdnig–Hoffmann-like syndrome (Tay et al., 2004). Muscle biopsy in these children shows the typical foci of polyglucosan, intensely PAS-positive and diastase-resistant (Fig. 7.6). Similar deposits are seen in the cardiomyocytes of
178
S. DIMAURO ET AL.
A
B
Fig. 7.6. Brancher enzyme deficiency. (A) The defect of this enzyme causes formation of an abnormal glycogen composed of poorly branched polymeric glucose with long peripheral glucose chains. This material appears as strongly PAS-positive polyglucosan bodies within the cytoplasm of muscle fibers (arrows), liver cells and other organs. The staining properties and ultrastructural features of the bodies closely resemble those of phosphofructokinase deficiency (see Figure 7.3). Paraffin section, PAS, bar ¼ 25 mm. (B) The histochemical reaction for acid phosphatase may show excessive activity in muscle fibers in brancher enzyme deficiency, most pronounced around the polyglucosan bodies. This markedly increased lysosomal enzyme activity is an exception to other non-lysosomal glycogen storage diseases. Cryosection, bar ¼ 25 mm.
children with cardiopathy and in motor neurons of infants with Werdnig–Hoffmann-like presentation (Tang et al., 1994; Tay et al., 2004). Myopathy has also been described in a few adults (Ferguson et al., 1983; Bornemann et al., 1996). A neurological variant of GBE deficiency presenting late in life is known as adult polyglucosan body disease (APBD); it is characterized by progressive upper and lower motor neuron dysfunction (sometimes simulating amyotrophic lateral sclerosis), sensory loss, sphincter problems and, inconsistently, dementia. In APBD, polyglucosan bodies have been described in the axons and axon hillocks of neurons in both gray and white matter. Numerous mutations in the GBE1 gene have been identified (Bao et al., 1996; Nambu et al., 2003; Bruno et al., 2004; Tay et al., 2004), suggesting some genotype–phenotype correlation (Bruno et al., 2004). Interestingly, the mutation found in patients with APBD (Lossos et al., 1998) appears to be relatively mild (Bao et al., 1996), which may explain the late onset of this disorder. There is no specific therapy, but liver transplantation is an option for children with liver cirrhosis or portal hypertension (Matern et al., 1999). 7.3.4. Lafora disease Clinically, Lafora disease (myoclonus epilepsy with Lafora bodies) is characterized by seizures, myoclonus and dementia. Onset is in adolescence, the course is rapidly progressive, and death occurs almost always
before 25 years of age. The pathologic signature of the disease are the bodies described by Gonzalo Rodriguez Lafora in 1911 (Lafora, 1911); these are round, basophilic, strongly PAS-positive intracellular inclusions seen in neuronal dendrites of the cerebral cortex, substantia nigra, thalamus, globus pallidus, and dentate nucleus. Polyglucosan bodies are also seen in muscle, liver, heart, skin, and retina, indicating that Lafora disease is a generalized glycogenosis. However, the obvious biochemical suspect, branching enzyme, is normal (Gambetti et al., 1971; Ponzetto Zimmerman and Gold, 1982). Linkage analysis localized the gene responsible for Lafora disease (EPM2A) to chromosome 6q24 and about 30 pathogenic mutations have been identified in patients (Minassian et al., 2000) The protein encoded by EPM2A, dubbed “laforin”, contains a carbohydratebinding module in the N-terminus and a dual-specificity phosphatase domain in the C-terminus, whose substrate remains unknown (Wang et al., 2002; Chan et al., 2005). It was suggested that laforin may play a role in the cascade of phosphorylation/dephosphorylation reactions controlling glycogen synthesis and degradation and that mutations in laforin may alter the ratio of glycogen synthetase/GBE in favor of the synthetase, but this mechanism remains to be proven. Mutations in EPM2A accounted for 48% of a large cohort of patients with Lafora disease (Chan et al., 2004), and pathogenic mutations were identified in a second gene (called NHLRC1 or EPMD2B), accounting for another 40% of patients. NHLRC1 encodes a protein
DISORDERS OF CARBOHYDRATE METABOLISM called malin, a putative E3 ubiquitin ligase. Both laforin and malin localize to the endoplasmic reticulum (ER) and it has been suggested that they operate in a related pathway protecting against polyglucosan accumulation (Chan et al., 2003).
Acknowledgements Part of this work was supported by a grant from the Muscular Dystrophy Association.
References Aasly J, van Diggelen OP, Boer AM, et al. (2000). Phosphoglycerate kinase deficiency in two brothers with McArdlelike clinical symptoms. Eur J Neurol 7: 111–113. Agamanolis DP, Askari AD, DiMauro S, et al. (1980). Muscle phosphofructokinase deficiency: two cases with unusual polysaccharide accumulation and immunologically active enzyme protein. Muscle Nerve 3: 456–467. Arad M, Benson DW, Perez-Atayde AR, et al. (2002). Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy. J Clin Invest 109: 357–362. Arad M, Maron BJ, Gorham JM, et al. (2005). Glycogen storage diseases presenting as hypertrophic cardiomyopathy. New Engl J Med 352: 362–372. Ausems MG, Verbiest J, Hermans MP, et al. (1999). Frequency of glycogen storage disease type II in The Netherlands: implications for diagnosis and genetic counseling. Eur J Hum Genet 7: 713–716. Bao Y, Kishnani P, Tang TT, et al. (1996). Hepatic and neuromuscular forms of glycogen storage disease type IV caused by mutations in the same glycogen-branching enzyme. J Clin Invest 97: 941–948. Bartram C, Edwards R, Clague J, et al. (1993). McArdle’s disease: a nonsense mutation in exon 1 of the muscle glycogen phosphorylase gene explains some but not all cases. Hum Mol Genet 2: 1291–1293. Bornemann A, Besser R, Shin YS, et al. (1996). A mild adult myopathic variant of type IV glycogenosis. Neuromuscul Disord 6: 95–99. Bresolin N, Ro YI, Reyes M, et al. (1983). Muscle phosphoglycerate mutase (PGAM) deficiency: a second case. Neurology 33: 1049–1053. Bruno C, Manfredi G, Andreu AL, et al. (1998). A splice junction mutation in the alpha-M gene of phosphorylase kinase in a patient with myopathy. Biochem Biophys Res Commun 249: 648–651. Bruno C, van Diggelen OP, Cassandrini D, et al. (2004). Clinical and genetic heterogeneity of branching enzyme deficiency (glycogenosis type IV). Neurology 63: 1053–1058. Burwinkel B, Rootwelt T, Kvittingen EA, et al. (2003a). Severe phenotype of phosphorylase kinase-deficient liver glycogenosis with mutations in the PHKG2 gene. Pediat Res 54: 834–839.
179
Burwinkel B, Hu B, Schroers A, et al. (2003b). Muscle glycogenosis with low phosphorylase kinase activity: mutations in PHKA1, PHKG1 or six other candidate genes explain only a minority of cases. Eur J Hum Genet 11: 516–526. Burwinkel B, Scott JW, Buhrer C, et al. (2005). Fatal congenital heart glycogenosis caused by a recurrent activating R531Q mutation in the gamma2-subunit of AMP-activated protein kinase (PRKAG2), not by phosphorylase kinase deficiency. Am J Hum Genet 76: 1034–1049. Chan EM, Young EJ, Ianzano L, et al. (2003). Mutations in NHLRC1 cause progressive myoclonus epilepsy. Nature Genet 35: 125–127. Chan EM, Omer S, Ahmed M, et al. (2004). Progressive myoclonus epilepsy with polyglucosans (Lafora disease). Evidence for a third locus. Neurology 63: 565–567. Chan EM, Andrade DM, Franceschetti S, et al. (2005). Progressive myoclonus epilpsies: EPM1, EPM2A, EPM2B. Adv Neurol 95: 47–57. Chen YT (2001). Glycogen storage diseases. In: CR Scriver, AL Beaudet, WS Sly, D Valle (Eds.), The Metabolic and Molecular Basis of Inherited Disease, Vol. 1, McGrawHill, New York, NY, pp. 1521–1551. Cohen-Solal M, Valentin C, Plassa F, et al. (1994). Identification of new mutations in two phosphoglycerate kinase (PGK) variants expressing different clinical syndromes: PGK Creteil and PGK Amiens. Blood 84: 898–903. Comi GP, Fortunato F, Lucchiari S, et al. (2001). B-enolase deficiency, a new metabolic myopathy of distal glycolysis. Ann Neurol 50: 202–207. DiMauro S (1985). Myoglobinuria and myopathies of storage disease. In: RB Conn, (Ed.), Current Diagnosis.Saunders, Philadelphia, PA, pp. 1037–1042. DiMauro S, Hartwig GB, Hays AP, et al. (1979). Debrancher deficiency: neuromuscular disorder in five adults. Ann Neurol 5: 422–436. DiMauro S, Miranda AF, Khan S, et al. (1981). Human muscle phosphoglycerate mutase deficiency: newly discovered metabolic myopathy. Science 212: 1277–1279. DiMauro S, Miranda AF, Olarte M, et al. (1982). Muscle phosphoglycerate mutase deficiency. Neurology 32: 584–591. DiMauro S, Dalakas M, Miranda AF (1983). Phosphoglycerate kinase deficiency: another cause of recurrent myoglobinuria. Ann Neurol 13: 11–19. DiMauro S, Bresolin N, Hay AP (1984). Disorders of glycogen metabolism of muscle. Crit Rev Clin Neurobiol 1: 83–116. DiMauro S, Hays AP, Tsujino S (2004). Nonlysosomal glycogenoses. In: AG Engel, C Franzini-Armstrong (Eds.), Vol. II, McGraw-Hill, New York, pp. 1535–1558. El-Schahawi M, Tsujino S, Shanske S, et al. (1996). Diagnosis of McArdle’s disease by molecular genetic analysis of blood. Neurology 47: 579–580. El-Schahawi M, Bruno C, Tsujino S, et al. (1997). Sudden infant death syndrome (SIDS) in a family with myophosphorylase deficiency. Neuromuscul Disord 7: 81–83. Engel AG, Hirschhorn R, Huie M (2004). Acid maltase deficiency. In: AG Engel, C Franzini-Armstrong (Eds.), Vol. 2, McGraw-Hill, New York, pp. 1559–1586.
180
S. DIMAURO ET AL.
Ewert R, Gulijew A, Wensel R, et al. (1999). Die Glykogenose Typ IV seltene Ursache einer Kardiomyopathie — Bericht einer erfolgreichen Herztransplantation. Z Kardiol 88: 850–856. Farrans VJ, Hibbs RG, Walsh JJ, et al. (1966). Cardiomyopathy, cirrhosis of the liver and deposits of a fibrillar polysaccharide. Am J Cardiol 17: 457–469. Ferguson IT, Mahon M, Cumming WJ (1983). An adult case of Andersen’s disease — type IV glycogenosis. A clinical, histochemical, ultrastructural and biochemical study. J Neurol Sci 60: 337–351. Fernandez-Cadenas I, Andreu AL, Gamez J, et al. (2003). Splicing mosaic of the myophosphorylase gene due to a silent mutation in McArdle disease. Neurology 61: 1432–1434. Gambetti PL, DiMauro S, Hirt L, et al. (1971). Myoclonic epilepsy with Lafora bodies. Arch Neurol 25: 483–493. Hadjigeorgiou GM, Kawashima N, Bruno C, et al. (1999). Manifesting heterozygotes in a Japanese family with a novel mutation in the muscle-specific phosphoglycerate mutase (PGAM-M) gene. Neuromuscul Disord 9: 399–402. Hagemans MLC, Janssens ACJW, Winkel LPF, et al. (2004). Late-onset Pompe disease primarily affects quality of life in physical health domains. Neurology 63: 1688–1692. Hagemans MLC, Winkel LPF, Hop WCJ, et al. (2005). Disease severity in children and adults with Pompe disease related to age and disease duration. Neurology 64: 2139–2141. Haller RG (2000). Treatment of McArdle disease. Arch Neurol 57: 923–924. Haller RG, Lewis SF (1991). Glucose-induced exertional fatigue in muscle phosphofructokinase deficiency. New Engl J Med 324: 364–369. Haller RG, Vissing J (2002). Spontaneous “second wind” and glucose-induced second “second wind” in McArdle disease. Arch Neurol 59: 1395–1402. Haller RG, Vissing J (2004a). Functional evaluation of metabolic myopathies. In: AG Engel, C Franzini-Armstrong (Eds.), Vol. 1, McGraw-Hill, New York, pp. 665–679. Haller RG, Vissing J (2004b). No spontaneous second wind in muscle phosphofructokinase deficiency. Neurology 62: 82–86. Hamano T, Mutoh T, Sugie H, et al. (2000). Phosphoglycerate kinase deficiency: an adult myopathic form with a novel mutation. Neurology 54: 1188–1190. Hays AP, Hallett M, Delfs J, et al. (1981). Muscle phosphofructokinase deficiency: abnormal polysaccharide in a case of late-onset myopathy. Neurology 31: 1077–1086. Horinishi A, Okubo M, Tang NL, et al. (2002). Mutational and haplotype analysis of AGL in patients with glycogen storage disease type III. J Hum Genet 47: 55–59. Kanno T, Maekawa M (1995). Lactate dehydrogenase M-subunit deficiency: clinical features, metabolic background, and genetic heterogeneities. Muscle Nerve Suppl. 3: S54–S60. Kanno T, Sudo K, Takeuchi I, et al. (1980). Hereditary deficiency of lactate dehydrogenase M-subunit. Clin Chim Acta 108: 267–276.
Kazemi-Esfarjani P, Skomorowska E, Dysgaard Jensen T, et al. (2002). Nonischemic forearm exercise test for McArdle disease. Ann Neurol 52: 153–159. Kiechl S, Kohlendorfer U, Thaler C, et al. (1999a). Different clinical aspects of debrancher deficiency myopathy. J Neurol Neurosurg Psychiatry 67: 364–368. Kiechl S, Willeit J, Vogel W, et al. (1999b). Reversible severe myopathy of respiratory muscles due to adult-onset type III glycogenosis. Neuromuscul Disord 9: 408–410. Kissel JT, Beam W, Bresolin N, et al. (1985). Physiologic assessment of phosphoglycerate mutase deficiency: incremental exercise test. Neurology 35: 828–833. Kreuder J, Borkhardt A, Repp R, et al. (1996). Inherited metabolic myopathy and hemolysis due to a mutation in aldolase A. New Engl J Med 334: 1100–1104. ¨ ber das Vorkommen amyloider KorLafora GR (1911). U perchen in Innern der Ganglienzellen. Virchows Arch Pathol Anat 205: 295–303. Laforet P, Richard P, Ait Said M, et al. (2006). A new mutation in PRKAG2 gene causing hypertrophic cardiomyopathy and muscular glycogenosis. Ann Neurol 16: 178–182. Lam C-W, Lee AT-C, Lam Y-Y, et al. (2004). DNA-based subtyping of glycogen storage disease type III: mutation and haplotype analysis of the AGL gene in Chinese. Mol Genet Metab 83: 271–275. Lee PJ, Deanfield JE, Biurch M, et al. (1997). Comparison of the functional significance of left ventricular hypertrophy in hypertrophic cardiomyopathy and glycogenosis type III. Am J Cardiol 79: 834–838. Lossos A, Meiner Z, Barash V, et al. (1998). Adult polyglucosan body disease in Ashkenazi Jewish patients carrying the Tyr329 Ser mutation in the glycogen-branching enzyme gene. Ann Neurol 44: 867–872. Lucchiari S, Donati MA, Melis D, et al. (2003). Mutational analysis of the AGL gene: five novel mutations in GSD III patients. Hum Mutat 23: 337. Mankodi A, Ashizawa T (2003). Echo of silence. Silent mutations, RNA splicing, and neuromuscular diseases. Neurology 61: 1330–1331. Martin MA, Rubio JC, Wevers RA, et al. (2003). Molecular analysis of myophosphorylase deficiency in Dutch patients with McArdle’s disease. Ann Hum Genet 68: 17–22. Martinuzzi A, Sartori E, Fanin M, et al. (2003). Phenotype modulators in myophosphorylase deficiency. Ann Neurol 53: 497–502. Matern D, Starzl TE, Arnaout W, et al. (1999). Liver transplantation for glycogen storage disease types I, III, and IV. Eur J Pediatr 158 Suppl 2: S43–S48. McArdle B (1951). Myopathy due to a defect in muscle glycogen breakdown. Clin Sci 10: 13–33. McConkie-Rosell A, Wilson C, Piccoli DA, et al. (1996). Clinical and laboratory findings in four patients with the non-progressive hepatic form of type IV glycogen storage disease. J Inherit Metab Dis 19: 51–58. Milan D, Jeon J-T, Looft C, et al. (2000). A mutation in PRKAG3 associated with excess glycogen content in pig skeletal muscle. Science 288: 1248–1251.
DISORDERS OF CARBOHYDRATE METABOLISM Miller CG, Alleyne GA, Brooks S (1972). Gross cardiac involvement in glycogen storage disease type III. Br Heart J 34: 862–864. Minassian BA, Ianzano L, Meloche M, et al. (2000). Mutation spectrum and predicted function of laforin in Lafora’s progressive myoclonus epilepsy. Neurology 55: 341–346. Morimoto A, Ueda I, Hirashima Y, et al. (2003). A novel missense mutation (1060G>C) in the phosphoglycerate kinase gene in a Japanese boy with chronic hemolytic anemia, developmental delay and rhabdomyolysis. Br J Haematol 122: 1009–1013. Moses SW, Parvari R (2002). The variable presentations of glycogen storage disease type IV: A review of clinical, enzymatic and molecular studies. Curr Mol Med 2: 177–188. Moses SW, Wanderman KL, Myroz A, et al. (1989). Cardiac involvement in glycogen storage disease type III. Eur J Paed 148: 764–766. Nakajima H, Kono N, Yamasaki T, et al. (1990). Genetic defect in muscle phosphofructokinase deficiency. Abnormal splicing of the muscle phosphofructokinase gene due to a point mutation at the 5’-splice site. J Biol Chem 265: 9392–9395. Nakajima H, Raben N, Hamaguchi T, et al. (2002). Phosphofructokinase deficiency: past, present and future. Curr Mol Med 2: 197–212. Nambu M, Kawabe K, Fukuda T, et al. (2003). A neonatal form of glycogen storage disease type IV. Neurology 61: 392–394. Nase S, Kunze KP, Sigmund M, et al. (1995). A new variant of type IV glycogenosis with primary cardiac manifestation and complete branching enzyme deficiency. In vivo detection by heart muscle biopsy. Eur Heart J 16: 1698–1704. Ookawara T, Dave V, Willems P, et al. (1996). Retarded and aberrant splicings caused by single exon mutation in a phosphoglycerate kinase variant. Arch Biochem Biophys 327: 35–40. Ponzetto Zimmerman C, Gold AM (1982). Glycogen branching enzyme in Lafora myoclonus epilepsy. Biochem Med 28: 83–93. Quinlivan R, Beynon RJ (2004). Pharmacological and nutritional treatment for McArdle’s disease (glycogen storage disease type V). The Cochrane Database of Systematic Reviews, CD003458. Quintanas B, Sanchez-Andrade A, Teijera S, et al. (2004). A new rare mutation (691delCC/insAAA) in exon 17 of the PYGM gene causing McArdle disease. Arch Neurol 61: 1108–1110. Raben N, Sherman J, Miller F, et al. (1993). A 50 splice junction mutation leading to exon deletion in an Ashkenazi Jewish family with phosphofructokinase deficiency (Tarui disease). J Biol Chem 268: 4963–4967. Raben N, Danon MJ, Lu N, et al. (2001). Surprises of genetic engineering: a possible model of polyglucosan body disease. Neurology 56: 1739–1745. Rossignol AM, Meyer M, Rossignol B, et al. (1979). La myocardiopathie de la glycogenose type III. Arch Fr Pediatr 36: 303–309.
181
Schroder JM, Dodel R, Weis J, et al. (1996). Mitochondrial changes in muscle phosphoglycerate kinase deficiency. Clin Neuropath 15: 34–40. Shen J-J, Chen Y-T (2002). Molecular characterization of glycogen storage disease type III. Curr Mol Med 2: 167–175. Sherman JB, Raben N, Nicastri C, et al. (1994). Common mutations in the phosphofructokinase-M gene in Ashkenazi Jewish patients with glycogenosis VII — and their population frequency. Am J Hum Genet 55: 305–313. Slonim AE, Balone L, Ritz S, et al. (2000). Identification of two subtypes of infantile acid maltase deficiency. J Pediatr 137: 283–285. Swoboda KJ, Specht L, Jones HR, et al. (1997). Infantile phosphofructokinase deficiency with arthrogryposis: clinical benefit of a ketogenic diet. J Pediatr 131: 932–934. Tang TT, Segura AD, Chen Y-T, et al. (1994). Neonatal hypotonia and cardiomyopathy secondary to type IV glycogenosis. Acta Neuropathol 87: 531–536. Tarui S, Okuno G, Ikua Y, et al. (1965). Phosphofructokinase deficiency in skeletal muscle. A new type of glycogenosis. Biochem Biophys Res Commun 19: 517–523. Tay SKH, Akman HO, Chung WK, et al. (2004). Fatal infantile neuromuscular presentation of glycogen storage disease type IV. Neuromuscul Disord 14: 253–260. Tonin P, Lewis P, Servidei S, et al. (1990). Metabolic causes of myoglobinuria. Ann Neurol 27: 181–185. Tonin P, Bruno C, Shanske S, et al. (1992). Phosphorylase b kinase deficiency in adult-onset myopathy. Neurology 42: 387. Toscano A, Tsujino S, Vita G, et al. (1996). Molecular basis of muscle phosphoglycerate mutase (PGAM-M) deficiency in the Italian kindred. Muscle Nerve 19: 1134–1137. Tsujino S, Shanske S, DiMauro S (1993a). Molecular genetic heterogeneity of myophosphorylase deficiency (McArdle’s disease). New Engl J Med 329: 241–245. Tsujino S, Shanske S, Sakoda S, et al. (1993b). The molecular genetic basis of muscle phosphoglycerate mutase (PGAM) deficiency. Am J Hum Genet 52: 472–477. Tsujino S, Shanske S, Goto Y, et al. (1994). Two mutations, one novel and one frequently observed, in Japanese patients with McArdle’s disease. Hum Mol Genet 3: 1005–1006. Tsujino S, Shanske S, Carroll JE, et al. (1995). Double trouble: combined myophosphorylase and AMP deaminase deficiency in a child homozygous for nonsense mutations at both loci. Neuromuscul Disord 5: 263–266. Van den Hout J, Van der Ploeg AT, Cromme-Dijkhuis A, et al. (2000). Recombinant human alpha-glucosidase from rabbit milk in Pompe patients. Lancet 356: 397–398. Van den Hout J, Kamphoven JHJ, Winkel LPF, et al. (2004). Long-term intravenous treatment of Pompe disease with recombinant human alpha-glucosidase from milk. Pediatrics 113: e448–e457. Vissing J, Haller RG (2003a). The effect of oral sucrose on exercise tolerance in patients with McArdle’s disease. New Engl J Med 349: 2503–2509. Vissing J, Haller RG (2003b). A diagnostic cycle test for McArdle’s disease. Ann Neurol 4: 539–542.
182
S. DIMAURO ET AL.
Vissing J, Schmalbruch H, Haller RG, et al. (1999). Muscle phosphoglycerate mutase deficiency with tubular aggregates: effect of dantrolene. Ann Neurol 46: 274–277. Wang J, Stuckey JA, Wishart MJ, et al. (2002). A unique carbohydrate binding domain targets the Lafora disease phosphatase to glycogen. J Biol Chem 277: 2377–2380.
Wehner M, Clemens PR, Engel AG, et al. (1994). Human muscle glycogenosis due to phosphorylase kinase deficiency associated with a nonsense mutation in the muscle isoform of the alpha subunit. Hum Mol Genet 3: 1983–1987. Winkel LPF, Van den Hout J, Kamphoven JHJ, et al. (2004). Enzyme replacement therapy in late-onset Pompe’s disease: a three-year follow-up. Ann Neurol 55: 495–502.
Handbook of Clinical Neurology, Vol. 86 (3rd series) Myopathies F. L. Mastaglia, D. Hilton-Jones, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 8
Disorders of lipid metabolism CORRADO ANGELINI* Department of Neurosciences, University of Padova, Padova, Italy
8.1. Introduction The oxidation of fat provides most of the energy that muscle requires both at rest, for maintaining muscle tone and resting metabolic activities, and during periods of moderately intense prolonged exercise when demand for adenosine triphosphate (ATP) increases substantially. Free fatty acids (FFA), mostly long-chain fatty acids (LCFA), are mobilized from body fat stores in response to the demands of exercise, and also in response to physiological or pathological stress (e.g., fasting, cold). They are transported in the circulation to muscle, where they are taken up by a series of passive and active processes, entering the mitochondria where they undergo b-oxidation. A brief description of the major steps in this process follows. 8.1.1. Lipid metabolism in muscle Uptake of FFA from the circulation into muscle appears to be by passive diffusion. Depending upon the metabolic demand of the muscle, the FFA can then either be stored as lipid droplets or undergo oxidative metabolism. Oxidative metabolism requires transport of the FFA into mitochondria which, unlike their entry into muscle fibers, is an active process. The mitochondrial membrane is the site of the main primary transfer sequence in all tissues. In normal mitochondria the inner mitochondrial membrane is impermeable to FFA and transport of acyl-moieties is accomplished by a complex series of reactions (Fig. 8.1). FFAs are first converted to fatty acylCoA esters by a thiokinase requiring ATP (acylCoA-synthetase). The transport of the acylmoieties across the membrane is facilitated by a specific carrier system that utilizes carnitine and outer carnitine
palmitoyltransferase (CPT1) and then a translocase and an inner carnitine palmitoyltransferase (CPT2). CPT1 is localized in the outer mitochondrial membrane and is inhibited by malonyl-coenzyme A, whereas CPT 2, which is malonylCoA-insensitive, reverses the action and forms fatty acylCoA which is then available within the mitochondria to undergo, through a series of enzymes located in the inner mitochondrial membrane, a well-described series of reactions (dehydrogenation, hydratation dehydrogenation and hydrolysis) termed b-oxidation that produces acetylCoA. Each cycle of b-oxidation produces a mole each of reduced nicotinamide adenine dinucleotide (NADH) and flavine adenine dinucleotide (FADH2). The NADH is reoxidized by donation of a pair of elections via NADH-CoQ reductase of the mitochondrial electron transport chain. Electrons from FADH2 are transferred via an electron transfer flavoprotein (ETF) and a specific iron-sulphur flavoprotein (ETF-DH). Many of the enzymes involved in b-oxidation show a degree of chain-length specificity. This is particularly the case for the three straight-chain acylCoA-dehydrogenases, termed very-long (>C14), medium (C14–C6) and short-chain acylCoA dehydrogenase. Similar chainlength specificities exist for the other enzymes involved in fatty acid oxidation (Table 8.1). A mitochondrial trifunctional protein associated with the inner mitochondrial membrane has been described that performs three different enzymatic activities for LCFA oxidation. Microsomal and peroxisomal pathways for the catabolism of fatty acids exist and are responsible in part, through activation of o-oxidation, for the characteristic organic acid profiles (e.g., dicarboxylic aciduria) that are seen in certain fatty acid disorders (Fig. 8.1).
*Correspondence to: Corrado Angelini, Department of Neurosciences, University of Padova, Via Giustiniani 5, 35128 Padova, Italy. E-mail:
[email protected], Tel: þ39-049-821-3625, Fax: þ39-049-875-1770.
C. ANGELINI
Inner memberane
184
CPT II
Acyl-carnitine O R
CAR Fatty Acyl CoA O SCoA
FAD
SCoA
FADH2
R
ETFRED
ETFDHOX
ETFOX
ETDHFRED
VLCAD O
Mitochondrial trifunctional protein
R
b a
a-b unsaturated compound ENOYL-CoA
LCEH Enoyl Hydratase
R
OH b a
O
SCoA
LCEHAD O 3-hydroxy AcylCoA dehydrogenase
LCKT Thiolase
R
b O
O
b Hydroxy compound NAD
NADH2 SCoA b KetoacyloCoA + HSCoA
R SCoA + CH3 CosCoA Fatty AcetylCoA + AcetylCoA (−2C)
Fig. 8.1. Scheme of proximal part of b-oxidation: when the capacity for mitochondrial b-oxidation is exceeded, as in the case of inborn errors of long chain fatty acid (LCFA) metabolism, alternative pathways (peroxisomal b-oxidation, o-oxidation) contribute significantly to total cellular fatty acid oxidation. This results in accumulation of dicarboxylic acids which can be identified in plasma or urine. Branched-chain amino acids and medium-chain triglycerides (MCT) are transported into mitochondria through a separate mechanism, i.e., carnitine octanoyl transferase (COT I/COTII). CPT1 is located in outer mitochondrial membrane, CPT2 is located in inner mitochondrial membrane. Camitial and carnitine acylcarnitine translocase participates in LCFA transfer.
Table 8.1 Defects of fatty acid oxidation 1. Carnitine transport - systemic - muscle 2. Carnitine palmitoyl transferase (CPT I and II) 3. Carnitine-acylcarnitine translocase 4. Very long-chain acylCoA dehydrogeanse (VLCAD) 5. Mitochondrial trifunctional protein (MTP) a-type 1: long-chain 3 hydroxyacylCoA dehydrogenase (LCHAD) b-type 2: long-chain enoylhydratase (LCEH) Long-chain ketothiolase (LCKT) 6. Medium-chain acylCoA dehydrogenase (MCAD) 7. Short-chain acylCoA dehydrogenase (SCAD) 8. Multiple acylCoA dehydrogenase (MAD) - riboflavin responsive (RR-MAD) - non-riboflavin responsive 9. Electron transfer flavoprotein (ETF) 10. ETF dehydrogenase
8.1.2. Lipid storage myopathies Although often referred to as lipid storage myopathies (LSM), disorders of fatty acid transport and metabolism do not always lead to visible lipid accumulation in muscle (Vockley and Whiteman, 2002). When present, the lipid excess is due to diversion of FFA to triglyceride synthesis. LSM is more likely with disorders affecting carnitine and the carnitine transport system, and with defects in the proximal part of the b-oxidation pathway (Angelini et al., 1992; Vockley and Whiteman, 2002; Angelmi et al., 2006). The presentation of these disorders in this chapter has been organized according to the pathway of FFA transfer and oxidation.
8.2. Carnitine transport defects Secondary carnitine deficiency is relatively common and causes include disorders of b-oxidation and of the mitochondrial respiratory chain, valproate therapy, other
DISORDERS OF LIPID METABOLISM drugs and hemodialysis. Metabolic dysfunction, such as a b-oxidation defect, leads to accumulation of acyl-CoA esters in the mitochondria. These combine with carnitine to form acylcarnitines which can escape the cell and be excreted in the urine, leading to depletion of carnitine. The acylcarnitine profile (shown by mass spectrometry) in blood and urine aids the diagnosis of such disorders. Conversely, primary L-carnitine deficiency is uncommon. Two forms are recognized and can be classified on the basis of clinical and biochemical criteria into systemic carnitine deficiency and muscle carnitine deficiency. 8.2.1. Primary systemic carnitine deficiency Clinical features (Table 8.2) include progressive cardiomyopathy and lipid storage myopathy, and recurrent Reye-like episodes with hypoglycaemia and hypoketonemia (Chapoy et al., 1980; Tein et al., 1990; Nezu et al., 1999). In several cases a defect of the carnitine “high-affinity” plasma membrane transporter (organic cation transporter or OCNT2) has been demonstrated in cultured fibroblasts, and genomic DNA can be screened for mutations in the corresponding SLC22A5 gene (Tang et al., 1999; Wang et al., 2000). Carnitine supplementation corrects cardiomyopathy and other clinical signs (Nezu et al., 1999). The Lcarnitine dose may vary from 100 to 600 mg/kg/day on the basis of the calculated carnitine depletion from muscle, liver, heart and kidney. Individually adjusted dosage may require plasma levels measurement. There are no major side effects of L-carnitine supplementation. Some patients are troubled by diarrhea or fishy body odour. In some cases a medium-chain triglyceride diet may be added. The benefit of long-term treatment has been demonstrated in several cases (Chapoy et al., 1980; Cederbaum et al., 2002; Cvitanovic et al., Table 8.2 Primary systemic carnitine deficiency Inheritance Gene Clinical presentation
Autosomal recessive OCTN2 organic cation transporter Progressive cardiomyopathy Muscle weakness Fasting hypoglycemia Urine: normal organic acid pattern Low total carnitine in plasma, urine and muscle Normal ratio carnitine/acylcarnitines Molecular biology: several point mutations reported
185
2003), although the longest reported surviving patient with an OCTN2 mutation died suddenly and a postmortem chest X-ray revealed cardiomegaly, a new finding after 20 years of previously successful treatment. 8.2.2. Primary muscle carnitine deficiency In primary muscle carnitine deficiency the clinical syndrome is confined to skeletal muscle (Engel and Angelini, 1973); the clinical features are episodes of fluctuating muscle weakness, affecting mostly limb and neck muscles, and severe myalgia. The first patient diagnosed with LSM and carnitine deficiency was initially treated with steroids because of a myalgia/ polymyositis like syndrome (Engel et al., 1973). These patients show, on fasting and in response to a high fat diet, appropriate ketogenesis. The carnitine levels in plasma and liver are normal, but in muscle the level is reduced (<15%). There is no organic aciduria. There is “in-vitro” stimulation by L-carnitine of labelled palmitate and oleate oxidation in muscle taken from such patients. The molecular basis of primary muscle carnitine deficiency is less clear than for primary systemic carnitine deficiency, but may involve a membrane “lowaffinity” carnitine transporter. In one child with Ondine syndrome and low muscle carnitine an abnormality of low affinity carnitine transport (Vergani and Angelini, 1999) was found in cultured muscle, which could have been due to either delayed maturation or an abnormal carnitine carrier protein (either reduced function or a reduction in carrier numbers). Treatment with oral L-carnitine replacement and medium-chain triglyceride diet has been successful in a number of cases (Angelini et al., 1976).
8.3. Carnitine palmitoyltransferase (CPT2) deficiency The most typical presentation of CPT2 deficiency is in young adults (Table 8.3), with episodes of muscle pain and rhabdomyolysis triggered by prolonged exercise, cold or fever (Trevisan et al., 1984). This adult, or “muscle”, form of CPT2 deficiency is the commonest disorder of muscle lipid metabolism. The rhabdomyolysis is associated with marked elevation of serum creatine kinase (upto 50 000 iu/l) and by myoglobinuria, which can precipitate renal failure/acute tubular necrosis. Less common presentations include an infantile form with cardiac and hepatic as well as skeletal muscle involvement, and a fatal neonatal form. The disease is autosomal recessive, but with a strong male predominance (Angelini et al., 1981), sometimes attributed to different levels of physical activity between the sexes although other factors are likely to be relevant. Intolerance to
186
C. ANGELINI
Table 8.3
Muscle isotope-exchange assay
CPT2 deficiency 6
Forward activity in platelets
exercise can also be observed in carriers of CPT 2 mutations suggesting a dominant-negative effect of this tetrameric protein (Trevisan et al., 1984; Orngreen et al., 2005). Muscle and platelet isotope-exchange reaction might be useful in diagnosing this disorder (Fig. 8.2) and by this assay it is possible to demonstrate intermediate activities in carrier platelets (Angelini et al., 1981) and by forward reaction different length of acylCoA-transferase are found in platelets demonstrating the presence of multiple transferase (Fig. 8.3; Angelini et al., unpublished work). Management is aimed at preventing myoglobinuric episodes, with their threat to renal function, and most importantly involves educating the patient to avoid prolonged exercise, particularly in association with fasting or cold. During an attack 5% glucose administered intravenously provides an alternative metabolic fuel to
nmoles/min/mg protein
Young adults Paroxysmal myoglobinuria Residual: malonyl-CoA insensitive CPT activity CPT gene is located in chromosome 1 Serine 113 to leucine is the most common missense mutation — 60% cases (429C>T)
5 4 3 2 Control
1
Patient C10
C8
C12
COT
C14
C15
CPT
Fig. 8.2. Carnitine palmityl transferase measured by isotopeexchange, low reaction in a CPT2-deficient patient with C12–C16 fatty acids.
free fatty acids. Forced alkaline diuresis is commonly advocated to protect renal function (Better and Stein, 1990), although the benefit is unproven. Alkalinization of the urine is intended to enhance the solubility and
9
C8
8
C10
7 6 C12
5 4 3
C16
2 1
C14 0
100
200
500
800
Acyl-CoA
Fig. 8.3. Carnitine palmityl transferase forward assay in normal platelets measured with different length fatty acids shows a higher activity with medium-chain fatty acids (C8 –C10) than with long-chain fatty acids (C14–C16).
DISORDERS OF LIPID METABOLISM thus clearance of myoglobin. One approach is an intravenous infusion of hypotonic sodium chloride and sodium bicarbonate (sodium chloride 110 mmol/l and bicarbonate 40 mmol/l) in 5% glucose solution to which 10 g/l mannitol is added in a 20% solution. The solution should be infused into a young adult of 75 kg weight at the rate of 12 l/day in order to obtain a diuresis of 8 l/day and to keep the urinary pH above 6.5.
8.4. Defects of b-oxidation Defects of fatty-acid oxidation may affect muscle alone or in conjunction with other tissues and organs, e.g., liver, heart (Table 8.4). For many of the different enzyme deficiencies the clinical feature are similar, i.e., the clinical picture in most patients is exercise-induced muscle pain and rhabdomyolysis. The diagnosis is often suggested by the characteristic pattern of the acylcarnitine profile on tandem mass spectrometry or, less helpfully, of that of organic acids excreted in the urine. Enzymatic and immunochemical analysis performed in fibroblasts and/or in muscle and liver mitochondria, or molecular genetic studies, will confirm the diagnosis. The major inborn errors of beta-oxidation are:
very long chain acyl-CoA deficiency (VLCAD) trifunctional enzyme deficiency medium-chain acyl-CoA deficiency (MCAD) short-chain acyl-CoA deficiency (SCAD) riboflavin-responsive multiple acylCoA-dehydrogenase (RR-MAD).
8.4.1. Very long chain acylCoA dehydrogenase (VLCAD) deficiency Very long chain acylCoA dehydrogenase (VLCAD) deficiency was first described in children (Hale et al.,
187
1985). Subsequent reports have shown that there are three typical clinical presentations: a first group has onset in the first few months of life, is associated with cardiomyopathy and recurrent episodes of hypoketotic hypoglycaemia, and has high mortality; a second group is characterized by recurrent episodes of hypoketotic hypoglycaemic coma following fasting, but no cardiomyopathy; a third group presents with lateonset rhabdomyolysis and myalgia after exercise, absence of cardiomyopathy, and is clinically very similar to the muscle form of CPT 2 deficiency. Deficient patients cannot oxidize C18–C16 fatty acids, whereas they can normally utilize shorter fatty acids (shorter than C14). Exercise-induced myoglobinuria is a common presentation in the later-onset group (Olgivie et al., 1994; Orngreen et al., 2004). Cardiomyopathy is a feature of the earlier-onset forms. Other distinctive laboratory findings include hypoglycemia, hypoketonuria, high serum ammonia and slight elevation of serum aminotransferases. Low ketones during severe hypoglycemia strongly suggest a specific defect of fatty acid oxidation. Liver biopsy reveals an increase in both macro- and microvescicular fat and mitochondrial abnormalities. 8.4.2. Trifunctional enzyme deficiency The trifunctional enzyme of b-oxidation (TFP) is a recently recognized mitochondrial multienzyme complex with three activities: long-chain 2-enoyl-CoA hydratase (LCEH), 3 hydroxy-acyl-CoA dehydrogenase (LCHAD) and 3-ketoacylCoA thiolase (LCKT). Enzyme defects are characterized by recurrent hypoketotic hypoglycemia, Reye-like episodes, cardiomyopathy and skeletal muscle weakness, but there is considerable phenotypic heterogeneity. Most patients have isolated LCHAD deficiency; fewer have variable deficiencies of each of the three components. The
Table 8.4 Clinical features in disorders of fatty acid metabolism
Systemic carnitine transporter Muscle carnitine Translocase CPT II VLCAD Trifunctional protein MCAD SCAD RR MAD
Cramps
Myoglobinuria
Myalgia
Weakness
Heart
Metabolic crisis
þ þ þ
þ þ
þ þ þ
þ þ þ þ
þ þ þ þ þ þ þ
þ
188
C. ANGELINI
disease is inherited as an autosomal-recessive trait. The common mutation for LCHAD deficiency is (G1528C) of the a-subunit and accounts for 60% of alleles. Onset of symptoms is typically in the first year of life, and is characterized by intermittent hypoglycemia, and progressive lethargy evolving into coma (Table 8.5). The episodes are typically triggered by fever, diarrhea or vomiting, which are associated with a catabolic state. Hepatomegaly, cardiomyopathy and muscle weakness are usually observed. Most patients described have had onset of symptoms in infancy or early childhood and have died within the first decade. TFP deficiency has therefore generally been regarded as a serious disorder of fatty acid oxidation with multiorgan involvement and usually fatal outcome in childhood. However Schaefer et al. (1996) reported a new clinical phenotype of TFP deficiency with late-onset of symptoms and prolonged survival beyond the third decade. All patients were members of the same family and presented in adult life with predominant muscle symptoms, i.e., attacks of exercise-induced myalgia and myoglobinuria, thus resembling the muscular form of CPT II deficiency, except that these patients had an associated peripheral neuropathy (an axonal sensory peripheral neuropathy with impairment of light touch below the knees with reduction of joint position sense in both feet). Because TFP is active with long and very long chain (C12–C24) fatty acids it is likely that in TFP deficiency fatty acids intermediates with toxic chain length accumulate in mitochondria. Long-chain fatty acids are known to affect several function of the inner mitochondrial membrane: they increase membrane permeability, inhibit transport function and uncouple oxidative phosphorylation, which may be due to a detergent-like effect of acyl-carnitines. In some patients with TFP deficiency, administration of a carbohydrate and a medium-chain triglyceride (MCT)-enriched diet has been successful in slowing disease progression.
In the three adult patients from the family with recurrent rhabdomyolysis and peripheral neuropathy reported by Schaefer et al. (1996), a low-fat/highcarbohydrate diet was beneficial in one patient, reducing the frequency of rhabdomyolytic episodes. 8.4.3. Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency Medium-chain acyl-CoA dehydrogenase deficiency is the most common error of fatty oxidation in the USA, UK and Northern Europe. It is manifested by a recurrent syndrome of somnolence, vomiting, coma, hypoglycemia, fatty infiltration of the liver and dicarboxylic aciduria. The crises are often precipitated by intercurrent infections. Skeletal and cardiac muscle involvement is uncommon. Mild myopathy may be seen in survivors, and very rarely the condition may present with adultonset exercise-induced rhabdomyolysis. Patients cannot oxidize the medium-chain fatty acids (C12–C6). The disorder becomes life-threatening during episodes of stress or fasting (Table 8.6), which result in decreased caloric intake and increased catabolism. Hepatomegaly due to fatty liver has been described in some cases. Seizures have been reported, but it should be noted that the patients may have normal development and growth, and no clinical sign of cardiomyopathy or myopathy. During the crisis, all patients develop hypoketotic hypoglycemia, with an increased ratio of FFA-to-ketone bodies, elevated serum aminotransferases, and mild hyperammonemia, probably due to increased proteolysis. Plasma and tissue carnitine is low (25% of control in liver and muscle), with increased acyl/free carnitine ratio. The secondary carnitine insufficiency observed in MCADdeficient patients is due not only to increased excretion of acyl-carnitines, with depletion of tissue carnitine, but also to defective reabsorption in the kidney.
Table 8.6 Table 8.5 Long-chain 3-hydroxyacyl CoA dehydrogenase (LCHAD) deficiency Children (0–9 months) Fasting hypoglycaemia, hypoketonaemia Reye-like syndrome Cardiomyopathy–hepatomegaly (cirrhosis) Pigmentary retinopathy; peripheral neuropathy Low carnitine and high acylcarnitines 3-hydroxydicarboxylic acids (C6–C14) in urine LCHAD activity: 14–30%
Medium-chain acyl-CoA-dehydrogenase (MCAD) deficiency Children Reye-like syndrome Fasting hypoglycaemia, non-ketotic Episodes of coma Low total plasma carnitine Decreased tissue carnitine Decreased octanoic oxidation in fibroblasts Medium-chain dicarboxylic aciduria Chromosome lp3l Common mutation 329 lysine to glutamic acid 90% of cases (986 A>G, K304E)
DISORDERS OF LIPID METABOLISM MCAD deficiency has been found in cases of Reyelike syndrome and in some cases of sudden infant death syndrome (SIDS). The first episodes of the disorder occur in the first 12–18 months of life. Incidence in the two sexes is similar. The mortality rate is 25% but can reach 60% in cases with delayed onset (second year of life). In half of the families there was a high incidence of sudden infant death in infancy (Table 8.7). The treatment is similar to other b-oxidation defects. Fasting and long intervals between meals should be avoided; a high-carbohydrate, low-fat diet should be administered and L-carnitine supplementation can be useful in preventing secondary carnitine insufficiency. Given the relatively high incidence of the disease (1/8930 in a newborn screening program in Pennsylvania; Ziadeh et al., 1995), the association with SIDS (Table 8.7), and the good prognosis with adequate dietary control, consideration should be given to neonatal screening by blood spot analysis. In peripheral blood DNA the identification of the A to G mutation, present in 90% of the patients, is obtained by restriction analysis (NcoI) of the relevant sequence amplified by the polymerase chain reaction. A survey of the literature indicates that there is a high prevalence of the mutated allele in babies of German and British heritage, whereas this mutation has been rarely found in neonates in the Mediterranean area. It is possible that the common mutation occurred in a single progenitor of a Germanic tribe. Prenatal diagnosis is possible using the same molecular analysis. 8.4.4. Short-chain acyl-CoA dehydrogenase (SCAD) deficiency Few patients with SCAD deficiency have been described and there is controversy over the appearance of a defective SCAD enzyme in fibroblasts. In SCAD deficiency the dicarboxylic aciduria is not striking. Table 8.7 Defects of fatty acid oxidation causing sudden infant death syndrome (SIDS) 10 – 20% incidence in siblings Death during sleeping hours or weekend (long interval between feedings) Males > females Subgroup (10%): fatty changes in liver or muscle Screening: urine organic acids and carnitine fractions by GC/ HPLC Common G to C mutation at nucleotide 1528 (1528>c) of the a-subunit account for 60% of mutant alleles in LCHAD deficiency
189
Many shorter chain length fatty acid residues are seen, such as ethylmalonic, butyric and methylsuccinic acids. In these patients the oxidation of C4–C6 fatty acids is compromised. Because MCAD catalyses 50% of C4 dehydrogenation, the diagnosis may be difficult and may require inhibition of MCAD with specific antisera. SCAD deficiency is associated with different clinical phenotypes: a severe infantile form (Coates et al., 1988) and a late-onset myopathic picture with carnitine insufficiency (Table 8.8). 8.4.5. Riboflavin-responsive multiple acyl-CoA dehydrogenase (RR-MAD) defects Although rare, this is an important disorder to recognize because it responds to treatment with riboflavin. However, the diagnosis is often missed because it is not considered (Antozzi et al., 1994; Vergani et al., 1996). Two main phenotypes are recognized. In childhood it presents with Reye-like episodes, hypoketotic hypoglycaemia and failure to thrive and glutaric aciduria type II (GA II), but without significant skeletal muscle involvement. This type of GA II is caused by defects in intramitochondrial acyl-CoA dehydrogenation due to deficiency in one of three molecules: the a- or b-subunits of the election transport flavoprotein or ETF dehydrogenase, and responds poorly to treatment. RR-MAD presents in adult life with fluctuating episodes of profound weakness, associated with secondary carnitine deficiency and glutaric aciduria type II (Table 8.9). A survey of published articles and of our own cases indicates that poor nutrition, alcoholism, pregnancy and gastrointestinal upset often trigger the attacks. The molecular basis of this condition is unclear. Riboflavin is an essential nutrient and is a precursor of flavoproteins (e.g., FAD) involved in fatty-acid metabolism including the short, medium, long and very-long chain acyl-CoA dehydrogenases (SCAD, MCAD, LCAD, VLCAD). The diagnosis is suggested by lipid storage myopathy and the characteristic acylcarnitine profile. Table 8.8 Short-chain acyl-CoA dehydrogenase (SCAD) deficiency A Infantile-generalized Poor weight gain Psychomotor retardation Fatal B Myopathic form (adult onset) Lipid storage myopathy Low free carnitine, increased acylcarnitines
190
C. ANGELINI
Table 8.9 Riboflavin-responsive multiple acyl-CoA dehydrogenase (RR-MAD) deficiency Myopathic form Adult onset Lipid storage myopathy Low SCAD, MCAD Low free carnitine, increased acylcarnitines, glutaric aciduria type 2 Riboflavin-responsive
of toxic intermediate metabolites is avoided and the development of most critical symptoms is minimized. Fat consumption should be restricted to 25% of total calories and have reduced amounts of long-chain fatty acids. Increased caloric intake from carbohydrates may be necessary during intermittent illness due to increased metabolic demands on the body. A low fat/high carbohydrate diet is beneficial in reducing rhabdomyolytic episodes in several disorders of fatty acid metabolism including CPT2 deficiency (Orngreen et al., 2003) and trifunctional enzyme deficiency (Schaefer et al., 1996). 8.6.1. Dietary treatments, special diets
Mitochondrial studies show reduced activity of SCAD, MCAD and complexes 1 and 2 of the respiratory chain in riboflavin-deficient medium, improving with the addition of riboflavin. It is difficult to explain the improvement of patients, and the increased enzyme activity, observed during riboflavin treatment. Riboflavinresponsive multiple acyl-CoA dehydrogenase deficiency may be due to different mechanism(s). Possible mechanisms of riboflavin deficiency include (i) decreased cellular riboflavin uptake and decreased FAD synthesis; (ii) decreased FAD transport into mitochondria; (iii) abnormal binding of FAD to apoenzymes; (iv) increased catabolism of FAD. The biochemical study, in isolated mitochondria and muscle, of FAD and FMM levels reveal heterogeneous mechanism(s) in patients with riboflavin deficiency (Vergani et al., 1999). It is important to recognize these patients since they improve, often dramatically, after riboflavin treatment (100–200 mg/day, orally).
8.5. Multisystemic triglyceride storage disorder This is a syndrome in which congenital ichthyosis, hepatosplenomegaly and multisystemic triglyceride storage are found. A hallmark of this disorder is the presence of vacuolated granulocytes (Jordan’s anomaly). The cultured fibroblasts had increased uptake but decreased oxidation of oleate (Angelini et al., 1980). MCT oil gave some improvement in our patient. The defect has been identified in a ABHD5 [abhydrolase domain containing 5 (CGI-58), a gene encoding an enzyme with an abhydrolase fold and esterase-lipase-thioesterase activity.
8.6. General recommendations for treatment of fatty acid disorders The main caution in defects of mitochondrial b-oxidation is the avoidance of fasting. By not allowing patients with such disorders to become dependent for energy needs on b-oxidation, as occurs during fasting, the accumulation
The current dietary treatment of long-chain fatty acids defects (high carbohydrate with medium-length-evenchain triglyceride and reduced long-chain fats) is effective and based on clinical experience. It is difficult to perform double-blind studies in fatty acid oxidation disorders, looking at prevention of cardiomyopathy, rhabdomyolysis and/or muscle weakness. A diet has been proposed that replaces dietary medium-even-chain fatty acids with medium-odd-chain fatty acids (Roe et al., 2002), which are precursors of acetyl-CoA and of anaplerotic propionyl-CoA, in order to restore energy production and improve cardiac and skeletal muscle function. It appeared effective in three children with VLCAD deficiency.
References Angelini C, Lucke S, Cantarutti F (1976). Carnitine deficiency of skeletal muscle: report of a treated case. Neurology 26: 633–637. Angelini C, Philippart M, Borrone C, et al. (1980). Multisystem triglyceride storage disorder with impaired long-chain fatty acid oxidation. Ann Neurol 7: 5–10. Angelini C, Freddo L, Battistella P, et al. (1981). Carnitine palmityl transferase deficiency: clinical variability, carrier detection, and autosomal-recessive inheritance. Neurology 31: 883–886. Angelini C, Vergani L, Martinuzzi A (1992). Clinical and biochemical aspects of carnitine deficiency and insufficiency: transport defects and inborn errors of beta-oxidation. Crit Rev Clin Lab Sci 29: 217–242. Angelini C, Federico A, Reichmann H, et al. (2006). Task force guidelines handbook: EFNS guidelines on diagnosis and management of fatty acid mitochondrial disorders. Eur J Neurol 13: 923–929. Antozzi C, Garavaglia B, Mora M, et al. (1994). Late-onset riboflavin responsive myopathy with combined multiple acyl-CoA dehydrogenase and respiratory chain deficiency. Neurology 44: 2153–2158. Better OS, Stein GH (1990). Early management of shock and prophylaxis of acute renal failure in traumatic rhabdomyolysis. New Engl J Med 322: 825–829.
DISORDERS OF LIPID METABOLISM Chapoy PR, Angelini C, Brown WJ, et al. (1980). Systemic carnitine deficiency: a treatable inherited lipid storage disease presenting as recurrent Reye’s syndrome. New Engl J Med 303: 1389–1394. Coates PM, Acili DE, Finocchiaro G, et al. (1988). Genetic deficiency of short chain acylcoenzyme A dehydrogenase in cultured fibroblasts from a patient with muscle carnitine deficiency and severe skeletal muscle weakness. J Clin Invest 81: 171–175. Cvitanovic Sojat L, Tein I, Lamhonwah AM, et al. (2003). Fourteen-year follow up of a girl with primary systemic carnitine deficiency due to a carnitina transporter defect and OCTN2 mutation. Paediatr Croat 47: 83–86. Engel AG, Angelini C (1973). Carnitine deficiency of human skeletal muscle with associated lipid storage myopathy: reports of a new syndrome. Science 179: 899–902. Engel AG, Angelini C, Nelson RA (1973). Identification of carnitine deficiency as a cause of human lipid storage myopathy. Int Cong Ser 333: 601–617. Hale DE, Batshaw ML, Coates PM, et al. (1985). Long-chain acylcoenzyme A dehydrogenase deficiency: an inherited cause of no ketotic hypoglicemia. Paediatr Res 19: 666–671. Nezu J, Tamai I, Oku A, et al. (1999). Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter. Nat Genet 21: 91–94. Ogilvie I, Pourfarzam M, Jackson S, et al. (1994). Very longchain acyl-coenzyme A dehydrogenase deficiency presenting with exercise induced myoglobinuria. Neurology 44: 463–473. Orngreen MC, Ejstrup R, Vissing J (2003). Effect of diet on exercise tolerance in carnitine palmitoyltransferase II deficiency. Neurology 61: 559–561. Orngreen MC, Norgaard MG, Sacchetti M, et al. (2004). Fuel utilization in patients with very long-chain acyl-CoA dehydrogenase deficiency. Ann Neurol 56: 279–283. Orngreen MC, Duno M, Ejstrup R, et al. (2005). Fuel utilization in subjects with carnitine palmitoyltransferase 2 gene mutations. Ann Neurol 57: 60–66.
191
Roe CR, Sweetman L, Roe DS, et al. (2002). Treatment of cardiomyopathy and rhabdomyolysis in long-chain fat oxidation disorders using an anaplerotic odd-chain triglyceride. J Clin Invest 110: 259–269. Schaefer J, Jackson S, Dick DJ, et al. (1996). Trifunctional enzyme deficiency: adult presentation of a usually fatal beta-oxidation defect. Ann Neurol 40: 597–602. Tang NL, Ganapathy V, Wu X, et al. (1999). Mutations of OCTN2, an organic cation/carnitine transporter, lead to deficient cellular carnitine uptake in primary carnitine deficiency. Hum Mol Genet 8: 655–660. Tein I, De Vivo DC, Bierman F, et al. (1990). Impaired skin fibroblast carnitine uptake in primary systemic carnitine deficiency manifested by childhood carnitine-responsive cardiomyopathy. Paediatr Res 28: 247–255. Trevisan CP, Angelini C, Freddo L, et al. (1984). Myoglobinuria and carnitine palmityltransferase (CPT) deficiency: studies with malonyl-CoA suggest absence of only CPTII. Neurology 34: 353–356. Vergani L, Angelini C (1999). Infantile lipid storage myopathy with nocturnal hypoventilation shows abnormal lowaffinity muscle carnitine uptake in vitro. Neuromuscul Disord 9: 320–322. Vergani L, Angelini C, Pegoraro E, et al. (1996). Hereditary protein C deficiency associated with riboflavin responsive lipid storage myopathy. Eur J Neurol 3: 61–65. Vergani L, Barile M, Angelini C, et al. (1999). Riboflavin therapy: biochemical heterogeneity in two adult lipid storage myopathies. Brain 122: 2401–2411. Vockley J, Whiteman DA (2002). Defects of mitochondrial beta-oxidation: a growing group of disorders. Neuromuscul Disord 12: 235–246. Wang Y, Taroni F, Garavaglia B, et al. (2000). Functional analysis of mutations in the OCTN2 transporter causing primary carnitine deficiency: lack of genotype–phenotype correlation. Hum Mutat 16: 401–407. Ziadeh R, Hoffman EP, Finegold DN, et al. (1995). Mediumchain acyl-CoA dehydrogenase deficiency in Pennsylvania: neonatal screening shows high incidence and unexpected mutation frequencies. Paediatr Res 37: 675–678.
Handbook of Clinical Neurology, Vol. 86 (3rd series) Myopathies F. L. Mastaglia, D. Hilton-Jones, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 9
Investigation of metabolic myopathies R. W. TAYLOR, P. F. CHINNERY, AND D. M. TURNBULL* Mitochondrial Research Group, School of Neurology, Neurobiology and Psychiatry, University of Newcastle upon Tyne, Newcastle upon Tyne, UK
9.1. General introduction Muscle contraction is dependent upon the high-energy molecule adenosine triphosphate (ATP), and deficiency of ATP synthesis leads to muscle fatigue and weakness. Carbohydrate metabolism, fatty acid oxidation and oxidative phosphorylation are all important in the generation of ATP from metabolic fuels, and defects of all three pathways can result in metabolic myopathies. This chapter focuses on the investigation of patients with suspected defects of these pathways. Detailed clinical descriptions of the patients and the pathways involved have been given in chapters 6, 7 and 8 and will only be summarized here.
9.2. Glycogen storage disorders 9.2.1. Introduction Glycogen storage disorders (the glycogenoses) are a group of rare inherited metabolic diseases due to abnormal synthesis or breakdown of glycogen. Most affect single cytoplasmic enzymes, with the exception of a-glucosidase (acid maltase) deficiency which involves the lysosomal glycogen degradation pathway. The glycogen storage disorders generally present clinically in one of two ways: exercise intolerance, muscle cramps and intermittent rhabdomyolysis, or progressive proximal weakness. Unusual presentations include insidious neuromuscular ventilatory failure observed in some adults with a-glucosidase deficiency. 9.2.2. Diagnosis of glycogen storage disorders The diagnosis of glycogen storage disorders is dependent on a variety of techniques including in-vivo metabolic testing, muscle histochemistry, measurement of enzyme
activity in muscle (or other tissues) and genetic analysis. By far the most common defect detected in adult practice is phosphorylase deficiency (McArdle’s disease) and we will concentrate on this defect, but describe the diagnostic investigation of the other glycogenoses. The serum creatine kinase is usually increased in the glycogenoses. 9.2.2.1. Myophosphorylase deficiency (McArdle’s disease, type V glycogenosis) In-vivo metabolic testing has commonly been used for the diagnosis of McArdle’s disease or to exclude the possibility of other defects of glycogen breakdown. In inexperienced hands, false-positive and false-negative results are common. The ischemic forearm exercise test is a simple, sensitive and specific test for disorders of muscle glycolysis, when levels of plasma ammonia and lactate are measured (Coleman et al., 1986; Sinkeler et al., 1986). The measurement of ammonia is important since ammonia production is high in patients with defects of glycolysis and blunted in healthy individuals in whom exercise effort is poor (Rumpf et al., 1981). Whilst this procedure is often used as a screening procedure, it is often extremely uncomfortable for patients, inducing cramp. Indeed, it has also been reported that the ischemic exercise test has been associated with rhabdomyolysis in the exercised arm (Meinck et al., 1982; Lindner et al., 2001). Recently, a non-ischemic forearm exercise test for McArdle’s disease and other disorders of glycolysis has been reported and it seems to be superior, in terms of efficacy and safety, to the non-ischemic test (Kazemi-Esfarjani et al., 2002). Other in-vivo metabolic testing has been performed including a bicycle exercise test (Vissing and Haller, 2003) and phosphorus magnetic resonance spectroscopy, but availability is limited and they are not required for routine diagnosis.
*Correspondence to: Professor D. M. Turnbull, Department of Neurology, The Medical School, University of Newcastle upon Tyne, NE2 4HH UK. E-mail:
[email protected], Tel: þ44-191-222-8565, Fax: þ44-191-222-8553.
194
R. W. TAYLOR ET AL.
Skeletal muscle histochemistry shows evidence of glycogen storage, and the absence of phosphorylase activity. Muscle phosphorylase deficiency can be confirmed biochemically (levels usually <5% of normal), but this is rarely necessary. In the majority of patients of European descent molecular genetic analysis reveals the R49X mutation (>70%) in the PYGM gene (Martin et al., 2001), which is either homozygous or compound heterozygous with another mutation in the coding region of the gene. Different common mutations are found in other populations (Tsujino et al., 1995a). In summary, despite the availability of exercise tests, enzymatic assay and molecular genetic studies, in most patients the diagnosis is achieved on the basis of clinical suspicion and the demonstration of glycogen accumulation and the absence of myophosphorylase activity on muscle biopsy. 9.2.2.2. Other glycogen storage disorders 9.2.2.2.1. a-glucosidase deficiency (acid maltase deficiency, Pompe’s disease, type II glycogenosis) Muscle biopsy reveals a vacuolar myopathy with glycogen accumulation and increased acid phosphatase activity. These features are non-specific and the diagnosis must be confirmed by enzyme assay either in muscle, fibroblasts or leukocytes. Genetic analysis of the GAA gene often reveals the underlying mutation, and there is a strong relationship between the type of mutation, the underlying biochemical defect and the clinical phenotype (Hermans et al., 2004). 9.2.2.2.2. Debranching enzyme deficiency (type III glycogenosis) Muscle biopsy reveals a vacuolar myopathy, and the diagnosis is confirmed by a biochemical assay in lymphocytes or muscle. Different clinical subtypes of debranching enzyme deficiency appear to be associated with different mutations in the AGL gene (Lucchiari et al., 2002). 9.2.2.2.3. Branching enzyme deficiency (type IV glycogenosis) Muscle biopsy reveals periodic-acidSchiff-positive, diastase-fast deposits. The diagnosis is confirmed by enzyme assay, and mutations may be found in the GBE gene (Bruno et al., 2004). 9.2.2.2.4. Phosphorylase b kinase (type VI glycogensis) Glycogen is deposited within muscle fibers (typically type II), but with normal muscle phosphorylase activity. The diagnosis is confirmed by an enzyme assay. Genetic analysis is complex because of the many subunits, and
even with exhaustive sequencing of known genes, the results are often negative (Burwinkel et al., 2003). 9.2.2.2.5. Phosphofructokinase (PFK) deficiency (Tauri’s disease, type VII glycogenosis) The forearm exercise test is associated with a flat lactate response, and a marked rise in ammonia levels, as in myophosphorylase deficiency. In myophosphorylase deficiency, the rise in venous ammonia can be abolished by infusing 5% dextrose, but in PFK deficiency disease this causes an even more dramatic rise in the ammonia level. Both disorders show a similar pattern of subsarcolemmal glycogen storage, but with normal phosphorylase activity in PFK deficiency. Patients with PFK deficiency often have evidence of hemolysis, with a reticulocytosis and increased bilirubin. The diagnosis is confirmed by biochemical assay of the muscle specific isoform of PFK, followed by PFK-M gene analysis (Raben and Sherman, 1995). 9.2.2.2.6. Phosphoglycerate kinase deficiency (type IX glycogenosis) Phosphoglycerate kinase deficiency is an X-linked disorder which can present either prominent myopathic or hemolytic features. A mixed phenotype has been observed, and central nervous system features have been observed (including mental retardation and epilepsy). A range of different mutations have been found in the PGK gene (Tsujino et al., 1995b). 9.2.2.2.7. Phosphoglycerate mutase deficiency (type X glycogenosis) Phosphoglycerate mutase deficiency typically causes prominent exercise intolerance and is associated with a moderate rise in lactate with a massive increase in ammonia on forearm exercise testing. This disorder has been associated with mutations in the gene (PGAMM) encoding the muscle-specific subunit of this dimeric enzyme. 9.2.2.2.8. b-enolase deficiency (type XIII glycogenosis) This enzyme defect has also been described with adultonset exercise intolerance and chronically increased serum creatine kinase (Comi et al., 2001). Mutations were found in the ENO3 gene, which encodes b-enolase, the isoform predominantly expressed in skeletal muscle.
9.3. Fatty-acid oxidation disorders 9.3.1. Introduction Since the first description of carnitine palmitoyltranferase (CPT) deficiency nearly 35 years ago (DiMauro and
INVESTIGATION OF METABOLIC MYOPATHIES
195
DiMauro, 1973), there has been a steady increase in both the number of different fatty acid oxidation disorders and the number of affected patients reported. Defects involving many of the different enzymes and transport proteins involved in fatty acid oxidation have been described (Rinaldo et al., 2002).
esters into the corresponding acylglycines and acylcarnitine with secondary carnitine deficiency. Fatty acid oxidation disorders may therefore be investigated by studying the concentration of these metabolites in body fluids and in our opinion this has considerably simplified the investigation of this complex group of disorders.
9.3.2. Clinical features of mitochondrial fatty acid oxidation disorders
9.3.3.1. Analysis of metabolites
For many of the different enzyme deficiencies the clinical features are similar. Muscle involvement is frequent which reflects the requirement of fatty acid oxidation for normal muscle function. In some patients this is reflected by exercise-induced muscle pain and rhabdomyolysis. The pain is characteristically only present after prolonged exercise and may occur after the exercise has been completed. In some patients physiological fasting or fasting secondary to infection or illness can induce an episode. The rhabdomyolysis can be severe and lead to profound muscle weakness and renal failure. In some patients there is no pain during acute episodes, the major clinical feature being proximal weakness. This can be severe and may be associated with respiratory compromise. In many of these patients there is also cardiac involvement and sometimes also liver involvement. 9.3.3. Diagnosis of mitochondrial fatty acid oxidation defects The investigation of fatty acid oxidation disorders is dependent upon biochemical and genetic studies. There are few indications for muscle biopsy in these patients; whilst fat accumulation may be present, we have observed normal biopsies in many adult patients with proven fatty acid oxidation defects, even during acute episodes. The extent of fat accumulation in muscle in normal subjects varies, dependent upon diet and activity levels, and absolute quantitation of fat content is not feasible or helpful. There are no histochemical assays for the enzymes of fatty acid oxidation. Since the clinical presentation of many genetic defects is similar — exercise-induced muscle pain with or without rhabdomyolysis — searching for an individual enzyme defect or genetic defect is less productive than generic tests which will identify all defects. The biochemical manifestations of fatty acid oxidation disorders include deficient production of energy yielding substrates (acetyl-CoA and ketone bodies) and accumulation of free fatty acids and toxic acyl-CoA intermediates proximal to the block in the pathway. This leads to the formation of dicarboxylic and hydroxyl-dicarboxylic acids from fatty acids, and the conversion of acyl-CoA
Analysis of metabolites is now a crucial part of the investigation of defects of fatty acid oxidation. However, flux through fatty acid oxidation may be low at times when the metabolic condition is stable and diagnostic metabolites may be below the limit of detection of some techniques. Fasting studies have been reported to be helpful under these circumstances, but are probably not necessary for detection of abnormal acylcarnitines. Fasting studies may also induce a metabolic crisis and are best done under the supervision of a clinician with extensive experience in this area. 9.3.3.1.1. Analysis of organic acids and acylglycines in urine The excretion of diagnostic organic acids has long played a role in the investigation of inborn errors of metabolism. However, whilst for many fatty acid oxidation defects abnormal organic acids are present in the urine, in others, such as carnitine transporter, CPT and carnitine:acylcarnitine translocase deficiency, there may be a normal or non-specific urinary organic acid pattern even under metabolic stress. Quantitative analysis of urinary acylglycines has been shown to be diagnostic in medium chain acyl-CoA dehydrogenase (MCAD) deficiency independent of clinical status (Costa et al., 2000), but is not diagnostic for many other disorders of fatty acid oxidation. Thus overall, whilst providing helpful information in many cases of fatty acid oxidation, analysis of these urinary metabolites is generally less helpful than newer techniques such as acylcarnitine analysis. 9.3.3.1.2. Analysis of acylcarnitine and free carnitine in blood or plasma Analysis of acylcarnitines on either whole dried blood spots or plasma have proved to be a very valuable tool for the detection of fatty acid oxidation disorders. Most known enzyme deficiencies can be detected by a disease specific change in the acylcarnitine profile or associated abnormalities in free carnitine levels (Fig. 9.1). Acylcarnitine analysis is performed by tandem mass spectrometry and the analytical time is short and sample handling is simple. The use of dried blood spots and the highly specific nature of the changes in acylcarnitines has
196
R. W. TAYLOR ET AL. 100
260.1 263.2
221.1
% 465.4 277.1 466.4
363.3
A
374.2 0 100
221.1 263.2
260.2
%
426.3 353.4
B
482.5 480.4 484.4
424.4
277.3
249.2
428.3 374.3
0
465.5 482.5 456.4 484.4 480.5
400.5
260.3
100
218.2 %
263.3
221.3
456.6 274.3 288.3
C
302.4316.4
344.5
372.4 353.5
400.5 398.4
428.5
454.6
482.6 484.6 480.6
0 263.3
100 221.3
465.6
260.3 %
462.7 456.5 353.5
277.4
D
288.4
318.4
498.7 500.8
454.6 426.5 424.4 398.5400.7 444.5
508.7
0 283.3
100
482.5 221.4
456.5
%
260.3
465.6
484.6
480.6 277.4
454.5
353.5 400.4
E
428.6
0 220
240
260
280
300
320
340
360
380
400
420
440
460
480
500
Date 520
Fig. 9.1. Carnitine and acylcarnitine profiles. Blood acylcarnitine profile from (A) a normal subject and patients with defects of fatty acid oxidation. (B) Very long-chain acyl-CoA dehydrogenase deficiency; (C) multiple acyl-CoA dehydrogenase deficiency (mild type); (D) mitochondrial trifunctional protein deficiency; (E) carnitine palmitoyltransferase II deficiency. m/z (mass/charge) values correspond to the molecular ions of butylated acylcarnitine species: free carnitine (m/z 218), free carnitine internal standard (m/z 221), C2-carnitine (m/z 260), C2-carnitine internal standard (m/z 263), C3-carnitine (m/z 274), C3-carnitine internal standard (m/z 277), C4-carnitine (m/z 288), C5-carnitine (m/z 302), C6-carnitine (m/z 316), C8-carnitine (m/z 344), C8-carnitine internal standard (m/z 353), C10-carnitine (m/z 372), C12-carnitine (m/z 400), C14:1-carnitine (m/z 426), C14-carnitine (m/z 428), C16-carnitine (m/z 456), C16-carnitine internal standard (m/z 465), 3-OH-C16-carnitine (m/z 472), C18:1-carnitine (m/z 482), C18-carnitine (m/z 484), 3-OH-C18:1-carnitine (m/z 498), 3-OH-C18-carnitine (m/z 500). Major diagnostic analytes are shown by arrow. Figure kindly provided by Dr M. Pourfarzam.
INVESTIGATION OF METABOLIC MYOPATHIES encouraged groups to consider even prenatal screening for fatty acid oxidation defects (Pollitt, 2001).
197
within the population with the carrier frequency of the K304E mutation being approximately 1:40 in people of Northern European descent.
9.3.3.2. In-vitro cell-based metabolic studies 9.3.3.2.1. Fatty acid oxidation rate This assesses the overall flux and integrity by measuring the generation of end-products after incubating the cells with radio-labelled fatty acids. These studies are usually performed using cultured skin fibroblasts and may employ fatty acids of different chain length to detect defects of short-, medium- and long-chain fatty acid oxidation. Whilst an extremely helpful test in skilled hands, flux can be normal in some of the milder cases of fatty acid oxidation disorder such as CPT2 deficiency. 9.3.3.2.2. Quantitative acylcarnitine analysis This involves incubating the cells with either radioactively-labeled or stable-isotopically labe-led fatty acids and analyzing the products formed. This has proved to be a very effective way of detecting a metabolic defect since the pathway is under flux conditions and altered patterns of metabolites are indicative of specific fatty acid oxidation defects.
9.4. Defects of mitochondrial oxidative phosphorylation 9.4.1. Introduction Defects of mitochondrial oxidative phosphorylation are an important cause of muscle disease and are often described as mitochondrial myopathies. The biochemistry and genetics of these disorders are much more complex than either glycogen storage disorders or fatty acid oxidation, predominantly due to the involvement of the mitochondrial genome (mtDNA). In addition, mitochondrial oxidative phosphorylation disorders — all of which are characterized by the inability of the cell to produce enough ATP on account of respiratory chain dysfunction — may present with a vast array of different clinical features, which makes them enter the differential diagnosis of many different neurological conditions. Because of this widespread tissue and organ involvement, the term mitochondrial cytopathy is preferred. 9.4.2. Clinical features of mitochondrial cytopathy
9.3.3.3. Enzyme studies Whilst the gold standard for any enzyme deficiency is confirming the abnormality by direct enzyme measurement, this is far from easy for fatty acid oxidation disorders. For example there is considerable overlap in substrate specificity and thus immunopreciptation of interfering enzymes may be necessary. For some enzymes the substrates are not commercially available and have to be synthesized. Thus the development of highly specific metabolite-based assays and direct genetic tests have superseded enzyme measurement in many cases. 9.3.3.4. Molecular genetic studies Defects of mitochondrial fatty acid oxidation are autosomal recessive and the genetic defects of several disorders have now been defined. Adult patients with CPT 2 deficiency often have a common point mutation (439C>T, S113L; Taroni et al., 1993), which has been reported in several different series and is present in about 50% of mutant alleles. The common point mutation for long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency is (1538G>C; Ijlst et al., 1996). In MCAD deficiency the mutation (985A>G, K304E) is present in homozygous form in 80% of patients (Yokota et al., 1990). These point mutations have proved useful in assessing the frequency of fatty acid oxidation defects
Skeletal muscle involvement may present with a variety of different phenotypes ranging from a fatal infantile myopathy to very mild ophthalmoparesis in late adult life (Taylor and Turnbull, 2005). These patients may also have involvement of many other tissues and organ systems and the myopathy may be only a minor part of their clinical syndrome. However, even in these patients investigation of muscle tissue is extremely important, not only to investigate a possible respiratory chain defect, but also to make a molecular genetic diagnosis, especially as many pathogenic mtDNA mutations are only expressed in this tissue. 9.4.3. Investigation of mitochondrial myopathies 9.4.3.1. Biochemical measurement in blood Except in children with systemic disease there are few biochemical clues as to the nature of the problem, over and above the clinical features. In some patients with mitochondrial myopathies the concentration of lactic acid is elevated in blood and/or CSF, but this is often a non-specific finding and often no increase in lactic acid is seen in adults. Physiological (Taivassalo et al., 2002) or magnetic resonance scanning (MRS; Chen et al., 2001) investigation of suspected mitochondrial myopathies has been proposed, but has little role in general neurological practice.
198
R. W. TAYLOR ET AL.
9.4.3.2. Genetic studies in blood or urinary epithelial cells If the history and examination are suggestive of a classic mitochondrial syndrome such as MERRF (myoclonic epilepsy and ragged red fibers) or LHON (Leber hereditary optic neuropathy), then investigation for the common mtDNA point mutations known to cause these syndromes should be undertaken in blood. For patients with symptoms suggestive of the MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and strokelike episodes) syndrome, investigation of the 3243A>G mutation in cells spun down from a urine sample is a much more reliable test, as levels of this mutation may be undetectable in blood (McDonnell et al., 2004; Shanske et al., 2004). Results of screening for specific mutations should, however, be interpreted with caution, as negative results do not exclude other forms of mitochondrial disease in a patient where there is a high index of clinical suspicion. In such cases, muscle biopsy is essential to further these investigations. 9.4.3.3. Histopathological and histochemical assessment of mitochondrial function in muscle The histological and histochemical analysis of the muscle biopsy remains an important investigation in patients suspected of mitochondrial cytopathy, not least because certain pathological hallmarks of mitochondrial disease may be revealed. One such hallmark is fibers showing a subsarcolemmal collection of abnormal mitochondria — ragged-red fibers — so named because of their reddish appearance following a Gomori trichrome stain. More appropriate techniques to evaluate mitochondrial involvement are specific histochemical enzyme reactions for the mitochondrial enzymes succinate dehydrogenase (SDH) and cytochrome c oxidase (COX; Fig. 9.2). SDH, part of complex II of the respiratory chain, contains
subunits encoded only by the nuclear genome and will also reveal subsarcolemmal accumulation of mitochondria in the presence of an mtDNA defect; this is the histochemical equivalent of a ragged red fiber. The COX reaction is particularly useful in evaluation of mitochondrial cytopathies because COX contains subunits encoded by both the mitochondrial and nuclear genome. A mosaic pattern of COX activity is highly suggestive of a heteroplasmic mtDNA disorder and the majority of ragged red fibers are COX-deficient. However, some patients with MELAS or point mutations in either MTND genes (Andreu et al., 1999a) or cytochrome b (Andreu et al., 1999b) may have muscle fibers showing mitochondrial proliferation but normal COX activity. In the case of a COX mosaic, the percentage of fibers deficient in COX can vary according to the underlying molecular defect, but may be as high as 95% in some cases involving tRNA- and mtDNA-encoded structural COX genes. In cases where only a very low percentage of COX-deficient fibers are present, sequential COX-SDH histochemistry (Sciacco et al., 1994) is extremely valuable for identifying abnormal fibers which might otherwise go undetected against a background of normal COX activity. We recommend that the sequential COX/SDH is routinely performed on muscle biopsies in which mitochondrial disease is suspected. A global decrease in the activity of COX is usually suggestive of a nuclear mutation in one of the ancillary proteins required for COX assembly and function such as SURF1 (Tiranti et al., 1998; Zhu et al., 1998) although a similar pattern is observed in some patients presenting with pathogenic, homoplasmic mitochondrial tRNA gene mutations (McFarland et al., 2002). Although often very informative, mitochondrial enzyme histochemistry should always be interpreted within the clinical context. Histochemical abnormalities are much more common in adults with mitochondrial
Fig. 9.2. For full color figure, see plate section. Histochemical analysis of mitochondrial function. Serial muscle sections from a patient with chronic progressive external ophthalmoplegia (CPEO) due to a single, large-scale mtDNA deletion reacted for (A) cytochrome c oxidase (COX) activity; (B) succinate dehydrogenase (SDH) activity; (C) sequential COX/SDH histochemistry. Several COX-deficient fibers, some of which show accumulation of mitochondria at the sarcolemma (ragged-red fibers), are highlighted.
INVESTIGATION OF METABOLIC MYOPATHIES disease than children. This in part reflects the more common involvement of the mitochondrial genome in adults compared to children. The assay of SDH activity will also detect patients deficient in complex II (Taylor et al., 1996a), but many patients with defects involving either complex I or complex III may have normal biopsy findings. Even patients with well-recognized phenotypes such as MELAS can present with a normal biopsy. Patients with multiple mtDNA deletions due to POLG mutations may also present with normal muscle histochemistry (Van Goethem et al., 2003a) as can patients with classic chronic progressive external ophthalmoplegia (CPEO) and a single mtDNA deletion (Schaefer et al., 2005). The presence of low levels (1–2% or less) of COXdeficient fibers must also be interpreted with caution. The clonal expansion of somatic mtDNA mutations is a recognized phenomenon of aging, which manifests as a small number of COX-deficient fibers. However, since in some mtDNA diseases, the number of COX-deficient fibers can be quite low, there is clearly a problem with overlap between the changes observed with aging and in those patients with low levels of COX-deficient fibers. Consequently, molecular genetic assays that can discriminate between multiple mtDNA deletions due to aging and those due to true mitochondrial disease are very valuable (Luoma et al., 2005). 9.4.3.4. Biochemical assessment of mitochondrial function Mitochondrial oxidative phosphorylation is an extremely complicated biochemical process and it is not surprising that biochemical assessments are challenging. Measurements of oxidative phosphorylation in different tissues are also important in cases when there is multisystem involvement. Ideally, these studies should be performed in centers that have considerable experience in these assays with established protocols and that offer a complete diagnostic program. The preparation of intact muscle mitochondria offers a wide range of diagnostic testing for mitochondrial biochemical abnormalities (Chretien et al., 1994). Rates of flux, substrate oxidation and ATP production are measured by polarography or using 14C-labelled substrates (Trijbels et al., 1997). However, due to the need to send biopsies to specialist centers, a more practical approach for many laboratories is to use frozen muscle samples. In these samples it is possible to measure the activities of all the respiratory chain complexes independently and expressing them as a ratio to the mitochondrial matrix enzyme citrate synthase or mitochondrial protein. Biochemical assays are more important in the investigation of pediatric cases since many children have
199
recessive mutations in nuclear-encoded structural or ancillary genes that severely compromise enzyme activity. In adults, the biochemical defect may be more subtle, and in some patients with proven mtDNA defects there may be no biochemical abnormality detected. Isolated defects involving one complex may be due to mutations of specific subunits. Multiple enzyme defects involving complexes I, III and IV are sometimes seen in patients harboring single, large-scale mtDNA deletions, mtDNA tRNA mutations or nuclear factors involved in mitochondrial translation (Jacobs and Turnbull, 2005). 9.4.3.5. Molecular genetic studies on muscle The molecular genetic investigation of suspected mitochondrial myopathies is very important since this may well define the mode of inheritance and the possibility of prenatal or preimplantation genetic diagnosis. The ability to give accurate genetic advice is one of the most important contributions clinicians can make in the presence of severe mitochondrial disease within a family since the treatment options are very limited. Pediatric cases are more likely to present with nuclear DNA defects than are adults (Shoubridge, 2001). A clear autosomal inheritance pattern (usually recessive) would support this but is absent in most cases. Those with isolated complex IV deficiency may harbor mutations in genes identified thus far that encode accessory proteins necessary for assembly of the COX holoenzyme complex: SURF1 (Tiranti et al., 1998; Zhu et al., 1998), SCO1 (Valnot et al., 2000a), SCO2 (Jaksch et al., 2000), COX10 (Valnot et al., 2000b) and COX15 (Antonicka et al., 2003) or LRPPRC (Mootha et al., 2003), the protein product of which is required for the translation of mtDNA subunits. Children with isolated complex I deficiency in whom myopathy may be a feature, are more likely to harbor mutations in one of the many nuclear-encoded structural subunits of this enzyme (Triepels et al., 2001), although accumulating data indicate that pathogenic mtDNA mutations are much more frequent in this pediatric population than previously predicted (Chol et al., 2003; Kirby et al., 2000, 2001, 2004, McFarland et al., 2004a). Useful clues to direct the investigation of adults may also be gained from understanding genotype–phenotype relationships for specific mitochondrial mutations and information concerning the inheritance pattern. Patients with histochemical evidence of a mosaic distribution of COX deficiency and autosomal-dominant inheritance should be screened for multiple mtDNA deletions, a disorder of intergenomic communication that is the result of mutations in one of several nuclear genes (Suomalainen and Kaukonen, 2001). Multiple mtDNA deletions may also be inherited in an autosomal-recessive fashion
200
R. W. TAYLOR ET AL.
however, or present with no family history at all (Agostino et al., 2003). Patients with this genotype typically present with CPEO and proximal myopathy, but this may be complicated by cerebellar ataxia or a sensory ataxia due to peripheral neuropathy (Van Goethem et al., 2003b). A clear pattern of maternal transmission would indicate a pathogenic mtDNA point mutation, although mtDNA heteroplasmy and the late clinical onset of many such mutations means that many relatives may report little that is specific to mitochondrial disease and a clear family history is not always apparent. Many reported point mutations, particularly those in the mtDNA cytochrome b gene that cause exercise intolerance, are sporadic in nature (Andreu et al., 1999b). This is also true of patients with CPEO or Kearns–Sayre syndrome (KSS) due to single, large-scale mtDNA deletions (Holt et al., 1988; Moraes et al., 1989) although rare cases of maternal transmission have been reported in this latter group (Bernes et al., 1993; Shanske et al., 2002). In CPEO, mtDNA deletions are only reliably detected in skeletal muscle and investigation of this tissue is essential to confirm the diagnosis. 9.4.3.5.1. mtDNA rearrangement disorders Rearrangements of the mitochondrial genome including single deletions, duplications and multiple mtDNA deletions have classically been detected by Southern blot (Fig. 9.3). Cases of mtDNA depletion, a disorder of mtDNA maintenance due to mutations in one of several nuclear genes, will also be detected if in addition to a mitochondrial probe, the blot is hybridized simultaneously with a probe to detect a nuclear gene (commonly 18S
1
2
3
4
5
6
rRNA; Taanman et al., 1997), although real-time PCR methods are increasingly being used. Pediatric patients may present with a myopathic presentation due to mtDNA depletion due to a mutation in the thymidine kinase 2 gene (Saada et al., 2001). Though the technique of Southern blotting remains the “gold-standard” test and will certainly detect all cases of single, mtDNA deletions, it may miss low levels of multiple mtDNA deletions in patients with only mild weakness (Deschauer et al., 2003). Numerous PCR-based assays now exist for the study of mtDNA deletions with long-range PCR routinely used by many laboratories as their initial screen for the presence of mtDNA rearrangements (Fromenty et al., 1996). Being PCR-based, these assays are very sensitive and as such require care in their interpretation. First, unlike Southern blotting that is quantitative down to its detection threshold of about 5% mutated mtDNA, many of the commercially available enzymes for long-range PCR preferentially amplify smaller templates, making quantification impossible. This means that in patients with single mtDNA deletions, only the rearranged mtDNA molecules are amplified, even in the presence of residual full-length, 16.6 kb (wildtype) mtDNA. Second, the sensitive nature of the amplification process means that the PCR of skeletal muscle DNA from normal, elderly controls often reveals low levels of smaller amplicons, indistinguishable from patients with mitochondrial disease. Similar to the finding of COX-deficient fibers on histochemistry, this is consistent with the presence of age-related, somatic mtDNA deletions (Melov et al., 1995). Long-range PCR techniques using shorter extension times may be more valuable in differentiating the
7
1
3 −9.9 kb
−16.6 kb
A
2
B
Fig. 9.3. Molecular genetic analysis of mtDNA rearrangements. (A) Southern blot, probed with a D-loop probe, of muscle mtDNA linearized with PvuII. Lanes 1 and 2 show control individuals; lanes 3–5 show patients harboring heteroplasmic, single deletions of the mitochondrial genome; lanes 6 and 7 are patients with multiple mtDNA deletion disorders. (B) Long-range PCR of mtDNA across the major arc to investigate possible mtDNA rearrangements. Lane 1: DNA size marker; lane 2: control DNA amplifying 9.9-kb wildtype product; lane 3: patient with multiple mtDNA deletion disorder showing many smaller amplimers in addition to the full-length product.
INVESTIGATION OF METABOLIC MYOPATHIES deletions seen in aging from those observed in patients with multiple mtDNA deletions syndrome (Luoma et al., 2005). Finally, in some cases where the clinical and histochemical findings are suggestive of a multiple mtDNA deletion disorder, the relative amount of deleted mtDNA can be determined in individual COX-deficient and COX-positive muscle fibers by real-time PCR (He et al., 2002). 9.4.3.5.2. Common mtDNA point mutations Because of its association with numerous clinical phenotypes including MELAS, CPEO, diabetes and deafness, the 3243A>G mutation is widely investigated, often by restriction fragment length polymorphism (RFLP) analysis as the A–G transition creates a novel restriction site for the restriction endonuclease HaeIII. Addition of a radioactive or fluorescent dNTP to the last cycle of the PCR permits accurate quantification of mutation load (Moraes et al., 1992), which provides useful information for determining genotype–phenotype correlations and for offering genetic advice. Muscle DNA should be studied as the mutation may be undetectable in blood in some patients (Chinnery et al., 1997), whilst others have reported that it disappears in blood cells over time (Rahman et al., 2001). As mentioned previously, the investigation of this mutation in urinary epithelial cells is particularly valuable if muscle material is not available. In addition to 3243A>G, the 8344A>G tRNALys mutation and the 8993T>G/C and 9176T>G/C mutations can be screened by PCR-based assays. The 8344A>G mutation is commonly found in patients with the MERRF syndrome (Shoffner et al., 1990) but can manifest in other guises including a syndrome of ataxia, myopathy, hearing loss and neuropathy (Austin et al., 1998) and Leigh syndrome (Santorelli et al., 1998). The
201
mutations at 8993 and 9176 in the MTATP6 gene are associated with the NARP (neuropathy, ataxia and retinitis pigmentosa) phenotype and also Leigh syndrome (Holt et al., 1990; Tatuch et al., 1992; Thyagarajan et al., 1995). 9.4.3.5.3. Searching for novel, pathogenic mtDNA mutations The next stage in the investigation of patients who are negative for common mutations often involves the analysis of the entire mitochondrial genome as this is more efficient and cost effective than screening for rarer mutations on an individual basis. By way of illustration, it is well established that >80% cases of MELAS are due to the 3243A>G mutation. However, four other mutations in the same gene [at positions 3252 (Morten et al., 1993), 3256 (Moraes et al., 1993), 3271 (Goto et al., 1991) and 3291 (Goto et al., 1994)], together with others in tRNAPhe (Hanna et al., 1998), tRNAVal (Taylor et al., 1996b), COIII (Manfredi et al., 1995) and ND5 (Corona et al., 2001; Santorelli et al., 1997) have also been described as causes of MELAS. Many laboratories including our own now sequence the entire mitochondrial genome to search for novel mutations (Taylor et al., 2001) or in some cases, even to exclude a mtDNA involvement before investigating candidate nuclear genes. 9.4.3.5.4. Assigning pathogenicity to a mtDNA mutation The advent of rapid, high-throughput, sequencing of mitochondrial genomes for diagnostic and other (e.g., evolutionary biology; Ingman et al., 2000) purposes has highlighted the extensive mtDNA sequence variation within human populations, with distinct clusters of sequence changes forming well-recognized haplogroups (Herrnstadt et al., 2002). Since the majority of mtDNA
Hair
Blood
Muscle
C A C G A C C A A T G A T A C G A A A A A C C A T C G T T
Control
Uncut
Patient tissues
Wild type mtDNA Mutant mtDNA
A
B
Fig. 9.4. For full color figure, see plate section. Mitochondrial DNA sequencing. In patients where a mtDNA point mutation is strongly suspected in the absence of common mutations, whole genome sequencing may be appropriate. (A) Sequence chromatogram from a patient with myopathy harboring the 14709T>C mutation (arrow), a mutation that has been characterized in several families. Whilst the chromatogram appears to show homoplasmic levels of the mutation (affecting all mtDNA copies) in muscle, PCR-RFLP analysis (B) clearly shows heteroplasmy at this site in both muscle and other tissues. Such tests are important to assign pathogenicity to novel mtDNA sequence changes as highlighted in the text.
202
R. W. TAYLOR ET AL.
sequence variants are neutral polymorphisms with no pathogenic significance, careful assessment of newlyidentified mutations must be made to establish a link with human disease (Fig. 9.4). DiMauro and Schon (2001) put forward canonical criteria which they suggest should be met in order to support a pathogenic role for a novel mtDNA mutation. More recently, there has been development of scoring schemes which use available evolutionary, structural and clinical data to evaluate the likely pathogenicity of mutations of the mitochondrial genome (McFarland et al., 2004b; Mitchell et al., 2006).
References Agostino A, Valletta L, Chinnery PF, et al. (2003). Mutations of ANT1, Twinkle, and POLG1 in sporadic progressive external ophthalmoplegia (PEO). Neurology 60: 1354–1356. Andreu AL, Tanji K, Bruno C, et al. (1999a). Exercise intolerance due to a nonsense mutation in the mtDNA ND4 gene. Ann Neurol 45: 820–823. Andreu AL, Hanna MG, Reichmann H, et al. (1999b). Exercise intolerance due to mutations in the cytochrome b gene of mitochondrial DNA. N Engl J Med 341: 1037–1044. Antonicka H, Mattman A, Carlson CG, et al. (2003). Mutations in COX15 produce a defect in the mitochondrial heme biosynthetic pathway, causing early-onset fatal hypertrophic cardiomyopathy. Am J Hum Genet 72: 101–114. Austin SA, Vriesendorp FJ, Thandroyen FT, et al. (1998). Expanding the phenotype of the 8344 transfer RNAlysine mitochondrial DNA mutation. Neurology 51: 1447–1450. Bernes SM, Bacino C, Prezant TR, et al. (1993). Identical mitochondrial DNA deletion in mother with progressive external ophthalmoplegia and son with Pearson marrowpancreas syndrome. J Pediatr 123: 598–602. Bruno C, van Diggelen OP, Cassandrini D, et al. (2004). Clinical and genetic heterogeneity of branching enzyme deficiency (glycogenosis type IV). Neurology 63: 1053–1058. Burwinkel B, Hu B, Schroers A, et al. (2003). Muscle glycogenosis with low phosphorylase kinase activity: mutations in PHKA1, PHKG1 or six other candidate genes explain only a minority of cases. Eur J Hum Genet 11: 516–526. Chen JT, Taivassalo T, Argov Z, et al. (2001). Modeling in vivo recovery of intracellular pH in muscle to provide a novel index of proton handling: application to the diagnosis of mitochondrial myopathy. Magn Reson Med 46: 870–878. Chinnery PF, Reading PJ, Walls TJ, et al. (1997). Recurrent strokes in a 34 year old man. Lancet 350: 560. Chol M, Lebon S, Benit P, et al. (2003). The mitochondrial DNA G13513A MELAS mutation in the NADH dehydrogenase 5 gene is a frequent cause of Leigh-like syndrome with isolated complex I deficiency. J Med Genet 40: 188–191. Chretien D, Rustin P, Bourgeron T, et al. (1994). Reference charts for respiratory chain activities in human tissues. Clin Chim Acta 228: 53–70. Coleman RA, Stajich JM, Pact VW, et al. (1986). The ischemic exercise test in normal adults and in patients with weakness and cramps. Muscle Nerve 9: 216–221.
Comi GP, Fortunato F, Lucchiari S, et al. (2001). Betaenolase deficiency, a new metabolic myopathy of distal glycolysis. Ann Neurol 50: 202–207. Corona P, Antozzi C, Carrara F, et al. (2001). A novel mtDNA mutation in the ND5 subunit of complex I in two MELAS patients. Ann Neurol 49: 106–110. Costa CG, Guerand WS, Struys EA, et al. (2000). Quantitative analysis of urinary acylglycines for the diagnosis of beta-oxidation defects using GC-NCI-MS. J Pharm Biomed Anal 21: 1215–1224. Deschauer M, Kiefer R, Blakely EL, et al. (2003). A novel Twinkle gene mutation in autosomal dominant progressive external ophthalmoplegia. Neuromuscul Disord 13: 568–572. DiMauro S, DiMauro PM (1973). Muscle carnitine palmityltransferase deficiency and myoglobinuria. Science 182: 929–931. DiMauro S, Schon EA (2001). Mitochondrial DNA mutations in human disease. Am J Med Genet 106: 18–26. Fromenty B, Manfredi G, Sadlock J, et al. (1996). Efficient and specific amplification of identified partial duplications of human mitochondrial DNA by long PCR. Biochim Biophys Acta 1308: 222–230. Goto Y, Nonaka I, Horai S (1991). A new mtDNA mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). Biochim Biophys Acta 1097: 238–240. Goto Y, Tsugane K, Tanabe Y, et al. (1994). A new point mutation at nucleotide pair 3291 of the mitochondrial tRNA(Leu(UUR)) gene in a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Biochem Biophys Res Commun 202: 1624–1630. Hanna MG, Nelson IP, Morgan-Hughes JA, et al. (1998). MELAS: a new disease associated mitochondrial DNA mutation and evidence for further genetic heterogeneity. J Neurol Neurosurg Psychiatry 65: 512–517. He L, Chinnery PF, Durham SE, et al. (2002). Detection and quantification of mitochondrial DNA deletions in individual cells by real-time PCR. Nucleic Acids Res 30: e68. Hermans MM, van Leenen D, Kroos MA, et al. (2004). Twentytwo novel mutations in the lysosomal alpha-glucosidase gene (GAA) underscore the genotype–phenotype correlation in glycogen storage disease type II. Hum Mutat 23: 47–56. Herrnstadt C, Elson JL, Fahy E, et al. (2002). Reducedmedian-network analysis of complete mitochondrial DNA coding-region sequences for the major African, Asian, and European haplogroups. Am J Hum Genet 70: 1152–1171. Holt IJ, Cooper JM, Morgan-Hughes JA, et al. (1988). Deletions of muscle mitochondrial DNA. Lancet 1: 1462. Holt IJ, Harding AE, Petty RK, et al. (1990). A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. Am J Hum Genet 46: 428–433. Ijlst L, Ruiter JP, Vreijling J, et al. (1996). Long-chain 3hydroxyacyl-CoA dehydrogenase deficiency: a new method to identify the G1528C mutation in genomic DNA showing its high frequency (approximately 90%) and identification of a new mutation (T2198C). J Inherit Metab Dis 19: 165–168.
INVESTIGATION OF METABOLIC MYOPATHIES Ingman M, Kaessmann H, Paabo S, et al. (2000). Mitochondrial genome variation and the origin of modern humans. Nature 408: 708–713. Jacobs HT, Turnbull DM (2005). Nuclear genes and mitochondrial translation: a new class of genetic disease. Trends Genet 21: 312–314. Jaksch M, Ogilvie I, Yao J, et al. (2000). Mutations in SCO2 are associated with a distinct form of hypertrophic cardiomyopathy and cytochrome c oxidase deficiency. Hum Mol Genet 9: 795–801. Kazemi-Esfarjani P, Skomorowska E, Jensen TD, et al. (2002). A nonischemic forearm exercise test for McArdle disease. Ann Neurol 52: 153–159. Kirby DM, Kahler SG, Freckmann ML, et al. (2000). Leigh disease caused by the mitochondrial DNA G14459A mutation in unrelated families. Ann Neurol 48: 102–104. Kirby DM, McFarland R, Ohtake A, et al. (2001). Mutations of the mitochondrial ND1 gene as a cause of MELAS. J Med Genet 41: 784–789. Kirby DM, Boneh A, Chow CW, et al. (2003). Low mutant load of mitochondrial DNA G13513A mutation can cause Leigh’s disease. Ann Neurol 54: 473–478. Lindner A, Reichert N, Eichhorn M, et al. (2001). Acute compartment syndrome after forearm ischemic work test in a patient with McArdle’s disease. Neurology 56: 1779–1780. Lucchiari S, Donati MA, Parini R, et al. (2002). Molecular characterisation of GSD III subjects and identification of six novel mutations in AGL. Hum Mutat 20: 480. Luoma PT, Luo N, Loscher WN, et al. (2005). Functional defects due to spacer-region mutations of human mitochondrial DNA polymerase in a family with an ataxiamyopathy syndrome. Hum Mol Genet 14: 1907–1920. Manfredi G, Schon EA, Moraes CT, et al. (1995). A new mutation associated with MELAS is located in a mitochondrial DNA polypeptide-coding gene. Neuromuscul Disord 5: 391–398. Martin MA, Rubio JC, Buchbinder J, et al. (2001). Molecular heterogeneity of myophosphorylase deficiency (McArdle’s disease): a genotype–phenotype correlation study. Ann Neurol 50: 574–581. McDonnell MT, Schaefer AM, Blakely EL, et al. (2004). Noninvasive diagnosis of the 3243A>G mitochondrial DNA mutation using urinary epithelial cells. Eur J Hum Genet 12: 778–781. McFarland R, Clark KM, Morris AA, et al. (2002). Multiple neonatal deaths due to a homoplasmic mitochondrial DNA mutation. Nat Genet 30: 145–146. McFarland R, Kirby DM, Fowler KJ, et al. (2004a). De novo mutations in the mitochondrial ND3 gene as a cause of infantile mitochondrial encephalopathy and complex I deficiency. Ann Neurol 55: 58–64. McFarland R, Elson JL, Taylor RW, et al. (2004b). Assigning pathogenicity to mitochondrial tRNA mutations: when “definitely maybe” is not good enough. Trends Genet 20: 591–596. Meinck HM, Goebel HH, Rumpf KW, et al. (1982). The forearm ischaemic work test — hazardous to McArdle patients? J Neurol Neurosurg Psychiatry 45: 1144–1146.
203
Melov S, Shoffner JM, Kaufman A, et al. (1995). Marked increase in the number and variety of mitochondrial DNA rearrangements in aging human skeletal muscle. Nucleic Acids Res 23: 4122–4126 [Published erratum appears in Nucleic Acids Res 23: 4938]. Mitchell AL, Elson JL, Howell N, et al. (2006). Sequence variation in mitochondrial complex I genes: mutation or polymorphism? J Med Genet 43: 175–179. Mootha VK, Lepage P, Miller K, et al. (2003). Identification of a gene causing human cytochrome c oxidase deficiency by integrative genomics. Proc Natl Acad Sci U S A 100: 605–610. Moraes CT, DiMauro S, Zeviani M, et al. (1989). Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns–Sayre syndrome. N Engl J Med 320: 1293–1299. Moraes CT, Ricci E, Bonilla E, et al. (1992). The mitochondrial tRNA(Leu(UUR)) mutation in mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS): genetic, biochemical, and morphological correlations in skeletal muscle. Am J Hum Genet 50: 934–949. Moraes CT, Ciacci F, Bonilla E, et al. (1993). Two novel pathogenic mitochondrial DNA mutations affecting organelle number and protein synthesis. Is the tRNA(Leu (UUR)) gene an etiologic hot spot? J Clin Invest 92: 2906–2915. Morten KJ, Cooper JM, Brown GK, et al. (1993). A new point mutation associated with mitochondrial encephalomyopathy. Hum Mol Genet 2: 2081–2087. Pollitt RJ (2001). Newborn mass screening versus selective investigation: benefits and costs. J Inherit Metab Dis 24: 299–302. Raben N, Sherman JB (1995). Mutations in muscle phosphofructokinase gene. Hum Mutat 6: 1–6. Rahman S, Poulton J, Marchington D, et al. (2001). Decrease of 3243 A->G mtDNA mutation from blood in MELAS syndrome: a longitudinal study. Am J Hum Genet 68: 238–240. Rinaldo P, Matern D, Bennett MJ (2002). Fatty acid oxidation disorders. Ann Rev Physiol 64: 477–502. Rumpf KW, Wagner H, Kaiser H, et al. (1981). Increased ammonia production during forearm ischemic work test in McArdle’s disease. Klin Wochenschr 59: 1319–1320. Saada A, Shaag A, Mandel H, et al. (2001). Myutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy. Nat Genet 29: 342. Santorelli FM, Tanji K, Kulikova R, et al. (1997). Identification of a novel mutation in the mtDNA ND5 gene associated with MELAS. Biochem Biophys Res Commun 238: 326–328. Santorelli FM, Tanji K, Shanske S, et al. (1998). The mitochondrial DNA A8344G mutation in Leigh Syndrome revealed by analysis in paraffin-embedded sections: revisiting the past. Ann Neurol 44: 962–964. Schaefer AM, Blakely EL, Griffiths PG, et al. (2005). Ophthalmoplegia due to mitochondrial DNA disease: the need for genetic diagnosis. Muscle Nerve 32: 104–107. Sciacco M, Bonilla E, Schon EA, et al. (1994). Distribution of wild-type and common deletion forms of mtDNA in normal
204
R. W. TAYLOR ET AL.
and respiration-deficient muscle fibers from patients with mitochondrial myopathy. Hum Mol Genet 3: 13–19. Shanske S, Tang Y, Hirano M, et al. (2002). Identical mitochondrial DNA deletion in a woman with ocular myopathy and in her son with Pearson syndrome. Am J Hum Genet 71: 679–683. Shanske S, Pancrudo J, Kaufmann P, et al. (2004). Varying loads of the mitochondrial DNA A3243G mutation in different tissues: implications for diagnosis. Am J Med Genet 130A: 134–137. Shoffner JM, Lott MT, Lezza AM, et al. (1990). Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNA(Lys) mutation. Cell 61: 931–937. Shoubridge EA (2001). Nuclear genetic defects of oxidative phosphorylation. Hum Mol Genet 10: 2277–2284. Sinkeler SP, Wevers RA, Joosten EM, et al. (1986). Improvement of screening in exertional myalgia with a standardized ischemic forearm test. Muscle Nerve 9: 731–737. Suomalainen A, Kaukonen J (2001). Diseases caused by nuclear genes affecting mtDNA stability. Am J Med Genet 106: 53–61. Taanman JW, Bodnar AG, Cooper JM, et al. (1997). Molecular mechanisms in mitochondrial DNA depletion syndrome. Hum Mol Genet 6: 935–942. Taivassalo T, Abbott A, Wyrick P, et al. (2002). Venous oxygen levels during aerobic forearm exercise: an index of impaired oxidative metabolism in mitochondrial myopathy. Ann Neurol 51: 38–44. Taroni F, Verderio E, Dworzak F, et al. (1993). Identification of a common mutation in the carnitine palmitoyltransferase II gene in familial recurrent myoglobinuria patients. Nat Genet 4: 314–320. Tatuch Y, Christodoulou J, Feigenbaum A, et al. (1992). Heteroplasmic mtDNA mutation (T-G) at 8993 can cause Leigh disease when the percentage of abnormal mtDNA is high. Am J Hum Genet 50: 852–858. Taylor RW, Birch-Machin MA, Schaefer J, et al. (1996a). Deficiency of complex II of the mitochondrial respiratory chain in late-onset optic atrophy and ataxia. Ann Neurol 39: 224–232. Taylor RW, Chinnery PF, Haldane F, et al. (1996b). MELAS associated with a mutation in the valine transfer RNA gene of mitochondrial DNA. Ann Neurol 40: 459–462. Taylor RW, Taylor GA, Durham SE, et al. (2001). The determination of complete human mitochondrial DNA sequences in single cells: implications for the study of somatic mitochondrial DNA point mutations. Nucleic Acids Res 29: E74.
Taylor RW, Turnbull DM (2005). Mitochondrial DNA mutations in human disease. Nat Rev Genet 6: 389–402. Thyagarajan D, Shanske S, Vazquez-Memije M, et al. (1995). A novel mitochondrial ATPase 6 point mutation in familial bilateral striatal necrosis. Ann Neurol 38: 468–472. Tiranti V, Hoertnagel K, Carrozzo R, et al. (1998). Mutations of SURF-1 in Leigh disease associated with cytochrome c oxidase deficiency. Am J Hum Genet 63: 1609–1621. Triepels RH, van den Heuvel L, Trijbels F, et al. (2001). Respiratory chain complex I deficiency. Am J Med Genet (Semin Med Genet) 106: 37–45. Trijbels FJ, Ruitenbeek W, Huizing M, et al. (1997). Defects in the mitochondrial energy metabolism outside the respiratory chain and the pyruvate dehydrogenase complex. Mol Cell Biochem 174: 243–247. Tsujino S, Shanske S, Nonaka I, et al. (1995a). The molecular genetic basis of myophosphorylase deficiency (McArdle’s disease). Muscle Nerve 3: S23–S27. Tsujino S, Shanske S, DiMauro S (1995b). Molecular genetic heterogeneity of phosphoglycerate kinase (PGK) deficiency. Muscle Nerve 3: S45–S49. Valnot I, Osmond S, Gigarel N, et al. (2000a). Mutations of the SCO1 gene in mitochondrial cytochrome c oxidase deficiency with neonatal-onset hepatic failure and encephalopathy. Am J Hum Genet 67: 1104–1109. Valnot I, von Kleist-Retzow JC, Barrientos A, et al. (2000b). A mutation in the human heme A:farnesyltransferase gene (COX10) causes cytochrome c oxidase deficiency. Hum Mol Genet 9: 1245–1249. Van Goethem G, Schwartz M, Lofgren A, et al. (2003a). Novel POLG mutations in progressive external ophthalmoplegia mimicking mitochondrial neurogastrointestinal encephalomyopathy. Eur J Hum Genet 11: 547–549. Van Goethem G, Martin JJ, Dermaut B, et al. (2003b). Recessive POLG mutations presenting with sensory and ataxic neuropathy in compound heterozygote patients with progressive external ophthalmoplegia. Neuromuscul Disord 13: 133–142. Vissing J, Haller RG (2003). A diagnostic cycle test for McArdle’s disease. Ann Neurol 54: 539–542. Yokota I, Indo Y, Coates PM, et al. (1990). Molecular basis of medium chain acyl-coenzyme A dehydrogenase deficiency. An A to G transition at position 985 that causes a lysine304 to glutamate substitution in the mature protein is the single prevalent mutation. J Clin Invest 86: 1000–1003. Zhu Z, Yao J, Johns T, et al. (1998). SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome. Nat Genet 20: 337–343.
Handbook of Clinical Neurology, Vol. 86 (3rd series) Myopathies F. L. Mastaglia, D. Hilton-Jones, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 10
Lysosomal myopathies ICHIZO NISHINO* National Center of Neurology and Psychiatry, Tokyo, Japan
10.1. Autophagy and the lysosomal system in muscle Autophagy is an intracellular bulk degradation process which is used by all cells to eliminate waste materials (Albert et al., 2001). This ubiquitous process begins with the sequestration of part of the cytoplasm by an isolation membrane, and often includes organelles such as mitochondria. For this mechanism, a vesicular structure of unknown origin extends and surrounds the cytoplasm to be degraded. The resultant sequestered cytoplasm is thus naturally surrounded by two isolation membranes. This sequestering vesicular structure is called an autophagosome, which by itself does not have a digestive capacity. Eventually the outer membrane of the autophagosome fuses with a lysosome or a late endosome, which delivers hydrolytic enzymes to digest the sequestered cytoplasm and the inner membrane of the autophagosome; from this fusion, an autophagic structure is derived and is called an autolysosome. Overall, this dynamic process is highly regulated by a number of molecules encoded by ATG genes. Autophagy is essential for cells to survive and it is known that yeasts deficient in autophagy rapidly die under nutrition-poor conditions. In the mouse, autophagy is critical for survival in the early neonatal starvation period. In mammals, autophagy plays an important role for the turnover of cellular components, particularly in response to starvation or glucagons. In normal muscle, however, autolysosomes or autophagosomes are morphologically unremarkable. Nevertheless, autophagy is considered to be essential for myocytes and the lysosomal system becomes prominent in certain muscle diseases. In muscle pathology, lysosomal abnormalities are seen in three types of vacuoles: (1) rimmed vacuoles; (2) autophagic vacuoles, which are usually large and
contain glycogen, seen specifically in acid maltase deficiency and (3) autophagic vacuoles with unique sarcolemmal features with acetylcholinesterase activity (AVSF), which are seen in Danon disease and other related myopathies. The most frequently encountered are rimmed vacuoles; however, these are most likely a secondarily induced lysosomal abnormality, as it will be discussed later. So far, only two primary lysosomal myopathies have been recognized: acid maltase deficiency and Danon disease. This review defines the lysosomal myopathies as hereditary myopathies characterized morphologically by the presence of autophagic vacuoles and classifies them into three groups: acid maltase deficiency, rimmed vacuolar myopathies and myopathies characterized by the presence of AVSF including Danon disease. Since acid maltase deficiency and the rimmed vacuolar myopathies are discussed in depth in other chapters, they will be described only briefly in this chapter and I will focus on details of AVSF myopathies.
10.2. Rimmed vacuolar myopathies Rimmed vacuoles are small spaces lined by many red granules (hence the term, “rim”) on modified Gomori trichrome staining. These vacuoles, however, are not true holes in the muscle fiber but are rather artifacts produced during the staining procedure. Ultrastructurally, rimmed vacuoles are clusters of autophagic vacuoles and myeloid bodies. These autophagic vacuoles probably detach easily from glass slides and move to the nearby myofibrils during the staining procedure. The regions where autophagic vacuoles had been clustered consequently become empty (vacuoles) and the surrounding areas are decorated by granular autophagic vacuoles (rims). This is one of the
*Correspondence to: Ichizo Nishino, M.D., Ph.D., Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawahigashi-cho, Kodaira, Tokyo 187-8502, Japan. E-mail:
[email protected], Tel: þ81-42-346-1712, Fax: þ81-42-346-1742.
206
I. NISHINO
most frequently encountered lysosomal abnormalities in muscle pathology. There are a number of hereditary muscle diseases that are characterized pathologically by the presence of rimmed vacuoles (Table 10.1), including distal myopathy with rimmed vacuoles (DMRV) and hereditary inclusion body myopathy (HIBM), which are now known to be the same disease (Nishino et al., 2002). Interestingly, none of the genes responsible for the diseases in this category encode lysosomal proteins. For example, the causative gene for DMRV/HIBM encodes a cytoplasmicallylocated enzymatic protein, UDP-GlcNac 2-epimerase/ ManNAc kinase that catalyzes the rate-limiting and succeeding steps in the sialic acid biosynthetic pathway (Eisenberg et al., 2001). Therefore, in this disease, the primary molecular defect resides outside of the lysosome, indicating that rimmed vacuoles are secondarily activated lysosomes and autophagic vacuoles. Most likely, mutations causing DMRV/HIBM and other diseases in this category result in the production of abnormal proteins or other substances that are normally degraded. One such substance is amyloid, which has been shown to be deposited in rimmed vacuolar myopathies including HIBM and sporadic inclusion body myositis. In fact, the overexpression of bAPP has been shown to induce inclusion body myositis-like phenotype both in vitro (McFerrin et al., 1998) and in vivo (Sugarman et al., 2002) although a lysosomal abnormality has not been specifically documented. The autophagic process is probably secondarily activated to degrade the abnormal protein. In support of this notion, other degradative systems, such as the ubiquitinproteasomal and even the apoptotic system are also commonly activated in many of the diseases in this category, indicating that the lysosomal abnormality is not the primary phenomenon. Therefore, all rimmed
vacuolar myopathies are plausibly secondary lysosomal myopathies.
10.3. Myopathies characterized by autophagic vacuoles with unique sarcolemmal features with acetylcholinesterase activity (AVSF) Autophagic vacuoles with unique sarcolemmal features with acetylcholinesterase activity in their vacuolar membranes (AVSF) delineate a group of at least five clinically different myopathies, including Danon disease and X-linked myopathy with excessive autophagy (Table 10.2; Sugie et al., 2005). At the time of writing this chapter, the causative gene is known only in Danon disease. Although we still do not know the function of the defective molecules in the remaining diseases, it is probably reasonable to hypothesize that these molecules may involve a lysosomal protein as in Danon disease or may have a close functional association with lysosomes as their pathological features are quite similar. AVSF express a virtually full set of sarcolemmal proteins, except for collagens IV and VI which are only minimally expressed, and have acetylcholinesterase activity on their membranes but lack acetylcholine receptors (Sugie et al., 2005). By electron microscopy, the vacuolar membranes have basal lamina on the luminal side of the membrane, confirming that the vacuolar membranes have sarcolemmal features. The acetylcholinesterase activity in the vacuolar membranes is useful in distinguishing AVSF myopathies from other lysosomal myopathies. In other lysosomal myopathies, including acid maltase deficiency and inclusion body myositis, intracytoplamic vacuoles that also express a range of sarcolemmal proteins in their membranes may occasionally be seen. However, acetylcholinesterase activity is not observed in such diseases.
Table 10.1 Causative genes for rimmed vacuolar myopathies Disease Hereditary inclusion body myopathy Distal myopathy with rimmed vacuoles LGMD2Gc Inclusion body myopathy 3 LGMD1A Oculopharyngeal muscular dystrophy Tibial muscular dystrophy (Udd myopathy) IBMPFD a
Inheritance a
AR AR AR ADd AD AD AD AD
AR: autosomal recessive; GNE: UDP-N-acetlyglucosamine 2-epimerase/N-acetylmannosamine kinase; c LGMD: limb-girdle muscular dystrophy; d AD: autosomal dominant. b
Locus
Gene product
9p1-q1 9p1-q1 17q12 17p13.1 5q31 14q11.2-q13 2q24.3 9p13-p12
GNEb GNE Telethonin Myosin heavy chain IIa Myotilin Poly (A) binding protein 2 Titin/connectin Valosin-containing protein
LYSOSOMAL MYOPATHIES Table 10.2
207
10.3.1. Danon disease
Autophagic vacuoles with unique sarcolemmal features (AVSF) myopathies
Disease
Inheritance
Locus
Gene product
Danon disease X-linked myopathy with excessive autophagy Infantile AVMc Adult-onset AVM with multiorgan involvement X-linked congenital AVM
XD?a XRb
Xq24 Xq28
LAMP-2 ?
? ?
? ?
? ?
XR
Xq28?
?
a
XD: X-linked dominant; XR: X-linked recessive; c AVM: autophagic vacuolar myopathy. b
In the muscle from AVSF myopathies such as Danon disease, at the light microscopic level, the autophagic vacuoles appear to be accumulations of lysosomes since they have acid phosphatase activity and express various lysosomal structural proteins including lysosomeassociated membrane protein-2 (LAMP-2) and lysosomal integral membrane protein-I (LIMP-1). By electron microscopy, these vacuoles have been shown to consist of clusters of autophagic vacuoles as indicated by the presence of various inclusions and cytoplasmic debris inside the vacuoles. These findings indicate that these autophagic vacuoles are autolysosomes. A number, but not all, of these autolysosomes are surrounded by membranes with sarcolemmal proteins, acetylcholinesterase activity and basal lamina. In Danon disease, the number of fibers with AVSF increase linearly with age while the fibers with autolysosomal accumulations decreased slightly, suggesting that AVSF are produced secondarily in response to autolysosomes. The mechanism for the development of AVSF is not known. One hypothesis is that the vacuolar membrane with basal lamina might be produced around clusters of autolysosomes. The membranes surrounding the autophagic vacuoles might have originated from the lysosomal membrane or the isolation membrane that elongates and develops into the membrane of the autophagosome (Mizushima et al., 2001), or is formed in situ and entirely de novo. The fact that most of the AVSF form enclosed spaces and that collagens IV and VI, which are believed to be mainly produced by the fibroblasts in the interstitium, are only minimally expressed in the vacuolar membranes may support the latter possibility although further studies are still necessary.
Danon disease, an X-linked vacuolar cardiomyopathy and skeletal myopathy, was originally described as “lysosomal glycogen storage disease with normal acid maltase” by Danon et al in 1981 because the patients had a disease clinicopathologically similar to acid maltase deficiency but had normal enzymatic activity (Danon et al., 1981). However, glycogen is not always increased and the vacuoles are much smaller than those observed in typical childhood-onset acid maltase deficiency (Fig. 10.1). In addition, the primary defect resides in lysosome-associated membrane protein2 (LAMP-2), a lysosomal structural protein rather than a glycolytic enzyme (Nishino et al., 2000). Therefore, Danon disease should not be considered a lysosomal glycogen storage disease. Danon disease is characterized clinically by the triad of hypertrophic cardiomyopathy, muscle weakness and mental retardation. All known probands are male. There are, however, patients who are females and they do become symptomatic, also developing cardiomyopathy but milder in nature and with later onset; the disease is therefore transmitted in an X-linked dominant mode of inheritance. The causative gene for Danon disease, lamp-2, is located on chromosome Xq24. Patients are born after normal pregnancies and deliveries. In a study of 20 male and 18 female patients, the age at onset ranged from 10 months to 19 years in males and from 12 to 53 years in females (Sugie et al., 2002). The actual onset could be earlier but has remained undetected because of the insidious nature and slow progression of the disease. All patients develop cardiomyopathy, which is the most severe and life-threatening manifestation. In male patients, cardiac symptoms, such as exertional dyspnea, begin during their teenage years. Hypertrophic cardiomyopathy and cardiac arrhythmias are common clinical signs. In a study of 38 patients with genetically confirmed Danon disease, age at death was 19 6 years for males and 40 7 years for females, clearly reflecting the milder phenotype in female patients (Sugie et al., 2002). Skeletal myopathy is usually mild and is evident in most male patients (90%), but is present in only one-third of female patients. Weakness and atrophy predominantly affect neck and shoulder-girdle muscles, but distal muscles can also be involved. All male patients show elevation in serum creatine kinase levels, even in those without apparent muscle symptoms. In contrast, serum creatine kinase is elevated in only 63% of female patients. Mental retardation is usually mild and is present in 70% of male patients. In our series, consisting of 18 individuals, there has been only one female patient with mental retardation (1/18, 6%). Brain magnetic resonance
208
I. NISHINO
Fig. 10.1. Muscle pathology of Danon disease. (A) Hematoxylin and eosin staining. Autophagic vacuoles are so tiny that they look more like basophilic granules. (B) Histochemistry for acid phosphatase. Autophagic vacuoles have mildly increased acid phosphatase activities. (C) Histochemistry for acetylcholinesterase. Some autophagic vacuoles have acetylcholinesterase activity in the vacuolar membranes (AVSF). (D) Periodic acid Schiff staining. Glycogen is mildly increased in the vacuoles.
imaging (MRI) of these patients is usually normal. In two autopsy cases, we found vacuolar changes in the neurones of the red nucleus; however, this abnormality does not directly account for the mental retardation. Muscle biopsies show many scattered intracytoplasmic vacuoles, which, on hematoxylin and eosin staining, often look like tiny basophilic granules. In addition, mild to moderate fiber size variation is observed (Fig. 10.1). Usually, no necrotic or regenerating fibers are seen. Interestingly, the vacuolar membranes show activity for acetylcholinesterase and non-specific esterase (Murakami et al., 1995). Normally, acetylcholinesterase is only present in specialized sarcolemma at the neuromuscular junction called junctional folds. In the vacuolar membranes, where acetylcholine receptors are usually not evident, immunoreactivity to acetylcholinesterase conclusively indicates that these membranes have features of sarcolemma. The sarcolemmal features of the vacuolar
membranes have been confirmed by immunohistochemical study for other sarcolemma-specific proteins, including dystrophin, sarcoglycans, dystroglycans, and laminin (Muntoni et al., 1994; Murakami et al., 1995). Autophagic vacuoles with these unique sarcolemmal features are now labeled as AVSF (Sugie et al., 2005). By electron microscopy, the intracytoplasmic vacuoles are seen typically to contain myelin figures, electron-dense bodies, and various cytoplasmic debris; these findings thereby substantiate the fact that they are autophagic vacuoles. Interestingly, basal lamina is sometimes seen along the inner surface of autophagic vacuoles, providing further evidence that the vacuolar membranes have features of sarcolemma (Fig. 10.2). Infrequently the sarcolemma and vacuolar membranes appear to be connected, giving an appearance similar to fiber splitting. By immunohistochemical and western blot analyses, LAMP-2 protein is absent in skeletal muscles regardless
LYSOSOMAL MYOPATHIES
Fig. 10.2. Electron microscopic findings in Danon disease. An autophagic vacuole contains various cytoplasmic debris and dense bodies. Sometimes, basal lamina is seen along the luminal side of the vacuolar membrane, confirming its sarcolemmal nature (arrowheads).
of the specific LAMP-2 gene mutation. Western blot analysis of the cardiac muscle in one patient also showed a complete absence of LAMP-2 protein. In contrast, other lysosomal membrane proteins, such as lysosomal integral membrane protein-I, are associated with the autophagic vacuoles in Danon disease. LAMP-2 is a type 1 membrane protein with a large luminal domain connected to a transmembrane region and a short cytoplasmic tail. The luminal domain is heavily glycosylated; most of the potential N-linked glycosylation sites are utilized, yielding a molecular mass of 90–120 kDa for the approximately 40-kDa core protein. LAMP-2 is abundantly expressed and is thought to coat the inner surface of the lysosomal membrane together with its autosomal paralog, LAMP-1. Therefore, LAMPs are thought to protect the lysosomal membrane and thus also the cytoplasm from proteolytic enzymes within the lysosomes. The cytoplasmic tail of LAMP-2 is short, consisting of only 11 amino acids, but has a well-conserved tyrosine residue which is thought to provide a crucial signal for trafficking of LAMP-2 molecules to lysosomes. Moreover, the cytoplasmic tail of LAMP-2 is thought to function as a receptor for the uptake of certain proteins into lysosomes for degradation in association with the 73-kDa heat shock cognate protein. The expression of LAMP-2 is increased in a variety of situations while LAMP-1 seems to be expressed constitutively; therefore, expression of LAMP-2 is likely to be specifically regulated (Kannan et al., 1995). Interestingly, a small fraction (2–3%) of LAMP-2 is present in the plasma membrane and its expression in the cell surface is increased in certain situations, including malignancy and scleroderma. Furthermore, LAMP-1 has recently
209
been shown to have a role in the fusion of lysosomal membrane and plasma membrane (Reddy et al., 2001). Most likely LAMP-2 also has a role in the fusion of the membranes and this may be related to the development of the unusual autophagic vacuoles with sarcolemma features. The LAMP-2 gene is located on Xq24, while the gene for LAMP-1 is on 13q34. The lamp-2 open reading frame consists of 1233 nucleotides and encodes 410 amino acids. Exons 1 through 8 and part of exon 9 encode a luminal domain, while the remainder of exon 9 encodes both a transmembrane domain and a cytoplasmic domain. Human exon 9 exists in two forms, 9A and 9B, that are alternatively spliced and produce two isoforms, LAMP-2A and LAMP-2B, respectively. LAMP-2A is expressed rather ubiquitously whereas LAMP-2B is expressed specifically in heart and skeletal muscles. Most of the mutations identified so far are stop-codon or outof-frame mutations that are predicted to truncate the protein, resulting in loss of the transmembrane and cytoplasmic domains. Therefore, the mutated products cannot function as a lysosomal membrane protein. Patients with genetically-confirmed Danon disease have been ethnically diverse, suggesting that this disorder can be seen in any ethnic group. This is a rare disease but most likely many cases have been overlooked because vacuolar changes can be subtle especially on hematoxylin and eosin stain. In fact, many hereditary cardiomyopathy cases have been found to be due to Danon disease (Arad et al., 2005; Yang et al., 2005). Since muscle pathology provides a diagnostic clue and skeletal muscle biopsy is much safer than cardiac biopsy it should be considered in male patients with cardiomyopathy and elevated creatine kinase level. 10.3.2. X-linked myopathy with excessive autophagy (XMEA) In 1988, Kalimo and colleagues reported a new type of autophagic vacuolar myopathy in a Finnish family (Kalimo et al., 1988). The disease is transmitted in an X-linked recessive manner. Clinically, this condition is characterized by slowly progressive muscle weakness and atrophy that spares cardiac and respiratory muscles. Muscle biopsy shows many tiny vacuoles; interestingly, the vacuolar membranes also have features of plasma membrane as in Danon disease. Autophagic vacuoles are seen in the cytoplasm. Because the muscle pathology resembles that of Danon disease, the two diseases are therefore likely to share similar molecular pathomechanisms. The characteristic pathological findings in XMEA are depositions of complement C5b-9 over the surface of muscle fibers and multilayered basal lamina along the sarcolemma, in addition to AVSF. These findings are
210
I. NISHINO
not seen in Danon disease. Furthermore, the presence of LAMP-2 in XMEA muscle clearly demonstrates that XMEA is distinct from Danon disease. In fact, the XMEA locus has been mapped to Xq28 (Minassian et al., 2002), while the gene encoding LAMP-2 is present on Xq24 (Nishino et al., 2000). This disease is discussed in another chapter in detail. 10.3.3. Infantile autophagic vacuolar myopathy There were two well-documented reports of infants with autophagic vacuolar myopathy described as having the infantile form of “lysosomal glycogen storage disease with normal acid maltase” (Yamamoto et al., 2001). Both patients presented with muscle weakness and hypotonia at birth and died early in life. Muscle biopsies showed extensive vacuolar changes with increased glycogen,
but acid maltase activity was normal in both patients. The vacuolar membranes had acetylcholinesterase activity in addition to the expression of various sarcolemmal proteins, demonstrating the features of AVSF (Fig. 10.3). This infantile disease is distinct from Danon disease because LAMP-2 protein is not deficient in the skeletal muscle and sequences of the LAMP-2 gene are normal (Yamamoto et al., 2001). Interestingly, as in XMEA muscle, complement C5b-9 stained the sarcolemma in one infantile patient. On electron microscopy, many vacuoles containing membrane-bounded glycogen particles, free glycogen particles and cytoplasmic degradation products were scattered in the cytoplasm. In addition, duplication of basal lamina into two layers was observed along portions of the sarcolemma. Multi-layered basal lamina was also seen in some fibers. Material apparently exocytosed from vacuoles accumulated under and between
Fig. 10.3. Muscle pathology of infantile autophagic vacuolar myopathy. (A) Hematoxylin and eosin staining. Autophagic vacuoles are so tiny that they look more like basophilic granules as in Danon disease. (B) Histochemistry for acid phosphatase. Autophagic vacuoles have much higher acid phosphatase activity than in Danon disease. (C) Histochemistry for acetylcholinesterase. Some autophagic vacuoles have acetylcholinesterase activity in the vacuolar membranes (AVSF). (D) Periodic acid Schiff staining. Glycogen is mildly increased in the vacuoles.
LYSOSOMAL MYOPATHIES the multiple layers of basal lamina. The deposition of complement C5b-9 over the surface of muscle fibers and the multiplication of basal lamina suggest that the pathological features of infantile autophagic vacuolar myopathy are more similar to those of XMEA rather than Danon disease. 10.3.4. Adult-onset autophagic vacuolar myopathy with multiorgan involvement There is one report of a patient with late-onset AVSF myopathy. The patient is a 41-year-old Japanese man with AVSF myopathy and with the involvement of other organs including eyes, heart, liver, lung and kidney (Kaneda et al., 2003). He was diagnosed to have achromatopsia since childhood and was found to have elevated creatine kinase and transaminase levels and arrhythmia
211
at age 23. He lost his vision by age 27 due to retinal pigmentary degeneration. At age 34, he began to suffer from exertional muscle pain. At age 36, liver biopsy was performed and showed that the liver capsule was thickened and adherent to the abdominal wall. From age 38, he gradually started to have difficulty standing up from the squatting position. At age 40, he began to experience dyspnea on effort. On physical examination, he had bilateral optic and macular atrophy. His proximal limb and trunk muscles were weak and atrophic, accompanied by scapular winging and Gowers’ sign. He had normal intelligence. Serum creatine kinase level was elevated to 534 iu/l. Muscle biopsy showed many fibers with multiple intracytoplasmic vacuoles that had high acid phosphatase activity (Fig. 10.4). Vacuolar membranes had virtually a full set of sarcolemmal proteins such as dystrophin, sarcoglycans and dystroglycans. In addition, AChE and
Fig. 10.4. Muscle pathology of adult-onset autophagic vacuolar myopathy with multiorgan involvement. (A) Hematoxylin and eosin staining. Autophagic vacuoles are so tiny that they look more like basophilic granules as in Danon disease. (B) Histochemistry for acid phosphatase. Autophagic vacuoles have much higher acid phosphatase activity than in Danon disease. (C) Histochemistry for acetylcholinesterase. Some autophagic vacuoles have acetylcholinesterase activity in the vacuolar membranes (AVSF). (D) Periodic acid Schiff staining. Glycogen is only mildly increased in the vacuoles.
212
I. NISHINO
nonspecific esterase activities were observed on the vacuolar membranes, clearly demonstrating that these vacuoles are AVSF. In addition, muscle fibers have multilayered basal lamina and complement C5b-9 is deposited along the sarcolemma, suggesting that the pathomechanism may be more similar to XMEA than to Danon disease. LAMP-2 was not absent in the muscle and sequence analysis of the LAMP-2 gene did not reveal any mutation, indicating that this disease is distinct from Danon diasease (Kaneda et al., 2003). 10.3.5. X-linked congenital autophagic vacuolar myopathy More recently, a new congenital form of X-linked autophagic vacuolar myopathy was reported (Yan et al., 2005).
In this family, seven male patients presented with similar clinical symptoms. The proband, a 7-year-old ChineseAmerican boy, had congenital hypotonia and hypoventilation requiring respiratory support. He also had poor sucking and dysphagia until 2.5 years. His motor milestones were delayed, as he was able to sit only at 9 months and walk with support at 2 years. Thereafter, his motor development deteriorated because of progressive muscle weakness, such that he could only crawl on the floor at 7 years of age. Upon evaluation, his serum creatine kinase level was elevated at 1,962 iu/l. Generalized muscle atrophy and weakness, with involvement of facial and neck muscles, were observed. In addition, he was noted to have a high-arched palate. Careful assessment indicated that his mental faculties were not impaired. Electrocardiogram revealed incomplete right bundle-branch block and echocardiography showed left ventricular
Fig. 10.5. Muscle pathology of X-linked congenital autophagic vacuolar myopathy. (A) Hematoxylin and eosin staining. Autophagic vacuoles are so tiny that they look more like basophilic granules as in Danon disease. (B) Histochemistry for acid phosphatase. Autophagic vacuoles have much higher acid phosphatase activity than in Danon disease. (C) Histochemistry for acetylcholinesterase. Some autophagic vacuoles have acetylcholinesterase activity in the vacuolar membranes (AVSF). (D) Periodic acid Schiff staining. Glycogen is only mildly increased in the vacuoles.
LYSOSOMAL MYOPATHIES
213
Fig. 10.6. Electron microscopic findings in X-linked congenital autophagic vacuolar myopathy. Many autophagic vacuoles are seen in the muscle fibers. Interestingly, basal lamina is often multilayered, as in XMEA (arrowheads), suggesting a common pathomechanism between the two disorders.
hypertrophy. Needle electromyogram (EMG) of the right biceps brachii revealed complex repetitive discharges without accompanying fibrillation potentials or positive sharp waves and low-amplitude, short-duration motor unit potentials with early recruitment. These findings on electrophysiology are compatible with a chronic myopathic condition. The 9-year-old elder brother of the proband was also hypotonic at birth with elevated CK levels (2000 iu/l). He experienced feeding difficulties and required assisted feeding through a nasogastric tube until 2 years of age. He was able to sit at 8 months and to walk at 21 months but became wheelchair-bound within 5 years. He had generalized muscle weakness and atrophy which did not spare the facial and neck muscles. No cardiac or central nervous system involvement was seen. In both patients there were some clinical similarities to congenital myopathies such as myotubular myopathy, including the facial features and in clinical course. In fact, myotubular myopathy was the clinical diagnosis before muscle biopsy. Muscle biopsy from the proband showed AVSF in addition to marked variation in fiber size with endomysial fibrosis (Fig. 10.5). Numerous muscle fibers contained intracytoplasmic vacuoles with acetylcholinesterase activity, as compared to XMEA or adult-onset autophagic vacuolar myopathy. There was marked sarcolemmal deposition of complement C5b-9 in most fibers. On electron microscopy, numerous electron dense granules accumulated in intracytoplasmic vacuoles. The severely affected muscle fibers were surrounded by multilayered basal lamina. Therefore, pathologically, this disease is also more similar to XMEA than to Danon disease (Fig. 10.6). In fact, LAMP-2 was not absent and no mutation was found in the LAMP-2 gene. Mapping of the disease in this family showed a possibility that the
causative gene may be localized in Xq28 where the XMEA gene is present, suggesting that this disease may be allelic to XMEA. 10.3.6. Conclusion AVSF delineate five autophagic vacuolar myopathies. Among these, the causative gene is known only in Danon disease. In the remaining four myopathies which include XMEA, infantile autophagic vacuolar myopathy, adult-onset autophagic vacuolar myopathy and X-linked congenital autophagic vacuolar myopathy, multilayered basal lamina and complement C5b-9 deposition along the vacuolar membranes are commonly shown, suggesting that they have a similar pathomechanism. In fact, the locus for X-linked congenital autophagic vacuolar myopathy is suggested to be the same region with XMEA. Therefore, these diseases could even be allelic as for each other. The identification of the causative gene for XMEA, which is currently underway, will answer this question. Furthermore, there will most likely be other diseases in this group of myopathies and the list of the diseases will probably expand rapidly.
References Alberts B, Johnston A, Lewis J, et al. (2001). Molecular Biology of the Cell, 4th edn. Garland Science, New York. Arad M, Maron BJ, Gorham JM, et al. (2005). Glycogen storage diseases presenting as hypertrophic cardiomyopathy. N Engl J Med 352: 362–372. Danon MJ, Oh SJ, DiMauro S, et al. (1981). Lysosomal glycogen storage disease with normal acid maltase. Neurology 31: 51–57. Eisenberg I, Avidan N, Potikha T, et al. (2001). The UDPN-acetylglucosamine 2-epimerase/N-acetylmannosamine
214
I. NISHINO
kinase gene is mutated in recessive hereditary inclusion body myopathy. Nat Genet 29: 83–87. Kalimo H, Savontaus ML, Lang H, et al. (1988). X-linked myopathy with excessive autophagy: a new hereditary muscle disease. Ann Neurol 23: 258–265. Kaneda D, Sugie K, Yamamoto A, et al. (2003). A novel form of autophagic vacuolar myopathy with late-onset and multiorgan involvement. Neurology 61: 128–131. Kannan K, Divers SG, Lurie AA, et al. (1995). Cell surface expression of lysosome-associated membrane protein2 (lamp2) and CD63 as markers of in vivo platelet activation in maligancy. Eur J Haematol 55: 145–151. McFerrin J, Engel WK, Askanas V (1998). Impaired innervation of cultured human muscle overexpressing beta APP experimentally and genetically: relevance to inclusionbody myopathies. Neuroreport 9: 3201–3205. Minassian BA, Aiyar R, Alic S, et al. (2002). Narrowing in on the causative defect of an intriguing X-linked myopathy with excessive autophagy. Neurology 59: 596–601. Mizushima N, Yamamoto A, Hatano M, et al. (2001). Dissectionof autophagosome formation using Apg5-deficient mouse embryonic stem cells. J Cell Biol 152: 657–667. Muntoni F, Catani G, Mateddu A, et al. (1994). Familial cardiomyopathy, mental retardation and myopathy associated with desmin-type intermediate filaments. Neuromuscul Disord 4: 233–241. Murakami N, Goto Y-I, Itoh M, et al. (1995). Sarcolemmal indentation in cardiomyopathy with mental retardation and vacuolar myopathy. Neuromuscul Disord 5: 149–155.
Nishino I, Fu J, Tanji K, et al. (2000). Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease). Nature 406: 906–910. Nishino I, Noguchi S, Murayama K, et al. (2002). Distal myopathy with rimmed vacuoles is allelic to hereditary inclusion body myopathy. Neurology 59: 1689–1693. Reddy A, Caler EV, Andrews NW (2001). Plasma membrane repair is mediated by Ca2þ-regulated exocytosis of lysosomes. Cell 106: 157–169. Sugarman MC, Yamasaki TR, Oddo S, et al. (2002). Inclusion body myositis-like phenotype induced by transgenic overexpression of bAPP in skeletal muscle. Proc Natl Acad Sci U S A 99: 6334–6339. Sugie K, Yamamoto A, Murayama K, et al. (2002). Clinicopathological features of genetically confirmed Danon disease. Neurology 58: 1773–1778. Sugie K, Noguchi S, Kozuka Y, et al. (2005). Autophagic vacuoles with sarcolemmal features delinetae Danon disease and related myopathies. J Neuropath Exp Neurol 64: 513–522. Yamamoto A, Morisawa Y, Verloes A, et al. (2001). Infantile autophagic vacuolar myopathy is distinct from Danon disease. Neurology 57: 903–905. Yan C, Tanaka M, Sugie K, et al. (2005). A new congenital form of X-linked autophagic vacuolar myopathy. Neurology 65: 1132–1134. Yang Z, McMahon CJ, Smith LR, et al. (2005). Danon disease as an underrecognized cause of hypertrophic cardiomyopathy in children. Circulation 112: 1612–1617.
Handbook of Clinical Neurology, Vol. 86 (3rd series) Myopathies F. L. Mastaglia, D. Hilton-Jones, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 11
Distal myopathies BJARNE UDD* Vaasa Central Hospital, Vaasa, Finland
Distal myopathies are a group of inherited primary muscle disorders characterized clinically by progressive muscular weakness and atrophy beginning in the hands, forearm, lower legs or feet. The term has previously been very important to make a clear distinction between myogenic pathologies and neurogenic causes of distal weakness and atrophy. However, recent extensive progress in understanding the molecular genetic background has shown that many gene defects underlying distal myopathies may cause not only a distal presentation but a variety of clinical phenotypes. Eventually, when most myopathies/dystrophies have been defined by their gene defect, distal myopathy as a category of classification may become less important. In the future, the molecular genetic definition may in turn be replaced by categories defining distinct molecular biological functions and pathways disrupted by the gene defects. Nevertheless, classification and grouping of disorders are aimed to help clinicians to make the correct diagnosis and find the cause of the disease. So far, clinicians have to rely on clinical features and results of laboratory investigations for the selection of genes to be tested. As the list of known genes associated with distal myopathy is limited (Table 11.1), the classification distal myopathy may still serve practical needs. If large scale efficient diagnostic tools become available for testing any myopathy regardless of phenotype, the classification distal myopathy will soon be replaced by etiology-based terms. The cotitles used in this chapter serve to indicate this development. The first well-documented large family defined as having a distal myopathy was reported in 1943 by Milhorat. Six patients in a dominant family with 12 affected males had distal leg weakness with onset in early adulthood. Later studies in this family showed desmin accumulations in muscle biopsy and a mutation
in the desmin gene has been reported (Sjo¨berg et al., 1999). The change of classification in this family illustrates current developments following the progress in molecular genetics. Molecular genetic definition by linkage was first established in an Australian family with an early-onset distal myopathy (Laing et al., 1995). At present, the only distal myopathy with larger known epidemiology to remain without a known gene defect is Welander distal myopathy (WDM), described originally in 72 Swedish pedigrees under the title of Myopathia distalis tarda hereditaria (Welander, 1951). For yet unknown reasons, the genes responsible for distal phenotypes seem to preferentially involve sarcomeric proteins, compared to the sarcolemmal protein defects associated with proximal muscular dystrophies (Fig. 11.1). A number of less well-established syndromes have appeared in the literature usually as descriptions of single families. In addition to the disorders listed in Tables 11.2 and 11.3, there are distal myopathies where a retrospective subdivision is difficult (Mehrotra et al., 1964; Murone et al., 1963; Huhn, 1966; Mamoli and Scarlato, 1969; Cabella and Candelero, 1970; Miller et al., 1979). Distal muscle weakness and atrophy is sometimes the presenting symptom and sign in myopathies characterized by other major findings. These conditions are noted only briefly in this chapter and GNEassociated hereditary inclusion body myopathy (hIBM) is extensively presented in the corresponding chapter.
11.1. Welander distal myopathy In her thesis in 1951 Welander described 249 patients with this disease (Welander, 1951). The initial symptoms were clumsiness in precise finger movements, beginning in the thumb or index fingers and spreading to the other
*Correspondence to: Bjarne Udd, M.D., Ph.D, Vaasa Central Hospital, 65130 Vaasa, Finland. E-mail:
[email protected], Tel: þ358-6-323-2885, Fax: þ358-6-323-2888.
216 Table 11.1 Distal myopathies with known gene defect Onset
Genetics
Type
OMIMa/reference
Age
Early symptoms
CKb
Muscle pathology
Inheritance
Protein/gene and locus
Miyoshi myopathy(MM)
#254130
15–30
10–100
Dystrophic
ARc
Dysferlin 2p13
Udd distal myopathy (TMD)
#600334
>35
Posterior lower leg, calf Anterior lower leg
1–4
ADd
Titin 2q31
Nonaka distal myopathy (DMRV; hIBM) Laing early-onset distal myopathy (MPD1)
#605820
15–30
Anterior lower leg
1–5
Dystrophic, rimmed vacuoles Rimmed vacuoles
AR
GNE 9p1-q1
#160500
1–25
Anterior lower leg
1–8
AD
MYH 7 14q
Markesbery–Griggs disease (LODM)
Markesbery, 1974
>40
Anterior and posterier lower leg
1–3
AD
ZASP 10q
Penisson-Besnier distal myopathy
Penisson-Besnier, 1998
50–60
Posterior lower leg
1–2
AD
Myotilin 5q31
Early-onset distal nebulin myopathy (EODNM)
Udd (personal communication)
1–10
Anterior lower leg
1–3
AR
Nebulin 2q21
a
OMIM: on-line Mendelian inheritance in man; CK ¼ serum creatine kinase; c AR ¼ autosomal recessive; d AD ¼ autosomal dominant; e TA ¼ tibialis anterior. b
Type 1 fiber atrophy in TAe muscle, (no) vacuoles Large vacuoles, sarcoplasmic dark masses Non-rimmed vacuoles, dark sarcoplasmic masses þ desmin þ dystrophin No nemaline bodies on light microscopy
DISTAL MYOPATHIES Laminin-2 Distal genes
Collagen VI
Dystroglycan complex
Sarcoglycan complex
a
LGMD2C-F
b
Caveolin-3 b
Sarcolemma Fukutin
217
d g a
a-DTN Dysferlin
LGMD2B
TRIM32
LGMD2H
Dystrophin Golgi complex
GNE Actin
FKRP
LGMD2I
Calpain 3
Sarcomere desmin Emerin
Filamin C LGMD2A
a-etinin LaminA/C
T-cap/telethonin LGMD2G Myotilin
Nucleus ZASP
Actin Nebulin
Myosin Tropomyosin/troponin
Tropomodulin Titin
TMD LGMD2J
FSH?
Fig. 11.1. Schematic figure showing the subcellular locations of proteins associated with muscular dystrophies and distal myopathies (encircled).
fingers (Figs 11.2A and B). Distal leg involvement developed later, with stumbling, difficulty in walking and, eventually, inability to stand on the heels or development of a steppage gait. Symptoms started in distal lower extremities in only 17 patients. Progressive weakness and wasting of small muscles of the hands and long extensors of the distal segments of the limbs was observed in follow-up studies. Although extensor muscles were most affected, involvement of distal limb flexors was present in 41% and was related to the duration of the illness. Interestingly, this early clinical observation has been firmly documented 50 years later by muscle imaging in almost all patients. Mahjneh et al. (2004) studied cohorts of patients with Welander distal myopathy (WDM) and mutation-verified patients with Udd distal myopathy (TMD), and found that involvement of posterior calf muscles in WDM was the most prominent difference in leg muscle affection between the two disorders. Proximal limb muscle weakness was observed in 14% and trunk muscle weakness in only 2%. The deep tendon reflexes
were preserved early in the disease, but after decades of symptoms Achilles reflexes were lost. Coldness of the hands and feet occurred in 90% of patients. Sensation was not impaired except for a mild alteration in vibration sense considered normal for the age group. Onset varied between 20 and 77 years (mean 47 years), with a maleto-female ratio of 1.5:1 and normal life span. The disease shows autosomal-dominant inheritance with slightly reduced penetrance. The possibility of a neurogenic component in WDM was first considered by Welander (Welander, 1951). Mild neurogenic features were later detailed by Borg and coworkers who found abnormalities of sensory function and sural nerve histology (Borg et al., 1987; 1989). Studies of young and middle-aged adults with early symptoms of WDM revealed distal sensory disturbances, especially for temperature sense, but no abnormalities of sensory nerve conduction velocities, nor any neurogenic findings in eight anterior tibial muscle biopsies (Borg et al., 1991b).
218 Table 11.2 Distal myopathies without known gene defect Onset
Genetics
Type
OMIMa/reference
Age
Early symptoms
CKb
Muscle pathology
Inheritance
Genetic locus
Welander distal myopathy (WDM) Distal myopathy with vocal cord and pharyngeal signs (MPD2) Distal myopathy with pes cavus and areflexia
#604454
>40
Hands, finger extensors
1–4
ADc
2p13
#606070
35–60
1–8
AD
5q31
#601846
15–50
Adult onset distal myopathy
Felice et al., 1999
20–40
Juvenile-adult onset distal myopathy Variable-onset distal myopathy Adult-onset distal myopathy (MPD3)
Williams et al., 2005 Sumner et al., 1971 Mahjneh et al., 2003
10–40
Asymmetric lower leg and hands þ dysphonia Anterior þ posterior lower leg, dysphonia þ dysphagia Foot drop þ mild proximal weakness Posterior–lateral lower leg
Dystrophic, rimmed vacuoles Rimmed vacuoles
15–50 >30
Forearm and/or lower leg Hands or anterior lower leg
Distal myopathy with respiratory failure
#607569
32–75
Anterior lower leg in some, and proximal in some
a
OMIM: on-line Mendelian inheritance in man; CK: serum creatine kinase; c AD: autosomal dominant. b
2–6
Dystrophic, rimmed vacuoles
AD
19p13
2–6
Non-specific mild changes in proximal muscle Myopathic–dystrophic
AD
2, 9, 14 excluded
AD
12 genetic loci excluded
1–2 1–4 1–2
Nonspecific Dystrophic, rimmed vacuoles, þ eosinophilic inclusions Dystrophic, rimmed vacuoles, þ eosinophilic inclusions þ amyloid þ desmin
AD AD
AD
Both 8p-q and 12q are linked 2, 9, 14 excluded
DISTAL MYOPATHIES
219
Fig. 11.2. Welander distal myopathy. (A,B) The hands of a 47-year-old woman with symptoms of hand and finger weakness for 4 years. Early signs of mild small hand muscle (thenar and hypothenar) atrophy are visible, as well as reduced finger extension, particularly of the index fingers.
11.1.1. Epidemiology There are no exact studies on epidemiology of WDM, but estimates based on patient numbers at different regional neuromuscular centers indicate a prevalence of about 5/ 100 000 in Sweden (Edstro¨m, personal communication). Outside Sweden, recent data have emerged from Finland where WDM has been identified in several families (von Tell et al., 2002). Duemler (1962) described a Swedish patient, living in the United States, with clinical and electromyographic findings similar to WDM. Dahlgaard (1960) reported a 72-year-old Danish woman with a 10- to 15-year progressive course of distal extremity weakness. Electromyography (EMG) and muscle biopsy indicated a myopathic process. 11.1.2. Molecular genetic findings Genetic studies in well-defined WDM families determined linkage of the disease to a locus on chromosome 2p13 close to, but outside, the Miyoshi myopathy limb˚ hlberg girdle muscular dystrophy 2B dysferlin locus (A et al., 1999; von Tell et al., 2003). All known genes in the linked locus have been sequenced without identification of the causative gene so far (von Tell, 2004). All patients with WDM in Sweden carry the same haplotype at the locus indicating one single common founder muta˚ hlberg et al., tion for the Swedish WDM population (A 1999). WDM families identified in Finland on clinical grounds also carry the identical haplotype (von Tell et al., 2002). Since no genealogical connections during the last four centuries between WDM families in Finland
and Sweden were found, the mutant gene has long been present in the Finnish population. In the original paper by Welander more than 90% of patients presented with the “typical” form described above (230 of 249 patients), in whom the disease progressed slowly and remained distal to the elbows and knees. Four percent were classified as “moderately atypical” (10 of 249 patients) and showed a more rapidly progressive course with weakness of finger and toe flexors and/or of proximal muscles at a relatively early stage of the disease (Welander, 1951). The same proportion of patients were “grossly atypical” (9 of 249), with involvement of proximal limb muscles and long flexors of the fingers and feet in early stages, and a much more rapid disease evolution leading to disability. These patients were thought to be homozygous for the abnormal gene (Welander, 1957), and even though they were no longer available for molecular analysis their offspring ˚ hlberg et al., 1999). Neverthewere all heterozygotes (A less, in one of the families included in the linkage studies, one patient was homozygous for the linked haplotype and he, indeed, displayed a much more severe myopathy ˚ hlberg et al., 1999). compared to typical WDM (A 11.1.3. Laboratory investigations and muscle pathology Serum creatine kinase (CK) may be normal or up to a threefold elevated level in patients with WDM (Edstro¨m, 1975). Nerve conduction velocities are normal, as by definition in all cases accepted as distal myopathy. EMG studies in patients with WDM show brief, short and
220
B. UDD
polyphasic motor unit potentials, and in severely affected muscles a decreased number of motor unit potentials. Spontaneous electrical activity at rest, fibrillation potentials, and “myotonic” discharges in WDM have been reported (Edstro¨m, 1975). Computed tomography (CT) and magnetic resonance imaging (MRI) both show fatty degeneration of affected muscles. In WDM, MRI showed replacement lesions in the anterior compartment and frequently in the soleus and gastrocnemius ˚ hlberg et al., 1994, Majhneh et al., muscles in the leg (A 2004). In her thesis Welander reported the findings of 55 muscle biopsy specimens taken from muscles with variable involvement (Welander, 1951). Early “incipient” changes were increased variation in fiber size, central nuclei and increased connective tissue. More marked alterations such as split fibers, vacuolation of some fibers, fatty deposition, and macrophage infiltration were found in later stages of the disease. At the end-stage, muscles showed marked replacement by connective and fatty tissue, with only a few muscle fibers remaining. Atrophic fibers were not arranged in groups. In 1975; Edstro¨m et al. reported the muscle biopsy findings in 13 Swedish patients with WDM. Early pathologic changes included increase of centralized nuclei, often in chains, and type 1 fiber atrophy. In advanced stages, the differentiation of type 1 and 2 fibers was blurred and ring fibers and sarcoplasmic masses were common. The early findings were considered similar to those of myotonic dystrophy. In a later series of patients with WDM fibers with rimmed vacuoles as well as angulated fibers, and type 1 fiber grouping were observed, interpreted as a neurogenic component in WDM (Borg et al., 1987). In 1994 the same investigators reported mild-to-severe changes in tibial anterior and soleus muscles, whereas the findings in vastus lateralis biopsies were ˚ hlberg et al., 1994). In the affected considered normal (A muscles rimmed vacuoles were found in atrophic fibers of both fiber types. In one out of seven biopsies, one group of atrophic type 1 fibers was encountered, but on the whole the authors found no obvious fiber type grouping. On electron microscopy tibialis anterior specimens revealed autophagic vacuoles harboring dense bodies, myelin figures and glycogen (Borg et al., 1987). Tubulofilamentous inclusions, like those in inclusion body myopathies (IBM), were also observed in WDM (Borg et al., 1991a). Welander reported autopsy findings in three “typical” patients who were symptomatic for 9–16 years (Welander, 1951). Histological studies revealed normal proximal arm muscles, “incipient” myopathic changes in thigh, calf, and forearm muscles and advanced myopathic changes in distal muscles. Spinal cord, ventral roots and peripheral nerves were normal.
11.1.4. Treatment and management There is no specific treatment for WDM. Ankle–foot orthoses are of benefit for foot drop.
11.2. Udd distal myopathy: tibial muscular dystrophy (TMD)/titinopathy The clinical findings in 66 Finnish patients with TMD were reported in 1993 (Udd et al., 1993). TMD is an autosomal-dominant disorder that presents after age 35, selectively involving the tibialis anterior and, in advanced stages, the long toe extensor muscles (Fig. 11.3A–D). Weakness at onset may be asymmetric and progression is slow. Mild-to-moderate proximal leg muscle weakness occurs after age 70 in a minority of the patients, but patients rarely become wheelchair-bound even at advanced age. Clinically, the sparing of short toe extensors (extensor digitorum brevis) is an important finding for distinction from neurogenic foot drop. Unlike in WDM, hand muscles are rarely affected in TMD. Despite this characteristic presentation, a recent study of 207 mutation-confirmed patients showed unexpected variants of the phenotype in 9% of the patients (Udd et al., 2005). These aberrant phenotypes included onset of weakness and atrophy in proximal leg muscles, involvement of upper limb muscles, onset of generalized weakness in childhood, persistent asymmetric and focal atrophies, and in one patient mild bulbar and facial weakness. All these aberrant phenotypes of muscle involvement were found in addition to the typical tibialis anterior lesion, except for one patient with proximal leg muscle involvement and one patient with posterior calf muscle involvement who presented without any anterior tibial muscle weakness (Udd et al., 2005).
11.2.1. Epidemiology Recent studies have shown a prevalence of TMD in Finland of more than 7/100 000 (Udd et al., 1998; 2005). Patients are found all over the country, although the origins of their families can be traced back to the west coast region of central Finland and to the SavoKarelia area of eastern Finland (Udd et al., 1993). TMD has also been identified in Sweden, Norway, Germany and Canada in descendants of Finnish immigrants. Moreover, TMD families have recently been identified in other populations without connections to the Finnish background in France, Belgium and Spain (de Seze et al., 1998; van den Bergh et al., 2003; Udd, personal communication, 2005).
DISTAL MYOPATHIES
221
Fig. 11.3. Tibial muscular dystrophy (TMD) (titinopathy). (A) Early changes in a 42-year-old woman with reduced ankle dorsiflexion for 5–6 years. Mild atrophy of the tibialis anterior is noted by the prominence of the ventral edge of the tibial bone. Note also preserved extensor digitorum brevis muscles. (B) Attempts to stand on the heels only makes the toes move upwards. (C) At a more advanced stage, anterior compartment atrophy also involves the long toe extensors. There is overt muscle atrophy in the lower legs, and mild foot drop with a hanging big toe. (D) Attempted ankle dorsiflexion results only in limited upwards movement of the toes due to the action of extensor digitorum brevis. (E) Computed tomography imaging of the lower leg muscles in a 42-year-old patient with tibial muscular dystrophy (TMD) showing fatty degenerative lesions in the anterior tibial muscle, while all other muscles are intact.
222
B. UDD
Fig. 11.3. (Continued) (F) Computed tomography (CT) scans of the lower legs in a 70-year-old patient with TMD reveal more extensive dystrophic replacement of muscle tissue in all anterior compartment muscles and also in medial gastrocnemius. (G) In a muscle biopsy from gastrocnemius, a muscle not usually affected clinically, dystrophic changes may be present without rimmed vacuolar change. (H) Light microscopic muscle biopsy findings in the tibialis anterior muscle of a 44-year-old patient with TMD showing mild dystrophic changes and a few rimmed vacuolated fibers. (I) Schematic outline of the proteins in the M-line of the sarcomere, with titin mutations in TMD.
11.2.2. Molecular genetic findings Tibial muscular dystrophy in the Finnish families was linked to a new myopathy locus on chromosome 2q31 in 1998 (Haravuori et al., 1998a). All TMD patients in Finland carry the same haplotype indicating a founder mutation. Patients with TMD in Germany, Sweden and Canada with known ancestry in Finland also carry the Finnish TMD haplotype. In one big consanguineous pedigree with a large number of TMD patients, eight members showed a totally different limb-girdle muscular dystrophy (LGMD) phenotype, five belonging to one nuclear family with childhood onset, and three belonging
to two different other nuclear families with early adultonset disease. These cases were all thought to be homozygotes for the dominant TMD gene (Udd, 1992). Molecular analysis, however, showed homozygosity for the TMD haplotype in the family with childhood-onset LGMD, but not in the others (Haravuori et al., 1998a). The linked region of interest on 2q31 contained only one known muscle gene, titin, that encodes the largest known single protein in man (Haravuori et al., 2001). Titin constitutes the third filament system in the sarcomere and, recently, mutations in the last exon, Mex6, were found in patients with TMD (Hackman et al., 2002). The mutated exon encodes for the C-terminus
DISTAL MYOPATHIES
223
Myosin
Obscurin? is4
m10 is7 m8
m4
is2
Kinase A169
P
capn3
nbr1
p62
MURF1
MURF2 T40
MURF1
A 169
Tm8raT51
T41
Kinase
m4
is2
m8
is4
Capn3
is7 m10
nbr1 p62
P
Myomesin
MURF2 M-prot Myosin
60
50
40
30
20
10
M49
0 M1
10
20 M4
30
40
50
60
nm
M6
I Fig. 11.3. (Continued) (I) Schematic outline of the proteins in the M-line of the sarcomere, with titin mutations in TMD with stars.
of the M-line segment of titin. The founder mutation (FINmaj) in Finnish TMD patients is a complex 11-bp insertion-deletion mutation changing four consecutive amino acids without breaking the reading frame (Hackman et al., 2002). In two unrelated French families a point mutation changing a lysine to proline was found in the same last Mex6 exon (Hackman et al., 2003). Later a third mutation in the same last exon was found in a Belgian TMD family (van den Bergh et al., 2003) and more unpublished mutations, also in the last Mex6 exon, have been identified in Spanish and other French families (Udd, personal communication). These mutations are available for diagnostic testing. In new unrelated patients with TMD searching for mutations by sequencing the last titin exons may be productive. Mutation testing identified the Finnish FINmaj mutation homozygously in all four available LGMD phenotype patients with childhood onset of disease. Since this phenotype behaves in a recessive fashion, it has been designated LGMD 2J (Udd et al., 2005).
11.2.3. Laboratory investigations and muscle pathology Patients with TMD have normal or only slightly elevated CK (Udd et al., 1993). In affected muscles EMG studies showed low-amplitude, short-duration motor unit potentials on moderate activity (Udd et al., 1991a). Increased insertional activity, frequent fibrillation potentials, and occasional high-frequency and complex repetitive discharges at rest may be obtained. In clinically unaffected muscles of the upper limbs polyphasic potentials may be recorded (Udd et al., 1993). Computed tomography and MRI provide accurate data on the selective involvement of individual muscles in TMD. Changes of fatty degeneration appear at the time of clinical weakness (Udd et al., 1991b). The evolution of selective involvement over time is very distinct in TMD. Together with the presenting weakness of ankle dorsiflexion, fatty degenerative changes appear in the anterior tibial muscle. After 10–15 years of symptoms, lesions
224
B. UDD
appear in the long toe extensor muscles, and in hamstring, gluteus minimus and tensor fasciae latae muscles (Fig. 11.3E–F; Udd et al., 1991b). Initially, the involvement may be asymmetric. Later, focal lesions may appear in apparently asymptomatic muscles, such as soleus, where other unaffected muscles mask the loss of power and prevent the lesion from being observed clinically (Udd et al., 1991b). Muscle specimens in TMD reveal myopathic alterations, including variation of fiber size, thin atrophic fibers, central nuclei, structural changes within the fibers, endomysial fibrosis and fatty replacement in the endstage muscle (Udd et al., 1992). Necrotic fibers, some showing phagocytosis, are rare in TMD. Fiber type differentiation was normal, both major fiber types being equally involved in the pathological process. There were no neurogenic findings. In 32 anterior tibial muscle biopsy specimens of patients with TMD, advanced dystrophic changes were noted in all and rimmed vacuoles in nine (Fig. 11.3G). Many rimmed vacuoles were acid phosphatase positive, while others were ubiquitin positive and, with rare exceptions, they were not lined by sarcolemmal membrane proteins (Fig. 11.3H). Congo red stains and immunohistochemistry for b-amyloid and amyloid precursor protein were negative in TMD specimens containing fibers with rimmed vacuoles, in contrast to sporadic inclusion body myositis. Immunostains for SMI-31, with an antibody cross-reacting with hyperphosphorylated tau protein, showed positivity in some apparently normal muscle fibers and very rarely in rimmed vacuolated fibers. Ultrastructural studies in TMD revealed overall wellpreserved sarcomere structure, even in the homozygote LGMD 2J mutants. Focal cytoplasmic and sarcomeric degradation products and occasional tubulofilamentous inclusions were encountered in the vacuolated fibers (Udd et al., 1993). Rimmed vacuoles in TMD are usually not membrane bound and thus do not fulfill the morphological criteria of autophagic vacuoles, even though the degradation space contains numerous small vesicles compatible with lysosomal components.
apoptotic myonuclei (Richard et al., 1995). In TMD/ LGMD 2J with secondary calpain-3 deficiency, clusters of apoptotic myonuclei were also detected, suggesting similarities in molecular pathology. Mutant titin is transcribed, translated and incorporated in the sarcomere as shown by immunohistochemistry using antibodies for different portions of the molecule. However, C-terminal antibodies that recognize the third last domain fail, indicating that the C-terminus is either conformationally changed 200 amino acids upstream of the mutations, or that the C-terminus is cleaved off in the mutant protein. The titin C-terminus is rich in epitopes for signaling, containing among others a catalytic kinase domain and having interactions with several signaling molecules (Hackman et al., 2003), but other ligands for the titin C-terminus are still to be identified (Fig. 11.3I). 11.2.5. Treatment and management Patients with foot drop can be helped with molded polypropylene orthoses. In a few patients with severe foot drop early in the disease course, surgical transposition of the tibialis posterior tendon has been applied with some functional benefit and the need for orthoses was reversed.
11.3. Markesbery–Griggs disease: late onset distal myopathy (LODM)/Zaspopathy In 1974, a family with six patients affected by distal myopathy with autosomal-dominant inheritance was reported (Markesbery et al., 1974). Weakness started in the anterior distal leg muscles between 43 and 51 years of age, then spread to the intrinsic hand and wrist extensor muscles, and eventually to the proximal limb and trunk muscles. In one patient, weakness remained limited to the distal leg muscles over 15 years. Facial, bulbar or respiratory muscles were not involved. The disease progressed slowly, did not alter the length of life, but caused loss of ambulation in senescence. Cardiomyopathy was present in one of the patients. 11.3.1. Molecular genetic findings
11.2.4. Molecular pathogenesis Titin constitutes the third filament system in the sarcomere and is a major constituent of muscle protein after myosin and actin. Even before the titin mutations were known, secondary calpain-3 deficiency was noted in TMD muscle, and particularly in the homozygous LGMD 2J patients (Haravuori et al., 2001). Primary calpain-3 defects cause LGMD 2A. Titin is known to bind calpain-3 at more than one location, including the N2A-line of I-band titin and in the C-terminus next to the mutations. Studies on LGMD 2A have shown
Because of the phenotypic similarity between TMD and LODM, the titin locus on 2q31 was readily tested as soon as the linkage assignment of TMD was known, using the identical 2q31 markers for genotyping. In fact, LODM seemed to be linked to the same locus with complete segregation of a certain 2q31 haplotype with the affected individuals, and a LOD score of 1.5 well in line with the calculated maximum for the family (Haravuori et al., 1998b). Extensive mutation search in the huge titin gene was not productive and no mutations were detected.
DISTAL MYOPATHIES With the reports of myotilin and alternatively spliced PDZ-domain containing protein (ZASP) mutations in subsets of myofibrillar myopathy patients (Selcen and Engel, 2004, 2005) these genes became candidates for LODM. The fact that muscle pathology in LODM had far more similarities with myofibrillar myopathies (MFM) than with TMD also supported the candidate gene approach. Sequencing of myotilin gave normal results, whereas the previously reported C523G mutation in ZASP was found in all patients in the family (Udd, personal communication, 2005). 11.3.2. Laboratory investigations and muscle pathology Patients with LODM have normal or only slightly elevated CK (Markesbery et al., 1974). EMG studies showed low-amplitude, short-duration motor unit potentials on moderate activity. Most patients have increased insertional activity, frequent fibrillation potentials and occasional high-frequency and complex repetitive discharges at rest (Markesbery et al., 1974). Muscle specimens in LODM reveal myopathic alterations, including variation of fiber size, central nuclei, structural changes within the fibers, endomysial fibrosis and fatty replacement of muscle (Markesbery et al., 1974). Necrotic fibers, some showing phagocytosis, and fibers with rimmed vacuoles are strikingly abundant in LODM. In addition, some fibers contain single or multiple non-rimmed vacuoles whose contents fail to stain for lipids or polysaccharides. In cryostat sections, a distinctive alteration in numerous fibers is the focal accumulation of homogeneous, granular material that stains blue-red with Gomori trichrome (Fig. 11.4A). None of
225
the morphologic studies indicated denervation. Fiber type differentiation was normal and both major fiber types were equally involved in the pathological process. Immunohistochemistry has shown desmin accumulations in the abnormal fibers (Fig. 11.4B). Ultrastructural studies showed a wide spectrum of alterations involving almost all portions of the muscle fiber (Markesbery et al., 1977). Early changes included dilation and vacuolization of the sarcoplasmic reticulum and streaming and disruption of the Z-disk. Clumps of Z-disk material were found without the periodicity of nemaline rods. Sarcoplasmic masses composed of glycogen granules, lipofuscin bodies, tiny vacuoles, degenerated myofilaments, Z-disk fragments and myeloid figures were common. Myofibrillar disorganization, disruption and fragmentation as well as widening of the intermyofibrillar spaces were frequent findings. In retrospect these alterations are compatible with reported changes in myofibrillar myopathy. The vacuoles are membrane-bound and contain osmiophilic vesicles, granular membrane structures, myeloid figures and other products of cytoplasmic degeneration and fit the morphological criteria of autophagic vacuoles. They are frequently at the fiber periphery and sometimes covered only by the basement membrane indicating that they may undergo exocytosis. Other vacuoles are relatively empty and contained only a few membranous whorls. Autopsy studies were conducted in two LODM patients (Markesbery et al., 1974). Wide sampling of muscles in one patient with moderately advanced clinical disease revealed mild myopathic changes in trunk muscles, intermediate changes in proximal limb muscles, and end-stage alterations in distal muscles. This patient also had mild degenerative changes in peripheral
Fig. 11.4. Markesbery–Griggs late-onset distal myopathy (zaspopathy). (A) Light microscopic muscle biopsy findings in a zaspopathy patient showing darker, homogeneous, granular material in the cytoplasm with Gomori trichrome. (B) Immunohistochemistry of the same biopsy shows increased focal desmin accumulation in abnormal fibers.
226
B. UDD
nerves and spinal roots possibly caused by his preexisting diabetes mellitus. He also had clinical evidence of a cardiomyopathy with cardiomegaly, congestive heart failure and intractable tachyarrhythmias requiring pacemaker implantation. At autopsy there was diffuse interstitial fibrosis and diffuse degenerative change in cardiac muscle fibers consistent with a cardiomyopathy. A brother who died in a more advanced clinical stage of the disease, but without cardiac involvement, showed similar, though more pronounced, changes in skeletal muscle in the same distribution. No alterations were found in his spinal cord or brain. 11.3.3. Molecular pathogenesis Alternatively spliced PDZ-domain containing protein (ZASP) is a component of the Z-disc and has known interaction with alpha-actinin (Fig. 11.1; Selcen and Engel, 2005). Further mechanisms by which mutated ZASP causes such widespread damage to the sarcomere structure are so far elusive. The reasons for the clinical similarity and the similar pattern of involved muscles as with TMD remain unknown, but some sharing of susceptibility for pathways involved in C-terminal titin mutations and ZASP mutations can be postulated. 11.3.4. Treatment and management Patients’ foot drop can be helped with molded polypropylene orthoses as with WDM and TMD diseases. ZASP mutations include potential cardiomyopathy, which should be monitored at least in later stages of the disease.
11.4. Miyoshi myopathy (MM)/distal dysferlinopathy In 1977, two sporadic cases of distal myopathy with onset at the age of 19 and 20 years were reported from the USA (Markesbery et al., 1977), and Miyoshi et al. described a series of similar patients in Japan (Miyoshi et al., 1977). All patients had weakness and atrophy starting in the distal lower extremities, particularly in the calf muscles (Fig. 11.5A). First symptoms were difficulty in climbing stairs, walking briskly, or running, and inability of patients to hop on one leg was a clinical clue. Weakness of the intrinsic foot and anterior compartment muscles may occur, but these muscles were often strikingly normal early in the disease (Miyoshi et al., 1986; Barohn et al., 1991). Proximal muscles were only minimally affected at the onset, as were hand muscles. Some patients had lost ankle and knee reflexes, but the majority showed normal tendon reflexes. Patients appeared as sporadic cases or in families indicating autosomal-recessive inheritance. MM shows slow progression towards proximal muscle involvement and after 10–20 years of disease duration there are similarities with the evolution of the LGMD 2B phenotype. Dysferlinopathy patients presenting with anterior-tibial rather than with calfmuscle weakness have also been reported (Illa et al., 2001), but imaging studies of these patients revealed marked fatty degeneration of the gastrocnemius and soleus muscles (Illa and Brown, 1999). This subtype was also described in two sisters (Scoppetta et al., 1997).
Fig. 11.5. Miyoshi myopathy (dysferlinopathy). (A) Calf muscle atrophy in a 22-year-old patient with Miyoshi myopathy. (B) Severe atrophy and replacement by adipose and connective tissue in soleus and gastrocnemii muscles on both legs.
DISTAL MYOPATHIES 11.4.1. Epidemiology Since molecular diagnosis for dysferlinopathy became available, through immunohistochemistry and immunoblotting using antidysferlin antibodies and direct DNA genetic analysis, patients with Miyoshi myopathy have been diagnosed in many different populations (Cupler et al., 1998; Linssen et al., 1998; Argov et al., 2000; Eymard et al., 2000; McNally et al., 2000). The disorder seems to occur with a frequency of about 1–2/1000 000. 11.4.2. Molecular genetic findings In 1995 linkage to chromosome 2p was reported in MM families (Bejaoui et al., 1995). Linkage to the same locus had been shown one year earlier in LGMD 2B, and both soon proved to be caused by mutations in a previously unknown gene, dysferlin (Bashir et al., 1998; Liu et al., 1998). The two phenotypes MM and LGMD 2B occurred in different individuals even within the same family (Illarioskin et al., 1996, Weiler et al., 1996, Illarioskin et al., 2000). Why identical homozygous mutation cause different phenotypes within the same family is not clarified. The anterior tibial phenotype reported by Illa et al. (2001) also occurred together with MM phenotype within the same family. Numerous different mutations have been reported and they are widely distributed along this large gene. Newer methodology for mutation screening using cDNA from muscle has been described (Thierren et al., 2005). Not all patients with MM-like phenotype have dysferlinopathy. In four families with adult and later onset of symptoms, linkage to the MM locus 2p was excluded (Linssen et al., 1998). In two of these families a genome wide screen suggested linkage to a locus on chromosome 10 (LOD 2.57). One family was unlinked to both loci. Thus, the phenotype is apparently genetically heterogeneous, and MM might be reserved for the dysferlin mutated form, whereas others may be termed MM-like phenotypes until their molecular etiology has been clarified. 11.4.3. Laboratory investigations and muscle pathology Patients with MM have very high serum CK values 10–100-fold the upper level of normal (Miyoshi et al., 1986; Barohn et al., 1991; Cupler et al., 1998), and this occurs even in preclinical stages of MM (Barohn et al., 1991). EMG shows increased insertional activity, fibrillation potentials and abundant small motor unit potentials with early recruitment (Miyoshi et al., 1977, 1986, Barohn et al., 1991). Muscle imaging with CT or MRI give clear insight in the involvement of different muscles
227
during the disease process, and can also be used for assessment of individuals at risk (Fig. 11.5B). Muscle biopsy shows non-specific myopathic/dystrophic features with abundant necrotic fibers, regenerating fibers, abnormal variation in fiber size and later connective tissue increase (Barohn et al., 1991). One autopsy has been reported, in a 68-year-old male patient (Miyoshi et al., 1986). Severe myopathic changes with necrotic fibers especially in the calves, and mild alterations in limb girdle, arm, and trunk muscles were reported. There was no pathology found in brain, spinal cord, nerve roots, or peripheral nerves. In many dysferlinopathy biopsies inflammatory infiltrates have been observed (Gallardo et al., 2002), and dysferlinopathy has been confused with polymyositis on many occasions. Immunohistochemistry and immunoblotting with antidysferlin antibodies showing dysferlin deficiency has become the gold standard for pathological assessment and diagnosis (Selcen et al., 2001). Immunoblots of MM muscle extracts accurately reveal dysferlin deficiency, whereas immunostaining of cryostat sections of MM muscle is less reliable. The currently available antidysferlin antibodies may stain the normal muscle surface only weakly, even at high concentration. However, dysferlin may be non-specifically overexpressed in regenerative fibers in any myopathic disorder. 11.4.4. Molecular pathogenesis Dysferlin is mainly a sarcolemmal protein with minor expression in the cytoplasm (Fig. 11.1). Dysferlin has no role in the dystrophin-associated protein complex and its exact functions are unclear (Matsuda et al., 1999). Dysferlin, by analogy to FER-1 gene in Caenorhabditis elegans and by having calcium-binding C2 domains, may have a role in membrane fusion and maintaining the structural integrity of the plasmalemma (Matsuda et al., 1999). Recent ultrastructural studies indicate numerous submicrometer-sized defects in the plasma membrane, replacement of the plasma membrane by small vesicles, frequently disintegrating small papillary projections, as well as numerous small subsarcolemmal vacuoles as early events in the pathology (Selcen et al., 2001). These findings support recent concepts on the role of dysferlin in maintaining muscle fiber surface membrane integrity. Dysferlin seems to interact with caveolin-3, a skeletal muscle protein important in the formation of caveolae. Mutations in caveolin-3 can cause a large variety of phenotypes such as LGMD 1C, rippling muscle disease and even distal myopathy (Tateyama et al., 2002). Dysferlin immunostaining is markedly attenuated in patients who harbor mutations in caveolin-3 (Matsuda et al., 2001; Tateyama et al., 2002). This suggests that one function
228
B. UDD
Patients with distal myopathy with onset in early adulthood of weakness in the lower legs, typically in the anterior compartment causing foot drop, were reported by Nonaka et al. (1981). Progression to posterior compartment and proximal muscles was always present and major disability was the usual outcome after 10–15 years of disease duration. Intrinsic muscles were also involved. DMRV followed an autosomal-recessive inheritance pattern. A similar disorder was described by Mongini et al. but no further molecular data have been reported (Mongini et al., 1989). After detection of the underlying GNE-gene defect this entity is now known to be allelic with and the same as hereditary inclusion body myopathy (hIBM).
may or may not be present. Characterization of the rimmed vacuoles showed variable acid phosphatase activity and some also in the sarcoplasm indicating increased lysosomal activity (Nonaka et al., 1981; Kumamoto et al., 1982). Ubiquitin expression was increased suggestive of increased non-lysosomal degradative activity as another part of the degradative pathogenesis (Kumamoto et al., 1982, 1994; Murakami et al., 1995; Kumamoto et al., 2000). At the ultrastructural level correlates of rimmed vacuoles appeared to be membranebound and to contain membranous myeloid bodies, filamentous material, degenerating organelles and cellular debris (Kumamoto et al., 1982; Mizusawa et al., 1987), but according to another study (Nonaka et al., 1981) the vacuoles were not membrane-bound. Others described fine filamentous bodies, small paracrystalline inclusions in mitochondria and myofibrillar alterations in DMRV (Isaacs et al., 1988). In a study of seven patients with DMRV, Mizusawa et al. (1987) found early proliferation of the Golgi apparatus, mitochondrial degeneration, and myofibrillar loss, followed by T-system proliferation and autophagosomes coalescing to form large autophagic vacuoles partially surrounded by a single membrane. Finally, tubulofilamentous inclusions like those occurring in sporadic IBM were also observed in DMRV (Sunohara et al., 1989). These morphological studies were mostly done before the gene defect in DMRV was known and, thus, it is not known whether all studied patients were GNE-mutated cases.
11.5.1. Molecular genetic findings
11.5.3. Molecular pathogenesis
After the gene was identified in autosomal-recessive hIBM (Eisenberg et al., 2001), DMRV in Japanese patients proved to be caused by mutations in the same GNE gene, confirming these are allelic identical disorders (Tomimitsu et al., 2002). Many different mutations in GNE have been reported in Japanese DMRV patient (Kayashima et al., 2002; Nishino et al., 2002), but one of them, V572L, is more common and accounts for a founder effect (Tomimitsu et al., 2002). See chapter 13 on hIBM in this volume.
For comprehensive details, see chapter 13.
11.5.2. Laboratory investigations and muscle pathology
An Australian family with autosomal-dominant EODM was first reported by Laing et al. (1995) as being linked to a new distal myopathy locus (MPD1) on chromosome 14q. Clinical findings in this family were to some extent similar to those in one of the first ever reports on distal myopathy: Gowers’ description of a patient in 1902 (Gowers, 1902). Recently, more families have been identified in various populations (Meredith et al., 2004). Weakness begins in the lower leg anterior compartment between 1 and 25 years of age with a characteristic severe atrophy and weakness of neck flexors, the
of dysferlin may be to subserve signaling functions of caveolae (Matsuda et al., 2001). Secondary calpain-3 defects have also been shown in patients with dysferlinopathies (Anderson et al., 2000), but the interaction of calpain-3 with dysferlin remains to be clarified. 11.4.5. Treatment and management There is no specific treatment available. Corticosteriods and azathioprine have not been of benefit in carefully studied MM cases (Barohn et al., 1991).
11.5. Nonaka myopathy: distal myopathy with rimmed vacuoles (DMRV)/GNE-disease
Creatine kinase values are normal or slightly elevated in DMRV patients and EMG shows abundant small motor units potentials and spontaneous discharges including positive sharp waves and fibrillations (Nonaka et al., 1981, 1985). Nonaka distal myopathy was defined as being characterized by rimmed vacuoles in muscle fibers (Nonaka et al., 1981; Kumamoto et al., 1982). Necrotic fibers
11.5.4. Treatment and management There is no specific treatment for DMRV. Ankle–foot orthoses benefit foot drop. Cardiac or pulmonary failure has not been reported.
11.6. Laing distal myopathy: early-onset distal myopathy (EODM)/myosinopathy
DISTAL MYOPATHIES sternocleidomastoid muscles. The disease progresses slowly, eventually resulting in weakness of finger flexors, shoulder, trunk, facial and tongue muscles. Scoliosis and tendon contractures, mainly in the ankles, are common (Fig. 11.6A). Cardiomyopathy has rarely been described (Hedera et al., 2003), and severe respiratory problems have not been encountered.
229
all fibers should be slow type 1 fibers in this muscle (Fig. 11.6C, D). Almost all type 1 fibers expressing slow myosin belong to the highly atrophic group and they also express fast myosin, suggesting a complete reprogramming of fiber type specifications due to the slow myosin MYH7 defect (Lamont et al., 2006). 11.6.3. Molecular pathogenesis
11.6.1. Molecular genetic findings After the first linkage report, subsequent investigations of phenotypically similar Italian (Scoppetta et al., 1995), German (Voit et al., 2001) and US (Hedera et al., 2003) families revealed linkage to the same 14q locus. Myosin genes MYH6 and MYH7 were positional candidates and MYH7 proved to be the causative gene (Meredith, 2001; Meredith et al., 2004). Interestingly, one mutation, K1617del, was independently detected in one German and one Austrian family (Zimprich et al., 2000; Meredith et al., 2004) without haplotypesharing at the locus, suggesting non-related mutations. This K1617del mutation also occurred as a de-novo mutation in one Finnish patient (Udd, personal communication) and may thus be a preferred mutational event. De-novo mutations have been identified in three out of seven families, indicating that de-novo mutations may be a common cause in this disorder and should, thus, be considered in isolated cases (Meredith et al., 2004). 11.6.2. Laboratory investigations and muscle pathology Serum CK is slightly elevated or normal in EODM and EMG shows early-recruiting short duration, low amplitude and polyphasic motor unit action potentials in all muscles studied. Spontaneous activity was found in the more severely affected muscles, without signs of neuropathy (Mastaglia et al., 2002). Muscle imaging is highly suggestive of the diagnosis showing, besides overall small muscle mass, very selective changes of degeneration in the anterior tibial muscles (Fig. 11.6B) and, at advanced age, also lesions in medial gastrocnemius and the proximal thigh muscles. The early atrophy of sternocleidomastoid muscles can also be captured (Lamont et al., 2006). On muscle biopsy no rimmed or other vacuoles were found in the reported biopsies of proximal muscles (Mastaglia and Laing, 1999). Findings in more affected anterior tibial muscle show very distinct pathology with bimodal fiber size distribution: large number of highly atrophic tiny fibers scattered and in groups, simulating group atrophy, and normally sized fibers. Practically all fibers express fast myosin, whereas normally only a small minority of fibers are type 2 fibers and almost
Mutations in MYH7 causing EODM are strictly located in the tail region of the slow myosin hexameric molecule (Fig. 11.3I; Meredith et al., 2004). This location is very close to the defined domain for interaction with titin, which is of interest regarding the phenotype, but the functional molecular consequences of the mutations in this part of the myosin filament are not known. Mutations in the ultimate C-terminus of slow myosin are known to cause hyaline body myopathy, with no preference for distal muscles, and mutations in the proximal neck, the head part and different mutations in the rod domain may cause cardiomyopathy (Blair et al., 2002; Richard et al., 2003). 11.6.4. Treatment and management There is no specific treatment for EODM. Scoliosis and contractures may need surgical intervention, and neck flexor weakness may cause retroposition of the head with consequences for breathing and swallowing. 11.6.5. Other entities possibly related to Laing’s distal myopathy Many disorders with distal muscle weakness from early infancy have been described (Magee and DeJong 1965; Heyck et al., 1968; van der Does de Willebois et al., 1968; Bethlem, 1980). In retrospect it is impossible to classify these further without molecular genetic information. A clinically distinct entity was reported by Magee and DeJong (1965). This is a dominantly inherited distal myopathy with onset by age 2 years in three patients. The initial symptoms were bilateral foot drop, with weakness of finger and wrists extensors developing in later childhood. One patient had hypertrophied calves. The disorder did not progress after the age 18 of years. Muscle biopsy and EMG confirmed the myopathic nature of this disorder. Van der Does de Willebois et al. (1968) reported three patients in one family with similar manifestations to those described by Magee and DeJong. In another large dominant family eight affected members had nonprogressive distal leg muscle weakness and pes cavus. One child in the family had distal leg, forearm, and deltoid weakness with onset before the age of 2 years. The child also had kyphoscoliosis, pes cavus, talipes valgus,
230
B. UDD
Fig. 11.6. Laing early-onset distal myopathy (myosinopathy). (A,B) The generalized reduced muscle bulk and contractures of the ankles, combined with scoliosis (operated) and neck flexor weakness, make an unusual posture. Magnetic resonance muscle imaging showing rather selective degenerative involvement of anterior tibial muscles and less severly soleus muscles. (C,D) Immunohistochemistry of tibialis anterior shows total reprogramming of fiber types. Normally this muscle has just 10–20% fast type 2 fibers whereas in this pathology practically all fibers express fast myosin (D). All highly atrophic fibers are slow myosin type 1 fibers (C), and they express both myosins.
DISTAL MYOPATHIES and joint contractures (Bautista et al., 1978). Muscle biopsy displayed selective atrophy of type 1 fibers.
11.7. Early-onset distal myopathy/ nebulinopathy Mutations in nebulin are a well known cause of autosomal-recessive nemaline myopathy (Wallgren-Pettersson and Laing, 2003). Besides generalized weakness and muscle atrophy of variable severity, the distal muscles are usually more involved than the proximal ones. Very recently, a number of patients with early-onset sporadic or recessive distal myopathy have been found to have nebulin mutations. Extensor muscles of hands and feet are severely affected but the progression is very mild and patients do not have major disability in adulthood. Muscle imaging reveals selective degeneration in the anterior tibial muscles (Fig. 11.7), EMG is myopathic and CK is normal or mildly elevated. Muscle biopsy shows scattered and grouped atrophic fibers. The reason for the disorder not to have been identified earlier as nebulinopathy is that the newly discovered missense mutations do not produce nemaline rods on light microscopy, despite multiple biopsies in some cases (Udd, personal communication, 2005). On electron microscopy, some small rod-like dense material associated with Z-disks may be observed, but in other patients there are just non-specific sarcomeric alterations without any rod-like material. Molecular diagnosis of this group of patients is currently laborious considering the large size of the gene.
11.8. Penisson-Besnier distal myopathy/ myotilinopathy Penisson-Besnier et al. have described an autosomal dominant French family with a very late onset of distal myopathy around the age of 60 years (Penisson-Besnier
231
et al., 1998). Weakness and atrophy was more severe in the posterior calf muscles than in the anterior lower legs muscles at onset. Later the patients experienced progression to proximal and upper limb muscles, although with retained walking ability even into later age. Cardiomyopathy was not observed in the patients. 11.8.1. Laboratory investigations and muscle pathology Muscle enzyme CK was either normal or mildly elevated. EMG showed myopathic changes with fibrillations and complex repetitive discharges. Muscle imaging confirmed the clinical findings of extensive involvement of calf muscles showing dystrophic fatty replacement and very mild proximal leg muscle involvement. Histopathology of proximal upper limb muscles showed a variety of pathological findings including multiple large nonrimmed vacuoles, focal sarcoplasmic desmin reactive masses that stained darker on Gomori trichrome, rimmed vacuoles, and IBM-like cytoplasmic and nuclear filaments on electron microscopy (Penisson-Besnier et al., 1998). 11.8.2. Molecular genetic findings Molecular linkage results for the titin locus on 2q31 were inconclusive and testing for C-terminal titin mutations was negative. Considering that the pathology resembled more that of the Markesbery-Griggs family and that of myofibrillar myopathies (MFM), the myotilin gene was a good candidate. Sequencing the MYOT gene showed that a mutation S60F, previously reported in MFM (Selcen and Engel, 2004), segregated completely with the affected patients in the family and was not present in healthy individuals (Penisson-Besnier et al., 2006). Myotilin is a component of the Z-disk of the sarcomere together with ZASP. It binds to a-actinin and is important
Fig. 11.7. Early-onset distal myopathy (nebulinopathy). Magnetic resonance muscle imaging of the lower legs in a 24-year-old woman with early-onset distal myopathy caused be homozygous missense mutation in nebulin, showing selective lesions in anterior tibialis muscles bilaterally.
232
B. UDD
for actin dynamics (Salmikangas et al., 2003), and accumulates with desmin in the abnormal fibers with disintegrated myofibrils (Fig. 11.8), but further molecular dysfunctions caused by the known mutations are not known. Interestingly, this is another muscle-specific protein that in some instances may cause a dystrophy with a predominant proximal LGMD-phenotype (LGMD 1A) (Hauser et al., 2000) and in others a very pronounced distal affection.
11.9. Distal myopathy with cardiomyopathy/ desminopathy One of the earliest reports on distal myopathy described a very large autosomal-dominant family with branches both in Europe and in North America (Milhorat and Wolff, 1943). This family later proved to have a mutation in the desmin gene (Sjo¨berg et al., 1999). Other myopathies more recently characterized as myofibrillar myopathies on morphological grounds share findings on muscle biopsy with desminopathy. (See chapter 12, Hereditary inclusion-body myopathies.)
11.10. Other distal myopathies: single families There have been a number of single families reported with distal myopathy. These may each represent a specific entity, but without replication by other reports or further molecular genetic data, a separation is not possible. Sumner et al., (1971) described six patients in an English family with autosomal-dominant distal myopathy. The clinical phenotype was variable within the family: one patient developed hand weakness at age 15, and
Fig. 11.8. Penisson-Besnier distal myopathy (myotilinopathy). Myotilin immunohistochemistry performed on a biceps muscle biopsy in a patient with myotilin S60F mutation showing abnormally located myotilin in fibres undergoing myofibril disintegration.
by age 30 ankle weakness appeared. The patient was still alive at age 62. In other family members, weakness began at a later age and in the anterior compartment of the lower leg. An Italian family with 10 affected members in three generations showed weakness in both anterior and posterior compartments of the lower legs starting between the second and sixth decades of life (Servidei et al., 1999). The disease progressed to the upper limbs and proximal muscles with considerable variation of severity. Two patients became wheelchair-bound in their sixth decade. Dysphagia and dysphonia were early signs, but facial and extraocular muscles were spared. Patients had pes cavus and tendon reflexes were lost. However, no atrophy of the intrinsic foot muscles to suggest neurogenic involvement was observed (Servidei et al., 1999). Electrophysiologically a mixed pattern of both myopathic and neurogenic findings were obtained. The family showed linkage on chromosome 19p13 with a LOD score of 3.03. Rimmed vacuoles were frequent on muscle biopsy accompanied by dystrophic changes, and characteristics of both lysosomal and non-lysosomal degradation was reported (DiBlasi et al., 2004). Felice et al. described a Polish kindred with four affected members from three generations with an autosomal dominant distal myopathy (Felice et al., 1999). Adult onset of weakness in the anterior muscles of the lower legs with slow progression to proximal muscles, upper limb extensors and truncal muscles was shown. The result was a combined steppage and waddling gait. Cataracts without myotonia occurred in three patients. Serum CK was mildly elevated and EMG showed myopathic changes. One proximal muscle biopsy showed mild non-specific myopathic change only. Because, at the time, all defined loci for distal myopathies were excluded by linkage the disease appeared to be a distinct disorder. A large US family with late adult-onset dominant distal myopathy associated with vocal cord and pharyngeal muscle weakness was reported by Feit et al. (1998). Patients had weakness and atrophy of anterolateral lower leg, finger extensor and shoulder muscles. These findings were often asymmetric together with paretic dysphonia and dysphagia (Feit et al., 1998). Muscle fibers showed abundant rimmed vacuoles, and the disease was mapped to a locus (MPD2) on chromosome 5q overlapping the myotilin locus. However, myotilin mutations have not been found (Feit, personal communication). A British family with seven affected patients was reported as a dominant distal myopathy with early failure of respiratory muscles (Chinnery et al., 2001). Later studies have shown considerable variability as some patients had more proximal weakness and some even respiratory
DISTAL MYOPATHIES problems at onset (Birchall et al., 2005). Onset varied from 32 to 75 years with weakness of ankle dorsiflexion in those with distal presentation. Nocturnal hypoventilation was an early problem with the need for nasal mask ventilation. One patient became non-ambulatory after 7 years, another remained ambulatory for 20 years after of onset of symptoms. Serum CK values were normal or slightly elevated and the EMG showed myopathic features. Recently, muscle imaging studies included a new family with a similar clinical phenotype and showed a highly pathognomonic pattern of muscle involvement, not described in other myopathies so far. Thigh muscles had selective involvement of semitendinosus and rectus femoris muscles, besides anterolateral involvement of lower leg muscles (Birchall et al., 2005). Muscle biopsy findings in clinically affected muscles contained dystrophic changes, rimmed vacuoles, and peculiar eosinophilic inclusions. The inclusions were congophilic and showed desmin, b-amyloid and phosphorylated-tau positivity, but they have not so far been identified on electron microscopy. Linkage studies excluded all known distal myopathy loci and further molecular definition is awaited. Mahjneh et al. have described a new autosomal dominant distal myopathy in a Finnish family (2003). Onset of symptoms occurred after age 30, in some patients with weakness of the intrinsic hand muscles and in others with asymmetric weakness in the anterior lower leg muscles (Fig. 11.9). There was slow progression and the disorder was difficult to distinguish from either WDM or TMD on grounds other than the slightly earlier onset. On muscle biopsy rimmed vacuoles were frequent and with eosinophilic inclusions. Genome-wide linkage study not only excluded the loci for other known distal myopathies but showed significant LOD score >3 for two separate loci, 8p22–q11 and 12q13–q22. Fine mapping of these loci showed that they both segregated chromosomes to affected and non-affected individuals identically (Haravuori et al., 2004). One candidate gene on each locus was sequenced without mutations.
233
Recently, a large Australian family with late onset dominant distal myopathy, presenting pronounced involvement of posterior calf muscles and sparing of anterior lower leg muscles, was described (Williams et al., 2005). Extensive molecular genetic studies excluded 12 different genetic loci implicated in distal myopathy phenotypes. CK was mildly elevated and patients complained of frequent cramps. Muscle imaging revealed an unusual posterolateral involvement on the legs and in the thighs a distinct semitendinosus and rectus femoris predilection. Muscle biopsy did not show rimmed vacuolar features nor any increase of desmin expression in the fibers. A long list of other reported inherited late-onset distal myopathies exists (Huhn, 1966; Ricker and Mertens, 1968; Swash et al., 1988; Ishpekova and Milanov, 1997; Uesaka et al., 1997; Fardeau and Tome´, 1998). Tomlinson et al. described the autopsy findings in a 44year-old male with an inherited early adult-onset distal myopathy and cardiomyopathy beginning in distal leg muscles and gradually spreading to the hands and proximal limb muscles (Tomlinson et al., 1974). Sternocleidomastoid and facial muscles were subsequently involved, and the EMG suggested both myopathy and neuropathy. Postmortem examination revealed severe fibroadipose replacement of muscles with some myopathic features, and a cardiomyopathy.
11.11. Distal phenotype in other myopathies The disorders described above were all reported as distal myopathies and can be searched for with those key words. However, there are many disorders which can present with a distal phenotype but were classified or reported under different headings (Table 11.3). This is a good example of the further development of molecular genetics serving as a new basis for classification of myopathies. Moreover, molecular genetics has disclosed allelic disorders or even identical gene defects
Fig. 11.9. Dominant distal myopathy in a Finnish family. Computed tomography muscle imaging of the lower legs in a 48year-old man belonging to the MPD3 distal myopathy family with a so-far unknown genetic defect. Involvement of the anterior tibial muscles is asymmetric and there are smaller lesions in the lateral peroneus brevis muscles.
234 Table 11.3 Distal phenotypes in other myopathies Genetics
Onset
Gene/protein and locus
Type
Age
Early symptoms
CKa
Muscle pathology
Inheritance
Myofibrillar myopathy
40–60
Lower legs and hands
1–3
ADc and sporadic
Myotilin 5q31
Myofibrillar myopathy
40–60
Lower legs and hands
1–3
AD and sporadic
ZASP 10q22–23
Myofibrillar myopathy
20–40
Distal leg and forearm þ cardiomyopathy
1–3
AD
Desmin 2q35
Myofibrillar myopathy
Adult
AD
40
1–3
aB-crystallin 11q22–23
Desmin-related with sarcoplasmic bodies Oculopharyngodistal myopathy OPDM Distal onset in telethoninopathy Caveolinopathy
AD
>40 in AD <40 in AR Early
Distal leg and hands þ cardiomyopathy Hands, thenar, finger flexors Lower leg and hands þ extraocular Lower leg, anterior
Rimmed and non-rimmed vacuoles, GTCb dark and hyaline structures, desmin þ Rimmed and non-rimmed vacuoles, GTC dark and hyaline structures, desminþ Dystrophic, rimmed vacuoles þ desmin bodies Desmin granulofilamentous Sarcoplasmic bodies
1–5
Rimmed vacuoles
AD and ARd
3–10
Rimmed vacuoles
AR
Telethonin 17q12
Early
hands
3–10
Reduced caveolin-3
AD
CAV3 3p25
a
CK: serum creatine kinase; GTC: Gomori trichrome stain; c AD: autosomal dominant; d AR: autosomal recessive. b
DISTAL MYOPATHIES that may present with highly variable phenotypes (Udd et al., 2005). 11.11.1. Myofibrillar myopathies (MFM) Recent progress has delineated different genes that underlie the muscle pathology characteristics of MFM: desmin, aB-crystallin, myotilin and ZASP (see also above; Selcen et al., 2004, 2005). Patients and families with dominant myofibrillar myopathy frequently present as distal myopathies (Horowitz and Schmalbruch, 1994; Nakano et al., 1996; Fidzianska et al., 1999; Dalakas et al., 2000; Sugawara et al., 2000). There is a wide range of onset, patterns of muscle involvement, and progression rate. Patients may have cardiomyopathy and respiratory muscle weakness. Accumulations of desmin-positive material, congophilic products of myofibrillar degradation, and ectopic accumulation of dystrophin, gelsolin and amyloid and cell cycle related proteins in muscle represent both unusual and unifying morphologic features. Desmin may, however, also be expressed in the cytoplasm of atrophic and regenerating fibers in other myopathies. A Swedish family with adult-onset dominant distal myopathy, starting in thenar and finger flexor muscles, extending in some patients to sternocleidomastoid weakness and cardiomyopathy was reported by Edstro¨m et al. (1980). Histopathological changes were relatively distinct with sarcoplasmic bodies and intermediate filament accumulation containing desmin. The sarcoplasmic bodies suggested abnormal turnover of intermediate filaments. X-ray microanalysis of these bodies revealed an increased content of sulfur (Edstro¨m and Wroblewiski, 1981). Re-evaluation of this family has shown that the onset can also be in proximal muscles (Edstro¨m, personal communication). The molecular genetic basis is unknown. 11.11.2. Telethoninopathy Mutations in telethonin cause recessive LGMD 2G, a rare disorder identified in only a few Brazilian families (Moreira et al., 1997). Muscle biopsy pathology included rimmed vacuoles. Telethoninopathy may present with distal weakness and atrophy. 11.11.3. Oculopharyngodistal myopathy Japanese families with late-onset dominant distal myopathy and prominent oculopharyngeal weakness, in one associated with cardiomyopathy, have been reported (Goto et al., 1977; Satoyoshi and Kinoshito, 1977). In other families the trait seemed to be autosomal recessive
235
(Scrimgeur and Mastaglia, 1984, Uyama et al., 1998). Recently, patients have been described from Europe and Thailand (van der Sluijs et al., 2004; Witoonpanich et al., 2004). 11.11.4. Caveolinopathy A defect caveolin-3 is the molecular cause of LGMD 1C. However, mutated caveolin-3 may also cause other phenotypes including “rippling muscle disease”, isolated hyperCKemia, and distal myopathy with pronounced atrophy of intrinsic muscles in hands and feet (Tateyama et al., 2002; Sotgia et al., 2003). 11.11.5. Distal myopathy with Paget’s disease Most patients with the (rare) combination of myopathy, Paget’s disease and frontotemporal dementia have a proximal muscle phenotype, and mutations in valosin-containing protein (VCP), which has a role in the ubiquitin-proteasome pathway (Song et al., 2005). One subgroup not linked to the VCP locus have onset of weakness in the anterior lower leg muscles, rimmed vacuoles on muscle biopsy and Paget’s disease. The underlying gene defect has not been reported. 11.11.6. Other entities Dominant late-onset weakness and atrophy of hand and lower leg muscles combined with cardiomyopathy was reported in a Swedish family. EMG showed prominent myotonia and the disorder was linked to a locus on chromosome 10q (Melberg et al., 1999). In a sporadic patient with distal myopathy both rimmed vacuoles and rods were found on muscle biopsy (Sieb et al., 1997). In a French family a dominant distal myopathy affected three young boys. The disorder presented at the start of ambulation with bilateral foot drop and calf muscle hypertrophy (Lapresle et al., 1972). Muscle biopsy findings suggested a mitochondrial myopathy. Later extensive studies on mitochondrial myopathies have not delineated specific distal myopathies, although a mitochondrial background was suggested in one patient with tubular aggregates on muscle biopsy (Garrard et al., 2002). In a large Dutch family distal weakness and atrophy in both hands and feet occurred between 5 and 15 years of age (Biemond, 1955). Ankle reflexes were lost but sensation was normal. The disorder remained limited to distal muscles and became stationary after age 50. Autopsy in one patient and a muscle biopsy from another showed both neurogenic and myopathic changes, making a clear distinction difficult (Biemond, 1966).
236
B. UDD
11.12. Differential diagnosis With the expansion of molecular genetics and molecular definition of many distal myopathies, the differential diagnostic procedure has paradoxically become both easier and more difficult. With only four distinct entities, defined on clinical grounds alone, in the 1980s, there is now a plethora of entities with different genetic causes for distal myopathy phenotypes. An additional problem for the diagnostic procedure is that many diseases (mostly genetic) known to cause characteristically a clinical presentation with proximal weakness may in some instances have a distal presentation (Table 11.4). This has prompted for consideration a large and everexpanding number of genes in distal myopathies, as well as questioning the basis of the classification. Diseases presenting with distal leg weakness must first be differentiated from neurogenic disorders. The diagnosis of distal myopathy requires robust determination that the weakness stems from a myopathy and not from motor neuropathy or anterior horn cell disorders, as well as exclusion of morphologically distinct entities. The axonal form of Charcot–Marie–Tooth (CMT) disease with late-onset distal weakness and normal or only slightly abnormal nerve conduction studies may cause confusion (Dyck, 1993). Usually the myopathic EMG and muscle histology of distal myopathies exclude CMT. The clinical features of distal forms of chronic spinal muscular atrophy closely mimic those of the distal myopathies. Electrophysiological studies reveal anterior horn cell dysfunction (changes of denervation with normal motor nerve conduction, and normal sensory nerve conduction studies) and muscle biopsy reveals features of neurogenic atrophy (McLeod and Prineas, 1971). In exceptional cases, the diagnosis may still remain undetermined. The adult form of myotonic dystrophy type 1, with its slowly progressive distal weakness and atrophy, is Table 11.4 Other differential diagnostic possibilities Facioscapulohumeral dystrophy Inclusion body myositis (s-IBM) Nemaline myopathy Myotonic dystrophies Scapuloperoneal syndromes Distal spinal muscular atrophy Focal motor neuron disease (e.g., Hirayama, Sobue) Central core disease Debranching enzyme deficiency Phosphorylase b kinase deficiency Lipid storage myopathy
arguably the most common “distal dystrophy” worldwide, and can be confused with some of the distal myopathies described in this chapter. The presence of myotonia, sternocleidomastoid and facial weakness, ptosis, and other characteristic features usually define myotonic dystrophy. DNA analysis for a (CTG)n expansion mutation facilitates the diagnosis. Type 2 myotonic dystrophy, with (CCTG)n expansion on 3q, is unlikely to cause diagnostic confusion although deep finger flexor weakness may be an early feature and some have calf weakness very late in the course of the disease (Day et al., 1999, 2003). Rare instances of distal weakness have been described in chronic polymyositis (Hollinrake, 1969; Van Kasteren, 1975; Carpenter et al., 1978). The more rapid evolution of weakness, presence of dysphagia, and inflammatory infiltrates in muscle, as well as abnormal irritability in proximal muscles in polymyositis, help to differentiate this disorder. Inclusion body myositis (s-IBM) often presents with anterior compartment leg or forearm weakness (Carpenter et al., 1978). Familial cases of otherwise typical IBM have been described (Baumbach et al., 1990; Neville et al., 1992). However, autoaggressive inflammatory infiltrates (partial invasion) and the increased expression of MHC class-1 antigen on immunohistochemistry differentiates this entity from the distal myopathies with rimmed vacuoles. MRI with maximal fat suppression sequences can also be used for distinction, as focal inflammatory changes can be detected in s-IBM but not in distal myopathy. In recent years, small congophilic inclusions and expression of multiple proteins that are also present in the brain in Alzheimer’s disease (b-amyloid, b-amyloid precursor protein, tau, ubiquitin, etc.) have been observed in vacuolated muscle fibers in s-IBM (Griggs et al., 1995; Askanas and Engel, 1998), and all vacuolated as well as non-vacuolated fibers show immunopositivity for aB-crystallin (Banwell and Engel, 2000). (See chapter 13 on inclusion body myositis.) Since many of these changes have been observed, to a minor extent, in h-IBM and rimmed vacuolar distal myopathies (Askanas and Engel, 1998; Tomimitsu et al., 2002), they are not clearly useful for differential diagnosis. However, congophilic deposits or b-amyloid immunoreactivity are unusual in vacuolated fibers in TMD or WDM. Patients with either facioscapulohumeral dystrophy (FSHD) or scapuloperoneal syndromes, presenting with anterior tibial muscle weakness before facial or shoulder weakness is evident, are not very rare and may cause diagnostic confusion. In FSHD isolated calf muscle involvement has been reported rarely. Mutation analysis is mandatory to identify “sporadic” cases of FSHD (van der Koi, 2000). Other myopathies can have scapuloperoneal distribution of muscle involvement
DISTAL MYOPATHIES with predominantly distal weakness, including nemaline myopathy (see above for nebulin mutated EODM; Brooke, 1977) and central core disease (Kratz and Brooke, 1980). In other disorders rare cases may have a distal presentation such as: centronuclear myopathy (Moxley et al., 1978), debrancher enzyme deficiency myopathy (glycogenosis type 3; DiMauro et al., 1979), phosphorylase b kinase deficiency (Clemens et al., 1990) and lipid storage myopathies (Salmon et al., 1971). A distal phenotype can also occur secondary to nephropathic cystinosis (Vester et al., 2000). Welander distal myopathy, with symptoms starting in the hands, is so distinctive that it is mimicked by few other neuromuscular disorders. Spinal muscular atrophy or amyotrophic lateral sclerosis can present with bilateral though often asymmetrical hand weakness. Hirayama’s disease, juvenile asymmetric upper limb spinal muscular atrophy, has an earlier age of onset, and weakness is most pronounced in thenar muscles (Willeit et al., 2001). Occasionally lesions of the cervical spinal cord, such as syringomyelia, as well as cervical ribs and bilateral lesions of the brachial plexus can cause distal arm and hand weakness and atrophy. A careful clinical examination and electrodiagnostic evidence of chronic neurogenic motor unit potentials usually establish the correct diagnosis.
11.13. Conclusions The number of recent reports suggests increasing awareness of distal myopathy. Some disorders regularly progress to eventually involve proximal muscle, whereas others remain distal throughout. Histopathology of the distal myopathies lacks pathognomonic findings. There is a gradual breakdown and loss of muscle fibers with replacement by fibrous and fatty connective tissue, similar to other forms of muscular dystrophy, frequently but not always with rimmed vacuolar myofibrillar degradation. The preferential involvement of distal muscles is governed by yet unknown genetic programs. Further insight into the distal dystrophies will be encountered with better understanding of the downstream effects of genetic defects on protein function and interaction pathways. For the identification of the molecular genetic cause in an individual patient with distal myopathy efficient new methods for large-scale survey of muscle genes will be needed.
References ˚ hlberg G, Jakobsson F, Fransson A, et al. (1994). DistribuA tion of muscle degeneration in Welander distal myopathy — a magnetic resonance imaging and muscle biopsy study. Neuromuscul Disord 4: 55–62.
237
˚ hlberg G, von Tell D, Borg K, et al. (1999). Genetic linkage A of Welander distal myopathy to chromosome 2p13. Ann Neurol 46: 399–404. Anderson LV, Harrison RM, Pogue R, et al. (2000). Secondary reduction in calpain 3 expression in patients with limb girdle muscular dystrophy type 2B and Miyoshi myopathy. Neuromuscul Disord 10: 553–559. Argov Z, Sadeh M, Mazor K, et al. (2000). Muscular dystrophy due to dysferlin deficiency in Libyan Jews. Clinical and genetic features. Brain 123: 1229–1237. Askanas V, Engel W (1998). Sporadic inclusion-body myositis and hereditary inclusion-body myopathies: current concepts of diagnosis and pathogenesis. Curr Opin Rheumatol 10: 530–542. Banwell B, Engel A (2000). aB-crystallin immunolocalization yields new insight into inclusion body myositis. Neurology 54: 1033–1041. Barohn RJ, Miller RG, Griggs RC (1991). Autosomal recessive distal dystrophy. Neurology 41: 1365–1369. Bashir R, Britton S, Strachan T, et al. (1998). A gene related to Caenorhabditis elegans spermatogenesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B. Nat Genet 20: 37–42. Baumbach LL, Neville HE, Ringel SP, et al. (1990). Familial inclusion body myositis: evidence for autosomal dominant inheritance. Am J Hum Genet 47: A48. Bautista J, Rafel E, Castilla JM, et al. (1978). Hereditary distal myopathy with onset in early infancy. J Neurol Sci 37: 149–162. Bejaoui K, Hirabayashi K, Hentati F, et al. (1995). Linkage of Miyoshi myopathy (distal autosomal recessive muscular dystrophy) to chromosome 2p12–14. Neurology 45: 494–498. Bethlem J (1980).In: Myopathies, 2nd ed.Elsevier NorthHolland, Amsterdam, pp. 59–60. Biemond A (1955). Myopathia distalis juveniles hereditaria. Acta Psychiatr Neurol Scand 30: 25–33. Biemond A (1966). Myopathia distalis juveniles. In: E ¨ ber Progressive MuskeldystroKuhn, (Ed.), Symposium U phien.Springer, Berlin, pp. 95–100. Birchall P, von der Hagen M, Bates D, et al. (2005). Subclinical semitendinosus and obturator externus involvement defines an autosomal dominant myopathy with early respiratory failure. Neuromuscul Disord 15: 595–600. Blair E, Redwood C, de Jesus Oliveira M, et al. (2002). Mutations of the light meromyosin domain of the betamyosin heavy chain rod in hypertrophic cardiomyopathy. Circ Res 90: 263–269. Borg K, Borg J, Lindblom U (1987). Sensory involvement in distal myopathy (Welander). J Neurol Sci 80: 323–331. Borg K, Solders G, Borg J, et al. (1989). Neurogenic involvement in distal myopathy (Welander). J Neurol Sci 91: 53–70. Borg K, Tome FM, Edstrom L (1991a). Intranuclear and cytoplasmic filamentous inclusions in distal myopathy (Welander). Acta Neuropathol 82: 102–114. Borg K, Ahlberg G, Borg J, et al. (1991b). Welander’s distal myopathy: clinical, neurophysiological and muscle biopsy
238
B. UDD
observations in young and middle aged adults with early symptoms. J Neurol Neurosurg Psychiatry 54: 494–498. Brooke MH (1977). In: A Clinician’s View of Neuromuscular Disease, Williams & Wilkins, Baltimore p. 209. Cabella G, Candelero G (1970). U’n caso di miopathia distale tardiva tipo Gowers–Welander. Sist Nerv 22: 266–269. Carpenter S, Karpati G, Heller I, et al. (1978). Inclusion body myositis: a distinct variety of idiopathic inflammatory myopathy. Neurology 28: 8–17. Chinnery P, Johnson MA, Walls TJ, et al. (2001). A novel autosomal dominant distal myopathy with early respiratory failure: clinico-pathologic characteristics and exclusion of linkage to candidate genetic loci. Ann Neurol 49: 443–452. Clemens PR, Yamamoto M, Engel AG (1990). Adult phosphorylase b kinase deficiency. Ann Neurol 28: 529–536. Cupler EJ, Bohlega S, Hessler R, et al. (1998). Miyoshi myopathy in Saudi Arabia: clinical, electrophysiological, histopathological and radiological features. Neuromuscul Disord 8: 321–326. Dahlgaard E (1960). Myopathia distalis tarda hereditaria. Acta Psychiatr Neurol Scand 35: 440–445. Dalakas M, Park KY, Semino-Mora C, et al. (2000). Desmin myopathy, a skeletal myopathy with cardiomyopathy caused by mutations in the desmin gene. N Engl J Med 342: 770–780. Day JW, Roelofs R, Leroy B, et al. (1999). Clinical and genetic characteristics of a five-generation family with a novel form of myotonic dystrophy (DM2). Neuromuscul Disord 9: 19–27. Day JW, Ricker K, Jacobsen JF, et al. (2003). Myotonic dystrophy type 2: molecular, diagnostic and clinical spectrum. Neurology 60: 657–664. de Seze J, Udd B, Haravuori H, et al. (1998). The first European tibial muscular dystrophy family outside the Finnish population. Neurology 51: 1746–1748. Di Blasi C, Moghadaszadeh B, Ciano C, et al. (2004). Abnormal lysosomal and ubiquitin-proteasome pathways in 19p13.3 distal myopathy. Ann Neurol 56: 133–138. DiMauro S, Hartwig GB, Hays A, et al. (1979). Debrancher deficiency: neuromuscular disorder in five adults. Ann Neurol 5: 422–431. Duemler LP (1962). Late distal myopathy: report of a case. Neurology 12: 547–550. Dyck PJ (1993). Inherited neuropathies: degeneration and atrophy affecting peripheral motor, sensory and autonomic neurons. In: PJ Dyck, PK Thomas, EH Lambert (Eds.), Vol 3, Saunders, Philadelphia, pp. 1065–1093. Edstro¨m L (1975). Histochemical and histopathological changes in skeletal muscle in late-onset hereditary distal myopathy (Welander). J Neurol Sci 26: 147–157. Edstro¨m L, Wroblewski R (1981). Sarcoplasmic bodies in distal myopathy compared with nemaline rods: X-ray microanalysis and histochemical observation. J Neurol Sci 49: 341–355. Edstro¨m L, Thornell LE, Eriksson A (1980). A new type of hereditary distal myopathy with characteristic sarcoplasmic bodies and intermediate (skeletin) filaments. J Neurol Sci 47: 171–189.
Eisenberg I, Avidan N, Potikha T, et al. (2001). UDP-NAcetylglucosamine 2-epimerase/N-Acetylemannosamine kinase is mutated in recessive hereditary inclusion body myopathy. Nat Genet 29: 83–87. Eymard B, Laforet P, Tome FM, et al. (2000). Miyoshi distal myopathy: specific signs and incidence (in French). Rev Neurol 156: 161–168. Fardeau M, Tome´ F (1998). Inclusion body myopathies. In: V Askanas, G Serratrice, W. K. Engel (Eds.), Inclusion Body Myositis and Myopathies. Cambridge University Press, Cambridge p. 257. Feit H, Silbergleit A, Schneider LB, et al. (1998). Vocal cord and pharyngeal weakness with autosomal distal myopathy: clinical description and gene localization to chromosome 5q31. Am J Hum Genet 63: 1732–1744. Felice K, Meredith C, Binz N, et al. (1999). Autosomal dominant distal myopathy not linked to the known distal myopathy loci. Neuromuscul Disord 9: 59–65. Fidzianska A, Drac H, Kaminska AM (1999). Familial inclusion body myopathy with desmin storage. Acta Neuropathol 97: 509–514. Gallardo E, Rojas-Garcia R, de Luna N, et al. (2002). Inflammation in dysferlin myopathy: immunohistochemical characterization of 13 patients. Neurology 57: 2136–2138. Garrard P, Blake J, Stinton V, et al. (2002). Distal myopathy with tubular aggregates: a new phenotype associated with multiple deletions in mitochondrial DNA? J Neurol Neurosurg Psychiatry 73: 207–208. Goto I, Kato H, Kase M, et al. (1977). Oculopharyngeal myopathy with distal and cardiomyopathy. J Neurol Neurosurg Psychiatry 40: 600–607. Gowers WR (1902). A lecture on myopathy and a distal form. Br Med J 2: 89–92. Griggs R, Askanas V, DiMauro S, et al. (1995). Inclusion body myositis and inclusion body myopathies. Ann Neurol 38: 705–713. Hackman P, Vihola A, Haravuori H, et al. (2002). Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin. Am J Hum Genet 71: 492–500. Hackman P, Vihola AK, Udd AB (2003). The role of titin in muscular disorders. Ann Med 35: 434–441. Haravuori H, Makela-Bengs P, Udd B, et al. (1998a). Assignment of the tibial muscular dystrophy (TMD) locus on chromosome 2q31. Am J Hum Genet 62: 620–626. Haravuori H, Ma¨kela¨-Bengs P, Udd B, et al. (1998b). Tibial muscular dystrophy and late onset distal myopathy are linked to the same locus on chromosome 2q. Neurology 50 (Suppl 4): A186(abstr). Haravuori H, Vihola A, Straub V, et al. (2001). Secondary calpain3 deficiency in 2q linked muscular dystrophy — titin is the candidate gene. Neurology 56: 869–877. Haravuori H, Siitonen HA, Mahjneh I, et al. (2004). Linkage to two separate loci in a family with a novel distal myopathy phenotype (MPD3). Neuromuscul Disord 14: 183–187. Hauser S, Horrigan SK, Salmikangas P, et al. (2000). Myotilin is mutated in limb girdle muscular dystrophy 1A. Hum Mol Genet 9: 2141–2147.
DISTAL MYOPATHIES Hedera P, Petty EM, Bui MR, et al. (2003). The second kindred with autosomal dominant distal myopathy linked to chromosome 14q: genetic and clinical analysis. Arch Neurol 60: 1321–1325. ¨ ber eine kongenitale Heyck H, Luders CJ, Wolter M (1968).U distale Muskeldystrophie mit benigner Progredienz Nervenarzt 39: 549–556. Hollinrake K (1969). Polymyositis presenting as distal muscle weakness: a case report. J Neurol Sci 8: 479–492. Horowitz S, Schmalbruch H (1994). Autosomal dominant distal myopathy with desmin storage: a clinicopathologic and electrophysiologic study of a large kinship. Muscle Nerve 17: 151–160. ¨ ber distale Myopathien insbesondere die Huhn VA (1996). U Myopathia distalis tarda (hereditaria). Fortschr Neurol Psychiatr 34: 589–597. Illa I, Brown R (1999). Distal anterior dystrophy: a distinct Spanish phenotype. Acta Myologica 3: 67–68. Illa I, Serrano-Munuera C, Gallardo E, et al. (2001). Distal anterior compartment myopathy: a dysferlin mutation causing a new muscular dystrophy phenotype. Ann Neurol 49: 130–134. Illarioshkin S, Ivanova-Smolenskaya IA, Tanaka H, et al. (1996). Clinical and molecular analysis of large family with three distinct phenotypes of progressive muscular dystrophy. Brain 119: 1895–1909. Illarioshkin S, Ivanova-Smolenskaya IA, Greenberg CR, et al. (2000). Identical dysferlin mutation in limb-girdle muscular dystrophy type 2B and distal myopathy. Neurology 55: 1931–1933. Isaacs H, Badenhorst ME, Whistler T (1988). Autosomal recessive distal myopathy. J Clin Pathol 41: 188–194. Ishpekova B, Milanov I (1997). Distal muscular dystrophy. Case reports. Electromyogr Clin Neurophysiol 37: 201–205. Kayashima T, Matsuo H, Satoh A, et al. (2002). Nonaka myopathy is caused by mutations in the UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase gene (GNE). J Hum Genet 47: 77–79. Kratz R, Brooke MH (1980). Distal myopathy. In: PJ Vinken, CW Bruyn (Eds.), Vol 40, Elsevier/North Holland, Amsterdam, pp. 471–483. Kumamoto T, Fukuhara N, Nagashima M, et al. (1982). Distal myopathy: histochemical and ultrastructural studies. Arch Neurol 39: 367–380. Kumamoto T, Ueyama H, Watanabe S, et al. (1994). Muscle fiber degradation in distal myopathy with rimmed vacuoles. Acta Neuropathol 87: 143–148. Kumamoto T, Ito T, Horinouchi H, et al. (2000). Increased lysosome-related proteins in the skeletal muscles of distal myopathy with rimmed vacuoles. Muscle Nerve 23: 1686–1693. Laing N, Laing BA, Meredith C, et al. (1995). Autosomal dominant distal myopathy: linkage to chromosome 14. Am J Hum Genet 56: 422–427. Lamont P, Udd B, Mastaglia FL, et al. (2006). Laing earlyonset distal myopathy: slow myosin defect with variable abnormalities on muscle biopsy. J Neurol Neurosurg Psychiatry 77: 208–215. Lapresle J, Fardeau M, Godet-Guillain J (1972). Myopathie distale et congenitale, avec hypertrophie des mollets pres-
239
ence d’anomahes mitochondriales a la biopsie musculaire. J Neurol Sci 17: 87–94. Linssen W, de Visser M, Notermans NC, et al. (1998). Genetic heterogeneity in Miyoshi type distal muscular dystrophy. Neuromuscul Disord 8: 317–320. Liu J, Aoki M, Illa I, et al. (1998). Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy. Nat Genet 20: 31–40. Magee KR, Dejong RN (1965). Hereditary distal myopathy with onset in infancy. Arch Neurol 13: 387–398. Mahjneh I, Haravuori H, Paetau A, et al. (2003). A distinct phenotype of distal myopathy in a large Finnish family. Neurology 61: 87–92. Mahjneh I, Lamminen AE, Udd B, et al. (2004). Muscle magnetic resonance imaging shows distinct diagnostic patterns in Welander and tibial muscular dystrophy. Acta Neurol Scand 110: 87–93. Mamoli A, Scarlato G (1969). Distal myopathy. Clinical, histological and electromyographic aspects of a sporadic case. Riv Neurobiol 15: 877–881. Markesbery WR, Griggs RC, Leach RP, et al. (1977). Late onset hereditary distal myopathy. Neurology 23: 127–134. Markesbery WR, Griggs RC, Herr B (1997). Distal myopathy: electron microscopic and histochemical studies. Neurology 27: 727–741. Mastaglia F, Laing N (1999). Distal myopathies: clinical and molecular diagnosis and classification. J Neurol Neurosurg Psychiatry 67: 703–707. Mastaglia FL, Phillips BA, Cala LA, et al. (2002). Early onset chromosome 14-linked distal myopathy (Laing). Neuromuscul Disord 12: 350–357. Matsuda C, Aoki M, Hayashi YK, et al. (1999). Dysferlin is a surface membrane-associated protein that is absent in Miyoshi myopathy. Neurology 53: 1119–1122. Matsuda C, Hayashi YK, Ogawa M, et al. (2001). The sarcolemmal proteins dysferlin and caveolin-3 interact in skeletal muscle. Hum Mol Genet 17: 1761–1766. McLeod JG, Prineas JW (1971). Distal type of chronic spinal muscular atrophy. Brain 94: 703–708. McNally EM, Ly CT, Rosenmann H, et al. (2000). Splicing mutation in dysferlin produces limb-girdle muscular dystrophy with inflammation. Am J Med Genet 91: 305–312. Mehrotra MP, Yadava SN, Gupta AK, et al. (1964). Distal myopathy. J Indian Med Assoc 49: 392–396. Melberg A, Oldfors A, Blomstrom-Lundqvist C, et al. (1999). Autosomal dominant myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy linked to chromosome 10q. Ann Neurol 46: 684–692. Meredith C (2001). Distal myopathy, University of Western Australia, PerthThesis. Meredith C, Herrmann R, Parry C, et al. (2004). Mutations in the slow skeletal muscle fiber myosin heavy chain gene (MYH7) cause Laing early-onset distal myopathy (MPD1). Am J Hum Genet 75: 703–708. Milhorat AT, Wolff HG (1943). Studies in diseases of muscle: XIII. Progressive muscular dystrophy of atrophic distal type:
240
B. UDD
Report on a family: report of autopsy. Arch Neurol Psychiatry 49: 655. Miller RG, Blank NK, Layzer RB (1979). Sporadic distal myopathy with early adult onset. Ann Neurol 5: 220–228. Miyoshi K, Iwasa M, Kawai H, et al. (1977). Autosomal recessive distal muscular dystrophy: a new variety of distal muscular dystrophy predominantly seen in Japan. Nippon Rinsho (Tokyo) 35: 3922. Miyoshi K, Kawai H, Iwasa M, et al. (1986). Autosomal recessive distal muscular dystrophy as a new type of progressive muscular dystrophy: seventeen cases in eight families, including an autopsied case. Brain 109: 31–54. Mizusawa H, Kurisaki H, Takatsu M, et al. (1987). Rimmed vacuolar distal myopathy: an ultrastructural study. J Neurol 234: 137–147. Mongini T, Doriguzzi C, Palmucci L, et al. (1989). Sporadic distal myopathy with early adult onset: a study of muscle biopsies and muscle cell cultures. Eur Neurol 29: 287–291. Moreira E, Vainzof M, Marie SK, et al. (1997). The seventh form of autosomal recessive limb-girdle muscular dystrophy is mapped to 17q11–12. Am J Hum Genet 61: 151–159. Moxley RT, Griggs RC, Markesbery WR, et al. (1978). Metabolic implications of distal atrophy: carbohydrate metabolism in centronuclear myopathy. J Neurol Sci 39: 247–260. Murakami N, Ihara Y, Nonaka I (1995). Muscle fiber degeneration in distal myopathy with rimmed vacuoles. Acta Neuropathol 89: 29–34. Murone I, Sato T, Shirakawa K, et al. (1963). Distal myopathy: nonhereditary distal myopathy. Clin Neurol (Tokyo) 3: 387–394. Nakano S, Engel AG, Waclawik AJ, et al. (1996). Myofibrillar myopathy with abnormal foci of desmin positivity. J Neuropathol Exp Neurol 55: 549–562. Neville H, Baumbach LL, Ringel SP, et al. (1992). Familial inclusion body myositis: evidence for autosomal dominant inheritance. Neurology 42: 897–902. Nishino I, Noguchi S, Murayama K, et al. (2002). Distal myopathy with rimmed vacuoles is allelic to hereditary inclusion body myopathy. Neurology 59: 1689–1693. Nonaka I, Sunohara N, Ishiura S, et al. (1981). Familial distal myopathy with rimmed vacuole and lamellar (myeloid) body formation. J Neurol Sci 51: 141–155. Nonaka I, Sunohara N, Satoyoshi E, et al. (1985). Autosomal recessive distal muscular dystrophy: a comparative study with distal myopathy with rimmed vacuole formation. Ann Neurol 17: 51–59. Penisson-Besnier I, Dumez C, Chateau D, et al. (1998). Autosomal dominant late adult onset distal leg myopathy. Neuromuscul Disord 8: 459–466. Penisson-Besnier I, Talyinen K, Dumez C, et al. (2006). Myotilinopathy in a late onset myopathy family. Neuromuscul Disord 16: 427–431. Richard I, Broux O, Allamand V, et al. (1995). Mutations in the proteolytic enzyme calpain3 cause limb-girdle muscular dystrophy type 2A. Cell 81: 27–40. Richard P, Charron P, Carrier L, et al. (2003). Hypertrophic cardiomyopathy: distribution of disease genes, spectrum
of mutations, and implications for a molecular diagnosis strategy. Circulation 107: 2227–2232. Ricker K, Mertens HG (1968). The differential diagnosis of the myogenic (facio)scapulo-peroneal syndrome. Eur Neurol 1: 275–279. Salmikangas P, van der Ven PF, Lalowski M, et al. (2003). Myotilin, the limb-girdle muscular dystrophy 1A (LGMD1A) protein, cross-links actin filaments and controls sarcomere assembly. Hum Mol Genet 12: 189–203. Salmon MA, Esiri MM, Ruderman NB (1971). Myopathic disorder associated with mitochondrial abnormalities, hyperglycaemia, and hyperketonaemia. Lancet 2: 290–293. Satoyoshi E, Kinoshita M (1977). Oculopharyngodistal myopathy: report of four families. Arch Neurol 34: 89–92. Scoppetta C, Casali C, La Cesa I, et al. (1995). Infantile autosomal dominant distal myopathy. Acta Neurol Scand 92: 122–126. Scoppetta C, Mercuri B, Di Lello R, et al. (1997). Autosomal recessive distal dystrophy. Ital J Neurol Sci 18: 271–276. Scrimgeour E, Mastaglia F (1984). Oculopharyngeal and distal myopathy. A case study from Papua New Guinea. Am J Med Genet 17: 763–771. Selcen D, Engel AG (2004). Mutations in myotilin cause myofibrillar myopathy. Neurology 62: 1363–1371. Selcen D, Engel AG (2005). Mutations in ZASP define a novel form of muscular dystrophy in humans. Ann Neurol 57: 269–276. Selcen D, Stilling G, Engel AG (2001). The earliest pathologic alterations in dysferlinopathy. Neurology 56: 1472–1481. Servidei S, Capon F, Spinazzola A, et al. (1999). A distinctive autosomal dominant vacuolar neuromyopathy linked to 19p13. Neurology 53: 830–837. Sieb J, VonOertzen J, Tolksdorf K, et al. (1997). Sporadic adultonset distal myopathy with rimmed vacuoles, 16–18 nm tubulofilaments and extensive rod formation. J Neurol Sci 146: 81–84. Sjo¨berg G, Saavedra-Matiz CA, Rosen DR, et al. (1999). A missense mutation in the desmin rod domain is associated with autosomal dominant distal myopathy, and exerts a dominant negative effect on filament formation. Hum Mol Genet 8: 2191–2198. Song EJ, Yim SH, Kim E, et al. (2005). Human Fas-associated factor 1, interacting with ubiquitinated proteins and valosin-containing protein, is involved in the ubiquitin-proteasome pathway. Mol Cell Biol 25: 2511–2524. Sotgia F, Woodman SE, Bonuccelli G, et al. (2003). Phenotypic behavior of caveolin-3 R26Q, a mutant associated with hyperCKemia, distal myopathy, and rippling muscle disease. Am J Physiol Cell Physiol 285: C1150–C1160. Sugawara M, Kato K, Komatsu M, et al. (2000). A novel de novo mutation in the desmin gene causes desmin myopathy with toxic aggregates. Neurology 55: 986–990. Sumner D, Crawfurd MD, Harriman DG (1971). Distal muscular dystrophy in an English family. Brain 94: 51–59. Sunohara N, Nonaka I, Kamei N, et al. (1989). Distal myopathy with rimmed vacuole formation. A follow up study. Brain 112: 65–83.
DISTAL MYOPATHIES Swash M, Schwarz MS, Thompson A, et al. (1988). Distal myopathy with focal granular degenerative change in vacuolated type 2 fibers. Clin Neuropathol 7: 249–253. Tateyama M, Aoki M, Nishino I, et al. (2002). Mutation in the caveolin-3 gene causes a peculiar form of distal myopathy. Neurology 58: 323–325. Thierren C, Dodig D, Karpati G, et al. (2005). Validation of Time- and Cost-Effective RNA based approach in detecting human dysferlin gene mutations. Neurology 64: A175(suppl). Tomimitsu H, Ishikawa K, Shimizu J, et al. (2002). Distal myopathy with rimmed vacuoles: novel mutations in the GNE gene. Neurology 59: 451–454. Tomlinson BE, Walton JN, Irving D (1974). Spinal cord limb motor neurones in muscular dystrophy. J Neurol Sci 22: 305–311. Udd B (1992). Limb-girdle type muscular dystrophy in a large family with distal myopathy: a homozygous manifestation of a dominant gene? J Med Genet 29: 383–390. Udd B, Kaarianen H, Somer H (1991a). Muscular dystrophy with separate phenotypes in a large family. Muscle Nerve 14: 1050–1058. Udd B, Lamminen A, Somer H (1991b). Imaging methods reveal unexpected patchy lesions in late onset distal myopathy. Neuromuscul Disord 1: 271–280. Udd B, Rapola J, Nokelainen P, et al. (1992). Nonvacuolar myopathy in a large family with both late adult onset distal myopathy and limb-girdle type muscular dystrophy. J Neurol Sci 113: 214–221. Udd B, Partanen J, Halonen P, et al. (1993). Tibial muscular dystrophy. Late adult-onset distal myopathy in 66 Finnish patients. Arch Neurol 50: 604–608. Udd B, Haravuori H, Kalimo H, et al. (1998). Tibial muscular dystrophy — from clinical description to linkage on chromosome 2q31. Neuromuscul Disord 8: 327–332. Udd B, Vihola A, Sarparanta J, et al. (2005). Titinopathies and extension of the M-line mutation phenotype beyond distal myopathy and LGMD2J. Neurology 64: 636–642. Uesaka Y, Nakamichi K, Kojima S, et al. (1997). Autosomal dominant distal myopathy with rimmed vacuoles and cytoplasmic inclusions: report of a family (in Japanese). Rinsho-Shinkeigaku 37: 1–6. Uyama E, Uchino M, Chateau D, et al. (1998). Autosomal recessive oculopharyngodistal myopathy in light of distal myopathy with rimmed vacuoles and oculopharyngeal muscular dystrophy. Neuromuscul Disord 8: 119–125. van den Bergh PY, Bouquiaux O, Verellen C, et al. (2003). Tibial muscular dystrophy in a Belgian family. Ann Neurol 54: 248–251. van der Does de Willebois AEM, Meyer AE, Simons AJ, et al. (1968). Distal myopathy with onset in early infancy. Neurology 18: 383–395.
241
van der Koi A, Visser MC, Rosenberg N, et al. (2000). Extension of the clinical range of facioscapulohumeral dystrophy: report of six cases. J Neurol Neurosurg Psychiatry 69: 114–116. van der Sluijs BM, ter Laak HJ, Scheffer H, et al. (2004). Autosomal recessive oculopharyngodistal myopathy: a distinct phenotypical, histological, and genetic entity. J Neurol Neurosurg Psychiatry 75: 1499–1501. van Kasteren BJ (1975). Polymyositis presenting with chronic progressive distal muscular weakness. J Neurol Sci 41: 307–316. Vester U, Schubert M, Offner G, et al. (2000). Distal myopathy in nephropathic cystinosis. Pediatr Nephrol 14: 36–38. Voit T, Kutz P, Leube B, et al. (2001). Autosomal dominant distal myopathy: further evidence of a chromosome 14 locus. Neuromuscul Disord 11: 11–19. von Tell D (2004). Welander Distal Myopathy: Gene Mapping and Analysis of Candidate Genes, The Karolinska Institute, StockholmThesis. von Tell D, Somer H, Udd B, et al. (2002). Welander distal myopathy outside the Swedish population: phenotype and genotype. Neuromuscul Disord 12: 544–547. von Tell D, Bruder CE, Anderson LV, et al. (2003). Refined mapping of the Welander distal myopathy region on chromosome 2p13 positions the new candidate region relomeric of the DYSF locus. Neurogenetics 4: 173–177. Wallgren-Pettersson C, Laing N (2003). Report on the 109th ENMC International Workshop: Nemaline Myopathy. Neuromuscul Disord 13: 501–507. Weiler T, Greenberg CR, Nylen E, et al. (1996). Limb-girdle muscular dystrophy and Miyoshi myopathy in an aboriginal Canadian kindred map to LGMD2B and segregate with the same haplotype. Am J Hum Genet 59: 872–878. Welander L (1951). Myopathia distalis tarda hereditaria. Acta Med Scand 141 (Suppl. 265): 1. Welander L (1957). Homozygous appearance of distal myopathy. Acta Genet 7: 321–325. Willeit J, Kiechl S, Kiechl-Kohlendorfer U, et al. (2001). Juvenile asymmetric segmental spinal muscular atrophy (Hirayama’s disease): three cases without evidence of “flexion myelopathy”. Acta Neurol Scand 104: 320–322. Williams DR, Reardon K, Roberts L, et al. (2005). A new dominant distal myopathy affecting posterior leg and anterior upper limb muscles. Neurology 64: 1245–1254. Witoonpanich R, Phankhian S, Sura T, et al. (2004). Oculopharyngodistal myopathy in a Thai family. J Med Assoc Thai 87: 1518–1521. Zimprich F, Djamshidian A, Hainfellner JA, et al. (2000). An autosomal dominant early adult-onset distal muscular dystrophy. Muscle Nerve 23: 1876–1879.
Handbook of Clinical Neurology, Vol. 86 (3rd series) Myopathies F. L. Mastaglia, D. Hilton-Jones, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 12
Hereditary inclusion body myopathy and other rimmed vacuolar myopathies ZOHAR ARGOV* AND STELLA MITRANI-ROSENBAUM Hadassah-Hebrew University Medical Centre, Jerusalem, Israel
Over the last three decades a unique group of adult-onset hereditary myopathies, usually with distal onset, has emerged. These neuromuscular disorders share histological and ultrastructural features similar to sporadic inclusion body myositis: presence of cytoplasmic autophagic (“rimmed”) vacuoles and of cytoplasmic inclusions composed of clusters of tubular filaments (Griggs et al., 1995; Askanas and Engel, 1998; Argov and Soffer, 2002). To separate these various conditions from the late-onset, inflammatory myopathy with a similar pathology a new nomenclature was suggested: sporadic inclusion body myositis (s-IBM) for the acquired condition (that is not transmitted by Mendelian rules although it may have some genetic predisposition) and hereditary inclusion body myopathies (h-IBM) for the group of heterogeneous familial myopathies (Askanas and Engel, 1993). This terminology, however, is not uniformly accepted. Several hereditary myopathies with similar histological features were classified as “distal myopathies”, because of their mode of presentation. Thus, chapter 11 on distal myopathies describes many conditions that could fall under the term h-IBM. Following our description of the genetic defect in the “prototypic” form of h-IBM, the Iranian– Jewish quadriceps-sparing myopathy (QSM) due to mutation in the gene called GNE (Eisenberg et al., 2001), it became clear that one of the “classical” forms of distal myopathies, the Nonaka type of distal myopathy with rimmed vacuoles (DMRV) is exactly the same condition as QSM (clinically and genetically). This has changed the overall classification of both h-IBM and distal myopathy groups. In this chapter we will continue to use the term hereditary inclusion body myopathy (in the singular form) and reserve it only for the GNE-related conditions
(also referred to as IBM2 by the McKusick classification). The chapter will be devoted to this worldwide condition but will also review some rare myopathies with rimmed vacuoles that are not described in the chapter on distal myopathy.
12.1. h-IBM diagnostic criteria These are the typical features that define the disease now termed hereditary inclusion body myopathy:
Isolated skeletal muscle disease, usually presenting with distal muscle weakness in the legs.
Onset in late teenage years or early adulthood. Mild elevation of serum creatine kinase (CK). Presence of several “rimmed” (autophagic) vacuoles
in an affected muscle sample, with few other pathological changes in the fibers. Inflammation is an extremely unusual feature. Detection of 15–21-nm tubofilamentous inclusions by electron microscopy (EM). Autosomal-recessive inheritance with mutations in the GNE gene.
It should be noted that in some patients not all these criteria are fulfilled, as will be discussed later.
12.2. Clinical features As mentioned above, h-IBM and DMRV present a very similar clinical picture and the description here applies to both conditions as well as to many isolated families from all over the world (Nonaka et al., 1981; Argov and Yarom, 1984; Sunohara et al., 1989; Sadeh et al., 1993; Sivakumar and Dalakas, 1996; Satayoshi et al., 1998).
*Correspondence to: Zohar Argov, MD, Department of Neurology, Hadassah University Hospital, Jerusalem 91120, Israel. E-mail:
[email protected], Tel: 972-2-6776-938, (Cellular): 972-523-232-191.
244
Z. ARGOV AND S. MITRANI-ROSENBAUM
The age of onset is usually in the third decade of life. Onset before the age of 15 years was not recorded and in our series of more than 120 patients, less than 3% approached a physician before age 20. Satayoshi et al. (1998) mention onset at age 10 in their large review of the DMRV syndrome, but this was before the defects in GNE were known and some of the patients may have had other distal myopathies. Onset after age 40 was also seen by us (Sadeh and Argov, 1998) and others (Sunohara et al., 1989) but this too is rare. However, asymptomatic elder persons (in their sixties) who are homozygous for common GNE mutations were detected both in the Middle-Eastern cluster and in a large cohort of Japanese patients (Nishino et al., 2002; Argov et al., 2003). This may suggest that very late onset could also occur. The initial symptom is typically a change in gait, sometimes first noticed by the patient’s family or friends. Weakness at onset is usually in the anterior compartment of the leg leading to bilateral foot drop, which may be slightly asymmetric. The posterior calf muscles become involved later and sometimes are spared until the more advanced stages of the disease. Very rarely patients are encountered where the onset of weakness was in the proximal musculature of the leg without distal weakness (Argov et al., 2003). As the disease progresses, the proximal leg muscles become affected. Usually, the iliopsoas is the first and the most affected of the hip muscles with a similar degree of weakness in the glutei, hamstrings and adductors. The quadriceps muscle remains strong (normal power or minimal reduction) even in older patients who are wheelchair-bound or bedridden. It should be emphasized that this unique pattern of QSM is present in h-IBM (Argov and Yarom, 1984), in DMRV (Sunohara et al., 1989) and numerous families with GNE defects reported worldwide. This facilitates the clinical recognition of this condition, as there is no other known myopathy with this distribution of weakness. In less than 5% of patients the quadriceps becomes very weak even to the same degree as the other hip muscles (Neufeld et al., 1995; Sunohara et al 1989; Sadeh and Argov 1998). Such patients will lose ambulation at an early stage of the disease. In the upper limbs, involvement in the scapular and very proximal muscles is initially found followed by weakening of the distal muscles of the arm and the hand at later stages. The early affliction of the finger flexors, considered to be typical for s-IBM, is observed in about 10% of patients. Neck flexors become affected too as the disease progresses. Mild facial muscle weakness was found in two families originating from the Egyptian Karaites (Argov et al., 1998). Tendon reflexes may be absent at the ankles, but are otherwise normal and subjective distal sensory symptoms (usually paresthesiae) are not accompanied by abnormal
findings on sensory examination. The heart, brain and other organs are not involved in h-IBM. Hereditary inclusion body myopathy is a slowly progressive neuromuscular disorder, but the rate of progression rate is variable. Most of the patients still walk on flat surfaces after 15 years of disease. Complete loss of ambulation occurs early if the quadriceps becomes involved, even within 5–7 years. Some of the patients reached the seventh and even eighth decade of life, but were markedly incapacitated, although the quadriceps were spared.
12.3. Laboratory tests 12.3.1. Creatine kinase Serum CK, and other enzymes of muscle origin, are usually modestly elevated. Some patients may have normal CK even at the onset of the disease. CK elevations to more than five times the normal range are very uncommon in h-IBM. 12.3.2. Electrophysiology The conventional concentric needle electromyography (EMG) frequently shows spontaneous activity in the tibialis anterior, but this is rare in other muscles. In most tested muscles, many units are small and polyphasic indicative of a myopathic disease (Sadeh et al., 1993). However, reduced recruitment with prolonged, large or even polyphasic units is also recorded in some affected muscles (Argov and Yarom, 1984). Motor and sensory conductions are normal even in those patients with sensory complaints and reduced tendon reflexes (Argov and Yarom, 1984; Sunohara et al., 1989; Sadeh et al., 1993). 12.3.3. Muscle biopsy The histological features of h-IBM are typical: vacuolated myofibers associated with variable degrees of neurogenic and myopathic features (Argov and Soffer, 2002). The number of vacuolated fibers in a mediummagnification field ranges from very few to many and they may be normal in size or atrophic and of both types. The appearance of the vacuoles varies from small, simple to multilobulated (Fig. 12.1). There is no correlation between the number of vacuoles and the severity of the disease and no study has given evidence of changes in the number of vacuoles during the course of the disease. On cryostat sections stained with haemoxylin and eosin (H&E), the vacuoles may appear to be rimmed by granular eosinophilic material (hence the term “rimmed” vacuoles; Fig. 12.1). These non-membrane bound vacuoles appear on EM to be filled with degradation products consisting of membranous whorls (“myeloid
HEREDITARY INCLUSION BODY MYOPATHY
245
Fig. 12.1. The typical vacuoles in h-IBM. (A) Simple small type with rimmed periphery (H&E stain). (B) Multilobulated structures (Gomori stain).
bodies”) and other debris (Fig. 12.2), thus fitting the description of “autophagic” vacuoles. In some h-IBM cases light microscopy identifies small, refractive eosinophilic inclusions in the cytoplasm, usually near the vacuoles, but unlike s-IBM intranuclear inclusions are infrequent. On immunohistochemistry, SM-31 monoclonal antibody, directed against 200-kDa phosphorylated neurofilaments and cross reacting with hyperphosphorylated tau, stains the inclusions (Mirabella et al., 1996). But the diagnostic hallmark of h-IBM is found mostly on EM studies: collections of 15–21-nm cytoplasmic tubofilaments (Fig. 12.3). Inflammation is absent in the vast majority of biopsies of patients with h-IBM and its absence was considered a major diagnostic criterion (Argov and Soffer, 2002). However, recently a few patients with genetically confirmed h-IBM have shown inflammation in a muscle sample: either a modest infiltrate in a perivascular region
Fig. 12.2. Ultrastructure of the autophagic vacuoles, showing the membrane whorls.
Fig. 12.3. A typical inclusion body composed of tubofilaments, as seen in EM.
(Argov et al., 2003) or more widespread inflammation with inflammatory markers (Krause et al., 2003; Yabe et al., 2003). Interestingly, Figarella-Branger et al., (1990) reported sporadic IBM with “minimal or no inflammation”. It is possible that some of these patients, especially the younger ones, may have been isolated cases of recessive h-IBM. In the context of probable h-IBM, the presence of inflammation should not discard this diagnosis. Non-specific myopathic changes seen in h-IBM are variation in fiber size, presence of hypertrophied fibers, central nuclei, fiber splitting and rare regenerating myofibers. Necrosis may infrequently be observed. Neurogenic changes may also be found in h-IBM muscle and include the presence of scattered angulated, atrophic fibers and nuclear clumps. This may be a predominating feature in some biopsies leading to erroneous diagnosis of a primary neurogenic disease.
246
Z. ARGOV AND S. MITRANI-ROSENBAUM
12.4. h-IBM molecular genetics The unique h-IBM cluster in Persian Jews gave us the opportunity to locate the gene responsible for this disease to chromosome 9 (Mitrani-Rosenbaum et al., 1996) using the classical positional cloning approach, and eventually to identify GNE as the disease-causing gene in this community (Eisenberg et al., 2001). A single homozygous mutation has been identified in the GNE gene in all h-IBM patients of Persian Jewish descent. This is a missense mutation, a T to C transition converting methionine to threonine at codon 712 (M712T). h-IBM patients originating from other Jewish communities outside Iran and non-Jewish families in the Middle East were also found to carry the same mutation, in its homozygous form (Eisenberg et al., 2001; Argov et al., 2003). Therefore this particular M712T mutation is referred to as the h-IBM “Middle-Eastern” mutation. Following the identification of GNE as the molecular basis of h-IBM in Persian Jews, various different mutations in the gene were identified worldwide in h-IBM suspected h-IBM patients from families of diverse nonJewish origins, such as Italians, Spanish, Greeks, Germans, Irish, Mexicans, Caucasian Americans, AfroAmericans from Georgia and from Bahamas and even Asians from India (Eisenberg et al., 2001; Broccolini et al., 2002; Darvish et al., 2002; Eisenberg et al., 2003; Vasconcelos et al., 2002; Del Bo et al., 2003; Krause et al., 2003; Broccolini et al. 2004; Huizing et al., 2004 and unpublished families tested in our laboratory). Numerous GNE mutations were also detected in the Japanese DMRV (“Nonaka disease”) (Kayashima et al., 2002; Arai et al., 2002; Nishino et al., 2002, Tomimitsu et al.,
R177C D176V
C13S P27S
I377fsX16 I200F
M171V
V367I R246Q
R11W
V331A
F528C A631V A631T
D378Y A524V
R162C
V216A
G206S G206fsX4
M712T
−COOH
M anNA c 6-kinase
G312R
I472T
R306Q A460V
H132Q G134V
G708S
T507P
UDP-GlcNAc 2-epimerase
R129Q
A630T
G559R
P283S
R202L
I557T
A519S
D225N
P36L
NH2−
2002, Yabe et al., 2003; Noguchi et al., 2004; Saito et al., 2004). The same defective gene provided the final proof that the clinically similar disorders h-IBM and DMRV are the same entity. In contrast to the single homozygous M712T Middle East genetic defect, most of the non-Middle Eastern h-IBM patients are compound heterozygotes for different GNE mutations. This is true also for the many Japanese families which interestingly do not appear to have developed the disease as the result of a single founder effect, except for a cluster of patients carrying a homozygous mutation V572L (Arai et al., 2002; Nishino et al., 2002). The product of the GNE gene is a 722-amino-acid protein, N-acetylglucosamine 2 epimerase/N-acetylmannosamime kinase, which is a bifunctional enzyme (Hinderlich et al., 1997). The two functions of the enzyme could be physically separated: mutation analysis of single highly conserved amino acids confirmed that the epimerase domain is located in the N-terminal part of GNE (up to amino acid 378), whereas the C-terminal part contains the kinase domain (from amino acid 410; Effertz et al., 1999). More than 50 different GNE mutations, mostly missense, have been identified to date in patients with myopathies (Fig. 12.4). These mutations do not cluster at a specific locus of GNE, but are dispersed along the genecoding exons, both in the epimerase- and in the kinasecoding sequences. The M712T homozygous mutation in Middle-Eastern patients occurs at the very end of the kinase region, at amino acid 712. In compound heterozygote individuals both mutations may occur in the kinase domain, in the epimerase domain (infrequent situation), or one mutation at each domain. However, GNE protein
C303X C303V
V572L
V696M
G576E
Y675H A600T
V421A R420X
I587T
Fig. 12.4. Schematic representation of the GNE gene and of the currently-identified mutations in h-IBM in the respective domains of the molecule, epimerase or kinase (only mutations occurring in the coding region have been drawn).
HEREDITARY INCLUSION BODY MYOPATHY is always present in all patients, since most mutations are missense mutations and no patient carrying two nonsense mutations has been reported. Interestingly, no correlation between genotype and phenotype has been found, and all mutation combinations result in a very similar phenotype. Therefore, it seems that h-IBM is not caused by an impairment of one of the specific enzymatic functions, but rather is the result of a comprehensive defect of the GNE molecule. The widespread distribution of mutations along the entire GNE gene suggests that a non-specific disruption of the catalytic activity, rather than the impairment of a solitary aspect of the GNE biochemistry is likely to underlie the h-IBM pathogenesis of L-IBM.
12.5. Epidemiology H-IBM is mostly prevalent in Iranian Jews with an estimated affliction rate of about 1:1500 adults, who are children of parents of the same community which is estimated to include about 150 000 adults (Argov and Mitrani-Rosenbaum, 1998). Estimation of carrier frequency in this community for the common M712T mutation is about 5% (Eisenberg et al., 2001). H-IBM patients of families originating from Jewish communities outside Iran, including Iraq, Afghanistan, Kurdistan, Uzbekistan and even Egypt, carry the same mutation in the GNE gene (Eisenberg et al., 2001; Argov et al., 2003). Indeed, historic events in the ancient Persian community allowed the tracing of these sparse Jewish populations as one single and same ethnic entity (Netzer, 1988). Furthermore, non-Jewish families in the Middle East, from the Karaite sect (which emerged from Judaism in the 10th century) and Moslem Arabs from Bedouin and Palestinian origins, were also found to carry the same mutation, in its homozygous form (Argov et al., 2003). In all these patients (more than 120), the same homozygous mutation was found within a common haplotype spreading over about 700 kb around the gene site. This ancient founder mutation (and DNA fragment) common to the Middle East was estimated to be more than 1300 years old (Argov et al., 2003). H-IBM/DMRV is also more prevalent in Japan and in neighboring countries (although there are distal myopathies with rimmed vacuoles in Japan that do not have GNE mutations), but their prevalence is unknown and numerous mutations were described from this region in a few dozens of recorded patients. At least one mutation, V572L, is very frequent and has probably a founder effect (Arai et al., 2002). It should be emphasized that h-IBM was diagnosed in numerous families with variable ethnic backgrounds from Asia, Europe North Africa and the Americas, thus it should be part of the differential diagnosis of distal myopathy worldwide.
247
12.6. GNE biochemistry N-acetylglucosamine 2 epimerase/N-acetylmannosamime kinase is the key enzyme in the metabolic pathway leading to the synthesis of sialic (neuraminic) acid (Keppler et al., 1999; Fig. 12.5). Sialic acids, the most abundant terminal monosaccharides on glycoconjugates in eukaryotic cells, comprise a family of more than 50 naturally occurring carboxylated amino sugars with a scaffold of nine carbon atoms, which are components of complex N-glycans and many O-glycans of glycoconjugates (Kelm and Schauer, 1997). Sialic acids may affect adhesion processes and thus are involved in a variety of biological functions, such as cell–cell interactions, cell migration and proliferation (Varki, 1997), inflammation, wound healing and metastasis (Edelman and Crossin, 1991; Hynes and Lander, 1992). The biosynthesis of sialic acids is initiated in the cytosol. The physiological precursor of all sialic acids is N-acetylmannosamine (ManNAc), which is produced from UDP-N-acetylglucosamine by GNE, the rate-limiting enzyme of sialic acid biosynthesis in vitro and in vivo. The first two steps of sialic acid biosynthesis are catalyzed by one of the two distinct functional domains of GNE. First, the UDPGlcNAc 2-epimerase domain forms ManNAc from UDP-GlcNAc with simultaneous release of UDP. Subsequently the ManNAc kinase domain phosphorylates ManNAc to create ManNAc 6-phosphate (Hinderlich et al., 1997; Effertz et al., 1999). Sialic acid is formed by condensation of N-acetylmannosamine-6-phosphate
GlcNAc-6-P GlcNAc-1-P
UDP-GlcNAc UDP-GlcNAc 2-epimerase
ManNAc ManNAc kinase
ManNAc-6-P NeuAc-9-P NeuAc CMP-NeuAc Glycoconjugate
Sialylated Sialyltransferase glycoconjugate
Fig. 12.5. GNE enzyme and the sialic acid biosynthetic pathway.
248
Z. ARGOV AND S. MITRANI-ROSENBAUM
and phosphoenolpyruvate and activated by CTP to form CMP-sialic acid. This is the activated nucleotide sugar of sialic acid, which is used as a substrate of sialyltransferases in glycoconjugate biosynthesis in the Golgi apparatus (Reutter et al., 1997). GNE is regulated by several different mechanisms, most importantly feedback inhibition of the epimerase activity by CMP–sialic acid (Kornfeld et al., 1964). Point mutations in the CMP–sialic acid binding site of GNE in man, resulting in the inactivation of the feedback inhibition, lead to the rare metabolic disease, sialuria, characterized by highly abundant production and secretion of sialic acid by patients (Seppala et al., 1999). Furthermore, it has been shown that GNE is phosphorylated by protein kinase C and that phosphorylation regulates its enzymatic activity (Horstkorte et al., 2000). Besides feedback inhibition by CMP–sialic acid, the activity of UDP-N-acetylglucosamine 2-epimerase is further regulated by different oligomeric states of the bifunctional enzyme. The fully active form of the enzyme, displaying both epimerase and N-acetylmannosamine kinase activities, is a hexamer consisting of 75-kDa subunits. In the absence of the epimerase substrate UDP-N-acetylglucosamine, the enzyme decays to a dimer displaying only kinase activity. Addition of UDP-N-acetylglucosamine to the dimeric enzyme results in reassembly of the hexamer (Hinderlich et al., 1997). The role of GNE as a key regulator of cell surface sialylation was shown by Keppler et al. (1999). Lymphocytes lacking the bifunctional enzyme are unable to synthesize sialic acids and lose their sialic acid dependent functions. This highly conserved enzyme has been cloned and characterized from rat, mouse and human (Sta¨sche et al., 1997, Horstkorte et al., 1999; Lucka et al., 1999). GNE is essential for embryonic development since specific knockout inactivation of the murine gene in mice results in drastic reduction of sialylation of embryonal cells and finally in embryonal lethality at day 8.5 (Schwarzkopf et al., 2002). These findings explain why no mutations have been detected in vivo in a combination which leads to the absolute abolishment of the GNE protein.
12.7. GNE function in h-IBM Investigations of the GNE enzymatic functions showed a slightly reduced epimerase activity in lymphocytes, myoblasts and myotubes from Jewish Middle-Eastern patients with h-IBM carrying the homozygous M712T mutation (Hinderlich et al., 2004; Salama et al., 2005) as well as, to various extents, in lymphocytes, fibroblasts, myoblasts and myotubes from Japanese patients presenting various different homozygous and heterozygous mutations at the epimerase and the kinase domains
(Nishino et al., 2002; Noguchi et al., 2004). As expected, cells carrying mutations in the epimerase domain showed lower epimerase activity than cells carrying kinase mutations. In addition, since kinase activity resulting from GNE cannot be technically measured in vivo (because of the contaminant similar activity of different other kinases in the cell, especially N acetyl mannosamine kinase), in-vitro experiments were performed with GNE recombinant proteins expressed in insect cells, carrying the M712T mutation and also various different mutations detected in non-Jewish non-Middle Eastern patients with h-IBM, either in the epimerase domain or the kinase domain. All of the 11 mutations analyzed (seven in the kinase domain and four in the epimerase domain of GNE) show a reduction of both epimerase and kinase activities (Hinderlich et al., 2004, Penner et al., unpublished data). However, the extent of the enzymatic activity reduction varied between 30% and 60%, and it is unclear how such partial reduction could lead to changes in sialic acid production, especially since the feedback inhibition mechanism remains intact. The importance of the oligomeric state of GNE was also analyzed in these in-vitro experiments, and it was shown that for all these mutations, including M712T, the hexameric structure of GNE was preserved (Penner et al, unpublished data). Studies by Noguchi et al. (2004) on patient cells carrying various mutations led to the same results for most of them, however few led to the disruption of GNE to dimers and monomers. Altogether it is clear that mutations in GNE impair its enzymatic activity to different extents, but not necessarily because of the disruption of the quaternary structure of the enzyme.
12.8. h-IBM and sialylation An evident hypothesis to explain h-IBM pathogenesis is a change of glycosylation or sialylation pattern caused by the mutations in GNE, possibly affecting a sialic acid dependent function. Recently, four different forms of congenital muscular dystrophy (muscle–eye–brain disease: Yoshida et al. 2001, Fukuyama congenital muscular dystrophy: Hayashi et al., 2001, limb girdle muscular dystrophy type 2I: Brockington et al., 2001, Walker– Warburg syndrome: Bertran-Valero de Bernabe et al., 2002) have been associated with mutations in genes encoding putative glycosyltransferases, suggesting that changes (decrease or increase) in sialylation caused by mutations in GNE could also cause the malfunctioning of proteins in h-IBM. An intensive analysis of patients’ cells was undertaken by either lectin staining, fluorescence activated cell sorting (FACS) analysis, western blot, or by direct membrane-bound sialic acid measurements to determine a possible sialylation defect (Hinderlich et al., 2004;
HEREDITARY INCLUSION BODY MYOPATHY Noguchi et al., 2004; Saito et al., 2004; Salama et al., 2005). The results of these experiments were inconclusive: while in most of the patients, including those carrying the M712T mutation, significant changes in sialylation could not be detected, in few h-IBM patients, with at least one mutation in the epimerase domain of GNE, modest to marked reduction in membrane sialylation was found. These observations suggest that there could be some correlation between a reduction in epimerase activity and hyposialylation. However, since there is no correlation between the genotype of patients and their phenotype (all patients present a very similar phenotype, independently of the localization of the mutations), it is difficult to point to overall hyposialylation as the primary cause of h-IBM. Nevertheless, the possibility always remains that not all but only specific glycoconjugates are affected by impaired sialylation. Following the discovery of aberrant glycosylated a-dystroglycan as the cause of the above-mentioned muscular dystrophies, it was tempting to examine the sialylation status of this protein in h-IBM. Reports from various laboratories describe no or inconsistent changes in the a-dystroglycan sialylation pattern, which in any case do not affect the laminin-binding pattern of a-dystroglycan and therefore its sarcolemmal connection is preserved (Noguchi et al., 2004; Saito et al., 2004; Broccolini et al., 2005). Thus, the hypothesis that dysfunction of a-dystroglycan is the primary cause in h-IBM (Huizing et al., 2004) seems less likely. It could, however, be speculated that glycoconjugates other than a-dystroglycan might be affected by subtle changes in sialylation, undetectable by current methods.
12.9. Diagnosis and differential diagnosis The diagnosis of h-IBM should follow the criteria described above, based first on the recognition of the clinical phenotype and the identification of the mode of inheritance, which should be recessive. Mild to no elevation of serum CK and typical biopsy features confirm the clinical diagnosis. In regions where few mutations in the GNE are common testing for them may eliminate the need for biopsy. But GNE sequencing should be sought in any recessively inherited distal myopathy with rimmed vacuoles. The differential diagnosis of h-IBM includes: 1. Sporadic IBM. The main distinctive points of this condition, as compared to h-IBM, are the later onset and the presence of diffuse inflammatory infiltrates. 2. Other distal myopathies with rimmed vacuoles. These other conditions have been discussed in chapter 11 on distal myopathies.
249
3. Charcot–Marie–Tooth (CMT) and other peroneal muscular atrophies. The early weakness of the peroneal muscles in h-IBM mimics these neurogenic conditions. The peripheral neuropathic forms of CMT are easily distinguishable by clinical examination and nerve conduction studies. More difficult differential diagnosis is the distal spinal muscular atrophy (SMA) form. In both h-IBM and distal SMA, EMG may show a non-distinctive mixed pattern and the serum CK is either not elevated or modestly raised in both. Biopsy showing grouping and other neurogenic features without vacuoles may make the SMA diagnosis more plausible. 4. Scapuloperoneal syndromes. If h-IBM presents itself at a more advanced stage, when it already affected the proximal musculature of the upper limbs and scapular region, it can mimic a scapuloperoneal syndrome (Argov and Yarom, 1984). One such family had histologic features compatible with h-IBM too, but was linked to chromosome 12 (Wilhelmsen et al., 1996). 5. Limb-girdle muscular dystrophy (LGMD). Some hIBM patients with proximal weakness beginning in the legs may be clinically indistinguishable from adult onset LGMD. Serum CK levels and a biopsy usually leads to the correct diagnosis. One should remember that in LGMD2G, rimmed vacuoles may be abundant.
12.10. The h-IBM enigmas 12.10.1. Why Quadriceps-Sparing? Quadriceps sparing is a unique phenomenon in clinical myology. In contrast to most other myopathies (hereditary and acquired) where the quadriceps is always one of the first and most severely impaired muscles, once the hIBM spreads to the proximal musculature in the vast majority of patients quadriceps sparing becomes evident. It is maintained through the disease life span and even in bedridden subjects (Sadeh and Argov, 1998). To date, no observation has been reported which points to a differential behavior of the quadriceps versus all other skeletal muscles, either during embryogenesis or development (Konigsberg, 1986). The GNE activity in the quadriceps is similar to other muscles in h-IBM (Salama et al., 2005). 12.10.2. What are the inclusion bodies? A major problematic issue in h-IBM is the basis of the observed myopathological changes. Both s-IBM and h-IBM are morphologically characterized by the presence of rimmed vacuoles within muscle fibers and
250
Z. ARGOV AND S. MITRANI-ROSENBAUM
tubofilamentous inclusions, 15–21 nm in external diameter, in the cytoplasm and the nucleus of the muscle fibers. However, none of these changes is specific for these disorders. Furthermore, the composition of the filaments is unknown. Thus, these disorders may share a common pathophysiological process with a similar mode of cell death, different from other dystrophies, but such process remains to be identified.
weakness is observed later in adulthood. Other less frequent features include reduced tendon reflexes, hand tremor and skeletal deformities. A cardinal histologic feature, in addition to the rimmed vacuoles, was a lack of type 2A muscle fibers. This led to the demonstration that a dominantly inherited missense mutation (Glu706Lys) in the myosin heavy chain (MyHC) IIA gene is responsible for this condition (Martinsson et al., 2000).
12.10.3. How does GNE defect cause a myopathy?
12.11.2. Inclusion body myopathy, paget’s disease and frontotemporal dementia (IBMPFD)
Although the role of GNE has been thoroughly recognized as a key enzyme in the biosynthetic pathway of sialic acid, the process by which the mutations in the enzyme lead to the h-IBM phenotype is not understood and no clear putative mechanism has emerged yet to explain the genotype–phenotype correlation. GNE activity in normal muscle tissue is very low and no specific function in myocytes has yet been determined. Although it is clear that GNE activity is further reduced in h-IBM patients, it appears that the remaining biochemical activity of the mutant enzyme is adequate to support sialic acid production and does not supply an a priori explanation for the pathology of the disease. To elucidate the pathophysiology of h-IBM it will be essential to unravel potential new pathways which involve GNE. A recent report by Krause et al. (2005) localizes the GNE protein not only in the cytosolic part of the Golgi apparatus but also in the nucleus, thus opening new functional possibilities for this molecule.
12.11. Other rimmed vacuolar myopathies The finding of “rimmed” vacuoles as the sole (or main) pathology in a muscle biopsy was reported in numerous other hereditary myopathies with variable phenotypes. Some have been found in a clinically distinct condition (e.g., oculopharyngodistal myopathy) while in others this was observed in single families (some with already defined linkage). Those disorders that present as distal myopathy were reviewed in chapter 11. Other conditions are described in this section. 12.11.1. Proximal myopathy with ophthalmoplegia and congenital contructures This phenotypically unique condition with a well-defined genetic basis was reported in one family from Sweden (Darin et al., 1998). The syndrome presents in most patients as newborn joint contractures. The contractures may resolve with time and the main feature of the condition, ophthalmoplegia, is detected in the first decade of life without generalized weakness. Progressive proximal
This is a syndrome of adult-onset (mean ¼ 42 years) proximal myopathy that progresses to later involve the distal muscles too (Watts et al., 2003). EMG is reported as myopathic with irritative features and CK levels are mildly raised. Muscle biopsy is typical for “rimmed” vacuolar myopathy. Paget’s disease manifesting as bone thickening starts at about the same time and dementia manifests on the average a decade later in more than one-third of patients. This dominantly inherited disorder was linked to chromosome 9, in the GNE region, but was later found to be associated with mutations in valosin-containing protein (Watts et al., 2004). Several missense mutations have been identified in more than a dozen of these families. 12.11.3. Progressive proximal weakness Dominantly inherited myopathy in a large family was reported from Denver (Neville et al., 1992). Proximal weakness in the lower limbs appears in adulthood affecting mainly the quadriceps. Distal leg muscles may become affected later. No genetic linkage was defined for this family as yet. Fardeau and Tome´ (1998) reviewed their series of patients with rimmed vacuoles and inclusion and also found a few patients with dominant inheritance. The short clinical report suggests some similarities to the Denver family. 12.11.4. Myopathy and brain white matter disease This condition was observed in a single French-Canadian family (Cole et al., 1988). Its mode of inheritance cannot be determined as all five affected siblings are males in one generation. Delayed motor milestones were the first sign, followed by clear proximal weakness in the lower limbs. Both brain CT and MRI showed dense white matter changes without clinical evidence for a brain disease. It should be noted that the reported family from Tunisia in which patients had IBM-like myopathy with white matter disease of the brain (Hentati et al., 1998)
HEREDITARY INCLUSION BODY MYOPATHY has now been confirmed to be an h-IBM family with the Middle Eastern GNE homozygous mutation (Hentati et al., 2002). The status of the brain finding in this inbred family is unclear. 12.11.5. Fascioscapulohumeral syndrome This French-Canadian family was reported only in an abstract form (McKee et al., 1992), its clinical and histological features were later personally reviewed by one of us (ZA). Hand muscle weakness at early childhood was reported by the mother who was evaluated after her two adolescent boys were investigated for proximal weakness in the legs. Marked facial weakness was common to all and probably started before the limb weakness. No pharyngeal weakness was observed. The biopsy was typical for an IBM-like condition without inflammation. the mode of inheritance is unclear. 12.11.6. Scapuloperoneal syndrome A single family with dominantly inherited myopathy and this particular weakness distribution was linked to chromosome 12 (Wilhelmsen et al., 1996). Rimmed vacuoles and tubofilamentous inclusion were found in muscle biopsy. 12.11.7. Oculopharyngodistal myopathy This is discussed in chapter 11, distal myopathies. 12.11.8. Neuromyopathy with bulbar weakness This is discussed in chapter 11, distal myopathies.
References Arai A, Tanaka K, Ikeuchi T, et al. (2002). A novel mutation in the GNE gene and a linkage disequilibrium in Japanese pedigrees. Ann Neurol 52: 516–519. Argov Z, Mitrani-Rosenbaum S (1998). Hereditary inclusion body myopathy (h-IBM) with quadriceps sparing: epidemiology andgenetics. In: V Askanas, G Serratrice, WK Engel (Eds.), Inclusion-body Myositis and Myopathies.Cambridge University Press, Cambridge, pp. 200–210. Argov Z, Soffer D (2002). Hereditary inclusion body myopathies. In: G Karpati, (Ed.), Structural and Molecular Basis of Skeletal Muscle Disease.ISN Neuropath Press, Basel, pp. 274–276. Argov Z, Yarom R (1984). “Rimmed vacuole myopathy” sparing the quadriceps: a unique disorder in Iranian Jews. J Neurol Sci 64: 33–43. Argov Z, Sadeh M, Eisenberg I, et al. (1998). Facial involvement in hereditary inclusion body myositis. Neurology 50: 1925–1926.
251
Argov Z, Eisenberg I, Grabov-Nardini G, et al. (2003). Hereditary inclusion body myopathy: the Middle Eastern genetic cluster. Neurology 60: 1519–1523. Askanas V, Engel WK (1993). New advances in inclusionbody myositis. Curr Opin Rheumatol 5: 732–741. Askanas V, Engel WK (1998). Newest approches to diagnosis of sporadic inclusion-body myositis and hereditary inclusionbody myopathies, including molecular-pathologic similarities to Alzheimer disease. In: V Askanas, G Serratrice, WK Engel (Eds.), Inclusion-Body Myositis and Myopathies. Cambridge University Press, Cambridge, pp. 3–78. Beltran-Valero de Bernabe D, Currier A, Steinbrecher A, et al. (2002). Mutations in the O-mannosyltranferase gene POMT1give rise to the severe neuronal migration disorder Walker–Warburg syndrome. Am J Hum Genet 71: 1033–1043. Broccolini A, Pescatori M, D’Amico A, et al. (2002). An Italian family with autosomal recessive inclusion-body myopathy and mutations in the GNE gene. Neurology 59: 1808–1809. Broccolini A, Ricci E, Cassandrini D, et al. (2004). Novel GNE mutations in Italian families with autosomal recessive hereditary inclusion-body myopathy. Hum Mutat 23: 632. Broccolini A, Gliubizzi C, Pavoni E, et al. (2005). a-dystroglycan does not play a major pathogenic role in autosomal recessive hereditary inclusion-body myopathy. Neuromuscul Disord 15: 177–184. Brockington M, Blake DJ, Prandini P, et al. (2001). Mutations in the fukutin-related protein gene (FKRP) cause a form of congenital muscular dystrophy with secondary laminin a2 deficiency and abnormal glycosylation of a-dystroglycan. Am J Hum Genet 69: 1198–1209. Cole AJ, Kuzniecky R, Karpati G, et al. (1988). Familial myopathy with changes resembling inclusion body myositis and periventricular leucoencephalopathy. Brain 111: 1025–1037. Darin N, Kyllerman M, Wahlstrom J, et al. (1998). Autosomal dominant myopathy with congenital joint contractures, ophthalmoplegia, and rimmed vacuoles. Ann Neurol 44: 242–248. Darvish D, Vahedifar P, Huo Y (2002). Four novel mutations associated with autosomal recessive inclusion body myopathy (MIM: 600737). Mol Genet Metab 77: 252–256. Del Bo R, Baron P, Prelle A, et al. (2003). Novel missense mutation and large deletion of GNE gene in autosomal-recessive inclusion-body myopathy. Muscle Nerve 28: 113–117. Edelman GM, Crossin KL (1991). Cell adhesion molecules: implications for a molecular histology. Ann Rev Biochem 60: 155–190. Effertz K, Hinderlich S, Reutter W (1999). Selective loss of either the epimerase or kinase activity of UDP-N-acetylglucosamine 2 epimerase/N-acetylmannosamine kinase due to site-directed mutagenesis based on sequence alignments. J Biol Chem 274: 28771–28778. Eisenberg I, Avidan N, Potikha T, et al. (2001). The UDPN-acetylglucosamine 2-epimerase/N-acetylemannosamine
252
Z. ARGOV AND S. MITRANI-ROSENBAUM
kinase is mutated in recessive hereditary inclusion body myopathy. Nat Genet 29: 83–87. Eisenberg I, Grabov-Nardini G, Hochner H, et al. (2003). Mutations spectrum of the GNE gene in hereditary inclusion body myopathy sparing the quadriceps. Hum Mutat 21: 99. Fardeau M, Tome´ F (1998). Inclusion body myopathies. In: V Askanas, G Serratrice, WK Engel (Eds.), Inclusion-Body Myositis and Myopathies.Cambridge University Press, Cambridge, pp. 252–260. Figarella-Branger D, Pellissier JF, Bianco N, et al. (1990). Inflammatory and non-inflammatory inclusion body myositis. Characterization of the mononuclear cells and expression of the immunoreactive class I major histocompatibility complex product. Acta Neuropathol (Berl) 79: 528–536. Griggs RC, Askanas V, DiMauro S, et al. (1995). Inclusion body myositis and myopathies. Ann Neurol 38: 705–715. Hayashi YK, Ogawa M, Tagawa K, et al. (2001). Selective deficiency of alpha-dystroglycan in Fukuyama-type congenital muscular dystrophy. Neurology 57: 115–121. Hentati F, Ben Hamida C, Belal S, et al. (1998). Familial autosomal-recessive inclusion-body myositis with asymptomatic leukoencephalopathy. In: V Askanas, G Serratrice, WK Engel (Eds.), Inclusion-Body Myositis and Myopathies. Cambridge University Press, Cambridge, pp. 211–220. Hentati F, Amouri R, Driss A, et al. (2002). Allelic heterogeneity of autosomal recessive inclusion body myopathy in Tunisia (abstr). J Neurol Sci 199 (Suppl. 1): S50. Hinderlich S, Stasche R, Zeitler R, et al. (1997). A bifunctional enzyme catalyzes the first two steps in N-acetylneuraminic acid biosynthesis of rat liver. Purification and characterization of UDP-N-acetylglucosamine 2 epimerase/N-acetylmannosamine kinase. J Biol Chem 272: 24313–24318. Hinderlich S, Salama I, Eisenberg I, et al. (2004). The homozygous M712T mutation of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase results in reduced enzyme activities but not in altered cellular sialylation in hereditary inclusion body myopathy. FEBS Lett 566: 105–109. Horstkorte R, Nhring S, Wiechens N, et al. (1999). Tissue expression and amino acid sequence of murine UDPN-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase. Eur J Biochem 260: 923–927. Horstkorte R, Nohring S, Danker K, et al. (2000). Protein kinase C phosphorylates and regulates UDP–N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase. FEBS Lett 470: 315–318. Huizing M, Rakocevic G, Sparks G, et al. (2004). Hypoglycosylation of alpha-dystroglycan in patients with hereditary IBM due to GNE mutations. Mol Genet Metab 81: 196–202. Hynes RO, Lander AD (1992). Contact and adhesive specificities in the associations, migrations and targeting of cells and axons. Cell 68: 303–322. Kayashima T, Matsuo H, Satoh A, et al. (2002). Nonaka myopathy is caused by mutations in the UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase gene (GNE). J Hum Genet 47: 77–79.
Kelm S, Schauer R (1997). Sialic acids in molecular and cellular interactions. Int Rev Cytol 175: 137–240. Keppler T, Hinderlich S, Langner J, et al. (1999). UDPGlcNAc 2-epimerase: a regulator of cell surface sialylation. Science 284: 1372–1376. Konigsberg IR (1986). The embryonic origin of muscle. 1st edn., In: AG Engel, BQ Banker (Eds.), Vol. 1, McGrawHill Book Company, NewYork, pp. 39–71. Kornfeld S, Kornfeld R, Neufeld E, et al. (1964). The feedback control of sugar nucleotide biosynthesis in liver. Proc Natl Acad Sci U S A 52: 371–379. Krause S, Schlotter-Weigel B, Walter MC, et al. (2003). A novel homozygous missense mutation in the GNE gene in a patient with quadriceps-sparing hereditary inclusion body myopathy associated with muscle inflammation. Neuromuscl Dis 13: 830–834. Krause S, Hinderlich S, Amsili S, et al. (2005). Localization of UDP-GlcNAc 2-epimerase/ManAc kinase (GNE) in the Golgi complex and the nucleus of mammalian cells. Exp Cell Res 304: 365–379. Lucka L, Krause M, Danker K, et al. (1999). Primary structure and expression analysis of human UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase, the bifunctional enzyme in neuraminic acid biosynthesis. FEBS Lett 454: 341–344. Martinsson T, Oldfors A, Darin N, et al. (2000). Autosomal dominant myopathy: missense mutation (Glu-706-Lys) in the myosin heavy chain IIa gene. Proc Natl Acad Sci U S A 97: 14614–14619. McKee D, Karpati G, Carpenter S, et al. (1992). Familial inclusion body myositis (IBM) mimics facioscapulohumeral dystrophy (FSHD) (abstr). Neurology 42 (Suppl. 3): 302. Mirabella M, Alvarez RB, Bilak M, et al. (1996). Difference in expression of phosphorylated tau epitopes between sporadic inclusion body myositis and hereditary inclusion body myopathies. J Neuropathol Exp Neurol 55: 774–786. Mitrani-Rosenbaum S, Argov Z, Blumenfeld A, et al. (1996). Hereditary inclusion body myopathy maps to chromosome 9p1-q1. Hum Mol Genet 5: 159–163. Neufeld MY, Sadeh M, Assa B, et al. (1995). Phenotypic heterogeneity in familial inclusion body myopathy. Muscle Nerve 18: 546–548. Netzer A (1988). The Jewish communities in Iran. In: Iranian Jews, Koresh House-World Center of Iranian Jews in Israel, Holon, pp. 3–20. Neville HE, Baumbach LL, Ringel SP, et al. (1992). Familial inclusion body myositis: evidence for autosomal dominant inheritance. Neurology 42: 897–902. Nishino I, Noguchi S, Murayama K, et al. (2002). Distal myopathy with rimmed vacuoles is allelic to hereditary inclusion body myopathy. Neurology 59: 1689–1693. Noguchi S, Keira Y, Murayama K, et al. (2004). Reduction of UDP-N acetylglucosamine 2-epimerase/N-acetylmannosamine kinase activity and sialylation in distal myopathy with rimmed vacuoles. J Biol Chem 279: 11402–11407.
HEREDITARY INCLUSION BODY MYOPATHY Nonaka I, Sunohara N, Ishiura I, et al. (1981). Familial distal myopathy with rimmed vacuole and lamellar (myeloid) body formation. J Neurol Sci 51: 141–153. Reutter W, Sta¨sche R, Stehling P, et al. (1997). The biology of sialic acids. Insights into their structure,metabolism and function in particular during viral infection. In: HJ Gabius, G Gabius (Eds.), Glycosciences. Status and Perspectives. Chapman and Hall, Weinheim, pp. 245–259. Sadeh M, Argov Z (1998). Hereditary inclusion body myopathy in Jews of Persian origin: Clinical and laboratory data. In: V Askanas, G Serratrice, WK Engel (Eds.), InclusionBody Myositis and Myopathies.Cambridge University Press, Cambridge, pp. 191–199. Sadeh M, Gadoth M, Hadar H, et al. (1993). Vacuolar myopathy sparing the quadriceps. Brain 116: 217–232. Saito F, Tomimitsu H, Arai K, et al. (2004). A Japanese patient with distal myopathy with rimmed vacuoles: missense mutations in the epimerase domain of the UDP-N-acetylglucosamine 2-epimerase N-acetylmannosaminekinase (GNE) gene accompanied by hyposialylation of skeletal muscle glycoproteins. Neuromuscul Disord 14: 158–161. Salama I, Hinderlich S, Shlomai Z, et al. (2005). No overall hyposialylation in hereditary inclusion body myopathy myoblasts carrying the homozygous M712T GNE mutation. Biochem Biophys Res Commun 328: 221–226. Satayoshi E, Sunohara N, Nonaka I (1998). Distal myopathy with rimmed vacuoles, inclusion-body myositis, and related disorders in Japan. In: V Askanas, G Serratrice, WK Engel (Eds.), Inclusion-Body Myositis and Myopathies. Cambridge University Press, Cambridge, pp. 244–251. Schwarzkopf M, Knobeloch KP, Rohde E, et al. (2002). Sialylation is essential for early development in mice. Proc Natl Acad Sci U S A 99: 5267–5270. Seppala R, Lehto VP, Gahl WA (1999). Mutations in the human UDP-Nacetylglucosamine 2-epimerase gene define the disease sialuria and the allosteric site of the enzyme. Am J Hum Genet 64: 1563–1569.
253
Sivakumar K, Dalakas MC (1996). The spectrum of familial inclusion body myopathies in 13 families and a description of a quadriceps-sparing phenotype in non-Iranian Jews. Neurology 47: 977–984. Sta¨sche R, Hinderlich S, Weise C, et al. (1997). A bifunctional enzyme catalyzes the first two steps in N-acetylneuraminic acid biosynthesis of rat liver. Molecular cloning and functional expression of UDP-N-acetyl-glucosamine 2-epimerase/ N-acetylmannosamine kinase. J Biol Chem 272: 24319–24324. Sunohara N, Nonaka I, Kamei N, et al. (1989). Distal myopathy with rimmed vacuoles formation: a follow-up study. Brain 112: 65–83. Tommitsu M, Ishikama K, Shimaso I, et al. (2002). Distal myopathy with rimmed vacuoles: Novel mutation in the GNE gene. Neurology 59: 454. Varki A (1997). Sialic acids as ligands in recognition phenomena. FASEB J 11: 248–255. Vasconcelos OM, Raju R, Dalakas MC (2002). GNE mutations in an American family with quadriceps-sparing IBM and lack of mutations in s-IBM. Neurology 59: 1776–1779. Watts GDJ, Thorne M, Kovach MJ, et al. (2003). Clinical and genetic heterogeneity in chromosome 9p associated hereditary inclusion body myopathy: exclusion of GNE and three other candidate genes. Neuromuscul Dis 13: 559–567. Watts GD, Wymer J, Kovach MJ, et al. (2004). Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat Genet 36: 377–381. Wilhelmsen KC, Blake DM, Lynch T, et al. (1996). Chromosome12-linked autosomal dominant scapuloperoneal muscular dystrophy. Ann Neurol 39: 507–520. Yabe I, Higashi T, Kikuchi S, et al. (2003). GNE mutations causing distal myopathy with rimmed vacuoles with inflammation. Neurology 61: 384–386. Yoshida A, Kobayashi K, Manya H, et al. (2001). Muscular dystrophy and neuronal migration disorder caused by mutations in glycosyltransferase POMGnT1. Dev Cell 1: 717–724.
Handbook of Clinical Neurology, Vol. 86 (3rd series) Myopathies F. L. Mastaglia, D. Hilton-Jones, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 13
Inclusion body myositis MICHAEL R. ROSE1* AND ROBERT C. GRIGGS2 1
King’s College Hospital, University of London, London UK
2
and University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
Yunis and Samaha (1971) first coined the term inclusion body myositis (IBM) in 1971 but the first recorded description of the disease was in 1967 when Chou (1967) reported an unusual case of “chronic polymyositis” in which muscle biopsy showed inflammatory infiltration with muscle fibers containing basophilic rimmed vacuoles and filamentous cytoplasmic and nuclear inclusions. There is a readily recognizable clinical phenotype for IBM although unusual variants do occur. From being an apparently rare entity IBM has now become the commonest acquired myopathy over the age of 50 years and for myologists, more common than its other inflammatory counterparts such as polymyositis and dermatomyositis. Although the inflammatory component is the predominant histological feature there are additional features of abnormal gene upregulation and protein deposition which may be the primary pathological change. IBM is usually a slowly progressive myopathy which causes considerable morbidity but does not directly cause mortality. The lack of any effective treatments makes it a challenge to manage.
13.1. Clinical features 13.1.1. Incidence and prevalence In the early-published series of cases, IBM was found to constitute between 17% (Carpenter et al., 1978) to 30% (Karpati et al., 1988) of all cases of inflammatory myopathy but later series have suggested that the percentage could be as high as 60 or 70% (Maat-Schieman et al., 1992). This accords with the experience of most myologists who find that IBM is more common than either polymyositis or dermatomyositis. However, this
perception could reflect the referral bias of large neuromuscular centers with untreatable IBM being referred while more tractable disorders are cared for locally. Population-based surveys have given an incidence of IBM for Goteborg, Sweden of 2.23106 per year (Lindberg et al., 1994) with prevalence figures of 4.9 in the Netherlands and 9.3 per million inhabitants in Western Australia (Badrising et al., 2000; Phillips et al., 2000). The prevalence adjusted for age over 50 years is 16106 to 35.5106 in these same studies. The wide range in these prevalence figures probably results from case ascertainment bias meaning that these figures are likely to be underestimates. There have been suggestions that IBM may be a new disease since early case series of “polymyositis” do not include atypical cases that we would now recognize as IBM (DeVere and Bradley, 1975). The population survey in the Netherlands showed a trend of rising prevalence of IBM since the first diagnosed case in 1982, however this may relate to increasing recognition of the disease and diagnosis of retrospective cases (van der Meulen et al., 2003). Inclusion-body myopathy is usually of late onset with more than 80% of cases occurring over the age of 50 years (Lotz et al., 1989), although childhood onset has been described (Riggs et al., 1989). In an Australian survey the mean age of onset was lower in women than men, being 49.8 years (range 37–56 years) and 60.0 years (range 32–83 years), respectively (Phillips et al., 2000). However this gender difference was less obvious in the Netherlands survey where age at onset for men was 59 years (range 40–75 years) and for females 60 years (range 39–77 years; Badrising et al., 2000). The male:female ratio is about 2:1 contrasting with the female predominance of polymyositis (Carpenter et al., 1978; Lotz et al., 1989; Badrising et al., 2000).
*Correspondence to: Michael R Rose BSc, MD, FRCP, Department of Neurology, King’s College Hospital, University of London, London, UK. E-mail:
[email protected], Tel: þ44-20-3299-8352.
256
M. R. ROSE AND R. C. GRIGGS
Nearly all cases of IBM are sporadic. Cases have been described of siblings and twins with a phenotype identical to sporadic inclusion body myositis and with inflammation in their muscle biopsies (Naumann et al., 1996; Sivakumar et al., 1997; Amato and Shebert, 1998). The question is whether these represent genuine familial “sporadic” IBM (s-IBM) implying a possible immunogenetic susceptibility or are actually cases of inclusion body myopathy (h-IBM). In the past this distinction could be made on the basis that cases of h-IBM had no inflammation on muscle biopsy but reports of genetically proven h-IBM with inflammation make this distinction more difficult (Yabe et al., 2003). However hereditary cases of s-IBM do share features in common with single cases of s-IBM and are distinct from h-IBM (Ranque-Francois et al., 2005). The hereditary s-IBM cases also have in common the HLA class II genotype which is seen in single cases of s-IBM but not seen in h-IBM cases (Koffman et al., 1998b).
13.1.2. Presentation The presentation of typical IBM reflects the insidious onset and progression of the disease and the often stereotyped pattern of muscle involvement. The first symptom is often one of sudden, unprovoked falls without loss of consciousness. Sometimes patients realize that this is due to buckling of the knees which is especially likely to happen when twisting or turning forces are imposed on the knees. Many patients have particular anxiety when descending stairs since this is more likely to provoke crumpling at the knees with falls. There is often a retrospective realization that there has in fact been a slow progression of leg weakness slowing the walking and causing difficulty with rising from chairs and going up inclines or stairs. Patients often attribute this declining mobility to “old age”. There may be later symptoms of foot drop and tripping due to ankle dorsiflexion weakness. By contrast the usual presentation of upper limb involvement is distal hand weakness which characteristically affects the long finger flexors. This can cause a variety of symptoms which may include golf clubs flying out of a weak hand grip, brief cases slipping out of the fingers and difficulty with tasks such as pulling up car door lock buttons, lifting car door handles and turning keys. Although distal limb involvement can be prominent compared to proximal disease (Carpenter et al., 1978) one series showed that while distal weakness occurred in half the cases, it exceeded proximal weakness in only one-third (Lotz et al., 1989). IBM may thus present with just proximal upper and lower limb weakness creating a wider differential diagnosis (see below).
An additional frequent symptom is dysphagia which is often overlooked unless enquired about directly. Incidence has been variously reported as “one-third” or “up to 60%” (Lotz et al., 1989). In one series it was reported in 16 out of 19 patients (Houser et al., 1998). The wide variation in incidence of dysphagia reflects the thoroughness with which the patient is questioned about this symptom. Even when initial enquiries suggest no dysphagia, when pressed patients may recall that there have been swallowing difficulties particularly for dry foods such as bread, or for meat. Often the patient has compensated by avoiding such foods, chewing more thoroughly and drinking more with meals, and so forgets that this was a problem until prompted. The length of time required for completing a meal is often helpful information; weight loss is a late occurrence. Other cranial nerve symptoms such as ptosis, diplopia, facial weakness and dysarthria are not a usual feature of IBM although there may be signs of facial weakness (see below). Occasionally patients complain of neck weakness. Pain is not a feature of IBM per se but may be present due to coexisting painful conditions such as osteoarthritis. Some patients get particular problems with a swollen painful knee that reflects undue mechanical strain on a knee coping with quadriceps weakness. The symptoms are often asymmetrical and sometimes have a unilateral onset. The asymmetry may be crossed for upper and lower limb, i.e., a weaker right hand with a weaker left leg. The asymmetry often persists as the disease progresses. 13.1.3. Examination Cranial nerve examination shows no retinal or ocular involvement with IBM. Despite the lack of facial symptoms in a third of cases examination shows mild weakness of eyelid or lip closure which is not a feature of inflammatory myopathies such as polymyositis and dermatomyositis. There may be neck flexion or extension weakness. In the limbs there is usually asymmetric wasting of the quadriceps and forearm flexors with the latter causing a very characteristic scooped appearance of the volar aspect of the forearm (Figs 13.1 and 13.2). The hand grip weakness is best detected by asking the patient to curl the distal joints of the fingers such that their fingertips reach the metacarpal heads. In advanced cases the finger joints beyond the metacarpal phalangeal (MCP) joints fail to flex at all. In milder cases formal power testing specifically focusing on distal finger flexion at posterior and distal interphalangeal (PIP and DIP) finger joints reveals the weakness even when conventional testing of MCP joint-related hand grip seems normal. There is often asymmetric weakness of biceps and triceps and in some cases shoulder
INCLUSION BODY MYOSITIS
257
et al., 1988; Danon and Friedman, 1989; Verma et al., 1991; Danon and Friedman, 1992; Zeman et al., 2000). In a proportion of patients it has been a severe presenting problem, preceding limb muscle weakness by years (Riminton et al., 1993). In contrast to the usually mild neck flexion or extension weakness that may occur with traditional IBM the neck flexion weakness can be severe enough to cause presentation with dropped head syndrome (Luque et al., 1994). Facioscapulohumeral and scapuloperoneal phenotypes have been described (McKee et al., 1992; Schlesinger et al., 1996). Fig. 13.1. An example of quadriceps wasting in a case of inclusion-body myositis
Fig. 13.2. An example of impaired finger flexion in a case of inclusion-body myositis; the patient is attempting to make a fist.
weakness at presentation. In one series of 15 cases all had more weakness of the non-dominant hand and it was suggested that this might be due to a protective effect of using the dominant hand more (Felice et al., 1998). In the lower limbs especially when the presentation is one of falls the quadriceps weakness has often progressed to loss of full knee extension against gravity, so called extension lag. Usually by the time falls are occurring knee extension lag is bilateral. Ankle dorsiflexion weakness is common. Reflexes particularly in the lower limbs may be absent and this may bring to mind alternative diagnoses such as peripheral neuropathy or anterior horn disease. There are no sensory findings attributable to IBM although patients may have age related loss of vibration sensation. 13.1.4. Atypical presentations While the dysphagia can be mild, it can become a major management problem as the disease progresses (Wintzen
13.1.4.1. Associated diseases There are no expected general medical findings associated with IBM. Early suggestions of cardiac involvement (Lotz et al., 1989) have not been substantiated. Patients have the usual incidence of age-related hypertensive or ischemic cardiac manifestations. Neuromuscular respiratory weakness is a late feature (Lotz et al., 1989; Lindberg et al., 1994) but it may rarely be an early feature (Voermans et al., 2004). Association with a variety of connective tissue and autoimmune diseases has been described including rheumatoid arthritis (Soden et al., 1994), Vitamin B12 deficiency (Khraishi et al., 1992), Sjo¨gren’s syndrome (Gutmann et al., 1985; Khraishi et al., 1992), chronic immune thrombocytopenia (Riggs et al., 1984), sarcoidosis (Danon et al., 1986), collagen vascular disease (Lane et al., 1985), common variable immune deficiency (Lindberg et al., 1990; Dalakas and Illa, 1995) and dermatomyositis (Koffman et al., 1998a). Two series have produced similar figures for the incidence of such diseases of 13% and 15% and in one series the 13 out of 99 cases displayed 11 different autoimmune diseases (Lotz et al., 1989; Rugiero et al., 1998). These are similar rates of association as are seen with known autoimmune diseases such as myasthenia gravis. Diabetes mellitus occurred in 20% of cases (Lotz et al., 1989). There is no association between IBM and malignancy. Cases have been described in association with viral infections such as hepatitis C (Alexander and Huebner, 1996) and retroviruses (Cupler et al., 1996).
13.2. Investigations 13.2.1. Blood tests The erythrocyte sedimentation rate (ESR) is normal and if elevated implies an alternative or coincidental diagnosis. Serum creatine kinase levels may be normal, or mildly elevated usually by 2–5 times normal but in rare cases up to 12-fold. Myositis-associated antibodies are not normally a feature of IBM and indeed it had been suggested that the presence of Jo-1 antibodies excluded IBM (Hengstman et al., 1998). However there have
258
M. R. ROSE AND R. C. GRIGGS
since been cases described with PM-sscl (Selva-O’Callaghan et al., 2003) and with Jo-1 antibodies (Koffman et al., 1998a; Hengstman et al., 2001). Non-specific autoantibodies are common (44%) with most being positive antinuclear antibodies (20%) followed by elevated anticardiolipin antibody (13%), positive SSA/Ro antibodies (10%) and in single percentage figures rheumatoid factor, SSB/La, anti-GM1, anti-Sm antibodies and anti-RNP antibody (Koffman et al., 1998a). 13.2.2. Electromyography Needle electromyography (EMG) is invariably abnormal. The commonest pattern is similar to that found in polymyositis: increased insertional activity with fibrillation potentials, positive sharp waves and short-duration/ small-amplitude motor unit potentials (MUPs). In about a third of cases there is a mixture of short-duration/ small-amplitude MUPs and long-duration/large-amplitude MUPs with a reduced interference pattern, the latter two features having been traditionally regarded as neurogenic (Joy et al., 1990). This mixed myopathic and “neurogenic” pattern on EMG has been regarded by some as specific for IBM (Joy et al., 1990) but others have described it in polymyositis (Mechler, 1974; Lotz et al., 1989), X-linked humeroperoneal neuromuscular disease (Waters et al., 1975), familial rimmed vacuolar myopathy sparing the quadriceps (Argov and Yarom, 1984) and sporadic distal myopathy (Vaccario et al., 1981). A small proportion of patients with s-IBM have a purely “neurogenic” EMG picture of normal- or long-duration/largeamplitude MUPs with a reduced interference pattern. Nerve conduction studies (NCS) can show mild slowing in more than a third of cases, particularly in those with “neurogenic” features on EMG (Lacy et al., 1982; Lotz et al., 1989; Joy et al., 1990). Vibratory and thermal thresholds were abnormal in five and four out of nine subjects (Arnardottir et al., 2003a). Single-fiber EMG (sfEMG) studies can show an increased fiber density and moderately abnormal jitter in severely affected muscles (Eisen et al., 1983; Joy et al., 1990). The “neurogenic” features seen neurophysiologically, as well as histologically (grouped fiber atrophy and small angulated fibers) has generated discussion as to whether there is a neurogenic component to IBM. However the technique of macroEMG shows only myogenic features (Luciano and Dalakas, 1997). The EMG “neurogenic” features may all be indicators of the chronicity of a myopathic process, perhaps occurring because the nerve fibers have become disconnected from the muscle (Desmedt and Borenstein, 1975). Nerve biopsies in s-IBM have shown mild non-specific reduction in myelinated fibers (Lacy et al., 1982; Ringel et al., 1987) or a mild axonal neuropathy (Lindberg et al., 1990).
13.2.3. Muscle imaging T1-weighted magnetic resonance images (MRI) of the forearms shows marbled brightness of the flexor digitorum profundus in the majority of those with IBM, sometimes preceding detectable weakness of that muscle. Other forearm flexor muscles are less often involved, particularly flexor digitorum superficialis, and the extensors show normal scan appearances (Sekul et al.,1997). This preferential MRI signal abnormality involvement of flexor digitorum profundus seems to persist even in more advanced cases but its absence does not exclude a diagnosis of IBM as it was not seen at all in two-thirds of cases (Phillips et al., 2001). The most typical MRI signal abnormality is that which selectively affects the medial gastrocnemius and the vasti with sparing of rectus femoris, and when this is combined with selective involvement of flexor digitorum profundus with sparing of flexor digitorum sublimis, makes IBM very likely (Phillips et al., 2001). 13.2.4. Muscle biopsy Muscle biopsy is essential for a definitive diagnosis of IBM (Figs 13.3, 13.4 and 13.5). Histochemical stains show variation in fiber size with both fiber hypertrophy and atrophy of both fiber types. The atrophic fibers may have an angulated appearance suggestive of denervated fibers. Hypertrophied fibers are more frequently seen in IBM than in other inflammatory myopathies, perhaps reflecting the chronicity of this condition (Verma et al., 1992). Fiber type grouping is unusual. There
Fig. 13.3. For full color figure, see plate section. Muscle biopsy of a case of inclusion-body myositis; Gomori trichrome stain; showing inflammatory infiltrates and rimmed vacuoles. Kindly supplied by Dr S. Al-Sarraj, Department of Neuropathology, King’s College Hospital, London, UK.
INCLUSION BODY MYOSITIS
Fig. 13.4. For full color figure, see plate section. Muscle biopsy of a case of inclusion-body myositis showing Congo red staining for amyloid. Kindly supplied by Dr S. Al-Sarraj, Department of Neuropathology, King’s College Hospital, London, UK.
Fig. 13.5. For full color figure, see plate section. Muscle biopsy of a case of inclusion-body myositis showing positive immunostaining with antibodies to b-4-amyloid. Kindly supplied by Dr S. Al-Sarraj, Department of Neuropathology, King’s College Hospital, London, UK.
may be an increase in endomysial connective tissue and in severely affected muscle, replacement of muscle fibers by fat and fibrous tissue. The presence of inflammatory infiltrates is an absolute requirement for the diagnosis of IBM. These are primarily endomysial and predominantly composed of T cells and macrophages. The T cells are CD4þ and CD8þ cells with the latter often invading non-necrotic muscle fibers (Arahata and Engel, 1984; 1988). A key but not pathognomonic feature of IBM is the presence of single or multiple rimmed vacuoles 2–15 mm in diameter which can occur in up to 10% of fibers (Carpenter et al., 1978). Sometimes the rimmed vacuoles can not be found despite a diligent search. Rimmed vacuoles are so called because of their granular basophilic (on haematoxylin and eosin) or red
259
(on Gomori trichrome) peripheral staining. These vacuoles do not contain glycogen or lipid and do not have the degree of acid phosphatase activity seen in similar vacuoles associated with some drug-induced myopathies and in lysosomal storage diseases such as acid maltase deficiency. On occasion the suspicion of IBM may not be confirmed until repeat biopsies can eventually show the rimmed vacuoles (van der Meulen et al., 1998). Haematoxylin and eosin stain may also show eosinophilic inclusions. Ragged red fibers representing subsarcolemmal accumulations of mitochondria are seen in excess of those expected for this age group suggesting that the pathogenesis of IBM includes impaired mitochondrial function (Rifai et al., 1995). In keeping with this there may be cytochrome oxidase-negative fibers. Muscle fiber capillary density is increased, contrasting with the decrease seen in dermatomyositis, and the normal density seen in idiopathic polymyositis (Carpenter et al., 1978). One of the additional muscle biopsy features required for a definite diagnosis of IBM is the demonstration of intracellular amyloid by Congo Red staining or fluorescence techniques (Mendell et al., 1991; Askanas et al., 1993b). Other features that may help in the diagnosis include the immunocytochemical demonstration of paired helical filaments using SMI-31 monoclonal antibody (Askanas et al., 1996c; Mirabella et al., 1996c). Positive antibody staining for ubiquitin is a feature of muscle biopsies in s-IBM and may allow this to be distinguished from other inflammatory myopathies that do not generally show any ubiquitin (Askanas et al., 1992; Prayson and Cohen, 1997). Electron microscopy (EM) shows that the rimmed vacuoles contain amorphous debris and whorls of membranous material. EM may also show the presence of amyloid and various abnormalities of mitochondrial structure. A more specific finding is that of tubulofilaments of 15–18 nm diameter and 1–5 nm in length. These may be intranuclear or cytoplasmic, the latter often in association with the rimmed vacuoles. They may be in random or parallel orientation and in compact or loose groups. They may allow a diagnosis of definite IBM in the absence of any demonstration of amyloid.
13.3. Diagnostic criteria The diagnosis of IBM is based upon a combination of clinical, laboratory and histological data (Table 13.1; Griggs et al., 1995). These criteria allow a definite diagnosis of IBM to be made on histological grounds regardless of the clinical phenotype. A definite diagnosis requires the histological evidence of inflammatory infiltrates with the demonstration of either amyloid or tubulofilaments (see above). These criteria also
260
M. R. ROSE AND R. C. GRIGGS
Table 13.1 Diagnostic criteria for inclusion-body myositis Inclusion criteria A. Clinical features 1. Duration of illness >6 months 2. Age of onset >30 years old 3. Muscle weakness: must affect proximal and distal muscles of arms and legs and patient must exhibit at least one of the following features: a. Finger flexor weakness b. Wrist flexor > wrist extensor weakness c. Quadriceps muscle weakness ( ¼ or < grade 4 MRC) B. Laboratory features 1. Serum creatine kinase <12 times normal 2. Muscle biopsy: a. Inflammatory myopathy characterized by mononuclear cell invasion of nonnecrotic muscle fibers b. Vacuolated muscle fibers c. Either: (i) Intracellular amyloid deposits (must use fluorescent method of identification before excluding the presence of amyloid) or (ii) 15–18-nm tubulofilaments by electron microscopy 3. Electromyography must be consistent with features of an inflammatory myopathy (however, long-duration potentials are commonly observed and do not exclude diagnosis of sporadic inclusion body myositis). C. Family history Rarely, inclusion-body myositis may be observed in families. This condition is different from hereditary inclusion-body myopathy without inflammation. The diagnosis of familial inclusion-body myositis requires specific documentation of the inflammatory component by muscle biopsy in addition to vacuolated muscle fibers, intracellular (within muscle fibers) amyloid, and 15–18-nm tubulofilaments. Associated disorders Inclusion body myositis occurs with a variety of other, especially immune-mediated conditions. An associated condition does not preclude a diagnosis of inclusion body myositis if diagnostic criteria (below) are fulfilled. Diagnostic criteria for inclusion-body myositis A. Definite inclusion-body myositis Patients must exhibit all muscle biopsy features including invasion of non-necrotic fibers by mononuclear cells, vacuolated muscle fibers and intracellular (within muscle fibers) amyloid deposits or 15–18-nm tubulofilaments. None of the other clinical or laboratory features are mandatory if muscle biopsy features are diagnostic. B. Possible inclusion-body myositis If the muscle shows only inflammation (invasion of non-necrotic muscle fibers by mononuclear cells) without other pathological features of inclusion-body myositis, then a diagnosis of possible inclusion-body myositis can be given if the patient exhibits the characteristic clinical (A 1,2,3) and laboratory (B1,3) features. Reproduced from Griggs et al., 1995, with permission from the Annals of Neurology
allow for a diagnosis of possible IBM where there is a typical clinical phenotype but an incomplete histological picture. Similar criteria have been endorsed by a workshop of the European Neuromuscular Centre (Muller-Felber et al., 2001). 13.3.1. Differential diagnosis The differential diagnosis of IBM is that of other inflammatory myopathies. Dermatomyositis usually presents acutely or subacutely rather than chronically. There is a proximal not distal emphasis to the weakness. There
may be associated characteristic cutaneous and other non-muscle features. The muscle pathology reflects the immune-complex-related vasculopathy which underlies this disease with perivascular B-cell-containing inflammatory infiltrates, muscle infarction and perifasicular atrophy. There are rare cases of dermatomyositis which after a disease-free interval have presented with IBM (McCoy et al., 1999). Also described is a case of overlap between IBM and dermatomyositis (Talanin et al., 1999). There is no doubt that the literature on polymyositis is contaminated by misdiagnosed cases of IBM. One has to speculate as to whether reported cases of polymyositis
INCLUSION BODY MYOSITIS with facial or distal weakness might not be rediagnosed as IBM nowadays (Hollinrake, 1969; Bates et al., 1973; Van Kasteren, 1979; Sundaram and Ashenhurst, 1981; Marconi et al., 1982). It is a frequent experience to diagnose IBM when reviewing patients with treatment-resistant polymyositis and so IBM should always be a suspected diagnosis in such cases. The practical clinical difficulty that may arise is in differentiating a case of evolving IBM, which has yet to develop all the characteristic histological features, from a case of polymyositis. Upon this distinction may rest the decision as to whether to start steroid treatment and the expectation of a response to such treatment. There is no evidence upon which to base a rational decision as to what constitutes an adequate trial of immunosuppressive treatment that will determine whether a case of inflammatory myopathy is responsive or not, particularly as late responders have been described (Rose et al., 1999). The presence of cytochrome oxidase negative fibers in what appears to be polymyositis predicts a poor response to steroid treatment but it is not yet clear whether it presages the appearance of IBM (Blume et al., 1997). Alternative differential diagnoses include other muscle diseases, which may have distal weakness, and other myopathies associated with rimmed vacuoles on muscle biopsy (Table 13.2). Of the alternative neurological diseases amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) is worthy of mention since this has obvious prognostic implications. When the needle EMG shows only neurogenic features the distinction between IBM and ALS/MND requires clinical vigilance with possible recourse to a muscle biopsy. Atypical presentations of IBM mentioned above will obviously have a wider differential diagnosis.
13.4. Management 13.4.1. General Since IBM generally occurs in an elderly population it is important to recognize that patients may have symptoms due to coexisting disease which, unlike IBM itself, may be eminently treatable. Thus cardiac and most respiratory symptoms should not be accepted as being due to IBM and should be investigated and treated on their merits. Respiratory symptoms might be associated with IBM if due to aspiration pneumonia in someone with severe dysphagia and impaired cough reflex. Neuromuscular respiratory failure is usually a late complication in severe cases of IBM. Pain is not a feature of IBM per se and may be due to coexisting arthritis or polymyalgia rheumatica. Arthritic changes in the knees seem particularly common and may relate to instability of the joint induced
261
Table 13.2 Differential diagnosis of inclusion-body myositis Inflammatory myopathies Polymyositis Dermatomyositis Myopathies with distal weakness Myotonic dystrophy Distal myopathies Rimmed vacuolar myopathies Familial IBM Limb-girdle muscular dystrophy With quadriceps sparing With excessive autophagy With dystrophin gene abnormality With electrical myotonia With leukodystrophy Distal Myopathies Oculopharyngeal dystrophies Other neuromuscular diseases Rigid spine Post-poliomyelitis syndrome Neuropathy; amyloid, vasculitic Spinal muscular atrophy Amyotrophic lateral sclerosis/motor neuron disease Multifocal neuropathy with conduction block Motor neuropathy
by quadriceps weakness. Lightweight ankle–foot orthoses may ameliorate the effects of foot drop. Unfortunately orthotic devices rarely help the tendency to falls resulting from quadriceps weakness. 13.4.2. Dysphagia Dysphagia in IBM may respond well to cricopharyngeal myotomy (Danon and Friedman, 1989; Verma et al., 1991). Dramatic response to intravenous immunoglobulin (IVIg) infusion has been reported in a small number of cases with prominent dysphasia (Cherin et al., 2002) and is interesting to note that there was a significant improvement in ultrasound monitored swallowing time during one intravenous immunoglobulin (IVIg) trial (Dalakas et al., 1997). 13.4.3. Exercise A resistance muscle strength training program in five patients over a 12-week period did not cause muscle fatigue nor any harm in terms of creatine kinase, serological markers or muscle biopsy parameters, and did result in an increase in dynamic muscle performance, although the functional benefit of this was uncertain (Spector et al.,
262
M. R. ROSE AND R. C. GRIGGS
1997). A second study with seven subjects using a home exercise program consisting of a walking and a resistive exercise program for 15 minutes each per day for 5 days a week over 12 weeks confirmed that the muscles were not damaged but did not show any benefit (Arnardottir et al., 2003b). 13.4.4. Drug treatment The prominence of inflammation in the histology of IBM has led to the assumption that this disease ought to respond to immunosuppressive or immunomodulating drugs. Thus most of these have been tried as listed in Table 13.3. The recognition that mitochondrial function is specifically impaired in IBM has also resulted in the use of treatments attempting to boost mitochondrial respiratory chain function (Table 13.3). Antioxidants have also been suggested treatment following recognition that markers of oxidative stress are increased in IBM (Yang et al., 1996). The gold standard for the efficacy of any treatment is the randomized controlled trial (RCT). Seven RCTs have been reported for IBM using single treatments such as intravenous immunoglobulin (Dalakas et al., 1997; Walter et al., 2000; Dalakas et al., 2001), b-interferon (bINF; Muscle Study Group and Rose, 2001; Muscle Study Group, 2004), methotrexate (MTX; Badrising et al., 2002), anabolic steroid (oxandralone; Rutkove et al., 2002). Two further trials used MTX in combination with anti-T lymphocte immunoglobulin (ATG; Lindberg et al., 2003), and MTX in combination with azathioprine Table 13.3 Treatments that have been used for inclusion-body myositis Immunosupressive and immunomodulatory Prednisolone (and other corticosteroids) Cyclophosphamide Chlorambucil Azathioprine Methotrexate Cyclosporin Total body irradiation Leukopheresis Plasma exchange Intravenous immunoglobulin Etanercept Campath 1H Mitochondrial Carnitine Ubiquinone/CoQ Antioxidants Vitamin E
(AZA, Leff et al., 1993); in both studies compared to treatment with MTX alone. IVIg was used with prednisolone in another trial (Dalakas et al., 2001). In terms of their quality all used appropriate diagnostic criteria, but two were not blinded (Leff et al., 1993; Lindberg et al., 2003) and all were underpowered to show anything other than a large treatment effect. This is due to the fact that the subject numbers are small and the treatment periods are short (Griggs and Rose, 1998; Rose et al., 1999). Thus while a trial may be negative in the sense that no positive benefit can be demonstrated none can rule out a possible benefit. The option of a meta-analysis of the RCTs to try and increase the power of these studies is thwarted by the fact that, with the exception of the IVIg trials (Dalakas et al., 1997 Walter et al., 2000; Dalakas et al., 2001), different interventions were used. There is non-randomized evidence in the form of case reports, and retrospective and uncontrolled studies where the problem of bias due to non-randomization or blinding of treatment is an issue. In addition many of these studies use inadequate outcome measures such as creatine kinase levels or subjective ratings of strength. CK values may be reduced by corticosteroid treatment in both inflammatory and non-inflammatory muscle diseases without any other clinical improvement and even without treatment quantitative let alone qualitative strength measures may appear to stabilize or “improve” in the short term (Rose et al., 2001). 13.4.4.1. Corticosteroids In the majority of cases corticosteroids do not appear to be of any benefit. There are occasional cases reported of “stabilization” for a period of months but this may just reflect the natural history of the disease (Rose et al., 2001). In rare cases improvement has been claimed but these have been uncontrolled trials often only published in abstract form with subsequent enquiry establishing that the improvements have not necessarily being maintained (Griggs and Rose, 1998). Where clear or sustained benefit with steroids has been claimed, cases have been distinguished by the coexistence of other autoimmune disease or the presence of myositis-associated antibodies (Lane et al., 1985; Hengstman et al., 2001; Ranque-Francois et al., 2005). This might either suggest a more steroid-responsive subgroup of IBM, or be a reflection of the effect of steroids upon a coexisting steroid-responsive condition. Two prospective open-label trials of prednisolone showed no worthwhile benefit and in one of these trials muscle biopsy following treatment, while showing reduction in inflammatory infiltrates, showed increase in the number of rimmed vacuoles and amyloid deposits (Lindberg et al., 1994; Barohn et al., 1995). Some experts still suggest that their practice is to give a course of
INCLUSION BODY MYOSITIS steroids in selected cases but with no consensus as to dose of steroid, duration of treatment or basis for selection of cases. 13.4.4.2. Cytotoxic drugs These have usually been added to corticosteroids following failure to respond to steroids alone. The response to cyclophosphamide, chlorambucil, azathioprine and cyclosporin is unimpressive in the small numbers reported (Griggs and Rose, 1998). Methotrexate has been studied in larger numbers with a few showing apparent stabilization or improvement but the study period has been short (Sayers et al., 1992; Joffe et al., 1993; Leff et al., 1993). One case improved with mycophenolate given for a year with deterioration when the drug was discontinued, and the authors claim that a further six unpublished cases have also benefited from this drug (Mowzoon et al., 2001). 13.4.4.3. Immunomodulating therapy Total body radiation, leukopheresis and plasma exchange have not shown convincing benefit (Kelly et al., 1984, 1986; Dau 1987; Miller et al., 1992). 13.4.4.4. Intravenous immunoglobulin Initial open-label prospective trials of intravenous immunoglobulin appeared to be promising (Soueidan and Dalakas, 1993; Amato et al., 1994; Mastaglia et al., 1998) but blinded randomized controlled trials have only shown a small benefit in less than a third of patients that does not seem to justify the expense and medical risks of this treatment (Soueidan and Dalakas, 1993; Dalakas et al., 1995, 1997; Walter et al., 2000). There is a suggestion that dysphagia may respond dramatically (Cherin et al., 2002) as mentioned above. The trial combining IVIg with prednisolone did not demonstrate benefit at all (Dalakas et al., 2001). One report claims a prolonged response to IVIg but this patient was unusual in having fasciculations which are not a feature of IBM and might have been due to another, perhaps autoimmune, neuromuscular condition (Mukunda et al., 2001). 13.4.4.5. Antioxidants and mitochondrial treatments There is no sound evidence for the efficacy of treatments designed to increase mitochondrial respiratory chain function such as carnitine or CoQ/ubiquinone, nor for drugs designed to reduce oxidative stress, such as vitamin E (Engel and Askanas, 1998). 13.4.4.6. Oxandrolone A single double-blind, placebo-controlled, crossover trial used 12 weeks of oral oxandrolone, an anabolic
263
steroid, 10 mg twice/day in 19 patients, 13 of whom completed the entire study. There were minimal adverse events and mean whole body strength, assessed by maximal voluntary isometric contraction testing, and stair climbing showed borderline significant improvements while whole body strength assessed by manual muscle testing did not (Rutkove et al., 2002). 13.4.4.7. Anti-T lymphocyte globulin A small open-label trial looked at the effects of anti-T lymphocyte globulin infusions. These were given in addition to MTX for 1 year and resulted in an increase in strength, as assessed by myometry in six muscles, of þ1.4% in five patients as opposed to the 11.1% decline in strength seen in the five patients taking MTX alone. The improvement was mainly confined to handgrip and wrist dorsal extension while knee extension and hip flexion strength declined by 10–15% (Lindbergh et al., 2003). 13.4.4.8. b-interferon Two double-blind placebo-controlled RCTs studied binterferon (Avonex) given intramuscularly for 24 weeks at doses of 30 mg or 60 mg per week to a total of 60 patients (half on placebo). There was no significant benefit seen but the studies were only powered to show safety and tolerability and not efficacy (Muscle Study Group, 2001; Muscle Study Group, 2004). However a case is reported of a good response to a 10-week course of high-dose binterferon in a case of s-IBM associated with hepatitis C; as well as increasing strength the hepatitis C viral load was reduced (Yakushiji et al., 2004). 13.4.5. What to do? Given the paucity of evidence base for treatment in IBM various experts have given their personal policies for treating IBM. Mastalgia quotes his practice as being that of a trial of low-dose prednisolone (0.6 mg/kg) and a steroid-sparing agent such as methotrexate (starting at 10 mg/week) or azathioprine (1.5–2.5 mg/kg/day), provided that such treatment is not contraindicated by the patient’s general medical condition and that the disorder is not too advanced. If patients improve or stabilize as judged by quantitative muscle strength testing the dose of prednisolone is gradually tapered and maintenance doses of the medications are continued. However if muscle strength continues to deteriorate or side effects develop, the treatment is stopped (Mastaglia et al., 2003). Dalakas states that he either does not use treatment or adds low-dose steroids combined with CoQ10 and an exercise program if the case is mild but uses IVIg if there is rapid worsening or exhibit
264
M. R. ROSE AND R. C. GRIGGS
significant life-threatening dysphagia (Dalakas, 2001). The authors do not generally treat IBM unless there is doubt about the diagnosis, with the possibility of there being a steroid responsive polymyositis, or where there is coexisting connective tissue disease.
13.5. Prognosis Retrospective studies have to contend with the uncertainty that may exist as to the onset of this insidious disease. Timing progression from the time of diagnosis may be inappropriate as the combination of its insidious onset, and either lack of recognition or misdiagnosis of this disease by the initial physician may contribute to a delay in final diagnosis that averages 3 years (Sayers et al., 1992), 4.4 years (Phillips et al., 2000) or 8 years (Badrising et al., 2000) and in some cases has been as long as three decades. Some studies have prospectively measured the rate of decline of muscle strength but using different and non-comparable methods (Lindberg et al., 1994; Peng et al., 2000; Rose et al., 2001). Eleven patients with untreated inclusion-body myositis showed a mean decline in muscle strength measured by fixed quantitative myometry of 4% from baseline in a 6-month period, but one-third of patients showed no change or slight improvements in strength during this period (Rose et al., 2001). In 18 patients serial measurements of the maximal voluntary muscle strength revealed a mean loss of muscle strength of 1.4% per month (Lindberg et al., 1994). Six patients showed a mean reduction in 10-point MRC scores of 17% over a 24.5-month period, this being equivalent to a reduction in mean modified MRC score of 3.87 points over 12 months. There was no difference between the rate of upper and lower limb deterioration in strength (Peng et al., 2000). It is difficult to translate these figures into predictions for decline of function. In one study 10 out of 14 patients required a walking stick 5 years after disease onset and three out of five surviving 10 years after diagnosis were wheelchairbound (Sekul and Dalakas, 1993). In a series of 78 patients 82% were using assistive devices. The time from first symptoms to the use of a walker seemed faster for those developing their symptoms at an older age; a mean of 3.2 for eighth-decade, compared with a mean of 17 years for fifth-decade onset of symptoms (Peng et al., 2000). It is uncertain whether this reflects a true change in disease behavior or the lack of reserve muscle and the presence of coincidental disease such as osteoarthritis contributing to the need for assistive devices. Death is usually from coexisting and unrelated disease rather than due to IBM per se as confirmed by the recorded cause of death in nine patients in one series (Peng et al., 2000). In this same series 30% had
suffered aspiration pneumonias, probably resulting from their dysphagia.
13.6. Etiology The precise etiology of IBM has yet to be defined, however any etiological hypothesis needs to incorporate several distinct features that have been found to occur in IBM. These features include an inflammatory component, the accumulation of various “alien” proteins, mitochondrial abnormalities, evidence for oxidative stress, involvement of heat shock proteins and myonuclear changes. Since many of these features are shared with the hereditary inclusion-body myopathies the possibility of a genetic susceptibility to sporadic IBM has been investigated. The notable absence of inflammation in most of the hereditary inclusion-body myopathies makes the study of the commonalities and differences in other pathological changes seen in the hereditary inclusion-body myopathies compared with those seen in IBM a useful research tool. 13.6.1. Inflammatory changes Immunohistochemical studies have established that the predominantly endomysial inflammatory infiltrate seen in IBM contains 74% T cells, 24% macrophages and virtually no B cells. The majority of the T cells are CD8þ, with some CD3þ and CD4þ cells. Although CD16þ natural killer cells are not seen, 29% of the CD3þ cells express CD57 and in vitro such cells can mediate cytotoxicity, albeit lectin-dependent rather than spontaneous as for natural killer cells. The CD8þ cells surround and invade non-necrotic muscle fibers and such invaded fibers are 5.5 times more frequent than necrotic fibers. Both the total number of T cells and the number invading muscle fibers is higher in IBM than is seen in either polymyositis or dermatomyositis. Just over a third of the invading CD8þ cells and a quarter of the surrounding but non-invading CD8þ express MHC class II and CD45RO markers typical of activated and antigenprimed T cells. Investigation of the T cell receptor repertoire of the infiltrating T cells shows an oligoclonal pattern rearrangement with increased frequency of the Vb3, Vb2 and Vb6 gene families with heterogeneity of the CDR3 domain sequence. This suggests that the T-cell response is triggered by a superantigen rather than by a muscle-specific antigen. All the invaded muscle fibers express HLA class 1 antigen on their surface suggesting a MHC class 1 restricted cytotoxic cell mediated attack on the fibers. Examination of cytokine expression in IBM shows prominent expression of IL-1a, IL-1b and TGF-b3 with lesser expression of TNFa/b (Lundberg et al., 1997;
INCLUSION BODY MYOSITIS Lundberg and Nyberg, 1998). There are two main pathways by which the activated T cells might destroy muscle fibers and there is evidence for both occurring in IBM. In favor of the perforin-granzyme pathway is the presence of perforin-positive cells in IBM, while in support of activation of the Fas–Fas ligand pathway is the demonstration of Fas in IBM muscle (Orimo et al., 1994; Goebels et al., 1996; Behrens et al., 1997; Fyhr and Oldfors, 1998). Both pathways induce apoptosis but no evidence has yet been found for this occurring in IBM so the precise mode by which T cells destroy invaded muscle fibers remains unclear (Schneider et al., 1996; Hutchinson, 1998). Despite the undoubted prominence of the inflammatory changes in s-IBM there is continuing doubt as to whether inflammation is the primary pathology or the one most involved with the cause of weakness in IBM particularly as there is little if any benefit of anti-inflammatory treatments. 13.6.2. Accumulation of alien proteins Studies of muscle biopsies in IBM have shown the cytoplasmic deposition of a variety of proteins normally only expressed in adult muscle at the neuromuscular junction including amyloid b precursor protein (AbPP), b amyloid, ubiquitin, prion protein, apolipoprotein E and presenilin. For amyloid and prion protein, increased levels of the appropriate mRNA have been found, suggesting that upregulation of these proteins’ genes has occurred. Hyperphosphorylated tau, not normally seen in muscle, is also present in IBM muscle samples (Askanas et al., 1991, 1993a; Sarkozi et al., 1994; Mirabella et al., 1996a). The mechanism for the increased transcription of these proteins is unclear but for AbPP the AP-1 transcription complex composed of c-Jun and CFos, the protein kinase C and the extracellular signalregulated kinase (ERK), all known to influence AbPP transcription, are increased in IBM muscle fibers (Wilczynski et al., 2000a, 2000b; Askanas and Engel, 2005). Proteins such as redox-factor 1 that increase the binding of proteins and transcription factors to the promotor region of genes such as AbPP are also increased in IBM muscle fibers (Broccolini et al., 2000). In muscle cell culture and in transgenic mice overexpression of AbPP can induce a vacuolar abnormality of muscle (Askanas et al., 1997; Fukuchi et al., 1998; Jin et al., 1998). In muscle cell cultures over-expressing AbPP the neuromuscular junction is abnormal and the muscle fibers cannot be innervated (McFerrin et al., 1998). Transgenic mice overexpressing wildtype prion protein become weak with evidence of a neuropathy and a myopathy albeit without the morphological features seen in IBM (Westaway et al., 1994).
265
As well as the up-regulation of proteins such as AbPP there is also evidence for impaired processing of these proteins that might contribute to their accumulation as well as to the production of toxic derivatives. Ab40 and Ab42 peptides are amongst the toxic derivatives of AbPP that are generated by two proteases, called b- and g-secretases that cleave amyloid-b at the N-terminal and C-terminal respectively. b-secretase activity has been identified with the glycosylated transmembrane proteins BACE1 and BACE2 while g-secretase activity has been identified with nicastrin and the presenilins PS1 and PS2. In IBM muscle fibers BACE1 and BACE2 are found in inclusions colocalizing with amyloid-b and they also coimmunoprecipitate with AbPP (Vattemi et al., 2001). Nicastrin, PS1 and PS2 are also seen in IBM muscle fibers in association with each other and with amyloid-b (Askanas et al., 1998; Askanas and Engel, 2005). Cystatin-C, an endogenous cysteine protease which also contributes to accumulation of amyloid-b is also seen in IBM muscle fibers (Vattemi et al., 2003). In contrast to the other abnormal proteins seen in IBM muscle, ApoE accumulation is not associated with increased mRNA suggesting that its excess may be due to transport from outside the muscle (Mirabella et al., 1996b). There is also an excess of free cholesterol and of caveolin-1 which is an intercellular transporter of cholesterol in IBM muscle particularly in association with AbPP. It is probable that free cholesterol and ApoE may contribute to the accumulation and misfolding of AbPP (Askanas and Engel, 2005). 13.6.3. Mitochondrial abnormalities Morphological, biochemical and mitochondrial DNA (mtDNA) defects are a feature of normal aging but the morphological changes in IBM namely the ragged red fibers, cytochrome oxidase negative fibers and ultrastructural mitochondrial abnormalities are greater than that seen in age matched controls (Oldfors et al., 1993; Rifai et al., 1995). It has been suggested that the increase in muscle capillary density seen in IBM might be a reaction to defective aerobic metabolism resulting from mitochondrial abnormalities (Carpenter et al., 1978). In situ hybridization studies have shown that the IBM cytochrome-negative fibers have accumulated mutant mtDNA containing a deletion and have reduced amounts of the wildtype mtDNA (Oldfors et al., 1993). Southern blotting and polymerase chain reaction techniques in IBM muscle samples show a low level of multiple mtDNA deletions including the common deletion seen in classical mitochondrial myopathies (Santorelli et al., 1996). However each individual cytochrome oxidase negative muscle fiber contains mutant mtDNA with only
266
M. R. ROSE AND R. C. GRIGGS
one type of deletion (Oldfors et al., 1995). In classic mitochondrial myopathies mtDNA deletions tend to occur in sites flanked by nucleotide repeat sequences and the same is true for the various deletions seen in IBM (Moslemi et al., 1997). This pattern of mutant mtDNA with multiple deletions is similar to that seen in autosomal-dominant mitochondrial myopathies with multiple deletions in which it is likely that the multiple deletions result from a defect in nuclear control of mtDNA replication. It is arguable as to whether the mitochondrial changes in themselves would be sufficient to account for the weakness seen in IBM. The morphological mitochondrial abnormalities seem outweighed by the more likely contributing factors such as the inflammation, muscle fiber necrosis and endomysial fibrosis. Nevertheless a similar degree of mitochondrial change appears to be sufficient to cause weakness in the classical mitochondrial myopathies. 13.6.4. Myonuclear abnormalities The precise chemical identity of the intranuclear 15–18-nm tubulofilaments seen in IBM is unknown but they may be derived from components of the nuclear matrix. It is possible that they have a role in the degradation of myonuclei, which is a feature of IBM, either by space-occupying effects or through more direct mechanisms. The presence in cytoplasm of these same tublofilaments particularly in association with the rimmed vacuoles may be evidence that myonuclear degradation is a particular feature of IBM and that rimmed vacuoles may mark the sites of myonuclear degeneration. The presence within vacuoles of a variety of tubular filaments similar to those seen in myonuclei lends some support to this hypothesis (Karpati and Carpenter, 2000). An unidentified protein which binds to single-stranded DNA of any sequence structure appears to be the earliest sign of myonuclear abnormality (Nalbantoglu et al., 1994). One potential candidate protein might be the nuclear replication protein A which is upregulated in IBM and does bind single-stranded DNA. However more myonuclei contain this replication protein A than show single-stranded DNA binding suggesting that a different protein is likely to be involved (Nalbantoglu et al., 1994). 13.6.5. Oxidative stress Neuronal nitric oxide synthetases (nNOS), inducible nitric oxide synthetases (iNOS) and nitrotyrosine are abnormally accumulated in vacuolated fibers of IBM and they are not seen in other inflammatory myopathies (Yang et al., 1996, 1997). These markers of increased oxidative stress might suggest that increased nitric oxide species may contribute to the pathophysiology
of IBM. Superoxide dismutase 1 (SOD1) and mRNA for SOD1 are also found in IBM vacuolated muscle fibers and may represent an attempt to limit the effects of oxidative stress in IBM (Askanas et al., 1996a). Oxidative stress increases redox-factor 1 activation which in turn increases AbPP transcription as mentioned above. 13.6.6. Heat-shock proteins There is overexpression of the small heat-shock protein aB-crystallin in IBM. This was not specific for IBM as it was also seen in the damaged muscle fibers obtained from other muscle diseases. However the finding of increased aB-crystallin deposition also in healthylooking fibers was specific to IBM and to two cases of treatment-resistant polymyositis thought to be potential cases of IBM suggesting that it might be an early primary pathological event occurring in response to an as yet unidentified biological stress (Banwell and Engel, 2000). 13.6.7. Genetic susceptibility The hereditary inclusion-body myopathies show that many of the pathological features of IBM can arise from genetic mechanisms. As IBM is an inflammatory, possibly autoimmune, myopathy, and because it has some association with autoimmune diseases one group of candidate susceptibility genes would be those thought to play a part in autoimmunity. One such group would be those within the major histocompatibility complex (MHC). Studies have shown an obvious increase in the frequency of DR3 with smaller increases in the frequencies of B8, DR1 and null alleles at the C4A locus in association with IBM (Garlepp et al., 1994; Sivakumar et al., 1997). The DR3/B8 haplotype is associated with other autoimmune diseases including polymyositis and dermatomyositis. It is also seen with systemic lupus erythematosis, selective IgA deficiency and common variable Ig deficiency, each of which have been described in association with IBM (Yood and Smith, 1985; Lindberg et al., 1994; Dalakas and Illa, 1995). Another group of candidate susceptibility genes would be those encoding for these proteins which show abnormal upregulation in IBM. No mutations of exons 16 and 17 of the amyloid precursor protein gene, such as seen in Alzheimer’s disease, have been found in IBM (Garlepp et al., 1998). Reports of an increase in the frequency of the homozygosity at codon 129 of the prion protein gene in IBM, such as seen in Creutzfeldt–Jacob disease, have been contradictory (Garlepp et al., 1998; Lampe et al., 1999). The pathogenic similarities between IBM and Alzheimer’s disease, as well as the finding of increased ApoE in IBM muscle, have also led to several studies of the e4 variant of the apolipoprotein E gene
INCLUSION BODY MYOSITIS since this allele is associated with some hereditary forms of Alzheimer’s disease as well as a susceptibility to sporadic Alzheimer’s disease. Again the results are contradictory with an increase in the e4 allele found by some (Garlepp et al., 1995) but not by others (Askanas et al., 1996b; Harrington et al., 1995). 13.6.8. Etiological hypothesis The main debate regarding any etiological hypothesis for IBM concerns the nature of the primary pathological event. Attempts to do this have relied on evidence that the change in question be it amyloid deposition, aB crystallin, etc., is seen in the absence of other pathology. The separate strands of evidence highlighted above can be linked in a variety of ways. One hypothesis is that some viral or other insult in genetically susceptible elderly persons triggers myonuclear degeneration and disturbance of gene function leading to upregulation of alien proteins one or more of which triggers the inflammatory response. Disturbed nuclear gene function may lead to impairment of mitochondrial replication and thus to the mitochondrial abnormalities found in IBM. Oxidative stress may be induced by the inflammation and would exacerbate the mitochondrial abnormalities. An alternative hypothesis places the inflammation at the forefront suggesting that this is enough in elderly and genetically susceptible individuals to initiate all the changes seen in IBM including vacuoles, mitochondrial abnormalities, oxidative stress and upregulation of b-amyloid precursor protein via cytokines. The presence of aB-crystallin prior to any other structural change suggests that the initiating stressor event may actually occur much earlier in life rather than being one to which the elderly are susceptible. However Serdaroglu in this volume gives an elegant argument for the role of senescence in modifying the biological response to insults that may explain the abnormalities seen in IBM.
13.7. Conclusions The increasing recognition of IBM may help us to better appreciate the early stages of this disease and thus appreciate the true sequence of the pathological changes. It is also possible that potential treatments have a greater chance of success if applied early in the course of the disease. If treatment serves to arrest or delay disease progression then early diagnosis becomes all the more imperative. There is interest in the increasing range of specific immunomodulatory treatments, based upon monoclonal antibodies or recombinant technology, that might yet have a better impact upon the inflammatory component of IBM. A current clinical trial is using
267
alemtuzumab (CampathW), an anti-CD52 antibody that leads to white cell depletion. It will be interesting to see whether or not there is improvement in the IBM with demonstrable removal of all white cell inflammatory infiltrates. A pilot study of etanercept, a TNFa receptor fusion protein that inhibits TNFa did not show any benefit except for handgrip but a bigger trial is needed to determine whether it has real potential (Barohn et al., 2006). The increasing understanding of the degenerative aspects of IBM opens up a further range of therapeutic options. There are a number of theoretical approaches that could reduce the presumed toxicity of misfolded proteins such as those derived from Ab and AbPP (Buxbaum 2006; May et al., 2006) The inflammatory and the degenerative aspects of IBM may lead to a fusion of therapies in that new immunocytotherapy approaches may be used to remove accumulated amyloid (McGavern, 2006). Some treatments such as statins may have a dual action in modifying the inflammatory and degenerative processes (Steinman, 2006). As such new therapies become available for testing there will be a clear need for adequately powered randomized controlled trials so as to reasonably answer the question as to whether a particular treatment is beneficial. RCTs in IBM are a particular challenge as the rate of disease progression is slow and the most likely outcome is that of arrest or slowing of progression. Detecting this response will require multicenter involvement in order to recruit sufficient numbers of patients, as well as longer-duration trials. The outcome measures will need to be both sensitive enough to detect real change in muscle performance and function, and practical and reliable for use in multiple centers.
References Alexander JA, Huebner CJ (1996). Hepatitis C and inclusion body myositis. Am J Gastroenterol 91: 1845–1847. Amato AA, Shebert RT (1998). Inclusion body myositis in twins. Neurology 51: 598–600. Amato AA, Barohn RJ, Jackson CE, et al. (1994). Inclusion body myositis: treatment with intravenous immunoglobulin. Neurology 44: 1516–1518. Arahata K, Engel AG (1984). Monoclonal antibody analysis of mononuclear cells in myopathies. I: Quantitation of subsets according to diagnosis and sites of accumulation and demonstration and counts of muscle fibers invaded by T cells. Ann Neurol 16: 193–208. Arahata K, Engel AG (1988a). Monoclonal antibody analysis of mononuclear cells in myopathies V. Identification and quantitation of T8þ cytotoxic and T8þ suppressor cells. Ann Neurol 23: 493–499. Arahata K, Engel AG (1988b). Monoclonal antibody analysis of mononuclear cells in myopathies. IV: Cell-mediated cytotoxicity and muscle fiber necrosis. Ann Neurol 23: 168–173.
268
M. R. ROSE AND R. C. GRIGGS
Argov Z, Yarom R (1984). Rimmed vacuole myopathy sparing the quadriceps. J Neurol Sci 64: 33–43. Arnardottir S, Alexanderson H, Lundberg IE, et al. (2003a). Sporadic inclusion body myositis: pilot study on the effects of a home exercise program on muscle function, histopathology and inflammatory reaction. J Rehabil Med 35: 31–35. Arnardottir S, Svanborg E, Borg K (2003b). Inclusion body myositis — sensory dysfunction revealed with quantitative determination of somatosensory thresholds. Acta Neurol Scand 108: 22–27. Askanas V, Engel WK (2005). Molecular pathology and pathogenesis of inclusion-body myositis. Microsc Res Tech 67: 114–120. Askanas V, Serdaroglu P, Engel WK, et al. (1991). Immunolocalization of ubiquitin in muscle biopsies of patients with inclusion body myositis and oculopharyngeal muscular dystrophy. Neurosci Lett 130: 73–76. Askanas V, Serdaroglu P, Engel WK, et al. (1992). Immunocytochemical localization of ubiquitin in inclusion body myositis allows its light-microscopic distinction from polymyositis. Neurology 42: 460–461. Askanas V, Alvarez RB, Engel WK (1993a). Beta-amyloid precursor epitopes in muscle fibers of inclusion body myositis. Ann Neurol 34: 551–560. Askanas V, Engel WK, Alvarez RB (1993b). Enhanced detection of congo-red-positive amyloid deposits in muscle fibers of inclusion body myositis and brain of Alzheimer’s disease using fluorescence technique. Neurology 43: 1265–1267. Askanas V, Sarkozi E, Alvarez RB, et al. (1996a). Superoxide dismutase 1 gene and protein in vacuolated muscle fibers of sporadic inclusion body myositis, hereditary inclusion body myoathy and in cultured human muscle after b-amyloid precursor gene transfer. Neurology 46: 487. Askanas V, Engel WK, Mirabella M, et al. (1996b). Apolipoprotein E alleles in sporadic inclusion-body myositis and hereditary inclusion-body myopathy [letter]. Ann Neurol 40: 264–265. Askanas V, Alvarez RB, Mirabella M, et al. (1996c). Use of anti-neurofilament antibody to identify paired-helical filaments in inclusion-body myositis. Ann Neurol 39: 389–391. Askanas V, McFerrin J, Alvarez RB, et al. (1997). Beta APP gene transfer into cultured human muscle induces inclusion-body myositis aspects. Neuroreport 8: 2155–2158. Askanas V, Engel WK, Yang CC, et al. (1998). Light and electron microscopic immunolocalization of presenilin 1 in abnormal muscle fibers of patients with sporadic inclusion-body myositis and autosomal-recessive inclusionbody myopathy. Am J Pathology 152: 889–895. Badrising UA, Maat-Schieman M, van Duinen SG, et al. (2000). Epidemiology of inclusion body myositis in the Netherlands: a nationwide study. Neurology 55: 1385–1388. Badrising UA, Maat-Schieman ML, Ferrari MD, et al. (2002). Comparison of weakness progression in inclusion body myositis during treatment with methotrexate or placebo. Ann Neurol 51: 369–372. Banwell BL, Engel AG (2000). aB crystallin immunolocalisation yields new insights into inclusion body myositis. Neurology 54: 1033–1041.
Barohn RJ, Amato AA, Sahenk Z, et al. (1995). Inclusion body myositis: explanation for poor response to immunosuppressive therapy. Neurology 45: 1302–1304. Barohn RJ, Herbelin L, Kissel JT, et al. (2006). Pilot trial of etanercept in the treatment of inclusion-body myositis. Neurology 66: S123–S124. Bates D, Stevens JC, Hudgson P (1973). “Polymyositis” with involvement of facial and distal musculature. One form of the fascioscapulohumeral syndrome? J Neurol Sci 19: 105–108. Behrens L, Bender A, Johnson MA, et al. (1997). Cytotoxic mechanisms in inflammatory myopathies. Co-expression of Fas and protective Bcl-2 in muscle fibres and inflammatory cells. Brain 120: 929–938. Blume G, Pestronk A, Frank B, et al. (1997). Polymyositis with cytochrome oxidase negative muscle fibres. Early quadriceps weakness and poor response to immunosuppressive therapy. Brain 120: 39–45. Broccolini A, Engel WK, Alvarez RB, et al. (2000). Redox factor-1 in muscle biopsies of patients with inclusion-body myositis. Neurosci Lett 287: 1–4. Buxbaum JN (2006). Treatment and prevention of the amyloidoses: can the lessons learned be applied to sporadic inclusion-body myositis? Neurology 66: S110–S113. Carpenter S, Karpati G, Heller I, et al. (1978). Inclusion body myositis: a distinct variety of idiopathic inflammatory myopathy. Neurology 28: 8–17. Cherin P, Pelletier S, Teixeira A, et al. (2002). Intravenous immunoglobulin for dysphagia of inclusion body myositis. Neurology 58: 326. Chou SM (1967). Myxovirus like structures in a case of human chronic polymyositis. Science 158: 1453–1455. Cupler EJ, Leon-Monzon M, Miller J, et al. (1996). Inclusion body myositis in HIV-1 and HTLV-1 infected patients. Brain 119: 1887–1893. Dalakas MC (2001). Progress in inflammatory myopathies: good but not good enough. J Neurol Neurosurg Psychiatry 70: 569–573. Dalakas MC, Illa I (1995). Common variable immunodeficiency and inclusion body myositis — a distinct myopathy mediated by natural killer cells. Ann Neurol 37: 806–810. Dalakas MC, Dambrosia JM, Sekul EA, et al. (1995). The efficacy of high dose intravenous immunoglogulin (IVIg) in patients with inclusion body myositis (IBM). Neurology 45 (Suppl. 4): 174S. Dalakas MC, Sonies B, Dambrosia J, et al. (1997). Treatment of inclusion-body myositis with IVIg: a double-blind, placebo-controlled study [see comments]. Neurology 48: 712–716. Dalakas MC, Koffman B, Fujii M, et al. (2001). A controlled study of intravenous immunoglobulin combined with prednisolone in the treatment of IBM. Neurology 56: 323–327. Danon MJ, Friedman M (1989). Inclusion body myositis associated with progressive dysphagia: treatment with cricopharyngeal myotomy. Can J Neurol Sci 16: 436–438. Danon MJ, Friedman M (1992). Inclusion body myositis with cricopharyngeus muscle involvement and severe dysphagia [letter; comment]. Muscle Nerve 15: 115.
INCLUSION BODY MYOSITIS Danon MJ, Perurena OH, Ronan S, et al. (1986). Inclusion body myositis associated with systemic sarcoidosis. Can J Neurol Sci 13: 334–336. Dau PC (1987). Leukocytapheresis in inclusion body myositis. J Clin Apher 3: 167–170. Desmedt JE, Borenstein S (1975). Relationship of spontaneous fibrillation potentials to muscle fibre segmentation in human muscular dystrophy. Nature 258: 531–534. DeVere R, Bradley WG (1975). Polymyositis: its presentation, morbidity and mortality. Brain 98: 637–666. Eisen A, Berry K, Gibson G (1983). Inclusion body myositis (IBM): myopathy or neuropathy? Neurology 33: 1109–1114. Engel WK, Askanas V (1998). Treatment of inclusion body myositis and hereditary inclusion body myopathy with reference to pathogenic mechanisms: personal experience. In: V Askanas, G Serratrice, WK Engel (Eds.), Inclusion body myositis and myopathies.1st edn,Cambridge University Press, Cambridge, pp. 351–382. Felice KJ, Relva GM, Conway SR (1998). Further observations on forearm flexor weakness in inclusion body myositis. Muscle Nerve 21: 659–661. Fukuchi K, Pham D, Hart M, et al. (1998). Amyloid-beta deposition in skeletal muscle of transgenic mice: possible model of inclusion body myopathy [see comments]. Am J Pathol 153: 1687–1693. Fyhr IM, Oldfors A (1998). Upregulation of Fas/Fas ligand in inclusion body myositis. Ann Neurol 43: 127–130. Garlepp MJ, Laing B, Zilko PJ, et al. (1994). HLA associations with inclusion body myositis. Clin Expl Immunol 98: 40–45. Garlepp MJ, Tabarias H, van Bockxmeer FM, et al. (1995). Apolipoprotein E epsilon 4 in inclusion body myositis. Ann Neurol 38: 957–959. Garlepp MJ, Blechynden L, Tabarias H, et al. (1998). Genetic factors in sporadic inclusion body myositis. In: V Askanas, G Serratrice, WK Engel (Eds.), Inclusion body myositis and myopathies.1st edn,Cambridge University Press, Cambridge, pp. 177–188. Goebels N, Michaelis D, Engelhardt M, et al. (1996). Differential expression of perforin in muscle-infiltrating T cells in polymyositis and dermatomyositis. J Clin Invest 97: 2905–2910. Griggs RC, Rose MR (1998). Evaluation of treatment for sporadic inclusion body myositis. In: V Askanas, G Serratrice, WK Engel (Eds.), Inclusion body myositis and myopathies.1st edn,Cambridge University Press, Cambridge, pp. 331–350. Griggs RC, Askanas V, DiMauro S, et al. (1995). Inclusion body myositis and myopathies. Ann Neurol 38: 705–713. Gutmann L, Govindan S, Riggs JE, et al. (1985). Inclusion body myositis and Sjogren’s syndrome. Arch Neurol 42: 1021–1022. Harrington CR, Anderson JR, Chan KK (1995). Apolipoprotein E type epsilon 4 allele frequency is not increased in patients with sporadic inclusion body myositis. Neurosci Lett 183: 35–38. Hengstman GJ, van Engelen BG, Badrising UA, et al. (1998). Presence of the anti-Jo-1 autoantibody excludes inclusion body myositis [letter]. Ann Neurol 44: 423.
269
Hengstman GJ, Ter Laak HJ, van Engelen BG, et al. (2001). Anti-Jo-1 positive inclusion body myositis with a marked and sustained clinical improvement after oral prednisone. J Neurol Neurosurg Psychiatry 70: 706. Hollinrake K (1969). Polymyositis presenting as distal muscle weakness. A case report. J Neurol Sci 8: 479–484. Houser SM, Calabrese LH, Strome M (1998). Dysphagia in patients with inclusion body myositis. Laryngoscope 108: 1001–1005. Hutchinson DO (1998). Inclusion body myositis: abnormal protein accumulation does not trigger apoptosis. Neurology 51: 1742–1745. Jin LW, Hearn MG, Ogburn CE, et al. (1998). Transgenic mice over-expressing the C-99 fragment of betaPP with an alphasecretase site mutation develop a myopathy similar to human inclusion body myositis [see comments]. Am J Pathol 153: 1679–1686. Joffe MM, Love LA, Leff RL, et al. (1993). Drug therapy of the idiopathic inflammatory myopathies: predictors of response to prednisone, azathioprine, and methotrexate and a comparision of their efficacy. Am J Med 94: 379–387. Joy JL, Oh SJ, Baysal AI (1990). Electrophysiological spectrum of inclusion body myositis. Muscle Nerve 13: 949–951. Karpati G, Carpenter S (2000). Myonuclear abnormalities may play a central role in the pathogenesis of muscle fibre damage in inclusion body myositis. In: V Askanas, G Serratrice, WK Engel (Eds.), Inclusion body myositis and myopathies.1st edn,Cambridge University Press, Cambridge, pp. 291–296. Karpati G, Carpenter S, Heller I, et al. (1988). Idiopathic inflammatory myopathies. Curr Opin Neurol Neurosurg 1: 806–814. Kelly JJ, Madoc-Jones H, Adelman L, et al. (1984). Treatment of refractory polymyositis with total body irradiation. Neurology 34 (Suppl. 1): 80. Kelly JJJr, Madoc-Jones H, Adelman LS, et al. (1986). Total body irradiation not effective in inclusion body myositis. Neurology 36: 1264–1266. Khraishi MM, Jay V, Keystone EC (1992). Inclusion body myositis in association with vitamin B12 deficiency and Sjogren’s syndrome. J Rheumatol 19: 306–309. Koffman BM, Rugiero M, Dalakas MC (1998a). Immunemediated conditions and antibodies associated with sporadic inclusion body myositis. Muscle Nerve 21: 115–117. Koffman BM, Sivakumar K, Simonis T, et al. (1998b). HLA allele distribution distinguishes sporadic inclusion body myositis from hereditary inclusion body myopathies. J Neuroimmunol 84: 139–142. Lacy JR, Simon DB, Neville HE, et al. (1982). Inclusion body myositis: electrodiagnostic and nerve biopsy findings. Neurology 32 (Suppl. 2): A202. Lampe J, Kitzler H, Walter MC, et al. (1999). Methionine homozygosity at prion gene codon 129 may predispose to sporadic inclusion-body myositis [letter]. Lancet 353: 465–466. Lane RJ, Fulthorpe JJ, Hudgson P (1985). Inclusion body myositis: a case with associated collagen vascular disease responding to treatment. J Neurol Neurosurg Psychiatry 48: 270–273.
270
M. R. ROSE AND R. C. GRIGGS
Leff RL, Miller FW, Hicks J, et al. (1993). The treatment of inclusion body myositis: a retrospective review and a randomised prospective trial of immunosuppressive therapy. Medicine 72: 225–235. Lindberg C, Oldfors A, Hedstrom A (1990). Inclusion body myositis: peripheral nerve involvement. Combined morphological and electrophysiological studies on peripheral nerves. J Neurol Sci 99: 327–338. Lindberg C, Persson L, Oldfors A, et al. (1990). Inclusion body myositis: association with immunodeficiency. J Neurol Sci 98: 178. Lindberg C, Persson LI, Bjorkander J, et al. (1994). Inclusion body myositis: clinical, morphological, physiological and laboratory findings in 18 cases. Acta Neurol Scand 89: 123–131. Lindberg C, Trysberg E, Tarkowski A, et al. (2003). Anti-Tlymphocyte globulin treatment in inclusion body myositis: A randomized pilot study. Neurology 61: 260–262. Lotz BP, Engel AG, Nishino H, et al. (1989). Inclusion body myositis. Observations in 40 patients. Brain 112: 727–747. Luciano CA, Dalakas MC (1997). Inclusion body myositis; no evidence for a neurogenic component. Neurology 48: 29–33. Lundberg IE, Nyberg P (1998). New developments in the role of cytokines and chemokines in inflammatory myopathies. Curr Opin Rheumatol 10: 521–529. Lundberg I, Ulfgren AK, Nyberg P, et al. (1997). Cytokine production in muscle tissue of patients with idiopathic inflammatory myopathies. Arthritis Rheum 40: 865–874. Luque FA, Rosenkilde C, Valsamis M, et al. (1994). Inclusion body myositis (IBM) presenting as the dropped head syndrome (DHS). Brain Pathol 4: 568. Maat-Schieman ML, Macfarlane JD, Bots GT, et al. (1992). Inclusion body myositis: its relative frequency in elderly people. Clin Neurol Neurosurg 94: S118–S120. Marconi G, Ronchi O, Taiuti R (1982). Polymyositis with severe distal muscular involvement. Acta Neurol (Napoli) 4: 340–346. Mastaglia FL, Phillips BA, Zilko PJ (1998). Immunoglobulin therapy in inflammatory myopathies. J Neurol Neurosurg Psychiatry 65: 107–110. Mastaglia FL, Garlepp MJ, Phillips BA, et al. (2003). Inflammatory myopathies: clinical, diagnostic and therapeutic aspects. Muscle Nerve 27: 407–425. May BCH, Govaerts C, Cohen FE (2006). Developing therapeutics for the diseases of protein misfolding. Neurology 66: S118–S122. McCoy AL, Bubb MR, Plotz PH, et al. (1999). Inclusion body myositis long after dermatomyositis: a report of two cases. Clin Exp Rheumatol 17: 235–239. McFerrin J, Engel WK, Askanas V (1998). Impaired innervation of cultured human muscle overexpressing betaAPP experimentally and genetically: relevance to inclusionbody myopathies. Neuroreport 9: 3201–3205. McGavern DB (2006). Immunotherapeutic relief from persistent infections and amyloid disorders. Neurology 66: S59–S64. McKee D, Karpati G, Carpenter S, et al. (1992). Familial inclusion body myositis (IBM) mimics fascioscapulohumeral dystrophy (FSHD). Neurology 42 (Suppl. 3): 302.
Mechler F (1974). Changing electromyographic findings during the chronic course of polymyositis. J Neurol Sci 23: 237–242. Mendell JR, Sahenk Z, Gales T, et al. (1991). Amyloid filaments in inclusion body myositis. Novel findings provide insight into nature of filaments. Arch Neurol 48: 1229–1234. Miller FW, Leitman SF, Cronin ME, et al. (1992). Controlled trial of plasma exchange and leukapheresis in polymyositis and dermatomyositis. New Engl J Med 326: 1380–1384. Mirabella M, Alvarez RB, Bilak M, et al. (1996a). Difference in expression of phosphorylated tau epitopes between sporadic inclusion-body myositis and hereditary inclusionbody myopathies [see comments]. J Neuropathol Exp Neurol 55: 774–786. Mirabella M, Alvarez RB, Engel WK, et al. (1996b). Apolipoprotein E and apolipoprotein E messenger RNA in muscle of inclusion body myositis and myopathies. Ann Neurol 40: 864–872. Mirabella M, Alvarez RB, Bilak M, et al. (1996c). Difference in expression of phosphorylated tau epitopes between sporadic inclusion-body myositis and hereditary inclusionbody myopathies. J Neuropathol Exp Neurol 55: 774–786. Moslemi AR, Lindberg C, Oldfors A (1997). Analysis of multiple mitochondrial DNA deletions in inclusion body myositis. Hum Mutat 10: 381–386. Mowzoon N, Sussman A, Bradley WG (2001). Mycophenolate (CellCept) treatment of myasthenia gravis, chronic inflammatory polyneuropathy and inclusion body myositis. J Neurol Sci 185: 119–122. Mukunda BN, Dileep KP, Smith HR (2001). Long-lasting effectiveness of intravenous immunoglobulin in a patient with inclusion-body myositis. Ann Intern Med 134: 1156. Muller-Felber W, Pongratz D, Reimers C (2001).64th ENMC International Workshop: therapeutic approaches to dermatomyositis, polymyositis, and inclusion body myositis. 29–31 January 1999, Naarden, The Netherlands, Neuromuscul Disord 11: 88–92. Muscle Study Group (2004). Randomized pilot trial of highdose betaINF-1a in patients with inclusion body myositis. Neurology 63: 718–720. Muscle Study Group, Rose MR (2001). Randomized pilot trial of INF1a (Avonex) in patients with inclusion body myositis. Neurology 57: 1566–1570. Nalbantoglu J, Karpati G, Carpenter S (1994). Conspicuous accumulation of a single-stranded DNA binding protein in skeletal muscle fibers in inclusion body myositis. Am J Pathol 144: 874–882. Naumann M, Reichmann H, Goebel HH, et al. (1996). Glucocorticoid-sensitive hereditary inclusion body myositis. J Neurol 243: 126–130. Oldfors A, Larsson NG, Lindberg C, et al. (1993). Mitochondrial DNA deletions in inclusion body myositis. Brain 116: 325–336. Oldfors A, Moslemi AR, Fyhr IM, et al. (1995). Mitochondrial DNA deletions in muscle fibers in inclusion body myositis. J Neuropathol Exp Neurol 54: 581–587. Orimo S, Koga R, Goto K, et al. (1994). Immunohistochemical analysis of perforin and granzyme A in inflammatory myopathies. Neuromuscul Disord 4: 219–226.
INCLUSION BODY MYOSITIS Peng A, Koffman BM, Malley JD, et al. (2000). Disease progression in sporadic inclusion body myositis: observations in 78 patients. Neurology 55: 296–298. Phillips BA, Zilko PJ, Mastaglia FL (2000). Prevalence of sporadic inclusion body myositis in Western Australia. Muscle Nerve 23: 970–972. Phillips BA, Cala LA, Thickbroom GW, et al. (2001). Patterns of muscle involvement in inclusion body myositis: clinical and magnetic resonance imaging study. Muscle Nerve 24: 1526–1534. Prayson RA, Cohen ML (1997). Ubiquitin immunostaining and inclusion body myositis: study of 30 patients with inclusion body myositis. Hum Pathol 28: 887–892. Ranque-Francois B, Maisonobe T, Dion E, et al. (2005). Familial inflammatory inclusion body myositis. Ann Rheum Dis 64: 634–637. Rifai Z, Welle S, Kamp C, et al. (1995). Ragged red fibers in normal aging and inflammatory myopathy. Ann Neurol 37: 24–29. Riggs JE, Schochet SSJr, Gutmann L, et al. (1984). Inclusion body myositis and chronic immune thrombocytopenia. Arch Neurol 41: 93–95. Riggs JE, Schochet SSJr, Gutmann L, et al. (1989). Childhood onset inclusion body myositis mimicking limb-girdle muscular dystrophy. J Child Neurol 4: 283–285. Riminton DS, Chambers ST, Parkin PJ, et al. (1993). Inclusion body myositis presenting solely as dysphagia. Neurology 43: 1241–1243. Ringel SP, Kenny CE, Neville HE, et al. (1987). Spectrum of inclusion body myositis. Arch Neurol 44: 1154–1157. Rose MR, Griggs R, Dalakas M (1999). Immunotherapy for inclusion body myositis (Protocol for a Cochrane Review). The Cochrane Library 4, Update Software. Rose MR, Levin KH, Griggs RC (1999). The dropped head plus syndrome: quantitation of response to corticosteroids. Muscle Nerve 22: 115–118. Rose MR, McDermott MP, Thornton CA, et al. (2001). A prospective longitudinal natural history study of inclusion body myositis; implications for clinical trials. Neurology 57: 548–550. Rugiero M, Koffman B, Dalakas MC (1998). Association of inclusion body myositis with autoimmune diseases and autoantibodies. Ann Neurol 38: 333. Rutkove SB, Parker RA, Nardin RA, et al. (2002). A pilot randomized trial of oxandrolone in inclusion body myositis. Neurology 58: 1081–1087. Santorelli FM, Sciacco M, Tanji K, et al. (1996). Multiple mitochondrial DNA deletions in sporadic inclusion body myositis: a study of 56 patients. Ann Neurol 39: 789–795. Sarkozi E, Askanas V, Engel WK (1994). Abnormal accumulation of prion protein mRNA in muscle fibers of patients with sporadic inclusion-body myositis and hereditary inclusion-body myopathy [see comments]. Am J Pathol 145: 1280–1284. Sayers ME, Chou SM, Calabrese LH (1992). Inclusion body myositis: analysis of 32 cases. J Rheumatol 19: 1385–1389.
271
Schlesinger I, Soffer D, Lossos A, et al. (1996). Inclusion body myositis: atypical clinical presentations. Eur Neurol 36: 89–93. Schneider C, Gold R, Dalakas MC, et al. (1996). MHC class I-mediated cytotoxicity does not induce apoptosis in muscle fibers nor in inflammatory T cells: studies in patients with polymyositis, dermatomyositis, and inclusion body myositis. J Neuropathol Exp Neurol 55: 1205–1209. Sekul EA, Dalakas MC (1993). Inclusion body myositis: new concepts. Semin Neurol 13: 256–263. Sekul EA, Chow C, Dalakas MC (1997). Magnetic resonance imaging of the forearm as a diagnostic aid in patients with sporadic inclusion body myositis. Neurology 48: 863–866. Selva-O’Callaghan A, Mijares-Boeckh-Behrens T, LabradorHorrillos M, et al. (2003). Anti-PM-Scl antibodies in a patient with inclusion body myositis. Rheumatology (Oxford) 42: 1016–1018. Sivakumar K, Semino-Mora C, Dalakas MC (1997). An inflammatory, familial, inclusion body myositis with autoimmune features and a phenotype identical to sporadic inclusion body myositis. Studies in three families. Brain 20: 653–661. Soden M, Boundy K, Burrow D, et al. (1994). Inclusion body myositis in association with rheumatoid arthritis. J Rheumatol 21: 344–346. Soueidan SA, Dalakas M (1993). Treatment of inclusion body myositis with high dose intravenous immunoglobulin. Neurology 43: 876–879. Spector SA, Lemmer JT, Koffman BM, et al. (1997). Safety and efficacy of strength training in patients with sporadic inclusion body myositis. Muscle Nerve 20: 1242–1248. Steinman L (2006). Controlling autoimmunity in sporadic inclusion-body myositis. Neurology 66: S56–S58. Sundaram MB, Ashenhurst EM (1981). Polymyositis presenting with distal and asymmetrical weakness. Can J Neurol Sci 8: 147–149. Talanin NY, Bushore D, Rasberry R, et al. (1999). Dermatomyositis with the features of inclusion body myositis associated with carcinoma of the bladder. Br J Dermatol 141: 926–930. Vaccario ML, Scoppetta C, Bracaglia R, et al. (1981). Sporadic distal myopathy. J Neurol 224: 291–295. van der Meulen MFG, Hoogendijk JE, Jansen GH, et al. (1998). Absence of characteristic features in two patients with inclusion body myositis. J Neurol Neurosurg Psychiatry 64: 396–398. van der Meulen MF, Bronner IM, Hoogendijk JE, et al. (2003). Polymyositis: an overdiagnosed entity. Neurology 61: 316–321. Van Kasteren BJ (1979). Polymyositis presenting with chronic progressive distal muscular weakness. J Neurol Sci, 41: 307–310. Vattemi G, Engel WK, McFerrin J, et al. (2001). Presence of BACE1 and BACE2 in muscle fibres of patients with sporadic inclusion-body myositis. Lancet 358: 1962–1964. Vattemi G, Engel WK, McFerrin J, et al. (2003). Cystatin C colocalizes with amyloid-beta and coimmunoprecipitates
272
M. R. ROSE AND R. C. GRIGGS
with amyloid-beta precursor protein in sporadic inclusionbody myositis muscles. J Neurochem 85: 1539–1546. Verma A, Bradley WG, Adesina AM, et al. (1991). Inclusion body myositis with cricopharyngeus muscle involvement and severe dysphagia [see comments]. Muscle Nerve 14: 470–473. Verma A, Bradley WG, Soule NW, et al. (1992). Quantitative morphometric study of muscle in inclusion body myositis. J Neurol Sci 112: 192–198. Voermans NC, Vaneker M, Hengstman GJ, et al. (2004). Primary respiratory failure in inclusion body myositis. Neurology 63: 2191–2192. Walter MC, Lochmuller H, Toepfer M, et al. (2000). High dose immunglobulin therapy in sporadic inclusion body myositis: a double blind, placebo-controlled study. J Neurol 247: 22–28. Waters DD, Nutter DO, Hopkins LC, et al. (1975). Cardiac features of an unusual X-linked humeroperoneal neuromuscular disease. New Engl J Med 293: 1017–1022. Westaway D, DeArmond SJ, Cayetano-Canlas J, et al. (1994). Degeneration of skeletal muscle, peripheral nerves, and the central nervous system in transgenic mice overexpressing wild-type prion proteins. Cell 76: 117–129. Wilczynski GM, Engel WK, Askanas V (2000a). Association of active extracellular signal-regulated protein kinase with paired helical filaments of inclusion-body myositis muscle suggests its role in inclusion-body myositis tau phosphorylation. Am J Pathol 156: 1835–1840.
Wilczynski GM, Engel WK, Askanas V (2000b). Cyclindependent kinase 5 colocalizes with phosphorylated tau in human inclusion-body myositis paired-helical filaments and may play a role in tau phosphorylation. Neurosci Lett 293: 33–36. Wintzen AR, Bots GT, de Bakker HM, et al. (1988). Dysphagia in inclusion body myositis. J Neurol Neurosurg Psychiatry 51: 1542–1545. Yabe I, Higashi T, Kikuchi S, et al. (2003). GNE mutations causing distal myopathy with rimmed vacuoles with inflammation. Neurology 61: 384–386. Yakushiji Y, Satoh J, Yukitake M, et al. (2004). Interferon beta-responsive inclusion body myositis in a hepatitis C virus carrier. Neurology 63: 587–588. Yang CC, Alvarez RB, Engel WK, et al. (1996). Increase of nitric oxide synthases and nitrotyrosine in inclusion-body myositis. Neuroreport 8: 153–158. Yang CC, Alvarez RB, Engel WK, et al. (1997). Nitric oxide induced oxidative stress in the muscle fibres of hereditary inclusion body myositis and sporadic inclusion body myositis. Neurology 48: A331. Yood RA, Smith TW (1985). Inclusion body myositis and systemic lupus erythematosus. J Rheumatol 12: 568–570. Yunis EJ, Samaha FJ (1971). Inclusion body myositis. Lab Invest 25: 240–248. Zeman RJ, Peng H, Danon MJ, et al. (2000). Clenbuterol reduces degeneration of exercised or aged dystrophic (mdx) muscle. Muscle Nerve 23: 521–528.
Handbook of Clinical Neurology, Vol. 86 (3rd series) Myopathies F. L. Mastaglia, D. Hilton-Jones, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 14
Autoimmune inflammatory myopathies MARINOS C. DALAKAS* Neuromuscular Diseases Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
14.1. Introduction The autoimmune inflammatory myopathies constitute a heterogeneous group of subacute, chronic and rarely acute, acquired diseases of skeletal muscle which have in common the presence of moderate to severe muscle weakness and inflammation in the muscle (Dalakas, 1991; Engel et al., 1994; Dalakas and Karpati, 2001; Hilton-Jones, 2001; Mastaglia and Phillips, 2002, Mastaglia et al, 2003; Dalakas, 2004a). The diseases are clinically important because they represent the largest group of acquired and potentially treatable myopathies. On the basis of clinical, demographic, histologic and immunopathological studies, the most common and clearly defined inflammatory myopathies, occurring in isolation or in association with other systemic disorders or viral infections, include polymyositis (PM), dermatomyositis (DM), and sporadic inclusion body myositis (s-IBM; Dalakas, 1991). Two other autoimmune inflammatory myopathies that appear distinct, although not well studied, are the necrotizing myopathies and the various forms of myofasciitis (Table 14.1; Dalakas, 2004). This review describes current knowledge in the clinical presentation, diagnosis, pathogenesis and treatment of these disorders. Some rare forms such as granulomatous myositis or localized forms of myositis remain descriptive and poorly characterized and, since they lack distinct clinicoimmunopathological phenotypes, will not be elaborated on.
IBM is more frequent in men over the age of 50 (Dalakas, 1991; Engel et al., 1994; Dalakas and Karpati, 2001; Hilton-Jones, 2001; Dalakas, 2002a; Mastaglia and Phillips, 2002; Sekul and Dalakas, 1993). The incidence of PM and DM as stand-alone disorders or in association with other systemic diseases is unknown. Estimates, ranging from 0.6 to 1 per 100 000 (Mastaglia and Phillips, 2002; Dalakas and Hohlfeld, 2003a) based on old diagnostic criteria (Bohan and Peter, 1975) may not be reliable, as discussed later, because very few of these studies had taken into consideration the distinction between PM and IBM. In all age groups, DM is the most common and PM the least common; IBM is the commonest myopathy above the age of 50. The prevalence of IBM worldwide is also unknown. In North America, IBM is a common inflammatory myopathy. At the National Institutes of Health (NIH), where a large number of patients are seen, we are being referred two or three new cases per week which translates to almost 100 new cases per year, for a tertiary and highly specialized center. The prevalence of IBM in Australia is reported to be 9.3 per 1 000 000 with an age-adjusted prevalence of 35.3/1 000 000 over the age of 50 (Phillips et al., 2000). A prevalence of 4.3/1000 000 has been reported in the Netherlands (Badrising et al., 2000). It remains puzzling however that in South Mediterranean countries such as Italy, Greece or Spain, as well as South America, Japan and India, the incidence of IBM appears to be low. Whether this reflects a truly low incidence or relates to under-recognition is unclear.
14.2. Epidemiology
14.3. Immunogenetics
Dermatomyositis affects both children and adults, and women more often than men; polymyositis is seen after the second decade of life and it is rare in childhood;
Genetic factors may play a role based on rare familial occurrences and the association with certain human leukocyte antigen (HLA) genes, especially DRB1
*Correspondence to: Professor Marinos C. Dalakas, MD, Chief, Neuromuscular Diseases Section, National Institutes of Health, BLDG 10 ROOM 4N248, Bethesda, MD 20892, USA. E-mail:
[email protected], Tel: þ1-301-496-9979, Fax: þ1-301-402-0672.
274
M. C. DALAKAS
Table 14.1 The most common autoimmune inflammatory myopathies a
Polymyositis Dermatomyositis Inclusion body myositis Necrotizing myositis Myofasciitis (eosinophilic, macrophagic, other) a
May occur in isolation or in association with other systemic, autoimmune or viral disorders.
*0301 alleles for PM and IBM (Shamin et al., 2000; Ramanan and Feldman, 2002). The HLA-DQA1 0501 allele may confer a genetic risk for juvenile DM and the tumor necrosis factor 308A polymorphism may be a contributing factor for the photosensitivity of DM (Reed and Ytterberg, 2002). A strong association of PM is also with DR3 in patients with Jo-1 antibodies (Love et al., 1991; Hollingsworth et al., 1998; Garlepp and Mastaglia, 2000). Emerging data on the genetic background of various ethnic groups may identify immune response genes that predispose certain populations to PM or DM (Shamin et al., 2002; Werth et al., 2002). There appears to be a strong association in s-IBM patients with the ancestral haplotype marked by DR3 and C4A*Q0 pointing to a susceptibility locus within the region close to MHC-II (Garlepp et al., 1994; 1998; Kok et al., 1999). Apolipoprotein E4 and variants in the mtDNA D-loop regions have been also associated with sIBM (Garlepp et al., 1995; Kok et al., 2000). However, no linkage to amyloid precursor protein or prion protein genes have been observed (Sivakumar et al., 1995; Cervenakova et al., 1996; Orth et al., 2000). An increased frequency of autoimmune diseases and DRB10301 and DQQ10201 alleles associated with DR and DQ haplotypes was also documented in up to 75% of IBM patients (Koffman et al., 1998). In a recent series of 52 IBM patients, 33% of them had other autoimmune disorders, such as multiple sclerosis, autoimmune thyroid disease, rheumatoid arthritis, or Sjo¨gren’s syndrome (Badrising et al., 2004). Interestingly, the frequency of the associated autoimmune disorders in this series was the same as the one noted for Lambert– Eaton myasthenic syndrome, a classic autoimmune disorder. Further, the B8-DR3-DR52-DQ2 haplotype was found in 67% of the patients, regardless of whether they had another autoimmune disease, a frequency identical to that seen in other autoimmune disorders such as myasthenia gravis or myasthenic syndrome (Badrising et al., 2004). The HLA-A haplotype was also associated
with earlier disease onset suggesting that immunoregulatory genes are inherently connected with the manifestation of the symptoms in patients with s-IBM.
14.4. General clinical features Both PM and DM present with a varying degree of muscle weakness that usually develops slowly, over weeks to months, but rarely acutely (Dalakas, 1991). Patients report difficulty with everyday tasks, such as getting up from a chair, climbing steps, stepping onto a curb, lifting objects or combing their hair. Fine-motor movements that depend on the strength of distal muscles, such as holding or manipulating objects, are affected late in the course of DM and PM, but fairly early in s-IBM due to prominent involvement of distal muscles, especially wrist and finger flexors and ankle dorsiflexors (Dalakas, 1991). Early involvement of the quadriceps muscle and buckling of the knees resulting in falls is common in s-IBM (Sekul and Dalakas, 1993). Facial muscles remain normal in DM and PM but mild-tomoderate facial muscle weakness is seen in the majority of patients with s-IBM (Sekul and Dalakas, 1993). The extraocular muscles are never affected in PM, DM or IBM, in contrast to myasthenia where these muscles are affected early (Dalakas, 1991). The neck-extensor muscles may be involved causing difficulty in holding up the head (head drop). In advanced, and rarely in acute cases, dysphagia with choking episodes and respiratory muscle weakness may occur. Dysphagia is more common in IBM and DM rather than PM. Sensation remains normal. The tendon reflexes are preserved but may be absent in severely weakened or atrophied muscles, especially in IBM where atrophy of the quadriceps and the distal muscles is common. Myalgia and muscle tenderness may occur in a small number of patients, usually early in the disease and more often in DM and PM in association with connective tissue disorders. Weakness in PM and DM progresses subacutely over a period of weeks or months and rarely acutely; by contrast, IBM progresses very slowly, over years, and its course may simulate latelife muscular dystrophies or slowly progressive motor neuron disorders.
14.5. Specific clinical features 14.5.1. Dermatomyositis Dermatomyositis occurs in both children and adults. It is a distinct clinical entity identified by a characteristic rash accompanying, or more often preceding muscle weakness. The skin manifestations include a heliotrope
AUTOIMMUNE INFLAMMATORY MYOPATHIES rash (blue–purple discoloration) on the upper eyelids often associated with edema, a flat red rash on the face and upper trunk and erythema of the knuckles (sparing the phalanges) with Gottron’s rash, a raised violaceous scaly eruption (Dalakas, 1991; Engel et al., 1994; Hilton-Jones, 2001; Mastaglia and Phillips, 2002; Dalakas and Hohlfeld, 2003a; Dalakas, 2004a). The Gottron rash or papules are prominent on metacarphophalangeal, proximal interphalangeal and distal interphalangeal joints (Fig. 14.1A; Callen, 2000). In contrast to systemic lupus erythematosus (SLE), the mesophalangeal joints are spared in DM (Plotz et al., 1989). The erythematous rash also occurs at the knees, elbows, malleoli, neck and anterior chest (often in a V sign) or back and shoulders (shawl sign), and may be exacerbated after exposure to the sun. At times, it may be pruritic. When chronic, the rash becomes scaly with a shiny appearance. Dilated capillary loops at the base of the fingernails with irregular, thickened and distorted cuticles are also characteristic (Fig. 14.1B). The lateral and palmar areas of the fingers may become rough with cracked, “dirty” horizontal lines, resembling mechanic’s hands (Fig. 14.1).
275
The weakness varies, from mild to severe, leading to quadraparesis. At times the muscle strength appears normal, hence the term “dermatomyositis sine myositis” or “amyopathic dermatomyositis” (Sontheimer, 2002). When muscle biopsy is performed in such cases however, significant perivascular and perimysial inflammation can be seen (Otero et al., 1992). Whether subclinical myopathy is present in all cases of amyopathic DM, or there are also cases limited to the skin, is unclear. Amyopathic and myopathic DM are probably part of the spectrum of DM affecting skin and muscle to a varying degree (Dalakas and Hohlfeld, 2003a). Rarely, when the rash is transient or poorly recognized (e.g., in people with dark skin), the term “dermatomyositis sine dermatitis” is appropriate. In such cases, a mistaken diagnosis of PM is considered, until a muscle biopsy confirms the correct diagnosis. In children, DM resembles the adult disease, except for more frequent extramuscular manifestations (discussed later). A common early abnormality in children is “misery”, defined as an irritable child that feels uncomfortable, has a red flush on the face, is fatigued, does not socialize and
Fig. 14.1. (A) Gottron’s rash; (B) calcifications; (C) dilatation of the capillary loops with microarrays at the base of the finger nails in a patient with dermatomyositis.
276
M. C. DALAKAS
has a varying degree of proximal muscle weakness (Dalakas, 1991). A tiptoe gait due to flexion contracture of the ankles is common (Dalakas, 2004; Dalakas and Hohlfeld, 2003a). Dermatomyositis usually occurs alone, but may overlap with systemic sclerosis and mixed connective tissue disease (Mimori, 1987; Rosenberg et al., 1988; Dalakas, 1991) or be associated with cancer (Callen 2001). Fasciitis and thickening of the skin, as seen in chronic cases, have also occured in patients with eosinophilia–myalgia syndrome (Illa et al., 1993), eosinophilic fasciitis and macrophagic myofasciitis (Gherardi et al., 1998). 14.5.2. Polymyositis Polymyositis is best defined as a subacute myopathy that evolves over weeks to months, affects adults but rarely children, and presents with weakness of the proximal muscles resulting in limitation of daily activities. Unlike DM in which the rash secures early recognition, the actual onset of PM cannot be easily determined (Dalakas, 1991). Polymyositis mimics many other myopathies and remains a diagnosis of exclusion. As summarized in Table 14.2, PM is a subacute inflammatory myopathy affecting adults, who do not have any of the following: rash, involvement of the extraocular and facial muscles, family history of a neuromuscular disease, history of exposure to myotoxic drugs or toxins, endocrinopathy, neurogenic disease, muscular dystrophy, biochemical muscle disorder (deficiency of a muscle enzyme) or IBM as excluded by muscle biopsy analysis (see below). It is now increasingly recognized that PM, occurring in isolation, is a rare and rather overdiagnosed disorder; it is more often seen in association with a systemic autoimmune or connective tissue disease, or with known viral or bacterial infections. The most common myopathy misdiagnosed as PM is IBM; this disease is often suspected in retrospect when a patient with presumed PM has not responded to therapy (Dalakas, 1991; Sekul and Dalakas, 1993). Particularly in men above the age of 50, a PM-like disease is IBM until proved otherwise. Other myopathies misdiagnosed as PM include toxic and endocrine myopathies, DM sine dermatitis and certain dystrophies. In a patient diagnosed as PM, the diagnosis should be challenged and reconsidered if the myopathic symptoms have developed slowly, especially before the age of 16, or if the symptoms consist predominantly of myalgia and fatigue, rather than muscle weakness (Table 14.2). 14.5.3. Inclusion-body myositis In patients over 50, IBM is the most common of the inflammatory myopathies. It is often misdiagnosed as PM and suspected only retrospectively when a patient
Table 14.2 Clinical characteristics of polymyositis 1. Myopathic weakness: evolves over weeks to months, spares facial and eye muscles and presents with difficulty climbing steps, rising from a chair, lifting objects, combing hair. 2. Disease onset: above the age of 18 3. The patient does not have: a. rash, characteristic of dermatomyositis; b. family history of neuromuscular diseases; c. exposure to myotoxic drugs, especially D-penicillamine, zidovudine and rarely statins; d. endocrine disease (hypothyroid, hyperthyroid, hypoparathyroid, hypercortisolism); e. neurogenic disease (excluded by electromyography and neurological examination); f. dystrophies and metabolic myopathies (excluded by history and muscle biopsy); g. inclusion-body myositis (IBM; excluded by clinical examination and muscle biopsy). 4. May be associated with another autoimmune or viral infection, such as: lupus, rheumatoid arthritis, Sjo¨gren’s syndrome, Crohn’s disease, vasculitis, sarcoidosis, primary biliary cirrhosis, adult celiac disease, chronic graft-versus-host disease, discoid lupus, ankylosing spondylitis, Behcet’s syndrome, myasthenia gravis, acne fulminans, dermatitis herpetiformis, psoriasis, Hashimoto’s disease, granulomatous diseases, agammaglobulinemia, hypereosinophilic syndrome, Lyme disease, Kawasaki disease, autoimmune thrombocytopenia, hypergammaglobulinemic purpura, hereditary complement deficiency, HIV and HTLV-1 infection. 5. Reconsider polymyositis (PM), if the diagnosis was based on the Bohan and Peter’s criteria, in patients with: a. disease onset below the age of 18; b. slow-onset myopathy that evolved over months to years (in such cases think of IBM or dystrophy); c. fatigue and myalgia, without muscle weakness, even if a transient CK elevation is seen (such patients may have fibromyalgia or fasciitis and their muscle biopsy is either normal or shows very few inflammatory cells in the endomysial septae); d. no typical histological features for PM.
with presumed PM does not respond to therapy (Dalakas, 1991). Weakness and atrophy of the distal muscles, especially foot extensors and deep finger flexors, occur in almost all cases of IBM and may be a clue to early diagnosis (Fig. 14.2A,B; Sekul and Dalakas, 1993). Some patients present with falls because their knees collapse due to early quadriceps weakness. Others present with weakness in the small muscles of the hands,
AUTOIMMUNE INFLAMMATORY MYOPATHIES
277
Fig. 14.2. Characteristic pattern of weakness in inclusion-body myositis. Note the atrophy of the quadriceps muscle (A) and the atrophy of the forearm with weakness in the finger flexors (B).
especially finger flexors, and complain of inability to hold certain objects, such as golf clubs, or perform certain tasks, such as turning keys or tying knots (Fig. 14.2). On occasion, the weakness and accompanying atrophy can be asymmetric and selectively involve the quadriceps, iliopsoas, triceps, biceps and finger flexors, resembling a lower motor neuron disease. Dysphagia is common, occurring in up to 60% of IBM patients, and may lead to episodes of choking. Facial muscle weakness is also common and at times prominent. Sensory examination is generally normal; some patients have mildly diminished vibratory sensation at the ankles that presumably is age-related. The distal weakness does not represent motor neuron or peripheral nerve involvement but results from the myopathic process affecting distal muscles as confirmed by macroelectromyographic (EMG) analysis (Luciano and Dalakas, 1997). The diagnosis is always made by characteristic findings on the muscle biopsy, as discussed below. Disease progression is slow but steady, and most patients require an assistive device such as cane, walker or wheelchair within several years of onset (Peng et al., 2000). In at least 20% of cases, IBM is associated with systemic autoimmune or connective tissue diseases (Koffman et al., 1998; Badrising et al., 2004). Familial aggregation has also been noted in coaffected siblings with typical IBM; such cases have been designated as familial inflammatory IBM (Sivakumar et al., 1997). This disorder is distinct from hereditary inclusion-body myopathy (h-IBM), which describes a heterogeneous group of
recessive and, less frequently, dominant, inherited syndromes (Sivakumar and Dalakas, 1996). The h-IBMs are non-inflammatory myopathies with clinical profiles distinct from sporadic IBM. A subset of h-IBM that spares the quadriceps muscles has emerged as a distinct entity. This disorder, originally described in Iranian Jews and now seen in many ethnic groups, is linked to chromosome 9p1 and results from mutations in the UDP-Nacetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene (Eisenberg et al., 2001).
14.6. Associated clincial findings (Table 14.3) 14.6.1. Extramuscular manifestations In addition to the primary myopathy, a number of extramuscular manifestations may be present to a varying degree in patients with PM or DM: 1. Systemic symptoms, such as fever, malaise, weight loss, arthralgia, and Raynaud’s phenomenon especially when inflammatory myopathy is associated with a connective tissue disorder. 2. Joint contractures, mostly in DM and especially in children, but also in patients with myofasciitis or in association with scleroderma. 3. Dysphagia and gastrointestinal symptoms due to involvement of the oropharyngeal striated muscles and upper esophagus. Dysphagia may be prominent
278
M. C. DALAKAS
Table 14.3 Conditions and factors associated with inflammatory myopathies Characteristic
Dermatomyositis (DM)
Polymyositis (PM)
Inclusion-body myositis
Age at onset of disease Familial association Extramuscular manifestations Associated conditions Connective-tissue diseasesa
Adults and children No Yes
>18 years No Yes
>50 years Yes, in some cases Yes
Yes, but only with scleroderma and mixed connective-tissue disease Yes, but only with scleroderma and mixed connective-tissue disease Rarely Yes, in up to 15% of cases Unproved No Rarely
Yes, with all
Yes, in up to 20% of cases
No
No
Frequently No Yesc Yesd Yes
Infrequently No Yesc No No
Overlap syndromeb Systemic autoimmune diseases Malignant conditions Viruses Parasites and bacteria Drug-induced myotoxicitye
a Up to 12% of patients with systemic sclerosis may develop a DM-like disease; and 5–8% of lupus patients may develop PM; PM is less often seen in patients with Sjo¨gren’s syndrome or rheumatoid arthritis. b Overlap denotes that certain signs are common to both disorders; in contrast, “association” denotes that two disorders may coexist. c With HIV (human immunodeficiency virus) and HTLV-I (human T-cell lymphotropic virus type I). d Includes parasitic (protozoa, cestodes and nematodes), tropical and bacterial myositis (pyomyositis). e Drugs include penicillamine (for dermatomyositis and polymyositis), zidovudine (for polymyositis), contaminated tryptophan (for a dermatomyositis-like illness) and rarely lipid-lowering drugs. Other myotoxic drugs may cause myopathy but not an inflammatory myopathy.
4.
5.
6.
7.
in the active stages of DM and is frequent in IBM. Gastrointestinal ulcerations due to vasculitis and infection were common in children with DM before the use of immunosuppressive drugs. Cardiac disturbances, including atrioventricular conduction defects, tachyarrythmias, dilated cardiomyopathy, and low ejection fraction (Haupt and Hutchins, 1982). Congestive heart failure and myocarditis may also occur, either from the disease itself if severe or from hypertension associated with longterm use of glucocorticoids. Pulmonary dysfunction, due to primary weakness of the thoracic muscles, interstitial lung disease or drug-induced pneumonitis (e.g., from methotrexate). It may cause dyspnea, non-productive cough or aspiration pneumonias (Hirakata and Nagai, 2000; Douglas et al., 2001). Interstitial lung disease may precede the myopathy or occur early in the disease, and develops in up to 10% of patients with PM or DM, the majority of whom have antibodies to t-RNA synthetases, as described below. Arthralgias, synovitis or deforming arthropathy, can occur in some patients with DM or PM. A deforming arthropathy of the interphalangeal joints with subluxation is common in some patients with anti-Jo-1 antibodies (described later). Subcutaneous calcifications, sometimes extruding on the skin and causing ulcerations and infections,
are seen in DM, primarily in children (Fig. 14.1C, Dalakas, 1995a). 14.6.2. Malignancies Although all the inflammatory myopathies may have a chance association with malignant lesions, especially in older age groups, the incidence of cancer is definitively increased in DM (Sigurgeirsson et al., 1992); a slightly increased incidence reported in PM (Buchbinder et al., 2001; Hill et al., 2001) needs confirmation with better diagnostic criteria. Ovarian, gastrointestinal, lung, breast cancers and non-Hodgkin lymphomas are the most common malignancies requiring continuous vigilance for early recognition, especially in older people and during the first 3 years following disease onset (Callen, 2001; 2002). In patients without risk factors, performing radiologic blind searches for occult malignancies may not be practical or fruitful (Dalakas, 1991; Callen, 2002). A complete annual physical examination with pelvic, breast (mammogram, if indicated), rectal (with colonoscopy, according to age and family history) and a chest film, should suffice. In Asians, where nasopharyngeal cancer is more common, a careful ear, nose and throat evaluation is suggested. The merit of the recent smallscale study showing that a blind search with abdominalpelvic and thoracic computed tomography (CT) scans increases the yield by 28% (Sparsa et al., 2002), needs
AUTOIMMUNE INFLAMMATORY MYOPATHIES 279 lupus, or Sjo¨gren’s syndrome are rare in DM, PM or IBM (Table 14.3; Dalakas, 1991).
confirmation. Whether searches with positron emission tomography (PET) scan should be utilized remains unclear as no prospective studies with this expensive investigative tool have been conducted. 14.6.3. “Overlap” syndrome
Polymyositis, dermatomyositis and IBM are seen in association with various autoimmune and connective tissue diseases (Table 14.3). The term “overlap syndrome” has been used loosely to emphasize this association but, in reality, it is only suitable to denote that certain clinical signs are common in both conditions. Accordingly, it is only DM, and not PM or IBM, that truly overlaps and only with systemic sclerosis and mixed connective tissue disease (Tables 14.2 and 14.3; Dalakas, 1991; Dalakas and Hohlfeld, 2003a). Some signs seen in these two conditions, such as sclerotic thickening of the dermis, contractures, esophageal hypomotility, microangiopathy and calcium deposits, are also present in DM but not PM; in contrast, concurrent signs of rheumatoid arthritis,
14.7. Diagnosis The clinical diagnosis of PM, DM or IBM is confirmed by three laboratory examinations: serum muscle enzymes, electromyography and muscle biopsy (Table 14.4; Dalakas, 1991; 2001a; 2001b; HiltonJones, 2001; Dalakas, 2004a). In certain cases of DM, a skin biopsy can be helpful. 14.7.1. Muscle enzymes The most sensitive enzyme is creatine kinase (CK), which in the presence of active disease can be elevated as much as 50-fold. Along with the CK, serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) and aldolase may be elevated. Although CK usually parallels disease activity, it can be normal in some patients with
Table 14.4 Diagnostic criteria for inflammatory myopathies Polymyositis Criterion
Definite
Probable
Dermatomyositis
Inclusion-body myositis
Myopathic muscle weaknessa
Yes
Yes
Yesb
Electromyographic findings Muscle enzymes
Myopathic
Myopathic
Myopathic
Yes; slow onset, early involvement of distal muscles, frequent falls Myopathic with mixed potentials
Elevated (up to 50-fold) “Primary” inflammation with the CD8/MHC-I complex and no vacuoles Absent
Elevated (up to 50-fold) Ubiquitous MHC-I expression but minimal inflammation and no vacuolesd
Elevated (up to 50-fold), or normal Perifascicular perimysial or perivascular infiltrates, perifascicular atrophy
Absent
Present
Muscle biopsy findingsc
Rash or calcinosis
Elevated (up to 10-fold), or normal Primary inflammation with CD/8MHC-1 complex; vacuolated fibers with ß-amyloid deposits; COXnegative fibers; signs of chronic myopathy f Absent
a Myopathic muscle weakness, affecting proximal muscles more than distal ones and sparing eye and facial muscles, is characterized by a subacute onset (weeks to months) and rapid progression in patients who have no family history of neuromuscular disease, no endocrinopathy, no exposure to myotoxic drugs or toxins, and no biochemical muscle disease (excluded on the basis of muscle-biopsy findings). b In some cases with the typical rash, the muscle strength is seemingly normal (dermatomyositis sine myositis); these patients often have new onset of easy fatigue and reduced endurance. Careful muscle testing may reveal mild muscle weakness. c See text for details. d An adequate trial of prednisone or other immunosuppressive drugs is warranted in probable cases. If, in retrospect, the disease is unresponsive to therapy, another muscle biopsy should be considered to exclude other diseases or possible evolution to inclusion body myositis. e If the muscle biopsy does not contain vacuolated fibers but shows chronic myopathy with hypertrophic fibers, primary inflammation with the CD8/MHC-I complex and COX-negative fibers, the diagnosis is probable inclusion body myositis. f If rash is absent but muscle biopsy findings are characteristic of dermatomyositis, the diagnosis is probable DM.
280
M. C. DALAKAS
active DM and IBM; in the active phases of PM, the CK is always elevated. 14.7.2. Electromyography Needle electromyography shows increased spontaneous activity with fibrillations, complex repetitive discharges and positive sharp waves. The voluntary motor units are myopathic with low-amplitude polyphasic units of short, and rarely long, duration (Uncini et al., 1990). Although not disease-specific, these findings are useful to confirm active myopathy. Presence of spontaneous activity may be helpful to distinguish active disease from steroid-induced myopathy, except in cases where the two coexist (Dalakas, 1991). 14.7.3. Muscle imaging Magnetic resonance imaging (MRI) or CT scanning do not provide specific enough images to be of diagnostic value. Although MRI of the forearms and the quadriceps muscles may show the selective patterns of muscle involvement in IBM (Sekul et al., 1997), it is rarely used for diagnostic purposes, except for patients with atypical disease and inconclusive muscle biopsies. The most practical reason to pursue an MRI for diagnostic purposes is to help determining an appropriate biopsy site in circumstances when the disease is very asymmetric or focal. The MRI shows multifocal or diffuse pattern of high signal intensity on T2-weighted images with fat-suppressive (STIR) techniques. However, a muscle biopsy is never MRI-needle guided and the surgeon may still miss the “hot” areas because the inflammation can be very “spotty” even in the same muscle. 14.7.4. Muscle biopsy The muscle biopsy is the most critical test for establishing the diagnosis (Dalakas, 1991; Engel et al., 1994; Dalakas, 2001a; Hilton-Jones, 2001; Mastaglia and Phillips, 2002; Dalakas and Hohlfeld, 2003a), but also the most common cause of misdiagnosis due to erroneous interpretation (Dalakas and Karpati, 2001; Dalakas 2002b). In DM the inflammation is predominantly perivascular or in the interfascicular septae and around rather than within the fascicles (Fig. 14.3; Dalakas, 1991; Engel et al., 1994; Dalakas and Karpati, 2001; Hilton-Jones, 2001; Mastaglia and Phillips, 2002; Dalakas and Hohlfeld, 2003a). The intramuscular blood vessels show endothelial hyperplasia with tubuloreticular profiles, fibrin thrombi, especially in children, and obliteration of capillaries (Banker, 1975; Carpenter et al., 1976; Engel et al., 1994; Dalakas and Karpati, 2001). The muscle fibers undergo phagocytosis and necrosis, often in groups
Fig. 14.3. For full color figure, see plate section. Perifascicular atrophy in dermatomyositis.
(microinfarcts) involving a portion of a muscle fasciculus, or at the periphery of the fascicle, resulting in perifascicular atrophy (Fig. 14.3). Perifascicular atrophy, characterized by 2–10 layers of atrophic fibers at the periphery of the fascicles, is diagnostic of DM, even in the absence of inflammation (Dalakas, 1991). The active skin lesions show perivascular inflammation with CD4þ cells in the dermis as described later; in chronic stages there is dilatation of superficial capillaries. Skin histopathology distinguishes DM from other papulosquamous disorders but not from cutaneous lupus (Callen, 2000). In PM multifocal lymphocytic infiltrates surround and invade healthy muscle fibers (Dalakas, 1991; Engel et al., 1994; Dalakas and Karpati, 2001; Hilton-Jones, 2001; Mastaglia and Phillips, 2002). The inflammation is “primary”, a term coined to indicate that lymphocytes (CD8þ cells) invade histologically healthy, MHC-class I-expressing muscle fibers (Fig. 14.4A,B; Arahata and Engel, 1984; 1988; Emslie-Smith and Engel, 1990). This lesion is referred to as the CD8/MHC-I complex (Fig. 14.5, as discussed later; Dalakas and Hohlfeld, 2003a). In chronic stages, connective tissue is increased and may react with alkaline phosphatase. When, in addition to “primary” inflammation, there are vacuolated muscle fibers with basophilic granular deposits around the edges (rimmed vacuoles) and congophilic amyloid deposits within or next to the vacuoles, the diagnosis of IBM is likely (Dalakas, 1995b; Griggs et al., 1995). To secure the histological diagnosis of PM, attention should be paid to the following: 1. Primary inflammation. This has become a sine qua non criterion because it distinguishes the endomysial inflammation of PM from other conditions, where macrophages may predominate, as seen in toxic and necrotizing myopathies or certain dystrophies (congenital, fascioscapulohumeral, or due to dystrophin and dysferlin deficiency; Dalakas and Hohlfeld, 2003a).
AUTOIMMUNE INFLAMMATORY MYOPATHIES 281 2. Processing frozen sections for enzyme histochemistry. Paraffin embedding causes misdiagnosis of IBM for PM because it dissolves the red-rimmed granular material and does not identify the vacuolated fibers. Also, metabolic myopathies, mitochondriopathies and the CD8/MHC complex, which can only be demonstrated by immunocytochemistry, are not identified on paraffin sections. 3. Repeating the biopsy. Because in PM the inflammation is spotty, a repeat biopsy from a different site should be considered if a patient fulfills the clinical criteria (Table 14.2) but the first biopsy was not diagnostic. Occasionally, MRI of the muscles can be useful to identify sites of putative inflammation and select the area for the repeated biopsy, as discussed earlier.
Fig. 14.4. For full color figure, see plate section. Crosssection of muscle from a polymyositis (PM) and sporadic inclusion-body myositis (s-IBM) patient. (A) Note the scattered endomysial inflammation in PM with lymphocytes invading non-necrotic muscle fibers. (B) Note two red-rimmed vacuolated fibers (left and right upper corner) not invaded by inflammatory cells in IBM. If the same vacuolated fibers are followed at considerable length in longitudinal sections, they remain devoid of autoinvasive inflammatory T cells. In contrast, the fibers surrounded by T cells are not vacuolated, degenerating or necrotic, but rather healthy-appearing fibers.
In IBM, the following occur (Fig. 14.4): (1) intense endomysial inflammation with T cells invading MHCI-expressing muscle fibers in a pattern identical to (but often more severe) that seen in PM (Figs 14.4, 14.5). Of interest, these fibers are almost never vacuolated or necrotic but rather healthy-appearing; (2) vacuolated fibers, not surrounded or invaded by T cells, that contain basophilic granular deposits distributed around the edge of slit-like vacuoles (rimmed vacuoles); (3) loss of fibers, replaced by fat and connective tissue, hypertrophic fibers and angulated or round fibers, scattered or in small groups; (4) eosinophilic cytoplasmic inclusions; (5) abnormal mitochondria characterized by the presence of ragged-red fibers or cytochromeoxidase (COX)-negative fibers; (6) tiny congophilic amyloid deposits within or next to the vacuoles, best visualized by Texas-red fluorescent optics; and (7) characteristic filamentous inclusions seen by electron microscopy in the vicinity of the rimmed vacuoles. Although demonstration of the filaments by electron
Fig. 14.5. For full color figure, see plate section. CD8/MHC-I complex in (A) polymyositis and (B) inclusion-body myositis.
282
M. C. DALAKAS
microscopy was previously thought to be essential for the diagnosis of IBM, currently this is not absolutely necessary if all the other characteristic light-microscopic features, including amyloid deposits, are present. It should be emphasized however, that such vacuoles including amyloid deposits can be seen in other vacuolar myopathies such as dysferlinopathies, myofibrillar myopathies, facioscapulohumeral muscular dystrophy (FSH), Emery–Dreifus muscular dystrophy, and even in chronic neurogenic conditions such as old poliomyelitis (Mora and Dalakas, 1998, Dalakas, 2004a; Ferrer et al., 2004; Selcen et al., 2004); thus they are not unique to IBM. As described below, under diagnostic criteria, in some patients with an acquired myopathy that fulfills the clinical criteria for PM or IBM, the muscle biopsy specimen may fail to confirm the suspected diagnosis; in such cases, a diagnosis of probable PM or probable IBM is assigned (Dalakas and Hohlfeld, 2003a). An intramuscular inflammatory response around nonnecrotic muscle fibers is an invariable feature of both PM and IBM, and the absence of inflammation raises a critical question about the diagnosis. It is not unreasonable in such cases to obtain another muscle biopsy specimen from a different site. If the biopsy shows edronic myopathy, widespread expressions of MHC-I but no T cell infiltrates or vacuoles, the diagnosis is either probable BM or probable IBM according to the clinical setting. When the patient has the typical clinical phenotype of IBM but the muscle biopsy shows only features of chronic inflammatory myopathy without the typical vacuoles, the diagnosis of probable IBM is also appropriate (Amato et al., 1996). If the biopsy sample is typical for DM but no rash is clinically detected, the diagnosis is probable DM (Dalakas and Hohlfeld, 2003a; Dalakas, 2004c).
14.8. Diagnostic criteria In view of the clinicopathologic and laboratory studies described above, the old criteria by Bohan and Peter (1975) have become obsolete because they cannot distinguish PM from IBM or other dystrophies, as repeatedly emphasized (Dalakas, 1991; Dalakas and Hohlfeld, 2003a; 2003b). Although several criteria for demographic and epidemiological studies have been proposed, criteria based on histopathology are essential because they provide the only means to diagnose PM and IBM accurately (Dalakas, 1991). The plea to validate the histopathology of PM and IBM may not be needed in my view because histopathology is inherently connected with the definition of PM and IBM (Dalakas and Hohlfeld, 2003b). Accordingly, the diagnosis of PM is definite if a patient has an acquired, subacute myopathy fulfilling the inclusion and exclusion criteria noted earlier (Table 14.2),
together with an elevated CK, and “primary” inflammation in the muscle biopsy (Table 14.4). When in such a patient the biopsy reveals widespread MHC-I antigen expression (Karpati et al., 1988; Emslie-Smith et al., 1989) but no T cells or vacuoles, the diagnosis is probable PM. The same histological picture but with signs of chronicity, i.e., large fibers, splitting and increased connective tissue may also be seen in some patients with the typical-for-IBM clinical phenotype (probable IBM; Amato et al., 1996). In the probable category, the diagnosis is guided by the clinical phenotype and is aided by a repeated muscle biopsy which I favor in an attempt to arrive at a definitive diagnosis. The diagnosis of dermatomyositis is definite if the myopathy is accompanied by the characteristic rash and histopathology. If no rash is detected but the biopsy is typical for DM, the diagnosis is probable DM; conversely, if the typical DM rash is present but muscle weakness is not apparent, the clinical diagnosis is amyopathic DM (Table 14.4).
14.9. Rare forms of inflammatory myopathy Other types of inflammatory myopathy diagnosed on the basis of distinctive clinical and histological features include infectious [parasitic, bacterial (pyomyositis)], granulomatous, and localized forms (Dalakas, 1991, Dalakas and Karpati, 2001; Hilton-Jones, 2001; Mastaglia et al., 2000). Two other forms, the necrotizing myopathy and myofasciitis are described below. 14.9.1. Myofasciitis 14.9.1.1. Eosinophilic myositis and myofasciitis This is a form of immune muscle disease affecting the muscle and the fascia. The most common is the eosinophilic myofasciitis characterized by eosinophilia in the peripheral blood and eosinophilic infiltrates in the endomysial tissue. The term “eosinophilic myositis” was coined by Layzer and colleagues in 1977 (Layzer et al., 1977) to describe cases in which eosinophilia was the most prominent type of inflammatory cell within the endomysial infiltrate. Some of these patients may have involvement of other organs (cardiac, pulmonary, bone marrow or skin) at some point in the course of their disease. Eosinophilic polymyositis can be seen in the context of parasitic infections, vasculitis (especially Churg–Strauss syndrome), mixed connective tissue disease, L-tryptophan-induced eosinophilia-myalgia syndrome (Hertzman et al., 1990; Illa et al., 1993), toxic oil syndrome, or idiopathic hypereosinophilic syndrome (Serratrice et al., 1990). When the pathology is predominant in the fascia, it presents with skin induration and pain and is often referred to as “eosinophilic fasciitis” (Shulman syndrome; Shulman, 1984). At times,
AUTOIMMUNE INFLAMMATORY MYOPATHIES the skin is spared and the pathology predominates in the perimysium; such cases are referred to as “eosinophilic perimyositis” (Huang and Chen, 1987; Kamm et al., 1987; Fang et al., 1988; Lakhanpal et al., 1987, Serratrice et al., 1990; Trueb et al., 1995). Accordingly, an eosinophilic inflammatory muscle disease can present either as typical polymyositis with proximal muscle weakness, or most often as fasciitis with a varying degree of involvement of the skin and subcutaneous tissue that is clinically manifested as focal or generalized myalgia, muscle induration, tenderness and cramps. Eosinophilic myositis has been recently reported in patients with mutations in the calpuim gene (Kraln et al., 2006). We have been increasingly aware of patients, often women, who present with muscle pain, fatigue and slightly elevated CK. Their strength is normal however although, very characteristically, they demonstrate a “give-way” weakness. These patients have been often characterized as having fibromyalgia or psychogenic disease but the persistent CK elevation along with aldolase suggests otherwise. It is not clear what these patients have but our suspicion — supported occasionally by histology — is that they have an indolent form of non-eosinophilic myofasciitis. The biopsy, if abnormal, shows HLA-DR-positive fibroblasts in the fascia (Dalakas, unpublished observations). Eosinophilic myositis may overlap with hypereosinophilic syndrome, eosinophilic fasciitis and eosinophilic perimyostis implying a continuum of inflammatory involvement that extends from the fascia into the perimysium and endomysium. Several cases of eosinophilic myositis and fasciitis have been associated with drugs, such as tranilast (an antiasthmatic), phenobarbital (Knutsen et al., 1986; Arase et al., 1990) or contaminated L-tryptophan (Hertzman et al., 1990; Turi et al., 1990; Seidman et al., 1991; Illa et al., 1993). The triggering factors in eosinophilic myositis are also unclear but trauma, drugs or a viral infection have been implicated. The cytokine interleukin-5 may play a role in inducing eosinophilia (Trueb et al., 1995). Activated eosinophils infiltrate tissues and degranulate, releasing cytotoxic factors such as cytotoxic granule protein, major basic protein and eosinophil cationic protein (Weller, 1991; Illa et al., 1993; Kaufman et al., 1988; Trueb et al., 1995). Eosinophil granule proteins are known to be toxic to cultured cardiac muscle (Tai et al., 1982), and may induce a similar effect to the skeletal muscle. Eosinophilic infiltration of skeletal muscle, however, does not account for all the parenchymal destruction because in many cases, in spite of peripheral eosinophilia, the eosinophilic infiltrates have been rare or transient within the muscle. Perimysial deposition of major basic protein has been demonstrated in some cases, and is thought to contribute to tissue damage (Illa et al., 1993; Kaufman et al., 1988).
283
14.9.1.2. Macrophagic myofasciitis This is another cause of fasciitis that seems to be a distinctive disorder identified in French patients who presented with myalgias, fatigue and mild muscle weakness (Gherardi et al., 1998). Muscle biopsy revealed pronounced infiltration of the connective tissue around the muscle (epimysium, perimysium and perifascicular endomysium) by sheets of PAS-positive macrophages and occasional CD8þ T-cells. Creatine kinase or erythrocyte sedimentation may be at times elevated. Most patients respond to glucocorticoid therapy, and the overall prognosis is favorable. The pathology is almost always seen at the sites of previous vaccinations, even several months later, and has been linked to a type of aluminum component used as a substrate for preparation of the vaccines. 14.9.2. Necrotizing myositis This is an important entity because it has been often labeled as PM. It presents with an acute or subacute onset of symmetric muscle weakness with high CK elevation, often in the fall or winter. The weakness can be very severe. There is frequently interstitial lung disease and at times cardiomyopathy. A number of these patients have anti-signal recognition protein (SRP) antibodies but whether this is a marker of the disease is unclear as the number of reported cases is rather small and the collection of cases from various centers vary. In our experience, some patients with necrotizing myositis developed the disease after viral infection; in some series, some patients had cancer (Bronner et al., 2003). The muscle biopsy is striking in demonstrating necrotic fibers invaded by macrophages but only rare, if any, T cell infiltrates. The MHC-I expression is only slightly upregulated in focal areas of the muscle. At times, the capillaries may be swollen resembling the “pipe-stem” capillaries. This is a severe form of myositis. The reported “pipe-stem capillary myositis” (Emslie-Smith and Engel, 1991) is probably part of the spectrum of necrotizing myositis often associated with cancer; in addition to necrotizing features and clinical severity in this form of necrotizing myositis there is also marked hyalinization and thickening of the capillary walls with deposition of membranolytic attack complex (MAC). In our experience, patients with the severe form of necrotizing myopathy do not respond to immunotherapy but there are reports of steroid responsiveness (Bronner et al., 2003).
14.10. Immunopathogenesis An autoimmune origin of PM and DM is supported by their association with other systemic autoimmune
284
M. C. DALAKAS
or connective tissue disorders, the presence of various autoantibodies (Targoff, 2002), their association with histocompatibility genes; the evidence of T-cellmediated myocytotoxicity or complement-mediated microangiopathy; the possible maternal microchimerism in juvenile forms (Reed et al., 2000) and their response to immunotherapies (Dalakas and Hohlfeld, 2003a). However, specific target antigens have not been identified and the agents initiating self-sensitization remain unknown. 14.10.1. Associated autoantibodies Autoantibodies against nuclear or cytoplasmic antigens, directed against ribonucleoproteins involved in protein synthesis (“antisynthetase antibodies”) or translational transport (“anti-signal-recognition particle antibodies”), are found in approximately 20% of patients (Table 14.5; Friedman et al., 1996; Hengstman et al., 2001; Targoff, 2002). These antibodies are useful clinical markers because of their frequent association with interstitial lung disease (ILD). The antibody against histidyl-tRNA synthetase, called anti-Jo-1, accounts for 80% of all the antisynthetases. Anti-Jo-1 seems also to confer specificity for identifying a small subset of patients with the combination of myositis, non-erosive arthritis, “mechanic’s hands,” Raynaud phenomenon and strong association with DR3, DRW52 and DQA1*0501 HLA haplotype, labeled antisynthethase syndrome. The significance of these antibodies remains unclear because they are not tissue or disease-subset specific, occur in less than 25% of PM or DM, are not pathogenic and can be seen in patients with ILD without myositis (Hengstman et al., 2002). A report that anti-SRP antibodies may be markers of aggressive disease with cardiomyopathy and poor response to therapies (Love et al., 1991), needs further confirmation (Hengstman et al., 2001). Other autoantibodies are: anti-Mi-2, found in DM and PM; anti-PM-Scl, found in DM associated with scleroderma and anti-KL6 associated with ILD (Table 14.5). 14.10.2. Immunopathology of dermatomyositis 14.10.2.1. Vascular endothelium The primary antigenic target in DM is the vascular endothelium of the endomysial capillaries. The disease begins when putative antibodies directed against endothelial cells activate complement C3 that forms C3b and C4b fragments leading to formation of C5b–9 MAC, the lytic componement of the complement pathway (Carpenter et al., 1976; Kissel et al., 1986; 1991). MAC, C3b and C4b are detected early in the patients’ serum (Basta and Dalakas, 1994) and deposited on
Table 14.5 Myositis-associated autoantibodies found in patients with polymyositis (PM), dermatomyositis (DM) and some patients with inclusion-body myositis (IBM) (Hengstman et al., 2001) Myositis-associated autoantibodiesa
Antigen
Anti-aminoacyl-tRNA synthetases (in 20% of patients) Anti-Jo-1b tRNAhissynthetasec Anti-PL-7 tRNAthr synthetase Anti-PL-12 tRNAala synthetase Anti-EJ tRNAglysynthetase Anti-OJ tRNAilesynthetase Anti-KS tRNAaspsynthetase SRP-complex Anti-signal recognition particle (SRP; <3% of patients) Other Anti-Mi-2 (10–15% of DM and Nuclear helicase PM) Anti-PM-Scl (15% of DM with Nuclear complex scleroderma) Anti-KL6 (in patients with Mucin-like glycoprotein interstitial lung disease (ILD)) (on alveoli or bronchial epithelial cells) a
The antibodies are found more often in PM and DM, and occasionally IBM, when the myositis is associated with another connective tissue disorder. b Some Jo-1-positive patients with PM or DM have the triad of nonerosive arthritis, interstitial lung disease and Raynaud phenomenon; 50% of them have ILD. c 7% of these patients have also antibodies against the cognate tRNAhis.
capillaries before inflammatory or structural changes are seen in the muscle (Fig. 14.6A,B; Carpenter et al., 1976; Kissel et al., 1986; 1991). Sequentially, the complement-mediated alterations begin with swollen endothelial cells followed by vacuolization, necrosis of capillaries, perivascular inflammation, ischemia and muscle fiber destruction (Fig. 14.6; Dalakas, 1991; Engel et al., 1994; Hohlfeld and Engel, 1994; Dalakas and Hohlfeld, 2003a). The characteristic perifascicular atrophy is a reflection of the endofascicular hypoperfusion which is prominent distally. Finally, there is marked reduction in the number of capillaries per muscle fiber with compensatory dilatation of the lumen of the remaining capillaries (Dalakas, 1995b, Dalakas and Hohlfeld, 2003).The release of cytokines and chemokines (Stein and Dalakas, 1993; Lundberg et al., 1995; Tews and Goebel, 1996, Confalonieri et al., 2000, De Bleecker et al., 2002; Raju et al., 2003) related to complement activation, upregulate VCAM-I and ICAM-I on the endothelial cells. These molecules serve
AUTOIMMUNE INFLAMMATORY MYOPATHIES
285
Fig. 14.6. For full color figure, see plate section. Membranolytic attack complex deposits and reduction of capillary density in dermatomyositis.
as ligands for the integrins VLA-4, LFA-I, and Mac-I expressed on T cells and facilitate their exit through the blood vessel wall to the perimysial and endomysial spaces (Fig. 14.7). Immunophenotypic analysis of the lymphocytic infiltrates demonstrates B cells, CD4þ cells and plasmacytoid and dendritic cells in the perimysial and perivascular regions, supporting the view that a humoral-mediated mechanism plays the major role in the disease. Other molecules upregulated in dermatomyositis include TGF-b (Amemiya et al., 2000a) and (in the perifascicular regions) the cathepsins and STAT-I, probably triggered by interferon-g (Gallardo et al., 2001). Using gene arrays, a number of adhesion molecules, cytokine and chemokine genes are upregulated in the muscles of DM patients. Most notable among those genes are the KAL-1 adhesion molecule, which is upregulated in vitro by TGF-b and may have a role in inducing fibrosis (Raju and Dalakas, 2005), and the myxovirus resistance MxA protein induced by interferon and is predominantly immunolocalized in the perifascicular regions (Greenberg et al., 2005). The cellular source of the abundant interferon a/b in DM is probably the large number of plasmacytoid dendritic cells suggesting that in DM the innate immune response is also involved in a pattern similar to systemic lupus erythromatosus (Greenberg et al., 2005). Gene
expression profiling in the muscles of genetically susceptible children with childhood DM has also shown interferon inducible genes implying virus-driven autoimmune dysregulation (Tezak et al., 2002). However, no viruses have been amplified from the muscles of these patients (Leff et al., 1992; Leon-Monzon and Dalakas, 1992). 14.10.2.2. Skin The histological picture of skin lesions in DM is characterized by dermal perivascular infiltrates consisting mainly of CD4þ cells, followed by macrophages (Hausmann et al., 1991). B lymphocytes are sparse and CD1aþ Langerhans cells are diminished in the epidermis but increased in dermal papillae. Skin biopsies of the Gottron’s papules have shown that the main cellular infiltrates consist of activated CD4þ lymphocytes (HLA-DR (þ), CD40Lþ) located in the perivascular areas of the upper dermis and subepidermally (Caproni et al., 2004). The CD8þ T cells are few. Upregulation of cytokines, chemokines and deposits of C5b-9 have also been observed in the skin lesions of DM patients (Magro and Crowson, 1997). These findings are consistent with a complement-activated humoral-mediated process, similar to the one described for the muscle, as noted earlier.
286
M. C. DALAKAS
Fig. 14.7. Proposed sequence of immunopathological changes in dermatomyositis. The disease probably begins with activation of complement and formation of C3 through the classic or alternative pathway by putative antibodies (Y) against endothelial cells. Activated C3 leads to formation of C3b, C3bNEO, and membranolytic attack complex (MAC) which is deposited in and around the endothelial cell wall of the endomysial capillaries. Deposition of MAC leads to destruction and reduced number of capillaries, with ischemia or microinfarcts most prominent in the periphery of the fascicle. Finally, a smaller than normal number of capillaries with a dilated diameter remain and perifascicular atrophy ensues. Not only the complement-fixing antibodies (Y) but also B cells, CD4þ T cells, and macrophages (MO) traffic to the muscle. The migration of cells from the circulation is facilitated by the vascular cell adhesion molecule (VCAM) and intercellular adhesion molecule (ICAM) whose expression on the endothelial cells is upregulated by the released cytokines. T cells and macrophages through their integrins very late activation antigen (VLA)-4 and leukocyte function-associated antigen (LFA)-1, bind to the VCAM and ICAM and transgress to the muscle through the endothelial cell wall.
The CD40 molecule is also upregulated on the basal keratinocytes, while the neighboring CD4þ T cells express CD40L, suggesting that the CD40-CD40-L system is also involved in the cutaneous manifestations of DM, probably via the upregulation of cytokines and chemokines, in a pattern analogous to the one noted in the muscle (Sugiura et al., 2000). Although the immunopathology of the skin has not been well studied as the muscle, it appears, based on these limited studies, that in DM a complement mediated endotheliopathy is a common final pathway for both the skin and the muscle. Future studies are needed to determine the role of dendritic cells, plasmacytoid cells, the APC function of keratinocytes or Langerhans cells and the immunomodulatory genes upregulated in the skin, as has already been done for the muscle. The cause of calcifications, which are more prominent in juvenile DM, is unclear. In two cases, the milk of calcium extracted from the subcutaneous collections was found to contain macrophages, IL6, IL1 and TNF-a suggesting activation of macrophages. These cases have also responded to alendronate (Mukamel et al., 2001).
14.10.3. Immunopathology of polymyositis and s-IBM Polymyositis and s-IBM are T- cell mediated diseases in which CD8þ cells invade major histocompatibility (MHC)-I-antigen expressing muscle fibers (Figs 14.5, 14.8; Arahata and Engel, 1984; 1988; Emslie-Smith and Engel, 1990; Hohlfeld and Engel, 1994).The immune components associated with this process are identical in both PM and s-IBM, in spite of poor response to immunotherapies of the latter, as described later. They are the following, as illustrated in Fig. 14.8: 14.10.3.1. Sensitized autoinvasive cytotoxic CD8+ T cells form an immunological synapse with muscle fibers expressing MHC-I class antigen 14.10.3.1.1. MHC expression In PM and s-IBM the CD8þ cells surround healthy, but MHC-I-class-antigen expressing, non-necrotic muscle fibers that they eventually invade (Arahata and Engel, 1986). Muscle fibers normally do not express detectable
AUTOIMMUNE INFLAMMATORY MYOPATHIES
287
Fig. 14.8. Molecules, receptors and their ligands involved in the transgression of T cells through the endothelial cell wall and recognition of antigens on muscle fibers of patients with sporadic inclusion-body myositis (s-IBM). Leukocyte function-associated antigen (LFA)-I/ intercellular adhesion molecule (ICAM)-I binding and T-cell receptor (TCR) scanning for antigen initiates the formation of an immunological synapse between major histocompatibility complex (MHC)-I and TCR. Stimulation is supported and enhanced by the engagement of costimulatory molecules BB1, ICOS and CD40 on the muscle fibers and their ligands CD28, CTLA-4, ICOS-L and CD40L on the autoinvasive T cells. Metalloproteinases facilitate the migration of T cells and their attachment to the muscle surface. Muscle fiber necrosis occurs via the perforin granules released by the autoaggressive T cells. A direct myocytotoxic effect exerted by the released IFN-g, IL1 or TNF-a may also play a role. Death of the muscle fiber is mediated by a form of necrosis rather than apoptosis, presumably because of the counterbalancing effect or protection by the antiapoptotic molecules such as Bcl-2, hILP and FLIP which are upregulated in PM and IBM muscles (Dalakas, 2001b). Fas is also expressed, but it does not mediate apoptosis in the muscle (Dalakas, 2001b, Dalakas and Hohlfeld, 2003a).
amounts of MHC class I or II antigens. In PM and IBM, however, widespread overexpression of MHC class I, and occasionally MHC-II, is seen even in areas remote from the inflammation (Fig. 14.5; Karpati et al., 1988; Emslie-Smith et al., 1989). In other chronic myopathies or dystrophies, and in contrast to s-IBM, the muscle fibers do not express the MHC-I antigen in a ubiquitous and consistent pattern (Dalakas, 2004c), or the costimulatory molecules described below. Furthermore, in dystrophies the occasionally seen autoinvasive T cells are not antigen-driven because they are clonally diverse, do not form the immunological synapse described
below and do not express the specific activation markers of cytotoxicity. In human myotubes, MHC molecules are upregulated by IFN-g (Hohlfeld and Engel, 1990; Mantegazza et al., 1991; Michaelis et al., 1993). Although in transgenic mice, MHC-I expression was thought to act as an inciting event triggering an atypical, non-inflammatory myopathy with “myositis-specific” antibodies (Nagaraju et al., 2000a), in human PM the upregulation of MHC-class I alone does not trigger T cell activation or endomysial infiltration (Nyberg et al., 2000). Another MHC molecule, the nonpolymorphic “non-classical” HLA-G, is
288
M. C. DALAKAS
upregulated in vitro by interferon-g and is expressed on muscle fibers of patients with PM (and IBM; Wiendl et al., 2000). Interestingly, HLA-G protects human muscle cells from immune-cell mediated lysis in vitro, suggesting that it might (partially) protect muscle fibers in vivo (Wiendl et al., 2003a). 14.10.3.1.2. Activated cytotoxic T cells In PM and IBM the T-cells are activated, as evidenced by their expression of memory and activation markers CD45RO and ICAM-I, as well as MHC-I and inducible costimulator (ICOS) on their surface (De Bleecker and Engel, 1995; Dalakas and Hohlfeld, 2003a); further, the ICOS-positive autoinvasive CD8þ T cells are cytotoxic overexpressing perforin and granzyme granules at the protein and mRNA level; these granules upon release induce muscle fiber necrosis (Fig. 14.8; Goebels et al., 1996; Schmidt et al., 2004; wiendl et al., 2003b). These cells have been cytotoxic in autologous myotubes (Hohlfeld and Engel, 1991). Thus, the perforin pathway seems to be the major cytotoxic effector mechanism. In contrast, the Fas-Fas-L-dependent apoptotic process is not functionally involved (Barry and Bleackley, 2002), despite expression of the Fas antigen on muscle fibers and of the Fas-L on the autoinvasive CD8þ cells (Schneider et al., 1996; Behrens et al., 1997; Schneider et al., 1999). The coexpression of the antiapoptotic molecules Bcl-2 (Behrens et al., 1997), FLICE [Fas-associated death domain-like IL1-converting enzyme-inhibitory protein (FLIP); Nagaraju et al., 2000], and human IAPlike protein (hILP; Li and Dalakas, 2006), may confer resistance of muscle to Fas-mediated apoptosis. 14.10.3.1.3. Rearrangement of the TCR gene of the endomysial T cells. The T cells recognize an antigen via the T cell receptor (TCR), a heterodimer of two a and b chains, encoded by multiple gene families in the V (variable), D (diversity), J (joining) and C (constant) regions of the TCR. The part of the TCR that recognizes an antigen is the CDR3 region, which is encoded by genes in the V-J and V-D-J segments of the TCR gene. If the endomysial T cells are selectively recruited by a specific autoantigen, the use of the V and J genes of the TCR should be restricted and the amino acid sequence in their CDR3 region should be conserved (Dalakas, 1998a). In patients with PM and IBM, but not in those with DM or dystrophies, only certain T cells of specific TCRa and TCRb families are recruited to the muscle from the circulation (Mantegazza et al., 1993; O’Hanlon et al., 1994; Fyhr et al., 1997; Bender et al., 1995; Benveniste et al., 2001; Nishio et al., 2001). Cloning and sequencing of the
amplified endomysial or autoinvasive TCR gene families has demonstrated a restricted use of the Jb gene with conserved amino acid sequence in the CDR3 region indicating that these cells are specifically selected and clonally expanded in situ. Furthermore, these specific T cell clones express perforin and they are autoinvasive indicating their cytotoxic potential against the muscle (Nishio et al., 2001). Immunocytochemistry combined with polymerase chain reaction and sequencing of the most prominent TCR families has shown that the autoinvasive, but not the perivascular, CD8þ endomysial cells are the clonally expanded cells (Fyhr et al., 1997; Bender et al., 1998). Using a proof-of-principle novel technique of CDR3 spectratyping combined with molecular laser-assisted microdissection and single-cell polymerase chain reaction, it was confirmed that the autoinvasive CD8 cells are clonally expanded, and these clones can be traced to the circulation (Hofbauer et al., 2003). Sequential muscle biopsy specimens obtained during a 19–22 month period in three patients with IBM has further shown a persistent clonal restriction of the same Vb families among the autoinvasive CD8þ cells (Amemiya et al., 2000b). The most frequently detected gene families among the autoinvasive CD8þ T cells were the Vb3, Vb5.1, Vb6.7 and Vb13. These cells did not only exhibit restricted usage of certain Vb gene families but also had a conserved aminoacid sequence homology in the complementary CDR3 determining region (Amemiya et al., 2000b). Of interest, in the CDR3 region only a small number of amino acids was found, suggesting that the MHC-I-expressing muscle fibers present limited number of antigenic peptides to the autoinvasive CD8þ T cells during the course of the disease. The observation that in s-IBM identical T cell clones with restricted amino acid sequence in the CDR3 region belong to autoinvasive T cells and persist for several years even in different muscles, has now been confirmed in several studies (Fyhr et al., 1997; Bender et al., 1998; Amemiya et al., 2000b; Muntzing et al., 2003). Collectively, in PM and s-IBM there is overwhelming evidence of clonal restriction of the autoinvasive endomysial T cells which are specifically recruited to the muscle and appear to expand in situ probably driven by the same antigen(s). In an important case of PM, a single clone of g/d T cells were the primary cytotoxic effectors (Hohlfeld et al., 1991; Pluschke et al., 1992; Wiendl et al., 2002). The g/d TCR of the pathogenic T cells was transfected into a TCR-deficient mouse hybridoma cell line (Wiendl et al., 2002). The transfectants could be stimulated with an as yet unknown autoantigen on human myoblasts (Wiendl et al., 2002); this is the first indication that at least in g/d T-cell mediated PM the autoaggressive T cells recognize genuine muscle antigens.
AUTOIMMUNE INFLAMMATORY MYOPATHIES 14.10.3.1.4. Presence of costimulatory molecules For the activation of T cells and antigen recognition, the presence of costimulatory molecules and their counterreceptors is fundamental. The clonally expanded autoinvasive CD8þ T cells mentioned above are primed to receive specific antigenic peptides presented by the MHC-I molecule expressed on the muscle fibers. For antigen presentation, however, these MHC-I-positive fibers should also express the B7 family of costimulatory molecules (B7–1, B7–2, BB1 or ICOS-L) while the autoinvasive CD8þ T cells express the counter receptors CD28, CTLA-4 or ICOS (Liang and Sha, 2002). Several studies have now confirmed that in PM and s-IBM muscles, the BB1 (CD80) is expressed on MHC-I-positive muscle fibers which make cell-to-cell contact with the CD28 or CTLA-4 ligands on the autoinvasive CD8þ T cells (Behrens et al., 1998; Murata and Dalakas, 1999). Further, the BB1, which is induced by interferon-g on human myoblasts, is a functional molecule playing a role in antigen presentation and T cell differentiation (Behrens et al., 1998). The concept of the immunological synapse between CD8þ cells and muscle fibers (Krummel and Davis, 2002) was expanded further with finding ICOS-L (inducible costimulator ligand), another B7-family molecule associated with memory T cells (Wiendl et al., 2003b). In PM and IBM, muscle fibers express ICOS-L while their autoinvasive T cells express ICOS (Schmidt et al., 2004), reinforcing the view that muscle fibers can behave as antigen presenting cells (APC). Further, the ICOS-positive T cells are cytotoxic, expressing perforin granules (Schmidt et al., 2004). Because ICOS-L is a functional molecule upregulated by TNF-a (Wiendl et al., 2003a), in PM and s-IBM the ICOS–ICOS-L interactions are fundamental in facilitating clonal expansion and costimulation of the effector functions of memory T cells. Another novel B7-family protein B7-H1, called PD-L1 (programmed death-l ligand) that mediates inhibition of T cell activation, was also expressed on muscle fibers in inflammatory myopathies (Wiendl et al., 2003b), suggesting that in the immunological synapse of muscle/CD8þ cells there is a balance of inflammatory stimuli that protect muscle fibers from excessive immune aggression. Although the muscle fibers can behave as APCs, information about the hematopoietic dendritic cells (DC), the most potent APCs in antigen presentation, is slowly emerging. Within the endomysial infiltrates of PM and DM there are rare mature DCs but abundant immature DCs expressing the CCL2-/CCR6 chemokine receptor complex (Page et al., 2004). The critical muscle microenvironment necessary for interaction of T cells, cytokines and chemokines with DC for maturation and antigen presentation however, remains still unclear. The
289
suggestion that local production of proinflammatory cytokines, such as IFN-g, IL1b, IL-17 and the chemokine CCL-20/CCR6 complex may contribute to breaking tolerance and homing of the immature DC to the muscle tissue, remains speculative. Histidyl-tRNA synthetase (Jo-1 antigen), liberated from the muscle by the effect of cytokines (e.g., IL-17), was also proposed as a potential triggering factor in recruiting immature DC to the sites of inflammation, acting also as chemoattractant in perpetuating the recruitment of T cells to the muscle. This interesting suggestion may be of limited significance because only 10% of myositis patients have Jo-1 antibodies. The role of dendritic cells in DM was described earlier. 14.10.3.1.5. Upregulation of cytokines, cytokine signaling, chemokines and metalloproteinases Cytokines and chemokines are the third important component in the immunological synapse because they are essential in enhancing the activation of T cells and the induction of costimulatory molecules. Polymerase chain reaction studies of muscle tissue have confirmed a varying degree of amplification of messenger RNA of the various cytokines including interleukin IL-1, IL-2, tumor necrosis factor a, interferon-g, signal transducer and activation of transcriptor (STAT; Illa et al., 1997), transforming growth factor b (TGF-b), granulocytemacrophage colony-stimulating factor, IL-6 and IL-10 (Lundberg et al., 1995; Dalakas, 1998a; De Bleecker et al., 1999; De Rossi et al., 2000; Figarella-Branger et al., 2003). Some of these cytokines can also exert a direct cytotoxic effect on the muscle fibers in vivo and on human myotubes in vitro. Chemokines, a class of small cytokines, are known participating molecules in the leucocyte recruitment and activation at the sites of inflammation. Among them, MCP-1 and MIP-1a are strongly upregulated in IBM muscles at the protein and mRNA level (DeBleecker et al., 2002; Figarella-Branger et al., 2003; Raju et al., 2003). The interferon-g-inducible chemokines Mig and IP-10, and the Mig’s receptor CXCR3 are also strongly expressed on the muscle fibers and on a subset of autoinvasive CD8þ cells (Raju et al., 2003). Because Mig and IP-10 are produced by myotubes upon INF-g stimulation, they could facilitate the recruitment of activated T cells to the muscle and contribute to self-sustaining nature of endomysial inflammation as commonly seen in sIBM (Raju et al., 2003). The presence of MCP-I and MIP-1a in the extracellular matrix and the possibility of in situ synthesis may have an effect in promoting tissue fibrosis in the late stages IBM. Cytokines and chemokines activate also adhesion molecules such as VCAM, ICAM-1, VLA-4 and metalloproteinases (MMPs), a family of calcium-dependent zinc endopeptidases involved in the
290
M. C. DALAKAS
remodeling of the extracellular matrix, and facilitate the transmigration of lymphocytes towards the muscle fiber. Among MMPs, the MMP-9 and MMP-2 are upregulated on the non-necrotic and MHC-I class expressing muscle fibers of patients with IBM (Choi and Dalakas, 2000; Kieseier et al., 2001). Further, MMP-2 immunostains the autoinvasive CD8þ T cells, which make cell-to-cell contact with muscle fibers, and immunoreacts with bamyloid and b-amyloid precursor protein (APP) deposits on the vacuolated fibers (Choi and Dalakas, 2000). Of interest, using gene array studies, the upregulated chemokine and cytokine genes is much higher in the muscles of patients with IBM compared to muscles of patients with dermatomyositis (Raju and Dalakas, 2005). 14.10.3.2. Association with viral infections and role of retroviruses Several viruses, including coxsackieviruses, influenza, paramyxoviruses, mumps, cytomegalovirus and Epstein– Barr virus have been indirectly associated with chronic and acute myositis. For the coxsackieviruses, an autoimmnune myositis triggered by molecular mimicry has been proposed because of structural homology between histidyl-transfer RNA synthetase that is the target of the Jo-1 antibody (see above) and genomic RNA of an animal picornavirus, the encephalomyocarditis virus. Very sensitive polymerase chain reaction (PCR) studies, however, have repeatedly failed to confirm the presence of such viruses in muscle biopsies from these patients (Leff et al., 1992; Leon-Monzon and Dalakas, 1992; Dalakas, 2004b). The best evidence of a viral connection in PM and IBM is with the retroviruses. Monkeys infected with the simian immunodeficiency virus and humans infected with HIV and human T cell lymphotropic virus (HTLV-1) develop PM or IBM. In humans infected with HIV or HTLV-1, an isolated inflammatory myopathy may occur as the initial manifestation of the retroviral infection or myositis may develop later in the disease course (Dalakas et al., 1986a; 1986b; Dalakas and Pezeshkpour, 1988; Morgan et al. 1989; Dalakas et al., 2004b). It appears that IBM is seen with rather unusual frequency in humans infected with HIV and HTLV-1 infection (Cupler et al., 1996; Ozden et al., 2001; Dalakas, 2006). This association is more than a coincidence because in retroviral-positive patients the disease always appears before the age of 50, but several years after the first manifestations of the retroviral infection (Cupler et al., 1996; Ozden et al., 2001; Dalakas, 2004b). At least seven HIV/HTLV-1 positive patients with IBM have been reported (Cupler et al., 1996; Ozden et al., 2001; Dalakas, 2004b) and we have seen six more cases the last 2 years (Dalakas, 2006), suggesting that the disease is now more frequently
recognized in HIV-positive patients who live longer and harbor the virus for several years. The clinical phenotype and muscle histology in HIV-IBM patients are identical to the retroviral-negative IBM. The predominant endomysial cells are CD8þ, cytotoxic T cells which along with macrophages, invade or surround MHC-I-antigenexpressing non-necrotic muscle fibers (Illa et al., 1991; Leon-Monzon et al., 1994). Using in-situ hybridization, PCR-reaction, immunocytochemistry and electronmicroscopy, viral antigens could not be detected within the muscle fibers but only in occasional endomysial macrophages (Illa et al., 1991; Leon-Monzon et al., 1993; 1994; Cupler et al., 1996; Dalakas, 2004b). We have interpreted these observations to suggest that in HIVand HTLV-1 IBM there is no evidence of persistent infection of the muscle fibers with the virus or viral replication within the muscle. The HIV/HTLV-1 IBM is caused by a clonally-driven subpopulation of activated T-cells that invade MHC-I-expressing muscle fibers in a pattern identical to the cytotoxic process seen in retroviral-negative IBM, as described above. Molecular immunological studies using tetramers have now shown that retrovirally-specific cytotoxic T cells are recruited within the muscle fibers and that the CDR3 region of the T cell receptor contains amino acid residues for specific HLA/viral peptide interaction (Saito et al., 2002; Ozden et al., 2004). These findings suggest that the chronic retroviral infection along with immune recognition are sufficient to trigger the inflammatory process that leads to sIBM (Ozden et al., 2004). In the retroviralpositive patients, the retroviral-positive endomysial macrophages may facilitate the autoimmune process by secreting cytokines, chemokines or nitric oxide (NO) which upregulate MHC-I or costimulatory molecules and enhance myocytotoxicity. The development of PM or IBM in HIV-positive patients should be distinguished from a toxic myopathy related to long-term therapy with zidovudine, which is characterized by fatigue, myalgia, mild muscle weakness and mild elevation of CK (Dalakas et al., 1990; Lewis and Dalakas, 1995). Zidovudine-induced myopathy, which generally improves when the drug is discontinued, is a mitochondrial disorder characterized histologically by the presence of “ragged red” fibers. Abnormal muscle mitochondrial and depletion of the muscle mitochondrial DNA by zidovudine results from inhibition of g-DNA polymerase, an enzyme found solely in the mitochondrial matrix. 14.10.3.3. Reconciling the immunopathologic with degenerative features in the pathogenesis of s-IBM It has now become clear that IBM is a complex disease. Our observation, based on more than 100 biopsies, that
AUTOIMMUNE INFLAMMATORY MYOPATHIES the vacuolated muscle fibers are very rarely invaded by T cells while the apparently intact fibers are those characterized by primary inflammation and autoaggressive T cells, has led us to propose that in IBM two processes occur in parallel: a primary immune process of CD8þ T cell-mediated cytotoxicity as defined above, and a degenerative process characterized by vacuolization and amyloid-related degenerative molecules. The factors supporting the autoimmune pathogenesis of sIBM, as described above and summarized in Table 14.6, include the following: 1) association with other autoimmune diseases and autoantibodies in frequency similar to those seen in classic autoimmune disorders such as myasthenia gravis (Koffman et al., 1998; Badrising et al., 2004); 2) occurrence of disease with the same sporadic phenotype in family members of the same generation (familial inflammatory IBM), as seen with other autoimmune disorders (Sivakumar and Dalakas, 1996); 3) strong association in up to 70% of patients with
Table 14.6 Factors supporting the immunopathogenesis of s-IBM 1. Immunogenetic association with DRb10301, DQb10201 alleles and B8-DR3-DR52-DQ2 haplotype; the HLA-Ahaplotype is associated with earlier disease onset. 2. Sporadic IBM can occur in family members of the same generation (familial inflammatory IBM), as seen with other autoimmune disorders. 3. Association with other autoimmune disorders and autoantibodies in frequency analogous to the one seen in other autoimmune disorders (i.e. myasthenia gravis, LEMS). 4. Increased association with paraproteinemia (22.8%) in frequency significantly higher than age-matched controls (2%). 5. Association with common variable immunodeficiency and natural killer cells. 6. Association with HIV and HTLV-1 infection, with increasingly recognized frequency (up to 13 cases reported). 7. The CD8þ autoinvasive T cells: a) surround MHC-I expressing fibers (MHC-I/CD8þ lesion); b) express perforin and activation markers of cytotoxicity; c) are clonally expanded with restricted aminoacid sequences in the CDR3 region of the T cell receptors (TCR); d) TCR families persist over time even in different muscles. 8. There is ubiquitous upregulation of MHC-I antigen and the co-stimulatory molecules BB1, ICOS-L and CD40 on muscle fibers, even on those not invaded by T cells, while the counterreceptors CD28, CTLA-4, ICOS and CD40L are overexpressed on the autoinvasive T cells. 9. There is strong upregulation of cytokines, chemokines and their receptors at the protein, mRNA and gene level.
291
HLA-class I, II antigens with the autoimmune-prone HLA-B8-DR3 ancestral haplotype (irrespective of the presence of coexisting autoimmune diseases) in frequency found in Lambert–Eaton myasthenic syndrome (LEMS; Badrising et al., 2004); 4) association with common variable immunodeficiency and natural killer cells (Dalakas and Illa, 1995); 5) association with paraproteinemias, in up to 22.8%, much beyond the frequency found in age-matched controls (2%), suggesting disturbed immunoregulation (Dalakas et al., 1987a); 6) the autoinvasive T cells are antigen-driven and form an immunological synapse, as described above; 7) frequent association with retroviruses as noted earlier; and 8) strong upregulation of cytokines, chemokines and their receptors at the protein, mRNA and gene level. The degenerative process of IBM is supported by the presence of vacuoles (almost always in fibers noninvaded by T-cells) along with deposits of b-amyloid within the vacuolated muscle fibers which immunoreact for APP, chymotrypsin, presenilin I, apolipoprotein E, phosphorylated tau and others (Askanas and Engel, 1988; 1998). It is unclear however whether these deposits directly contribute to disease pathogenesis or are secondary phenomena. Vacuoles are observed in several myopathies, that lack inflammation such as hereditary IBM due to GNE mutations, X-linked Emery–Dreifus muscular dystrophy (Fidzianska et al., 2004), rigidspine syndrome, other proximal and distal myopathies such as myofibrillar myopathies or dysferlinopathies, and even in chronic neurogenic conditions such as postpolio (Ferrer et al., 2004; Selcen et al., 2004; Dalakas, 2006). The intracellular accumulation of amyloidrelated proteins AbPP, phosphorylated tau, presenilin1, apolipoprotein-E, g-tubulin, clusterin, a-synuclein, gelsolin, oxidative stress proteins and all the components of the catalytic core of the proteasomes have been recently found to be equally expressed in sIBM and myofibrillar myopathies (Ferrer et al., 2004; Selcen et al., 2004; Ferrer et al., 2005), leading to the conclusion that these accumulations may not be unique to the vacuoles of s-IBM. Although it remains unclear whether they are the primary or the secondary process in IBM, the accumulation of these proteins may be fundamental in understanding the ongoing stressor mechanisms that lead to muscle fiber degeneration not only in IBM but also in the other myopathies where they also accumulate. A fundamental issue in s-IBM may be the relationship between cytokines, amyloid and chronic inflammation, an area also relevant in Alzheimer’s disease. In s-IBM, cytokines, such as IL-1b derived by macrophages and T cells, are in excess and colocalize with b-APP (Dalakas, 1998b). Because b-APP enhances IL-1b production and IL-1b upregulates b-APP and
292
M. C. DALAKAS
b-APP gene expression (IL1b$b-APP$IL1b$ inflammation), an interaction between amyloid and inflammatory mediators has been proposed (Dalakas, 1998a; 2004c). There appears to be a linear relationship between the mRNA of upregulated cytokines and chemokines with that of degenerating molecules bAPP, Tau and ubiquitin suggesting a role of the proinflammatory markers in enhancing degeneration (Schmidt et al., 2005). The immunogenicity of b-amyloid was recently studied in healthy elderly subjects and patients with Alzheimer disease compared to young/middle-age adults (Monsonego et al., 2003). Strong Ab-reactive and HLA-restricted T cell responses against the immunogenic Ab1–42 peptide were found in the elderly, suggesting that Ab is presented as an antigen by APCs in the context of MHC-TCR interaction (Monsonego et al., 2003). Whether in s-IBM Ab can serve as antigen processed by the APC-functioning muscle fibers leading to antigen-specific T cell activation remains unclear.
14.11. Treatment with immunomodulating agents 14.11.1. Polymyositis and dermatomyositis The goals of therapy in inflammatory myopathies is to improve activities of daily living by increasing muscle strength and improving extramuscular manifestations, such as skin rash, dysphagia, dyspnea, arthralgia or fever. Unfortunately, there are only a handful of controlled clinical trials, conducted mostly in DM and IBM. Overall, DM responds better than PM (especially if the presentation is acute and the treatment starts early), whereas IBM shows minimal, transient or no response (Dalakas, 2003). Although when the strength improves, the serum CK falls concurrently, the reverse is not always true because therapies (i.e., plasmapheresis) may reduce only the serum CK without improving strength (Dalakas, 1991). Unfortunately, this has been misinterpreted as “chemical improvement”, and has formed the basis for the common habit of “chasing” or “treating” the CK level instead of the muscle weakness (Dalakas, 1991). The following agents are used in the treatment of PM and DM (Dalakas, 1991; Mastaglia et al., 1997; Mastaglia, 2000; Hilton-Jones, 2001; Mastaglia and Phillips, 2002; Oddis, 2002; Choy and Isenberg, 2002).
initiated as early in the disease as possible. After an initial period of 3–4 weeks, prednisolone is tapered slowly over a period of 10 weeks to 1mg/kg every other day. Then, if there is evidence of efficacy and no serious side effects, the dosage is further reduced by 5 or 10 mg every 3–4 weeks until the lowest possible dose that controls the disease is reached. The efficacy of prednisolone is determined by an objective increase in the muscle strength and activities of daily living, which almost always occurs by the third month of therapy. A feeling of increased energy or a reduction of the CK level without a concomitant increase in muscle strength is not a reliable sign of improvement. If prednisolone provides no objective benefit after ~3 months of high-dose therapy, the disease is probably unresponsive to the drug and tapering should be accelerated while the next-in-line immunosuppressive drug is started. Although controlled trials have not been performed, almost all patients with true PM or DM respond to glucocorticoids to some degree and for some period of time; in general, DM responds better than PM (Dalakas, 2003). The long-term use of prednisolone may cause increased weakness associated with a normal or unchanged CK level; this effect is referred to as steroid myopathy. In a patient who previously responded to high doses of prednisolone, the development of increased weakness may be related to steroid myopathy or to disease activity that either will respond to a higher dose of glucocorticoids or has become glucocorticoid-resistant. In these circumstances, the decision to raise or lower the prednisolone dosage may be influenced by reviewing the patient’s history of muscle strength (especially with respect to mobility), serum CK levels, and changes in medications during the preceding 2 months. In uncertain cases, the prednisolone dosage can be adjusted arbitrarily: judged by the changes in the patient’s strength, the cause of the weakness is usually evident in 2–8 weeks (Dalakas, 1994). 14.11.1.2. Pulse steroid therapy
14.11.1.1. Glucocorticoids
Initial pulse therapy with 1 g IV methylprednisolone given every day for 3 days may be preferable in aggressive cases (Matsubara et al., 1994). In DM, especially the elderly patients, monthly IV pulses have been beneficial based on anecdotal reports (Genge and Karpati, 1997). Although never tested with control studies, IV steroids may be especially useful in patients who cannot secure infusion of monthly high-dose immunoglobulin (see below).
Although controlled trials have not been performed, oral prednisolone is the initial treatment of choice; the effectiveness and side effects of this therapy determine the future need for stronger immunosuppressive drugs. High-dose prednisone, at least 1 mg/kg per day, is
14.11.1.3. Combined steroid with immunosuppressive therapy from the outset In severe cases, combined therapy of steroids with another immunosuppressant such as methotrexate or
AUTOIMMUNE INFLAMMATORY MYOPATHIES
293
azathioprine has been shown to be associated with a lower relapse rate or better long-term outcome (Bunch et al., 1980; Mastaglia et al., 1999).
et al., 1998; Cherin et al., 2002). Neither plasmapheresis or leukapheresis appears to be effective in PM and DM (Miller et al., 1992).
14.11.1.4. Immunosuppressive drugs
14.11.1.6. Sequential empirical approach The following sequential empirical approach to the treatment of PM and DM is our preferred plan:
Approximately 75% of patients ultimately require treatment with immunosuppressive drugs. Treatment is generally initiated when a patient fails to respond adequately to glucocorticoids after a 3-month trial, the patient becomes glucocorticoid-resistant, glucocortoidrelated side effects appear, attempts to lower the prednisolone dose repeatedly result in a new relapse, or rapidly progressive disease with evolving severe weakness and respiratory failure develops (Dalakas, 1994; 2003). Drug selection is largely empirical, with choices based on personal experiences, relative efficacy, and safety. The following agents are commonly used: 1. Azathioprine is well tolerated, has few side effects, and appears to be as effective for long-term therapy as other drugs. The dose is up to 3 mg/kg daily. 2. Methotrexate has a faster onset of action than azathioprine. It is given orally starting at 7.5 mg weekly for the first 3 weeks (2.5 mg every 12 h for three doses), with gradual dose escalation by 2.5mg per week to a total of 25 mg weekly. A rare side effect is methotrexate pneumonitis, which can be difficult to distinguish from the interstitial lung disease of the primary myopathy associated with Jo-1 antibodies (described above). 3. Cyclophosphamide (0.5–1 g/m2 intravenously monthly for 6 months) has limited success (Cronin et al., 1989) and significant toxicity although some successes have been reported (Bombardieri et al., 1989). 4. Chlorambucil has variable results. 5. Cyclosporin has inconsistent and mild benefit (Grau et al., 1994). 6. Mycophenolate mofetil has recently shown some effectiveness (Chaudhry et al., 2001). 14.11.1.5. Immunomodulating procedures In a double-blind study of patients with refractory DM, intravenous immunoglobulin (IVIg) improved not only the strength and rash but also the underlying immunopathology (Dalakas, 1998b; Dalakas et al., 1993). The benefit can be impressive but most of the times is shortlived (8 weeks); repeated infusions every 6–8 weeks are often required to maintain improvement. A dose of 2 g/kg divided over 2–5 days per course is recommended. A controlled double-blind study in PM is not completed (probably because of the rarity of the disease), but uncontrolled observations suggest that IVIg is beneficial in the majority of PM patients (Cherin et al., 1991; Mastaglia
Step 1: high-dose prednisolone. Step 2: azathioprine, methotrexate or mycophenolate. In aggressive cases, steps 1 and 2 may be combined from the outset. Step 3: IVIg. Step 4: a trial, with guarded optimism, of one of the following agents, chosen according to the patient’s age, degree of disability, tolerance, experience with the drug, and the coexisting conditions: cyclosporin, chlorambucil or cyclophosphamide. These are used individually or in various combinations with steps 1–3 as dictated by disease severity. Patients with interstitial lung disease may benefit from aggressive treatment with cyclophosphamide. Common pitfalls leading to failure of steroid or immunosuppressive treatment are inadequate initial dose of prednisolone or cytotoxic drugs, short duration of therapy or quick tapering, early development of preventable side effects necessitating early discontinuation of prednisolone, and wrong diagnosis. A patient with presumed PM who has not responded to any form of immunotherapy most likely has IBM or another disease. In these cases, a repeat muscle biopsy and a more vigorous search for a putative “other disease” are recommended. In addition to IBM, the most often misdiagnosed disorders are metabolic myopathy such as phosphorylase deficiency, a dystrophic process with endomysial inflammation resembling polymyositis, drug-induced myopathy, or an endocrinopathy. Calcinosis, a manifestation of DM, is difficult to treat; however, new calcium deposits may be prevented if the primary disease responds to the available therapies. Diphosphonates, aluminum hydroxide, probenecid, colchicine, low doses of warfarin, calcium blockers and surgical excision have all been tried without success. 14.11.2. Inclusion body myositis In spite of the above described primary immune factors, s-IBM remains resistant to most immunotherapies, justifying the contention that it could be more of a degenerative disease rather than autoimmune. However IBM is not the only immune disease unresponsive to such therapies. Primary progressive multiple sclerosis is a classic example where immune and degenerative features coexist
294
M. C. DALAKAS
and the disease is resistant to therapies. Although the common immunotherapeutic agents, such as corticosteroids, azathioprine, methotrexate, cyclosporin and cyclophosphamide, are generally ineffective in patients with s-IBM, some patients have responded to immunomodulating therapies to a certain degree or for short periods (Mowzoon et al., 2001; Dalakas, 2003). For example, prednisolone together with azathioprine or methotrexate have been disappointing (Badrising et al. 2002), but most experts try these agents for a few months in newly diagnosed patients because occasional patients feel subjectively or even objectively stronger. Also, after these drugs are discontinued some patients feel weaker, prompting some clinicians to maintain in some patients a low-dose, every-other-day prednisolone or weekly methotrexate in an effort to halt disease progression, even though there is no objective evidence or controlled study to support this practice. In two double-blind studies of IVIg in IBM, minimal benefit in up to 30% of the patients was found (Dalakas et al., 1997b; Walter et al., 2000); the strength gains, however, were not of sufficient magnitude to justify the routine use of this drug. A second controlled trial combining IVIg with prednisone was ineffective in 36 patients with IBM (Dalakas et al., 2001). IVIg has also improved the dysphagia of IBM in both a controlled study and uncontrolled series (Soueidan and Dalakas, 1993; Dalakas et al., 1997b; Cherin et al., 2002) suggesting that more specific or potent agents may be promising. Among these agents currently considered are the available monoclonal antibodies directed against T cell regulatory pathways, such as CD56 (CAMPATH), costimulatory molecules (CD28/CTLA-4), adhesion molecules (integrins/LFA-1/ICAM), and cytokines (TNF-a), or those against B cells (CD20; Dalakas, 2003). Towards this direction, the results based on a 12-month, open, randomized trial in 11 patients with IBM, using anti-T-lymphocyte globulin (ATG) combined with methotrexate, are of interest (Lindberg et al., 2003). Increased strength by 1.4% was noted in six patients, randomized to ATG and methotrexate; in contrast five patients randomized to methotrexate alone lost 11.1% of their strength (p¼0.021) during the study period (Lindberg et al., 2003). The study is significant in suggesting that an aggressive anti-T-cell agent may be beneficial, offering further justification for using other similar therapies. A relevant study using alemtuzumab (CAMPATH), a T-cell-depleting monoclonal antibody against CD52, is now in progress at the NIH (MC Dalakas, principal investigator). CAMPATH is even a stronger agent than ATG because it causes T cell depletion for at least 6 months. It is anticipated that depletion of the T cells from the periphery will also result in T cell depletion from the muscle. At the time of writing, four patients have
completed the study. Other promising agents along these lines include rapamycin, which acts via a calcineurinindependent pathway to prevent the translation of mRNA for key cytokines, and natalizumab, a recently approved drug for multiple sclerosis, which blocks the transmigration of T cells across the endothelial cell wall (Dalakas, 2003).
14.12. Physical therapy Although the effect of exercise progress has not been systematically studied, we are advocating physical therapy from the beginning of therapy because we have observed that type II atrophy related to disuse, steroids, inactivity or possibly due to inflammatory factors such as cytokines, i.e., TNF-a, is very common in patients with all inflammatory myopathies. Others also agree with an exercise program (Phillips and Mastaglia, 2000). In IBM, we have found that a 12-week isotonic training program increased the isometric torque and improved the functional activities without causing muscle damage or enhancing the degree of inflammation. An occasional rise in the CK level is transient (Spector et al., 1997). We believe that a carefully prescribed resisted exercise program and aerobic training are essential in the management of patients with PM, DM and IBM and should start from the outset of therapies.
14.13. Prognosis Although accurate data from large series is not available, in a small cohort the 5-year survival rate for treated patients with PM and DM was approximately 95% and the 10-year survival 84% (Marie et al., 2001); death is usually due to pulmonary, cardiac or other systemic complications. Patients severely affected at presentation or treated after long delays, those with severe dysphagia or respiratory difficulties, older patients and those with associated cancer have a worse prognosis (Maugars et al., 1996; Sultan et al., 2002). DM responds more favorably to therapy than PM and thus has a better prognosis. Most patients improve with therapy, and many make a full functional recovery, which is often sustained with maintenance therapy. Up to 30% may be left with some residual muscle weakness. Relapses may occur at anytime. IBM has the least favorable prognosis of the inflammatory myopathies. Most patients will require the use of an assistive device such as a cane, walker, or wheelchair within 5–10 years of onset (Sekul and Dalakas, 1993; Peng et al., 2000). In general, the older the age of onset in IBM, the more rapidly progressive is the course.
AUTOIMMUNE INFLAMMATORY MYOPATHIES
295
14.14. Common errors, misconceptions, and practical guidelines in the diagnosis and management of PM and DM
10. It is rare for acute or active phase of DM, especially in non-cancer associated disease, not to respond to treatments to some extent and for a period of time.
Based on our own experience and that of others in major neuromuscular centers, the diagnosis and treatment of DM and PM could be improved by modifying many common practices, as follows:
References
1. Exclude all conditions that mimic PM taking into account that the old Bohan and Peter’s criteria are obsolete because they cannot separate PM from IBM or other toxic, necrotizing and dystrophic myopathies. 2. Polymyositis as a stand-alone entity is infrequent and rare in childhood; IBM is a more common disorder. 3. Endomysial inflammation also occurs in nonimmune myopathies (dystrophies, metabolic myopathies, or after a muscle injury). 4. A muscle tested with needle electromyography should not be used for biopsy for at least 1 month. 5. Elevation of AST, ALT and LDH in patients presenting with fatigue may direct attention towards liver disease and result in an unnecessary liver biopsy; the CK level should be checked in such patients to exclude myogenic origin of the “liver-enzyme” elevation. 6. Active PM should present with muscle weakness; patients manifesting only myalgias and normal strength do not have PM. 7. Polymyositis without “primary” inflammation (the CD8þ/MHC-I complex) should be questioned. 8. The goal of therapy is to improve strength based on increased activities of daily living; the CK is a good indicator of disease activity but not the target of therapy; “chasing” or “treating” the CK level instead of muscle strength is not advisable. 9. Because PM is potentially treatable, every effort should be made to treat these patients early. However, when in such cases treatment has only reduced CK level but not improved strength, the patient should be re-evaluated and the muscle biopsy re-examined; a second biopsy might be needed to secure the correct diagnosis which is often IBM or a dystrophy; in these cases, we discontinue immunosuppressive drugs. On the other hand, maintenance of low-level immunosuppressive therapy with azathioprine or methotrexate, following concurrently the changes in strength and CK level, is advisable to prevent further deterioration for patients who have considerably improved but their strength is not fully restored.
Amato AA, Gronseth GS, Jackson CE, et al. (1996). Inclusion body myositis: clinical and pathological boundaries. Ann Neurol 40: 581–586. Amemiya K, Semino-Mora C, Granger RP, et al. (2000a). Downregulation of TGF-b1 mRNA and protein in the muscles of patients with inflammatory myopathies after treatment with high-dose intravenous immunoglobulin. Clin Immunol 94: 99–104. Amemiya K, Granger RP, Dalakas MC (2000b). Clonal restriction of T-cell receptor expression by infiltrating lymphocytes in inclusion body myositis persists over time: studies in repeated muscle biopsies. Brain 123: 2030–2039. Arahata K, Engel AG (1984). Monoclonal antibody analysis of mononuclear cells in myopathies. II. Phenotypes of autoinvasive cells in polymyositis and inclusion body myositis. Ann Neurol 16: 209–215. Arahata K, Engel AG (1986). Monoclonal antibody analysis of mononuclear cells in myopathies III. Immunoelectron microscopy aspects of cell-mediated muscle fiber injury. Ann Neurol 19: 112–125. Arahata K, Engel AG (1988). Monoclonal antibody analysis of mononuclear cells in myopathies. V. Identification and quantitation of T8þ cytotoxic and T8 suppressor cells. Ann Neurol 23: 493–499. Arase S, Kato S, Nakanishi H, et al. (1990). Eosinophilic polymyositis induced by tranilast. J Dermatol 17 (3): 182–186. Askanas V, Engel WK (1988). Sporadic inclusion body myositis and hereditary inclusion-body myopathies. Arch Neurol 55: 915–920. Askanas V, Engel WK (1998). Sporadic inclusion-body myositis and hereditary inclusion-body myopathies: current concepts of diagnosis and pathogenesis. Curr Opin Rheumatol 10: 530–542. Badrising UA, Maat-Schieman M, van Duinen SG, et al. (2000). Epidemiology of inclusion body myositis in the Netheralnds: a nationwide study. Neurology 55: 1385–1387. Badrising UA, Maat-Schieman M, Ferrari MD, et al. (2002). Comparison of weakness progression in inclusion body myositis during treatment with methotrexate or placebo. Ann Neurol 51: 369–372. Badrising UA, Schrender GM TH, Giphart MJ, et al. (2004). Associations with autoimmune disorders and HLA class I, and II antigens in inclusion body myositis. Neurology 63: 2396–2398. Banker BQ (1975). Dermatomyositis of childhood. Ultrastructural alterations of muscle and intramuscular blood vessels. J Neuropathol Exp Neurol 35: 46–75. Barry M, Bleackley RC (2002). Cytotoxic T lymphocytes: all roads lead to death. Nat Rev Immunol 2: 401–409.
296
M. C. DALAKAS
Basta M, Dalakas MC (1994). High-dose intravenous immunoglobulin exerts its beneficial effect in patients with dermatomyositis by blocking endomysial deposition of activated complement fragments. J Clin Invest 94: 1729–1735. Behrens L, Bender A, Johnson MA, et al. (1997). Cytotoxic mechanisms in inflammatory myopathies: co-expression of Fas and protective Bcl-2 in muscle fibres and inflammatory cells. Brain 120: 929. Behrens L, Kerschensteiner M, Misgeld T, et al. (1998). Human muscle cells express a functional costimulatory molecule distinct from B7.1 (CD80) and B7.2 (CD86) in vitro and in inflammatory lesions. J Immunol 161: 5943–5951. Bender A, Ernst N, Iglesias A, et al. (1995). T cell receptor repertoire in polymyositis: clonal expansion of autoaggressive CD8 T cells. J Exp Med 181: 1863–1868. Bender A, Behrens L, Engel AG, et al. (1998). T-cell heterogeneity in muscle lesions of inclusion body myositis. J Neuroimmunol 84: 86–91. Benveniste O, Cherin P, Maisonobe T, et al. (2001). Severe perturbations of the blood T cell repertoire in polymyositis, but not dermatomysitis patients. J Immunol 167: 3521–3529. Bohan A, Peter JB (1975). Polymyositis and dermatomyositis. N Engl J Med 292: 344–347, 403–407. Bombardieri S, Hughes GRV, Neri R, et al. (1989). Cyclophosphamide in severe polymyositis. Lancet 1: 1138–1139. Bronner IM, Hoogendijk JE, Wintzen AR, et al. (2003). Necrotising myopathy, an unusual presentation of a steroidresponsive myopathy. J Neurol 250 (4): 480–485. Buchbinder R, Forbes A, Hall S, et al. (2001). Incidence of malignant disease in biopsy-proven inflammatory myopathy. Ann Intern Med 134: 1087–1095. Bunch TW, Worthington JW, Combs JJ, et al. (1980). Azathioprine and prednisone for polymyositis: a controlled clinical trial. Ann Intern Med 92: 365–369. Callen JP (2000). Dermatomyositis. Lancet 355: 53–57. Callen JP (2001). Relation between dermatomyositis and polymyositis and cancer. Lancet 357: 85–86. Callen JP (2002). When and how should the patient with dermatomyositis or amyopathic dermatomyositis be assessed for possible cancer? Arch Dermatol 138: 969–971. Caproni M, Torchia D, Cardinali C (2004). Infiltrating cells, related cytokines and chemokine receptors in lesional skin of patients with dermatomyositis. Br J Dermatol 151: 784–791. Carpenter S, Karpati G, Rothman S, et al. (1976). The childhood type of dermatomyositis. Neurology 26: 952–962. Cervenakova L, Sivakumar K, Nagel J, et al. (1996). Is hereditary inclusion body myopathy a “familial prion disease”? Ann Neurol 40: 128. Chaudhry V, Cornblath DR, Griffin JW, et al. (2001). Mycophenolate mofetil: a safe and promising immunosuppressant in neuromuscular diseases. Neurology 56: 94–96. Cherin P, Herson S, Wechsler B, et al. (1991). Efficacy of intravenous immunoglobulin therapy in chronic refractory polymyositis and dermatomyositis. An open study with 20 adult patients. Am J Med 91: 162–168.
Cherin P, Pelletier S, Teixeira A, et al. (2002). Results and longterm follow-up of intravenous immunoglobulin infusions in chronic, refractory polymyositis: an open study with thirtyfive adult patients. Arthritis Rheum 46: 467–474. Choi YC, Dalakas MC (2000). Expression of matrix metalloproteinases in the muscle of patients with inflammatory myopathies. Neurology 54: 65–71. Choy EHS, Isenberg DA (2002). Treatment of dermatomyositis and polymyositis. Rheumatology (Review) 41: 7–13. Confalomeri P, Bernasconi P, Megna P, et al. (2000). Increased expression of beta-chemokines in muscle of patients with inflammatory myopathies. J Neuropathol Exp Neurol 59: 164–169. Cronin ME, Miller FW, Hicks JE, et al. (1989). The failure of intravenous cyclophosphamide therapy in refractory idiopathic inflammatory myopathy. J Rheumatol 16: 1225–1228. Cupler EJ, Leon-Monzon M, Miller J, et al. (1996). Inclusion body myositis in HIV-I and HTLV-I infected patients. Brain 119: 1887–1893. Dalakas MC (1991). Polymyositis, dermatomyositis and inclusion-body myositis. N Engl J Med 325: 1487–1498. Dalakas MC (1994). How to diagnose and treat the inflammatory myopathies. Semin Neurol 92: 365–369. Dalakas MC (1995a). Calcifications in dermatomyositis. N Engl J Med 333: 978. Dalakas MC (1995b). Immunopathogenesis of inflammatory myopathies. Ann Neurol 37 (Suppl. 1): S74–S86. Dalakas MC (1997). Intravenous immunoglobulin therapy for neurological diseases. Ann Intern Med 126: 721–730. Dalakas MC (1998a). Molecular immunology and genetics of inflammatory muscle diseases. Arch Neurol 55: 1509–1512. Dalakas MC (1998b). Controlled studies with high-dose intravenous immunoglobulin in the treatment of dermatomyositis, inclusion body myositis and polymyositis. Neurology 51: 537–545. Dalakas MC (2001a). Progress in inflammatory myopathies: good but not good enough. Editorial. J Neurol Neurosurg Psychiatry 70: 569–573. Dalakas MC (2001b). The molecular and cellular pathology of inflammatory muscle diseases. Curr Opin Pharmacol 1: 300–306. Dalakas MC (2002a). Understanding the immunopathogenesis of inclusion body myositis: present and future prospects. Rev Neurol 158: 948–958. Dalakas MC (2002b). Muscle biopsy findings in inflammatory myopathies. Rheum Dis Clin North Am 28: 779–798. Dalakas MC (2003). Therapeutic approaches in inflammatory myopathies. Semin Neurol 23: 199–206. Dalakas MC (2004a). Polymyositis, dermatomyositis and inclusion body myositis. In: AS Fauci, DL Kasper, E Braunwald, et al. (Eds.), Harrison’s Principles of Internal Medicine. 16th edn., McGraw-Hill, New York, pp. 2540–2545. Dalakas MC (2004b). Viral related muscle disease. In: AG Engel, (Ed.), Myology.3rd edn.,McGraw Hill, New York, pp. 1389–1417.
AUTOIMMUNE INFLAMMATORY MYOPATHIES Dalakas MC (2004c). Inflammatory disorders of muscle: progress in polymyositis, dermatomyositis and inclusion body myositis. Curr Opin Neurol 17: 561–567. Dalakas MC (2006). Inflammatory, immune, and viral aspects of inclusion-body myositis. Neurology 66: S33–S38. Dalakas MC, Hohlfeld R (2003a). Polymyositis and dermatomyositis. Lancet 362: 971–982. Dalakas MC, Hohlfeld R (2003b). Diagnostic criteria for polymyositis and dermatomyositis. Lancet 362: 1762–1763. Dalakas MC, Illa I (1995). Common variable immunodeficiency and inclusion body myositis: a distinct myopathy mediated by natural killer cells. Ann Neurol 37: 806–810. Dalakas MC, Karpati G (2001). The inflammatory myopathies. In: G Karpati, D Hilton-Jones, RC Griggs (Eds.), Disorders of Voluntary Muscle. 7th edn., Cambridge University Press, Cambridge, pp. 636–659. Dalakas MC, Pezeshkpour GH (1988). Neuromuscular diseases associated with human immunodeficiency virus infection. Ann Neurol 23 (S): 38–48. Dalakas MC, London WT, Gravell M, et al. (1986a). Polymyositis in an immunodeficiency disease in monkeys induced by a type D retrovirus. Neurology 36: 569–572. Dalakas MC, Pezeshkpour GH, Gravell M, et al. (1986b). Polymyositis in patients with AIDS. JAMA 256: 2381–2383. Dalakas MC, Illa I, Pezeshkpour GH, et al. (1990). Mitochondrial myopathy caused by long–term zidovudine therapy. N Engl J Med 332: 1098–1105. Dalakas MC, Illa I, Dambrosia JM, et al. (1993). A controlled trial of high-dose intravenous immunoglobulin infusions as treatment for dermatomyositis. N Engl J Med 329: 1993–2000. Dalakas MC, Illa I, Gallardo E, et al. (1997a). Inclusion body myositis and paraproteinemia: incidence and immunopathologic correlations. Ann Neurol 41: 100–104. Dalakas MC, Sekul EA, Cupler EJ, et al. (1997b). The efficacy of high dose intravenous immunoglobulin (IVIg) in patients with inclusion-body myositis (IBM). Neurology 48: 712–716. Dalakas MC, Koffman BM, Fujii M, et al. (2001). A controlled study of intravenous immunoglobulin combined with prednisone in the treatment of IBM. Neurology 56: 323–327. De Bleecker J, Engel AG (1995). Immunocytochemical study of CD45 T cell isoforms in inflammatory myopathies. Am J Pathol 146: 1178. De Bleecker JL, Meire VI, Declercq W, et al. (1999). Immunolocalization of tumor necrosis factor-alpha and its receptors in inflammatory myopathies. Neuromuscul Disord 9: 239. De Bleecker JL, De Paepe B, Vanwalleghem IE, et al. (2002). Differential expression of chemokines in inflammatory myopathies. Neurology 58: 1779–1785. De Rossi M, Bernasconi P, Baggi F, et al. (2000). Cytokines and chemokines are both expressed by human myoblasts: possible relevance for the immune pathogenesis of muscle inflammation. Int Immunol 12: 1329–1335. Douglas WW, Tazelaar HD, Hartman TE, et al. (2001). Polymyositis-dermatomyositis associated interstitial lung disease. Am J Respir Crit Care Med 164: 1182–1185.
297
Eisenberg I, Avidan N, Potikha T, et al. (2001). The UDPN-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene is mutated in recessive hereditary inclusion body myopathy. Nat Genet 29: 83–87. Emslie-Smith AM, Engel AG (1990). Microvascular changes in early and advanced dermatomyositis: a quantitative study. Ann Neurol 27: 343–356. Emslie-Smith AM, Engel AG (1991). Necrotizing myopathy with pipestem capillaries, microvascular deposition of the complement membrane attack complex (MAC), and minimal cellular infiltration. Neurology 41 (6): 936–939. Emslie-Smith AM, Arahata K, Engel AG (1989). Major histocompatibility complex class I antigen expression, immunolocalization of interferon subtypes and T-cell- mediated cytotoxicity in myopathies. Hum Pathol 20: 224–231. Engel AG, Hohlfeld R, Banker BQ (1994). The polymyositis and dermatomyositis syndromes. In: AG Engel, C Franzini-Armstrong (Eds.), Myology.2nd edn. McGrawHill Book Co, New York, pp. 1335–1383. Fang MA, Verity MA, Paulus HE (1988). Subacute perimyositis. J Rheumatol 15 (8): 1291–1293. Ferrer I, Martin B, Castano JG, et al. (2004). Proteasomal expression, induction of immunoproteasome subunits, and local MHC class I presentation in myofibrillar myopathy and inclusion body myositis. J Neuropathol Exp Neurol 63: 484–498. Ferrer I, Carmona M, Blanco R, et al. (2005). Involvement of clusterin and the aggresome in abnormal protein deposits in myofibrillar myopathies and inclusion body myositis. Brain Pathol 15: 101–108. Fidzianska A, Rowinska-Marcinska K, HausmanowaPetrusewicz I (2004). Coexistence of X-linked recessive Emery–Dreifuss muscular dystrophy with inclusion body myositis-like morphology. Acta Neuropathol 104: 197–203. Figarella-Branger D, Civate M, Bartoli C, et al. (2003). Cytokines, chemokines, and cell adhesion molecules in inflammatory myopathies. Muscle Nerve 28 (6): 659–682. Friedman AW, Targoff IN, Arnett FC (1996). Interstitial lung disease with autoantibodies against aminoacyl-tRNA synthetases in the absence of clinically apparent myositis. Semin Arthritis Rheum 26: 459–467. Fyhr IM, Moslemi AR, Mosavi AA, et al. (1997). Oligoclonal expansion of muscle infiltrating T cells in inclusion body myositis. J Neuroimmunol 79: 185–189. Gallardo E, Rojas-Garcia R, de Luna N, et al. (2001). Inflammation in dysferlin myopathy: immunohistochemical characterization of 13 patients. Neurology 57 (11): 2136–2138. Garlepp MJ, Mastaglia FL (2000). Autoantibodies in inflammatory myopathies. Am J Med Sci 319: 227–233. Garlepp MJ, Laing B, Zilko PJ, et al. (1994). HLA associations with inclusion body myositis. Clin Exp Immunol 98: 40–45. Garlepp MJ, Tabarias H, van Bockxmeer FM, et al. (1995). Apolipoprotein Ee4 in inclusion body myositis. Ann Neurol 38: 957–959. Garlepp MJ, Blechynden L, Tabarias H, et al. (1998). Genetic factors in sporadic inclusion body myositis. In: V Askanas, G Serratice, WK Engel (Eds.), Inclusion Body Myositis
298
M. C. DALAKAS
and Myopathies.Cambridge University Press, Cambridge, pp. 177–185. Genge A, Karpati G (1997). Intermittent, high-dose intravenous glucocorticoid (GC) treatment (Rx) is preferred to high dose oral GC administration in adult dermatomyositis (DM). Neurology 48: A321. Gherardi RK, Coquet M, Cherin P, et al. (1998). Macrophagic myofasciitis: an emerging entity. Lancet 352: 347–352. Goebels N, Michaelis D, Engelhardt M, et al. (1996). Differential expression of perforin in muscle-infiltrating T cell in polymyositis and dermatomyositis. J Clin Invest 97: 2905. Grau JM, Herrero C, Casademont J, et al. (1994). Cyclosporine A as first choice for dermatomyositis. J Rheumatol 21: 381–382. Greenberg SA, Pinkus JL, Pinkus GS, et al. (2005). Interferonalpha/beta-mediated innate immune mechanisms in dermatomyositis. Ann Neurol 57 (5): 664–678. Griggs RC, Askanas V, Di Mauro S, et al. (1995). Inclusion body myositis and myopathies. Ann Neurol 38: 705–713. Haupt HM, Hutchins GM (1982). The heart and cardiac conduction system in polymyositis-dermatomyositis: a clinicopathologic study of 16 autopsied patients. Am J Cardiol 50: 998–1006. Hausmann G, Herrero C, Cid MC, et al. (1991). Immunopathologic study of skin lesions in dermatomyositis. J Am Acad Dermatol 25: 225–230. Hengstmann GJD, van Engelen BGM, Egberts WT MV, et al. (2001). Myositis-specific autoantibodies: overview and recent developments. Curr Opin Rheumatol 13: 476–482. Hengstman GJD, Brouwer R, Vree Egberts WTM, et al. (2002). Clinical and serological characteristics of 125 Dutch myositis patients. J Neurol 249: 69–75. Hertzman PA, Blevins WL, Mayer J, et al. (1990). Association of the eosinophilia-myalgia syndrome with the ingestion of tryptophan. N Engl J Med 322: 869–873. Hill CL, Zhang Y, Sigurgeirsson B, et al. (2001). Frequency of specific cancer types in dermatomyositis and polymyositis: a population-based study. Lancet 357: 96–100. Hilton-Jones D (2001). Inflammatory myopathies. Curr Opin Neurol 14: 591–596. Hirakata M, Nagai S (2000). Interstitial lung disease in polymyositis and dermatomyositis. Curr Opin Rheumatol 12: 501–508. Hofbauer M, Wiesener S, Babbe H, et al. (2003). Clonal tracking of autoaggressive T cells in polymyositis by combining laser microdissection, single-cell PCR and CDR3 spectratype analysis. Proc Natl Acad Sci U S A 100: 4090–4095. Hohlfeld R, Engel AG (1990). Induction of HLA-DR expression on human myoblasts with interferon-gamma. Am J Pathol 136: 503–508. Hohlfeld R, Engel AG (1991). Coculture with autologous myotubes of cytotoxic T cells isolated from muscle in inflammatory myopathies. Ann Neurol 29: 498–507. Hohlfeld R, Engel AG (1994). The immunobiology of muscle. Immunol Today 15: 269–274.
Hohlfeld R, Engel AG, Ii K, et al. (1991). Polymyositis mediated by T lymphocytes that express the g/d receptor. N Engl J Med 324: 877–881. Hollingsworth PN, Garlepp MJ, Dawkins RL (1998). Autoimmune diseases of muscle. In: NR Rose, I MacKay (Eds.), The Autoimmune Diseases.3rd edn. Academic Press, San Diego, pp. 663–686. Huang KW, Chen XH (1987). Pathology of eosinophilic fasciitis and its relation to polymyositis. Can J Neurol Sci 14 (4): 632–637. Illa I, Nath A, Dalakas MC (1991). Immunocytochemical and virological characteristics of HIV-associated inflammatory myopathies: similarities with seronegative polymyositis. Ann Neurol 29: 474–481. Illa I, Dinsmore S, Dalakas MC (1993). Immune-mediated mechanisms and immune activation of fibroblasts in the pathogenesis of eosinophilia-myalgia syndrome induced by L-tryptophan. Hum Pathol 24 (7): 702–709. Illa I, Gallardo E, Gimeno R, et al. (1997). Signal transducer and activator of transcription 1 in human muscle: implications in inflammatory myopathies. Am J Pathol 151: 81–88. Kamm MA, Dennett X, Byrne E (1987). Relapsing eosinophilic myositis — a cause of pseudothrombophlebitis in an alcoholic. J Rheumatol 14 (4): 831–834. Karpati G, Pouliot Y, Carpenter S (1988). Expression of immunoreactive major histocapability complex products in human skeletal muscles. Ann Neurol 23: 64–72. Kaufman LD, Kephart GM, Seidman RJ, et al. (1988). The spectrum of eosinophilic myositis. Clinical and immunopathogenic studies of three patients, and review of the literature. Arthritis Rheum 36 (7): 1014–1024. Kieseier BC, Schneider C, Clements JM, et al. (2001). Expression of specific matrix metalloproteinases in inflammatory myopathies. Brain 124: 341–351. Kissel JT, Mendell JR, Rammohan KW (1986). Microvascular deposition of complement membrane attack complex in dermatomyositis. N Engl J Med 314: 329–334. Kissel JT, Halterman RK, Rammohan KW, et al. (1991). The relationship of complement-mediated microvasculopathy to the histologic features and clinical duration of disease in dermatomyositis. Arch Neurol 48: 26–30. Knutsen AP, Shah M, Schwarz KB, et al. (1986). Graft versus host-like illness in a child with phenobarbital hypersensitivity. Pediatrics 78: 581–584. Koffman BM, Sivakumar K, Simonis T, et al. (1998). HLA allele distribution distinguishes sporadic inclusion body myositis from hereditary inclusion body myopathies. J Neuroimmunol 84: 139–142. Kok CC, Croager EJ, Witt CS, et al. (1999). Mapping of a candidate region for susceptibility to inclusion body myositis in the human major histocompatibility complex. Immunogenetics 49: 508–516. Kok CC, Boyt A, Gaudieri S, et al. (2000). Mitochondrial DNA variants in inclusion body myositis and Alzheimer’s disease. Neuromuscul Disord 10: 604–611. Krummel MF, Davis MM (2002). Dynamics of the immunological synapse: finding, establishing and solidifying a connection. Curr Opin Immunol 14: 66–74.
AUTOIMMUNE INFLAMMATORY MYOPATHIES Lakhanpal S, Lie JT, Conn DL, et al. (1987). Pulmonary disease in polymyositis/dermatomyositis: a clinicopathological analysis of 65 autopsy cases. Ann Rheum Dis 46: 23–29. Layzer RB, Shearn MA, Satya-Murti S (1977). Eosinophilic polymyositis. Ann Neurol 1 (1): 65–71. Leff RL, Love LA, Miller FW, et al. (1992). Viruses in the idiopathic inflammatory myopathies: absence of candidate viral genomes in muscle. Lancet 339: 1192–1195. Leon-Monzon M, Dalakas MC (1992). Absence of persistent infection with enteroviruses in muscles of patients with inflammatory myopathies. Ann Neurol 32: 219–222. Leon-Monzon M, Lamperth L, Dalakas MC (1993). Search for HIV proviral DNA and amplified sequences in the muscle biopsies of patients with HIV-polymyositis. Muscle Nerve 16: 408–413. Leon-Monzon M, Illa I, Dalakas MC (1994). Polymyositis in patients infected with HTLV-I: the role of the virus in the cause of the disease. Ann Neurol 36: 643–649. Lewis W, Dalakas MC (1995). Mitochondrial toxicity of antiviral drugs. Nat Med 1: 417–422. Li M, Dalakas MC (2000). Expression of human IAP-like protein in skeletal muscle: an explanation for the rare incidence of muscle fiber apoptosis in T-cell mediated inflammatory myopathies. J Neuroimmunol 106: 1–5. Liang L, Sha WC (2002). The right place at the right time: novel B7 family members regulate effcetor T cell function. Curr Opin Immunol 14: 384–390. Lindberg C, Trysberg E, Tarkowski A, et al. (2003). Anti-Tlymphocyte globulin treatment in inclusion body myositis: a randomized pilot study. Neurology 61: 260–262. Love LA, Leff RL, Frazer DD, et al. (1991). A new approach to the classification of idiopathic inflammatory myopathy: myositis-specific autoantibodies define useful homogeneous patient groups. Medicine 70: 360–374. Luciano CA, Dalakas MC (1997). Inclusion body myositis: no evidence for a neurogenic component. Neurology 48: 29–33. Lundberg I, Brengman JM, Engel AG (1995). Analysis of cytokine expression in muscle in inflammatory myopathies, Duchenne’s dystrophy and non-weak controls. J Neuroimmunol 63: 9–16. Magro CM, Crowson AN (1997). The immunofluorescent profile of dermatomyositis: a comparative study with lupus erythematosus. J Cutan Pathol 24: 543–552. Mantegazza R, Hughes SM, Mitchell D, et al. (1991). Modulation of MHC class II antigen expression in human myoblasts after treatment with IFN-gamma. Neurology 41: 1128–1132. Mantegazza R, Andreetta F, Bernasconi P, et al. (1993). Analysis of T cell receptor repertoire of muscle infiltrating T lymphocytes in polymyositis: restricted V a/b rearrangements may indicated antigen-driven selection. J Clin Invest 91: 2880–2886. Marie I, Hachulla E, Hatron PY, et al. (2001). Polymyositis and dermatomyositis: short term and longterm outcome, and predictive factors of prognosis. J Rheumatol 28: 2230–2237.
299
Mastaglia FL (2000). Treatment of autoimmune inflammatory myopathies. Curr Opin Neurol 13: 507–509. Mastaglia FL, Phillips BA (2002). Idiopathic inflammatory myopathies: epidemiology, classification and diagnostic criteria. Rheum Dis Clin North Am 28: 723–741. Mastaglia FL, Phillips BA, Zilko PJ (1997). Treatment of inflammatory myopathies. Muscle Nerve 20: 651–664. Mastaglia FL, Phillips BA, Zilko PJ (1998). Immunoglobulin therapy in inflammatory myopathies. J Neurol Neurosurg Psychiatry 65: 107–110. Mastaglia FL, Phillips BA, Zilko PJ, et al. (1999). Relapses in idiopathic inflammatory myopathies. Muscle Nerve 22: 1160–1161. Mastalgia FL, Garlepp MJ, Phillips BA, et al. (2003). Inflammatory myopathies: clinical, diagnostic and therapeutic aspects. Muscle Nerve 27: 407–425. Matsubara S, Sawa Y, Takamori M, et al. (1994). Pulsed intravenous methylprednisolone combined with oral steroids as the initial treatment of inflammatory myopathies. J Neurol Neurosurg Psychiatry 57: 1008. Maugars YM, Berthelot JM, Abbas AA, et al. (1996). Longterm prognosis of 69 patients with dermatomyositis or polymyositis. Clin Exp Rheumatol 14: 263–274. Michaelis D, Goebels N, Hohlfeld R (1993). Constitutive and cytokine-induced expression of human leukocyte antigens and cell adhesion molecules by human myotubes. Am J Pathol 143: 1142–1149. Miller FW, Leitman SF, Cronin ME, et al. (1992). A randomized double-blind controlled trial of plasma exchange and leukapheresis in patients with polymyositis and dermatomyositis. N Engl J Med 326: 1380–1384. Mimori T (1987). Scleroderma-polymyositis overlap syndrome: clinical and serologic aspects. Int J Dermatol 26: 419–425. Monsonego A, Zota V, Karni A, et al. (2003). Increased T cell reactivity to amyloid b protein in older humans and patients with Alzheimer disease. J Clin Invest 114: 415–422. Morgan OSC, Rodgers-Johnson P, Mora C, et al. (1989). HTLV-1 and polymyositis in Jamaica. Lancet ii: 1184–1187. Mowzoon N, Sussman A, Bradley WG (2001). Mycophenolate (CellCept) treatment of myasthenia gravis, chronic inflammatory polyneuropathy and inclusion body myositis. J Neurol Sci 185: 119–122. Mukamel M, Horey G, Mimori M (2001). New insight into calcinosis of juvenile dermatomyositis: a study of composition and treatment. J Pediatr 138: 763–766. Muntzing K, Lindberg C, Moslemi AR, et al. (2003). Inclusion body myositis: clonal expansions of muscle-infiltrating T cells persist over time. Scand J Immunol 58: 195–200. Murata K, Dalakas MC (1999). Expression of the costimulatory molecule BB-1, the ligands CTLA-4 and CD28 and their mRNA in inflammatory myopathies. Am J Pathol 155: 453–460. Nagaraju K, Casciola-Rosen L, Rosen A, et al. (2000a). The inhibition of apoptosis in myositis and in normal muscle cells. J Immunol 164: 5459–5465. Nagaraju K, Raben N, Loeffler L, et al. (2000b). Conditional up-regulation of MHC class I in skeletal muscle
300
M. C. DALAKAS
leads to self-sustaining autoimmune myositis and myositis-specific autoantibodies. Proc Natl Acad Sci U S A 97: 9209–9214. Nishio J, Suzuki M, Miyasaka N, et al. (2001). Clonal biases of peripheral CD8 T cell repertoire directly reflect local inflammation in polymyositis. J Immunol 167: 4051–4058. Nyberg P, Wikman AL, Nennesmo I, et al. (2000). Increased expression of interleukin 1a and MHC class I in muscle tissue of patients with chronic, inactive polymyositis and dermatomyositis. J Rheumatol 27: 940–948. Oddis CV (2002). Idiopathic inflammatory myopathy: management and prognosis. Rheum Dis Clin North Am 28: 979–1001. O’Hanlon TP, Dalakas MC, Plotz PH, et al. (1994). Predominant T cell receptor variable and joining gene expression by muscle-infiltrating lymphocytes in the idiopathic inflammatory myopathies. J Immunol 152: 2569–2576. Orth M, Tabrizi SJ, Schapira AH (2000). Sporadic inclusion body myositis not linked to prion protein codon 129 methionine homozygosity. Neurology 55 (8): 1235. Otero C, Illa I, Dalakas MC (1992). Is there dermatomyositis (DM) without myositis? Neurology 42: 388. Ozden S, Gessain A, Gout O, et al. (2001). Sporadic inclusion body myositis in a patient with human T cell leukemia virus type 1-associated myelopathy. Clin Infect Dis 32: 510–514. Ozden S, Cochet M, Mikol J, et al. (2004). Direct evidence for a chronic CD8þ-T-cell-mediated immune reaction to tax within the muscle of a human T-cell leukemia/lymphoma virus type 1-infected patient with sporadic inclusion body myositis. J Virol 78: 10320–10327. Page G, Miossex P (2004). Paired synovium and lymph nodes from rheumatoid arthritis patients differ in dendritic cell and chemokine expression. J Pathol 204: 28–38. Peng A, Koffman BM, Malley JD, et al. (2000). Disease progression in sporadic inclusion body myositis: observations in 78 patients. Neurology 55: 296–298. Phillips BA, Mastaglia FL (2000). Exercise therapy in patients with myopathy. Curr Opin Neurol 13: 547–552. Phillips BA, Zilko PJ, Mastaglia FL (2000). Prevalence of sporadic inclusion body myositis in Western Australia. Muscle Nerve 23: 970–972. Phillips BA, Zilko PJ, Garlepp MJ, et al. (2002). Seasonal occurrences of relapses in inflammatory myopathies: a preliminary study. J Neurol 249: 441–444. Plotz PH, Dalakas M, Leff RL, et al. (1989). Current concepts in the idiopathic inflammatory myopathies: polymyositis, dermatomyositis and related disorders. Ann Intern Med 111: 143–157. Pluschke G, Ruegg D, Hohlfeld R, et al. (1992). Autoaggressive myocytotoxic T lymphocytes expressing an unusual gd T cell receptor. J Exp Med 176: 1785–1789. Raju R, Dalakas MC (2005). Gene expression profile in the muscles of patients with inflammatory myopathies: effect of therapy with IVIg and biological validation of clinically relevant genes. Brain 128: 1887–1896. Raju R, Vasconcelos OM, Semino-Mora C, et al. (2003). Expression of interferon-gamma inducible chemokines
in the muscles of patients with inclusion body myositis. J Neuroimmunol 141: 125–131. Ramanan AV, Feldman BM (2002). Clinical features and outcomes of juvenile dermatomyositis and other childhood onset myositis syndromes. Rheum Dis Clin North Am 28: 833–857. Reed AM, Ytterberg SR (2002). Genetic and environmental risk factors for idiopathic inflammatory myopathies. Rheum Dis Clin North Am 28: 891–916. Reed AM, Picornell YJ, Harwood A, et al. (2000). Chimerism in children with juvenile dermatomyositis. Lancet 356: 2156–2157. Rosenberg NL, Carry MR, Ringel SP (1988). Association of inflammatory myopathies with other connective tissue disorder and malignancies. In: MC Dalakas, (Ed.), Polymyositis and Dermatomyositis. Butterworths, Boston, pp. 37–69. Saito M, Higuchi I, Saito A, et al. (2002). Molecular analysis of T cell clonotypes in muscle-infiltrating lymphocytes from patients with human T lymphotropic virus type 1 polymyositis. J Infect Dis 186: 1231–1241. Schmidt J, Rakocevic G, Raju R, et al. (2004). Upregulated inducible costimulator and ICOS-ligand in inclusion body myositis muscle: significance for CD8þ T cell cytotoxicity. Brain 127: 1182–1190. Schmidt J, Raju R, Salajegheh M, et al. (2005). Distinct interplay between inflammatory and degeneration-associated molecules in sporadic IBM. Neurology 64 (Suppl. 1): A331–A338. Schneider C, Gold R, Dalakas MC, et al. (1996). MHC class I mediated cytotoxicity does not induce apoptosis in muscle fibers nor in inflammatory T cells: studies in patients with polymyositis, dermatomyositis, and inclusion body myositis. J Neuropathol Exp Neurol 55: 1205–1209. Schneider C, Dalakas MC, Toyka KV, et al. (1999). T cell apoptosis in inflammatory neuromuscular disorders associated with human immunodeficiency virus infection. Arch Neurol 56: 79–83. Seidman RJ, Kaufman LD, Sokoloff L, et al. (1991). The neuromuscular pathology of the eosinophilia–myalgia syndrome. J Neuropathol Exp Neurol 50 (1): 49–62. Sekul EA, Dalakas MC (1993). Inclusion body myositis: new concepts. Semin Neurol 13: 256–263. Sekul EA, Chow C, Dalakas MC (1997). Magnetic resonance imaging of the forearm as a diagnostic aid in patients with sporadic inclusion body myositis. Neurology 48: 863–866. Selcen D, Ohno K, Engel AG (2004). Myofibrillar myopathy: clinical, morphological and genetic studies in 63 patients. Brain 127: 439–451. Semino-Mora C, Dalakas MC (1988). Rimmed vacuoles with B-amyloid and ubiquitinated filamentous deposits in the muscles of patients with long-standing denervation (post-poliomyelitis muscular atrophy): similarities with inclusion body myositis. Human Pathol 29: 1128–1133. Serratrice G, Pellissier JF, Roux H, et al. (1990). Fasciitis, perimyositis, myositis, polymyositis, and eosinophilia. Muscle Nerve 13 (5): 385–395.
AUTOIMMUNE INFLAMMATORY MYOPATHIES Shamin EA, Rider LG, Miller FW (2000). Update on the genetics of the idiopathic inflammatory myopathies. Curr Opin Rheumatol 12: 482–491. Shamin EA, Rider LG, Pandey JP, et al. (2002). Differences in idiopathic inflammatory myopathy phenotypes and genotypes between Mesoamerican Mestizos and North American Caucasians. Arthritis Rheum 46: 1885–1893. Shulman LE (1984). Diffuse fasciitis with hypergammaglobulinemia and eosinophilia: a new syndrome? J Rheumatol 11 (5): 569–570. Sigurgeirsson B, Lindelo¨f B, Edhag O, et al. (1992). Risk of cancer in patients with dermatomyositis or polymyositis: a population-based study. N Engl J Med 326: 363–367. Sivakumar K, Dalakas MC (1996). The spectrum of familial inclusion body myopathies in 13 families and a description of a quadriceps-sparing phenotype in non-Iranian Jews. Neurology 47: 977–984. Sivakumar K, Cervenkova L, Dalakas MC, et al. (1995). Exons 16 and 17 of the amyloid precursor protein gene in familial inclusion body myopathy. Ann Neurol 38: 267–269. Sivakumar K, Semino-Mora C, Dalakas MC (1997). An inflammatory, familial, inclusion body myositis with autoimmune features and a phenotype identical to sporadic inclusion body myositis. Studies in three families. Brain 120: 653–661. Sontheimer RD (2002). Dermatomyositis: an overview of recent progress with emphasis on dermatologic aspects. Dermatol Clin 20: 387–408. Soueidan SA, Dalakas MC (1993). Treatment of inclusionbody myositis with high-dose intravenous immunoglobulin. Neurology 43: 876–879. Sparsa A, Liozon E, Herrmann F, et al. (2002). Routine vs extensive malignancy search for adult dermatomyositis and polymyositis. Arch Dermatol 138: 885–890. Spector SA, Lemmer MS, Koffman BM, et al. (1997). Safety and efficacy of strength training in patients with sporadic inclusion body myositis. Muscle Nerve 20: 1242–1248. Stein DP, Dalakas MC (1993). Intercellular adhesion molecule-I expression is upregulated in patients with dermatomyositis (DM). Ann Neurol 34: 268. Sugiura T, Kawaguchi Y, Harigai M, et al. (2000). Increased CD40 expression on muscle cells of polymyositis and dermatomyositis: role of CD40–CD40 ligand interaction in IL-6, IL-8, IL-15 and monocyte chemoattractant protein1 production. J Immunol 164: 6593–6600. Sultan SM, Ioannou Y, Moss K, et al. (2002). Outcome in patients with idiopathic inflammatory myositis: morbidity and mortality. Rheumatology 41: 22–26.
301
Tai PC, Hayes DJ, Clark JB, et al. (1982). Toxic effects of human eosimophil products on isolated rat heart muscles in vitro. Biochem J 204: 75–80. Targoff IN (2002). Laboratory testing in the diagnosis and management of idiopathic inflammatory myopathies. Rheum Dis Clin Norht Am 28: 859–890. Tews DS, Goebel HH (1996). Cytokine expression profiles in idiopathic inflammatory myopathies. J Neuropathol Exp Neurol 55: 342–347. Tezak Z, Hoffman EP, Lutz JL, et al. (2002). Gene expression profiling in DQA1*0501þ children with untreated dermatomyositis: a novel model of pathogenesis. J Immunol 168: 4154–4163. Trueb RM, Becker-Wegerich P, Hafner J, et al. (1995). Relapsing eosinophilic perimyositis. Br J Dermatol 133 (1): 109–114. Turi GK, Solitare GB, James N, et al. (1990). Eosinophilia– myalgia syndrome (L-tryptophan-associated neuromyopathy). Neurology 40 (11): 1793–1796. Uncini A, Lange DJ, Hayes AP, et al. (1990). Long-duration polyphasic motor unit potentials in myopathies: a quantitative study with pathological correlation. Muscle Nerve 13: 263–267. Walter MC, Lochmuller H, Toepfer M, et al. (2000). Highdose immunoglobulin therapy in sporadic inclusion body myositis: a double-blind, placebo-controlled study. J Neurol 247: 22–28. Weller PF (1991). The immunobiology of eosinophils. N Engl J Med 324 (16): 1110–1118. Werth VP, Callen JP, Ang G, et al. (2002). Associations of tumor necrosis factor a and HLA polymorphisms with adult dermatomyositis: implications for a unique pathogenesis. J Invest Dermatol 119: 617–620. Wiendl H, Behrens L, Maier S, et al. (2000). Muscle fibers in inflammatory myopathies and cultured myoblasts express the nonclassical major histocompatibility antigen HLA-G. Ann Neurol 48: 679–684. Wiendl H, Malotka J, Holzwarth B, et al. (2002). An autoreactive gd TCR derived from a polymyositis lesion. J Immunol 169: 515–521. Wiendl H, Mitsdoerffer M, Hofmeister V, et al. (2003a). The nonclassical MHC molecule HLA-G protects human muscle cells from immune-mediated lysis: implications for myoblast transplantation and gene therapy. Brain 126: 176–185. Wiendel H, Mitsdoerffer M, Schneider D, et al. (2003). Muscle fibers and cultured muscle or cells express the B7.1/2 related costimulatory molecule ICOSL: implications for the pathogenesis of inflammatory myopathies. Brain 126: 1026–1035.
Handbook of Clinical Neurology, Vol. 86 (3rd series) Myopathies F. L. Mastaglia, D. Hilton-Jones, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 15
Infective myopathies LEILA CHIMELLI* Department of Pathology, School of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
15.1. Introduction Infective myopathies include a group of inflammatory myopathies due to an identified infective agent — viral, bacterial, fungal or parasitic (Table 15.1), which have, generally, a good prognosis (Attarian and Azulay, 2001). Most are closely related to economic and sanitary conditions, poverty, cultural and dietary habits. In the past, except for those related to immunodeficiency, most infective myopathies were confined to particular geographic regions. Nowadays, because all countries are within easy reach of travelers, some of these diseases are becoming more common in areas where they had not been seen before. Many types of viral infections can cause transient inflammatory myopathies. Acute myositis occurs in patients with serologic or virologic evidence of recent viral infection. The clinical syndrome, although usually mild, may be severe, with rhabdomyolysis. Several different viruses cause myositis, the best known being the influenza and Coxsackie viruses which are myotropic, but immunological mechanism also play a role in viral myositis (Chimelli and Silva, 2002). Myopathies relating to retroviruses, such as human immunodeficiency virus (HIV) and human T lymphotropic virus type 1 (HTLV-1), are well documented (Dalakas, 2004). It is expected that prevention, widespread control of blood donors, massive use of antiretroviral agents and eventually vaccination may reduce the number of infected patients. Other acute viral infections may occur in either sporadic or epidemic form; the latter, particularly arboviruses, may be prevented controlling the proliferation of the transmitter insect. Skeletal muscles appear to be relatively resistant to bacterial and fungal invasion. Even in cases of severe
bacteremia, abscess formation in muscles is uncommon. However, an increase in frequency of bacterial and fungal myositis in the last few decades is due to the growing number of immunocompromised patients. Pyomyositis and clostridial myositis are the commonest examples, although others may occasionally be seen. In some cases, muscle biopsy is recommended in order to achieve an early diagnosis and treatment with appropriate drugs. The alterations induced by parasites in skeletal muscle are either focal, resulting in well-localized inflammation, or diffuse, resulting in polymyositis. Within muscle tissue each parasite displays distinctive features that permit its recognition. Protozoa are usually located within the fibers, while cestodes and nematodes may be found within or between the fibers, either situation leading to a local mass and calcification. The muscle involvement reflects either a systemic parasitic infection or a specific predilection of the organism for muscle, as in trichinosis. Muscle biopsy is highly recommended in order to achieve an early diagnosis. In this chapter, a brief account of the main infective myopathies is given; a few less frequent conditions in which the muscle may be involved are also mentioned.
15.2. Viral myositis 15.2.1. Influenza virus myositis This is characterized by a distinctive clinical syndrome occurring within the first week after an attack of influenza, presenting as severe pain, tenderness, and sometimes swelling, usually of the calf, but sometimes also of the thigh muscles, that usually resolves spontaneously in about one week. Rhabdomyolysis and myoglobinuria may occur. It is caused by two immunologic types of influenza viruses (A, B), genera of the family
*Correspondence to: Leila Chimelli, Servic¸o de Anatomia Patolo´gica, Hospital Universita´rio, Universidade Federal do Rio de Janeiro, Ilha do Funda˜o, 21941–590, Rio de Janeiro, Brazil. E-mail:
[email protected]
304
L. CHIMELLI
Table 15.1 Classification of infective myopathies Viral myositis Acute myositis Influenza A and B Coxsackie Subacute/chronic myositis Retroviral-related myopathies HIV-related myopathy HTLV-1 polymyositis Hepatitis C virus Others Epstein–Barr, parainfluenza, cytomegalovirus, respiratory, syncytial virus, herpes simplex, herpes zoster, echovirus, adenovirus, arbovirus (dengue), West Nile virus, hepatitis B virus Bacterial myositis Pyomyositis (Staphylococcus aureus, Streptococcus pyogenes and others) Clostridial myositis Malignant necrotizing streptococcal myositis Others (tuberculosis, actinomycosis, Lyme disease, leptospirosis, leprosy) Fungal myositis Candidiasis, Cryptococcosis, Mucormycosis, Sporotricosis, Histoplasmosis. Parasitic myositis Protozoan Toxoplasmosis Trypanosomiasis Sarcosporidiosis Microsporidiosis Malaria Cestodes Cysticercosis Hidatidosis or echinococcosis Nematodes Trichinosis Other parasitic diseases Coenurosis, Sparganosis, visceral larva migrans, (toxocara canis), cutaneous larva migrans (Ancylostoma canis), dracunculosis, etc.
Orthomixoviridae, known to cause infection of the upper and middle respiratory tract (Dalakas, 2004). Influenza A, the most studied member of the family, contains eight segments of minus-sense single-strand RNA molecules in the form of ribonucleoprotein (Weis et al., 1988). In most studies, the incidence of myositis has not been determined. According to Hu et al. (2004) acute childhood myositis associated with influenza occurs mostly in influenza B infection. In a retrospective study they analyzed 197 children with influenza virus; 73 had
influenza A and 124 had influenza B infection. The rates of benign acute childhood myositis in influenza A and influenza B were 5.5% and 33.9% respectively. In the elderly, a high incidence of acute myositis with type A influenza virus infection has been reported (Yoshino et al., 2000). Although influenza virus infection induces strong, persistent and strain-specific immunity, new antigenic strains emerge periodically to cause epidemics, chiefly in winter and spring. The myositis is probably not related to viral infection of the muscle itself, as the virus usually remains confined to the respiratory tract and draining lymph nodes. It may be caused by one or more cytokines (pyrogens) produced in the respiratory tract and released into the bloodstream to produce systemic signs of viral infection. However, the susceptibility of human muscle to the virus has been demonstrated in tissue culture and the recovery of influenza viruses from muscle biopsies of few patients supports a causal relationship, but clinical timing of the myalgia suggests mediation by an immunogenic mechanism (Chimelli and Silva, 2002). Few cases have been studied pathologically. Muscle biopsies performed in 17 patients showed necrosis of a few muscle fibers without inflammatory reaction in 9 of 12 specimens during the first 24 hours of muscle symptoms. Most fibers were normal at these early stages of myositis. Four specimens obtained 5–10 days after the onset of the illness contained some necrotic muscle fibers, while three had, in addition, signs of regeneration and interstitial clusters of mononuclear and polymorphonuclear leucocytes. Morphological findings are illustrated in Fig. 15.1. Although electron microscopy (EM) in some cases did not demonstrate virus-like particles in muscle, in one adult with severe necrotizing myopathy and myoglobinuria in which influenza B virus was isolated, EM showed viral particles within membrane-bound vacuoles near the sarcolemma (Dalakas, 2004). Clinically, acute influenza virus myositis is usually a benign and self-limited disorder of children, the calf muscles being predominantly affected, but rarely the muscle disease is generalized and severe with myoglobinuria and a risk of renal failure. In adults, the syndrome varies more than in children and it tends to be more severe (Attarian and Azulay, 2001; Agyeman et al., 2004), although one child reported by Tabbutt et al. (2004) had a severe myositis and myocarditis in the course of influenza B virus infection. Myalgia, the commonest manifestation, starts about a week after the onset of influenza and persists for another week or two; there may be muscle tenderness and swelling, weakness, a moderate rise in serum creatine kinase (CK) levels and electromyographic changes.
INFECTIVE MYOPATHIES
305
Fig. 15.1. For full color figure, see plate section. Influenza virus myositis. (A) Rhabdomyolisis (upper picture) with invasion by macrophages, and myofiber regeneration with basophilia and enlarged nuclei with prominent nuclei (lower picture). (B) Interstitial clusters of mononuclear and polymorphonuclear leucocytes.
The occurrence of infections with influenza virus may decrease as vaccination becomes more popular in most parts of the world. Even without any specific treatment, the prognosis is usually good (bed rest, analgesics and antipyretics suffice to alleviate myalgia and fever), despite the occasional occurrence of associated myocarditis (Greaves et al., 2003; Tabbutt et al., 2004), which may be responsible for sudden death in patients performing vigorous exercises during the acute phase of the illness.
15.2.2. Acute Coxsackie virus myositis Coxsackie virus infection may cause widespread acute myositis, which may be severe with myoglobinuria. It produces epidemics in summer and fall. Meningitis, herpangina, pericarditis, myocarditis, gastroenteritis and upper respiratory tract infection may be present in the course of the infection. A few patients develop symptoms of epidemic pleurodynia (Bornholm disease), a self-limiting acute inflammatory myopathy, particularly
306
L. CHIMELLI
children 5–15 years of age. Coxsackie viruses belong to the genus enterovirus of the Picornaviridae, a family of small, non-enveloped, positive-strand RNA viruses (Melnick, 1996) and are divided into groups A (23 serotypes) and B (six serotypes). Myositis is usually caused by the group B, and particularly B5 is associated with epidemic pleurodynia. The virus is transmitted by contact with infected individuals and materials such as sewage. Viremia occurs early in the infection and the virus is shed in feces for days or occasionally weeks. The virus is myotropic but immunological mechanisms may play a role in the pathogenesis of the disease. Evidence that enteroviruses can be myotoxic is derived from animal experiments in which infection with certain Coxsackie viruses cause myositis and myocarditis. Healthy human muscle in culture can be infected with these viruses providing additional support for their myotoxic potential (Dalakas, 1995). Although few cases have been defined pathologically, in some acute Coxsackie virus myositis, particularly in adults, with myoglobinuria, muscle biopsy has shown rhabdomyolysis or regenerating fibers and mononuclear inflammatory cells. Fiber necrosis may selectively involve type I fibers, all in the same stage of necrosis or regeneration depending upon the time of the biopsy. Intracytoplasmic crystalline arrays of virus-like particles were seen by EM in one case but doubt has been cast on whether or not they truly represented virus particles (Dalakas, 2004). Clinically, non-specific muscle aches, often exacerbated by exercise, usually not associated with weakness or with changes in muscle enzymes, are the main complaints. The symptoms slowly resolve within 7 days. Bornholm disease presents with acute onset of severe pain and tenderness in the muscles of the chest, back, shoulders or abdomen. Fodili and van Bommel (2003) reported a case of Coxsackie B virus infection that coursed with severe rhabdomyolysis, myoglobinuria and acute renal failure. Cases of sudden death associated with strenuous physical activity during the acute phase of Coxsackie virus infection were due to myocardial involvement (Roberts, 1986). 15.2.3. Retrovirus-related myopathies HIV and HTLV belong to Retroviridae family, which have reverse transcriptase, an enzyme that transcribes viral RNA into provirus DNA, which is integrated into host-cell genome. HIV-1 is the human prototype of the genus Lentivirus. Its life cycle begins with the binding of the viral attachment protein (SU) with their specific receptor, CD4 present at the T-helper cell surface (Coffin, 1996).
15.2.3.1. HIV-related myopathies Excluding the neurogenic atrophies, muscle involvement in HIV-infected patients usually falls into one of the following categories: 1. HIV myopathy, a myopathy that meets the criteria for polymyositis in the majority of patients, and those for acquired nemaline myopathy in some. 2. Zidovudine myopathy, a reversible mitochondrial myopathy, is discussed in chapter 16 on toxic myopathies. 3. The HIV-wasting syndrome and other AIDSassociated cachexia. 4. Opportunistic infections and tumor infiltration. 5. Vasculitis and iron deposition (Gherardi, 1994). 6. Fox et al. (2005) have added inclusion-body myositis and cholesterol-lowering agent myopathy to the spectrum of HIV-associated myopathies. The term HIV myopathy is used to designate the morphological spectrum of a clinically homogeneous myopathy characterized by subacute onset and slow progression. Muscle involvement may occur at all stages of HIV infection, and represents the first manifestation of the disease in some patients; therefore one must consider screening for HIV in every patient who has symptoms of acquired primary inflammatory myopathy. With improved treatment and survival of AIDS patients, the prevalence of HIV myopathy, which is seen almost exclusively in adults, has increased (Dalakas, 2004). Immunopathologic studies have shown that HIV antigen is detectable only in interstitial mononuclear cells, not in muscle cells. CD8þ cells and macrophages invade or approach muscle cells expressing MHC-1 antigen in the first stage of muscle cell destruction. The immunological features of HIV myopathy are similar to those found in idiopathic polymyositis, suggesting that HIV infection can trigger the immune disturbance that leads to the development of the polymyositis syndrome. It has been proposed that this immune response results from molecular mimicry, since retroviral polypeptides coded for by the gag gene react with certain antiribonuclear proteins in the cell. Studies suggest that the HIV proviral genome is not integrated into the muscle fiber DNA. Therefore, HIV-polymyositis seem to be due to a remote effect of the virus on the muscle tissue, possibly mediated by cytokines and interferon. On the other hand, HIV seroconversion may be associated with myalgia and myoglobinuria, suggesting that HIV may directly invade muscle cells early in the infection (Dalakas, 2004). Histologically, there are perivascular, perimysial or endomysial inflammatory cells, mostly lymphocytes and macrophages, surrounding necrotic fibers (Fig. 15.2).
INFECTIVE MYOPATHIES
307
Fig. 15.2. For full color figure, see plate section. HIV myositis. Endomysial lymphocytes and macrophages surrounding muscle fibers.
CD8þ cells expressing activation antigens such as MHC class II (HLA-DR) antigens, and sarcolemmal expression of MHC class 1 (HLA-ABC) antigens are observed in the fibers. HIV antigens are seldom observed in endomysial CD4þ cells and are not detected in muscle fibers themselves. Nemaline (rod) bodies may occur and occasionally are the predominant finding; more commonly, they are associated with inflammatory infiltrate or the use of AZT. EM shows disorganization of myofibrillar structures, occasionally rods and osmiophilic cytoplasmic degradation products. In some cases there are tubuloreticular inclusions in the capillary endothelial cells (Dalakas, 2004). To determine the clinical course and optimum treatment of HIV-associated myositis, Johnson et al. (2003) evaluated a series of 64 patients referred for the presence of elevated CK levels or muscle weakness. The median duration of HIV infection prior to diagnosis of myositis was 4.3 years (range 0–11 years) and occurred at any stage of HIV infection. They had a relatively good prognosis and responded well to immunosuppressive therapy. In addition to the clinical syndrome similar to those in patients with adult polymyositis, some patients may develop a subacute limb girdle myopathy. Proliferative myositis, forming a focal mass (Wlachovska et al., 2004), and multinodular polymyositis, have also been reported in patients with AIDS, the latter in association with hepatitis C coinfection (Richardson et al., 2001). The HIV wasting syndrome is characterized by extreme fatigue, muscle wasting with normal CK levels and mild proximal muscle weakness, which is disproportionate to the loss of muscle bulk. Biopsies show severe type II fiber atrophy.
Opportunistic infections in muscles in HIV are seldom recognized. They mainly include focal pyogenic infection (pyomyositis), but cytomegalovirus (CMV), Cryptococcus neoformans, Mycobacterium avium intracellularis, microsporidiosis, and Toxoplasma gondii have been reported. 15.2.3.2. HTLV-1 polymyositis This is an inflammatory myopathy with features of polymyositis, associated with HTLV-1 infection, occurring either alone or as a late complication of tropical spastic paraparesis (TSP), the syndrome particularly associated with HTLV-1 infection. Seroepidemiologic studies revealed a high HTLV-I seropositive rate (>10%) among healthy adults in south-western Japan and moderate rates in the Caribbean, West Africa, Colombia, Brazil, Peru, Papua New Guinea, Seychelles, Ivory Coast and Australia. It is sparsely endemic elsewhere (Gottuzo et al., 2000). Circulating HTLV-1 antibodies were found in 85% of Jamaican patients with polymyositis, and HTLV1-polymyositis has been frequently observed in TSP patients submitted to muscle biopsy in Caribbean countries (Smadja et al., 1995). Transmission involves several cells but mainly CD4 lymphocytes, occurs in a manner similar to that described for HIV, but is less effective in whole blood transfusion and in needle sharing by intravenous drug users. Vertical transmission occurs postnatally. The primary endomysial cells are CD8þ cytotoxic T cells which, along with macrophages, invade or surround necrotic MHC-1 positive muscle fibers. This suggests the occurrence of a T-cell-mediated and MHC-1 restricted
308
L. CHIMELLI
cytotoxic process, identical to that described for HIV myopathy (Dalakas, 2004). Histologically, there is perimysial or interstitial inflammatory response, muscle fiber necrosis and phagocytosis. Immunocytochemical studies reveal viral antigens only in occasional CD4þ perimysial lymphoid cells but not within the muscle fibers, although the presence of HTLV1-antigen in some remaining muscle fibers has been demonstrated with PCR (Chimelli and Silva, 2002). An autopsy study of a patient with acute HTLV1associated myelopathy, complicated with encephalopathy and systemic inflammation, has also shown lymphocytic myositis (Puccioni-Sohler et al., 2003). Histological features of inclusion body myositis have also been observed in HTLV-1 infected patients (Littleton et al., 2002). The initial symptoms in polymyositis related to HTLV-1 are muscle weakness and elevated CK levels. Respiratory failure has also been reported in association with HTLV-1 neuromuscular disease (Littleton et al., 2002). There is no proven effective therapy for diseases associated with HTLV1 infection. Progression is usually not associated with HTLV1 replication; as a result, antiretroviral drugs have not been effective. There is a general consensus that myositis related to HTLV-1 shows a relatively poor response to immunosuppressant therapy (Gilbert et al., 2001). 15.2.4. Myositis during infection with other viruses Acute benign myositis in children with a good prognosis, occurring mainly in wintertime, may also be caused by herpes simplex, parainfluenza virus or respiratory syncytial virus (Mujgan Sonmez et al., 2004). Other agents causing viral myositis include Epstein–Barr virus infection, leading to mononucleosis, CMV, West Nile virus, echovirus and adenovirus, the latter two occasionally coursing with rhabdomyolysis and myoglobinuria (Melnick, 1996; Chimelli and Silva, 2002). External ophthalmoplegia due to ocular myositis in a patient with ophthalmic herpes zoster infection has been reported by Krasnianski et al. (2004); orbital myositis may occur even before eruption of cutaneous skin lesions (Kawasaki and Borruat, 2003). Chronic generalized myositis has occurred as a complication of chronic active Epstein–Barr virus infection (Uchiyama et al., 2005). In addition, many arboviruses, such as dengue and yellow fever, can induce acute myositis, producing pain in joints, tendons and muscles. In 15 biopsies in patients with dengue (Malheiros et al., 1993), a syndrome coursing with severe myalgia, fever, cutaneous rash and headache, mild-to-moderate perivascular mononuclear
infiltrate was observed in 12. Three of them had rare foci of myonecrosis. CK was mildly elevated in three patients. A recent autopsy report of a patient with West Nile virus encephalitis, documented a myositis characterized by foci of endomysial T-lymphocyte inflammation and scattered single muscle fiber necrosis with T-lymphocyte infiltration also present in nerve fibers, suggesting that the virus may reach the central nervous system (CNS) via peripheral nerves (Smith et al., 2004). Hepatitis C virus has been associated with inflammatory myopathy, as demonstrated by PCR and immunohistochemical studies which showed T lymphocytes, macrophages, immunoglobulins, MHC-I, and the neoantigens of the terminal C5b-9 complement membrane attack complex (MAC). MAC deposition and the presence of HCV-RNA in the muscle of a patient suggested that direct involvement of the virus leading to complement activation might be important in inducing muscle damage (Villanova et al., 2000). However, Di Muzio et al. (2003) reported a case of myositis associated with chronic hepatitis C virus, with necrotic and regenerating fibers, scarce perivascular inflammation, deposits of immunoglobulin G, C3, fibrinogen and MAC in muscle vessel walls, and non-uniform expression of MHC-I antigens among muscle fibers. Hepatitis C virus antigen and RNA were detected in infiltrating cells but not within muscle fibers or endothelial cells, suggesting that humoral-mediated immune mechanisms, not directly related to hepatitis C virus infection of muscle structures, may sustain the local inflammatory reaction. As mentioned previously, HIV and hepatitis C coinfection has been associated with multinodular polymyositis (Richardson et al., 2001). A case of polymyositis associated with hepatitis B infection has been reported by Nojima et al. (2000). The myositis repeatedly worsened 2 months after the exacerbation of hepatitis, suggesting a close association between hepatitis B infections and myositis.
15.3. Bacterial myositis 15.3.1. Pyomyositis Pyomyositis, a localized zone of suppuration of muscle with formation of large abscesses, is also called tropical pyomyositis because of its common occurrence in tropical climates. Although it has been recognized in temperate areas, the affected individual has in most cases been on a recent visit to a tropical area. It is much more common in men than in women (Attarian and Azulay, 2001). In the vast majority of cases (85%), Staphylococcus aureus can be cultured from the muscle abscesses (Carpenter and Karpati, 2001); it has also been reported to be caused by Streptococcus pyogenes, Salmonella
INFECTIVE MYOPATHIES and Pneumococcus, and in 5% of cases no organisms can be found (Collazos et al., 1996; 1999). It may occur without any antecedent illness or other predisposing features or may be associated with trauma, malnutrition, diabetes mellitus, acute viral infection, suppurative arthritis, osteomyelitis, underlying muscle abnormalities, hematogenous spread of a bacterial infection even with negative blood cultures, or be a rare complication of muscle biopsy or intramuscular injection of certain drugs. In up to 50% of cases there is a history of trauma to the affected muscles (Chauhan et al., 2004). Non-tropical pyomyositis is seen most frequently in the elderly bedridden who develop abscesses from bedsores, injected-drug users, following burns, or in immunocompromised patients such as in AIDS and after chemotherapy for cancer, splenectomy and use of steroids (Al-Tawfiq et al., 2000; Demir et al., 2000; Hossain et al., 2000). As for the pathogenesis, the predilection of this disease for the tropics is unexplained. The source of infection is often obscure; there may be only a trivial scratch of the overlying skin; subclinical myopathy, secondary to malignancy or drugs used in treating malignancy, or both, may predispose to pyomyositis (Keith and Bramwell, 2000). Since the initial inflammation may be mainly lymphocytic with later arrival of neutrophils, the bacterial invasion may be merely a secondary process that develops in an acute primary inflammatory focus of unknown origin. The pathogenesis in AIDS is unknown but may be due to deficits of neutrophil functioning and the common colonization of patients by Staph. aureus (Al-Tawfiq et al., 2000). The abscess is visible as a zone of muscle destruction with a core containing polymorphonuclear leucocytes and surrounded by a fibrous capsule. Adjacent fibers may be compressed or necrotic. The initial dense inflammatory infiltrates are mainly lymphocytic and only later is there massive invasion of neutrophils. In tropical cases, eosinophils may be present (Fig. 15.3). The necrotic process may extend beyond the muscle fibers to the vessels and interstitial tissues. Commonly involved muscles are quadriceps, glutei, pectoralis major, biceps, iliopsoas, gastrocnemius, abdominal and spinal muscles. The condition presents with painful swelling of a muscle, but early diagnosis is often missed because of lack of specific signs, unfamiliarity with the disease, atypical manifestations and a wide differential diagnosis (Chauhan et al., 2004). Bilateral involvement occurs more frequently in patients with AIDS. The swelling is initially hard and woody but becomes fluctuant in a few days, requiring surgical drainage. Needle aspiration may reveal pus, often containing Staph. aureus. There may be fever, leucocytosis with eosinophilia and raised CK. Diagnostic
309
techniques like ultrasound and computed tomography (CT)/magnetic resonance imaging are very useful in diagnosis, revealing an enhancing lesion with a fluid density. The diagnosis is confirmed either by biopsy or aspiration of pus from the affected muscles. Hematogenous dissemination and myoglobinuria have been reported. Despite considerable muscle destruction, functional recovery is usually good, after drainage and appropriate antibiotic therapy (Chauhan et al., 2004). 15.3.2. Clostridial myositis Clostridial myositis causing gas gangrene is rare and develops subsequent to contamination of severe deep lacerating puncture wounds of the limbs, or after compound comminuted fractures or burns. It is caused by Clostridium welchii, that produces a toxin and a number of enzymes including collagenases and hyaluronidase, which by its action on the cell membrane may be responsible for initiating necrosis of muscle fibers and interstitial tissues, vascular congestion, fibrin exudation, and hemorrhage. Although rare in civilian practice it still occurs, particularly in tropical regions but also occasionally in temperate climates. It may develop rarely without trauma, usually in a debilitated patient with a bowel carcinoma. Muscle becomes greatly softened presumably due to the enzyme activity of clostridial organisms. There is extensive fiber necrosis, and infiltration with polymorphonuclear leukocytes. If the infection is controlled and necrotic muscle tissue is removed, muscle regeneration will occur but in the end-result is often marked fibrosis and atrophy. Clinically there are local and systemic signs. Local signs include pain, swelling, serosanguineous exudates, and brownish discoloration of the overlying skin. The systemic signs, due to clostridial exotoxin, are those of sepsis: fever, tachycardia and prostration (Wadia and Katrak, 1999; Chimelli, 2002). 15.3.3. Malignant necrotizing streptococcal myositis Also known as “flesh-eating infection”, malignant necrotizing streptococcal myositis, associated with shock and organ failure, with or without necrotizing fasciitis, is a rare and life-threatening disease, most often caused by group A beta-hemolytic Streptococcus pyogenes (Chimelli, 2002; Dalal et al., 2002; Subramanian and Lam, 2003). It usually presents as a post-operative complication, but rarely appears following trauma or without apparent cause. It seems that absence of immunity against certain streptococcal proteins increases the severity of infection. In this disease, there appears to be a “super-antigen” operating. S. pyogenes has a
310
L. CHIMELLI
Fig. 15.3. For full color figure, see plate section. Tropical pyomyositis. (A) An intramuscular abscess consisting of a collection of leucocytes and cellular debris, better seen in the right. (B) A detail of the inflammatory infiltrate, consisting if neutrophils, eosinophils and lymphocytes.
number of strategies for evading the host’s defenses: (1) M protein, an antiphagocytic surface component; (2) a protease that cleaves C5a so that it no longer attracts phagocytes; and (3) surface proteins related to M protein that bind the Fc portions of antibodies, host proteases inhibitors, or other plasma proteins (Salyers and Whitt, 1994). The disease may be lethal, not only due to its severity, but also because of difficulty in diagnosis during its
early stages. Management requires early diagnosis (CT scan may be helpful), a combined medical-surgical approach, and intensive fluid and nutritional support.
15.3.4. Myositis due to other bacterial infections Myositides due to tuberculosis, syphilis or actinomycosis are rare and most reports date back many decades.
INFECTIVE MYOPATHIES A recent report by Wang et al. (2003) described 35 cases of tuberculous myositis. The routes of infection were contiguous spread in 22 patients (62.8%), hematogenous spread in 10 (28.6%) and traumatic inoculation in 3 (8.6%). The infection spreads into the muscle as a caseating granulomatous mass (Fig. 15.4). Myositis due to Mycobacterium chelonae has also been reported in association with immunosuppression (Hajjaji et al., 2004). Antituberculous drugs include rifampicin (600 mg orally), isoniazid (300 mg orally) and ethambutol, 25 mg/kg orally initially, then 15 mg/kg (maximum, 25g). Involvement of muscle in actinomycosis usually results from direct extension from a neighboring infective focus in the pleura or skin, leading to the formation of abscesses and fistulae which discharge purulent material containing the characteristic yellow granules which are composed of colonies of the infective agent (Wadia and Katrak, 1999). Orbital myositis associated with Borrelia burgdorferi (Lyme disease) infection, has been reported in a patient with diplopia and prior symptoms consistent with manifestations of Lyme disease (Carvounis et al., 2004). Bartonella infection has caused myositis in children (Al-Matar et al., 2002) and leptospirosis may also cause myositis (Rajajee et al. 2002). The diagnosis of leptospirosis should always be considered when the serum CK is elevated in a febrile patient with renal and liver disease. The lesions consist of single fiber necrosis and varying degrees of degeneration and infiltration of muscle fibers and endomysium by inflammatory cells. Muscle involvement appears to result from the spirochetal invasion, but leptospires are rarely found unless muscle is subjected to silver staining techniques. Although the efficacy of
Fig. 15.4. For full color figure, see plate section. Tuberculous myositis. (A) A granuloma consisting of epithelioid cells and multinucleated giant cell is seen inside the muscle. (Courtesy of Dr Fernando Rosman.)
311
antimicrobial agents in the treatment of leptospirosis is controversial, data suggest that they shorten the duration of illness and reduce the likelihood of complications. Doxycycline, 0.1 g orally twice daily for 7 days, may favorably affect the course of leptospirosis when treatment is initiated within 2–4 days after the onset of symptoms. Penicillin G, 6 million units I.V. daily for 7 days can be used in late, severe, leptospirosis. The involvement of skeletal muscle in leprosy may be due to the infection, or secondary to peripheral neuropathy. There may be an interstitial inflammatory myopathy particularly in the lepromatous form, where acid-fast bacilli are detected inside large macrophages present in the perimysium, and a granulomatous reaction, in the tuberculoid form. The inflammation, also seen in nerve branches, may be responsible for the denervation (Werneck et al., 1999). The combined use of sulfone, rifampicin and clofazimine is effective in treating leprosy.
15.4. Fungal myositis Fungal infections in muscle are uncommon. However, as in other systems, there has been an increase incidence during the last few decades due to the growing number of immunocompromised patients, the widespread use of immunosuppressive drugs, a larger aging population with an increased number of malignancies, and the spread of AIDS (Chimelli and Mahler-Arau´jo, 1997). Sporotricosis, histoplasmosis, mucormycosis, aspergillosis, candidiasis and cryptococcosis may cause myositis. Muscular involvement is usually localized to one muscle or muscle group as a result of abscess formation such as in sporotrichosis and histoplasmosis. Mucormycosis, in its rhinocerebral form, can spread into the ocular muscles and produce ophthalmoplegia, proptosis, edema of the lids and occasionally blindness (Chimelli, 2002). A fatal Aspergillus fumigatus myositis has been reported, affecting the psoas and paravertebral muscles in an immunocompetent patient (Javier et al., 2001). The likely portal of entry in this patient was direct inoculation during infiltration of steroid for back pain. Diffuse muscular involvement is almost always associated with disseminated candidiasis, frequently in patients with systemic malignancy, or in cryptococcosis in immunosuppressed patients (O’Neill et al., 1998). Myositis resulting from disseminated cryptococcosis in association with hepatitis C cirrhosis (Flagg et al., 2001), and paraspinal cryptococcal myositis without evidence of disseminated disease associated with a large B-cell lymphoma (Sharma et al., 2002) has been reported. Candidiasis is manifested by widespread muscle weakness with muscle tenderness, and is associated with
312
L. CHIMELLI
hemorrhagic necrosis, accompanied by acute inflammation. Fungi can be observed in sections stained with methenamine silver (Fig. 15.5). Antifungal drugs include the azoles (ketoconazole, fluconazole) and amphotericin B. The choice depends on the severity of the infection, the underlying condition and the immune state of the host; amphotericin is preferred in severe cases. As for opportunistic fungal infections, particularly candidiasis, management should include attempts to correct any factor that can predispose to fungal overgrowth.
15.5. Parasitic infections 15.5.1. Protozoan infections 15.5.1.1. Toxoplasmosis Although only rarely found at muscle biopsy, Toxoplasma gondii has previously been regarded as a possible cause of polymyositis. The intracellular protozoan encysts most commonly in skeletal muscle, myocardium and brain. Domestic cats are definitive hosts and the main reservoir, where the entire life cycle is completed. Humans may acquire the infection through intake of undercooked meat of infected animals containing cysts, ingesting oocysts from feces-contaminated
hands or food, organ transplantation, blood transfusion or transplacental transmission (Turner and Scaravilli, 2002). After ingestion of oocysts or cysts, bradyzoites are released into the digestive tract where, after binary fission, tachyzoites proliferate intracellularly, disrupt host cells and enter leukocytes, disseminating widely. As the host immune response develops, they may persist indefinitely encysted as bradyzoites. Immunosuppression favors a newly acquired infection or reactivation of a chronic one with disease dissemination to lymph nodes, muscle, myocardium, liver and especially CNS (Banker, 2004). In muscle, there may be myofiber necrosis and an overt inflammatory reaction with lymphocytes (some CD4þ cells and rare CD20þ cells), macrophages and at times giant cells. Toxoplasma may be recognized at light microscopy within cysts ranging from 10 to 100 mm laden with thousands of tightly packed bradyzoites, or in macrophages or other cells, especially muscle, as oval or crescent-shaped trophozoites 2–8 mm in length (Gherardi et al., 1992). Immunohistochemistry is useful to demonstrate free trophozoites in necrotic areas. MHC class I and II antigens have been reported present in blood vessels and inflammatory cells even in the absence of organisms (Matsubara et al., 1990). According to
Fig. 15.5. For full color figure, see plate section. Myositis due to Candida. A collection of hyphae is seen inside the muscle. They are stained with PAS (B) and Grocott (C). (Courtesy of Dr Fernando Rosman.)
INFECTIVE MYOPATHIES Calore et al. (2000), the presence of the parasite in myofibers is not enough to induce an inflammatory myositis with muscle cell necrosis, suggesting that immunological disturbances may contribute to the development of myositis. In fact, Plonquet et al. (2003) reported a case of biopsy-proven toxoplasmic myositis in a non-HIVinfected patient that led to recognition of idiopathic CD4 lymphocytopenia, a rare condition typically associated with opportunistic infections. Toxoplasmosis in immunocompetent hosts is often asymptomatic, but 10–20% of patients with acute infection may develop mild febrile symptoms and lymphadenopathy, which remit spontaneously. Myalgia and rash may express mild acquired infection, which may course with polymyositis and dermatomyositis syndromes. Given the association between toxoplasmosis and polymyositis, it is still controversial whether the latter is an immunological complication of the former, or whether treatment-induced immunosuppression predisposes to infection. Since IgG titers may be high after primary infection, high or rising IgM levels seem a more reliable indicator of acute infection. Real-time PCR is sensitive to detect toxoplasma DNA in human blood, CSF or amniotic fluid (Kupferschmidt et al., 2001). Combined administration of pyrimethamine and sulfonamides (sulfadiazine) for 3–6 weeks is the treatment of choice. In adults, a loading dose of 200 mg of pyrimethamine is given on the first day of treatment, followed by the usual dosage of 50–75 mg/day. Sulfadiazine is usually given to adults in a loading dose of 0.4 g, followed by 1–2 g four times daily. 15.5.1.2. American trypanosomiasis (Chagas’ disease) Chagas’ disease is a protozoan infection caused by Trypanosoma cruzi and transmitted by reduviid bugs (Triatoma magista), which carry the parasites in their feces. It is endemic in South America (especially Brazil) and Central America, and considered an important socioeconomic problem due to its high prevalence and mortality. The prevalence of the infection in the USA has increased in the last decade due to the increased emigration of Latin Americans. As the insects bite, the parasites are eliminated in the feces and can enter through the skin wound, around which a firm nodule develops. Transmission can also occur through blood transfusion, breastfeeding, transplacentally, accidentally in laboratories and through organ transplants. After the acute phase, when circulating parasites are numerous, their number decreases, and in the chronic phase, the host immune response seems to be more important in the development of the lesions (Chimelli and Scaravilli, 1997).
313
In muscle and other tissues, the parasites multiply and collect within cells, which then rupture, resulting in inflammation and local damage. The inflammatory infiltrates consist of histiocytes, lymphocytes, and plasma cells in the perimysium, particularly perivascular, but may extend into the endomysium. Parasites are detected in clusters among the inflammatory cells and within histiocytes and muscle fibers, which show various stages of degeneration and regeneration in addition to inflammation of vessel walls (Chimelli and Scaravilli, 1997). Neurogenic atrophy due to lesions in anterior horn neurons and motor nerves is noted in the chronic phase (Taratuto et al., 1978). In congenital infection, muscle fibers may also be infected. Circulating antibodies as well as immune complexes consisting of IgG and complement are bound to the plasma membrane of skeletal muscle and endothelial cells (Banker, 2004). It has multiple clinical expressions, with particular involvement of the heart and digestive system causing megavisceras. In the acute phase clinical manifestations are directly related to the parasitism: swollen eyelids and face, toxemia, febrile illness hepatosplenomegaly and enlarged lymph nodes. In addition, there may be weakness, myalgia and erythema, suggesting dermatomyositis. In the chronic phase, in addition to the cardiac and digestive symptoms, a peripheral neuropathy leads to muscle denervation. The diagnosis is made by serological tests (Chimelli and Scaravilli, 1997). However, Zhang and Tarleton (1999), using in-situ PCR analysis for the detection of kinetoplast DNA of Trypanosoma cruzi in murine models of Chagas’ disease, demonstrated an absolute correlation between the persistence of parasites and the presence of disease in muscle tissue. Therefore, clearance of parasites from tissues, presumably by immunologic mechanisms, correlates with reduction of inflammatory responses and the resolution of the disease. Nifurtimox and benznidazole are the drugs of choice. The latter has to be used with caution because of its toxicity. For the acute phase 8–10 mg/kg/day of nifurtimox or 5–7.5 mg/kg/day of benznidazole for 30–60 days consecutively, and divided into two or three daily doses is recommended. Patients less than 40 kg body weight can take up to 12 mg/kg/day of nifurtimox and up to 7.5 mg/kg/day of benznidazole for 30–60 days. For recent chronic infections (children under 12 years) or individuals infected in the last 10 years, the treatment should be with 8 mg/kg/day of nifurtimox or 5 mg/kg/ day of benznidazole for 30–60 days. 15.5.1.3. African trypanosomiasis African trypanosomyasis or sleeping sickness is caused by Trypanosoma brucei gambiense (West African) and
314
L. CHIMELLI
Trypanosoma brucei rhodesiense (East African), protozoa transmitted by the bite of the tsetse fly. Muscle is affected during the second stage of the disease, 1–5 weeks after the bite, when the patient complains of malaise and fever as a part of the systemic disease. There is myocarditis and polymyositis manifested by an infiltration of perimysium and endomysium by lymphocytes, plasma cells and histiocytes (Chimelli and Scaravilli, 1997). Trypanosomes can be detected in a blood smear only when the concentration is more than 2000 organisms per milliliter. Serum immunoglobulins are elevated, particularly IgM. The genetic sequences unique to this parasite can be documented by DNA probe (Banker, 2004). Eflornithine is effective therapy for West African trypanosomiasis. The recommended first-line regimen for adults is by slow intravenous infusion of 100 mg/kg every 6 hours for 14 days. East African trypanosomiasis is treated with suramin. As there is risk of anaphylactic shock with suramin, it is recommended to start treatment with a test dose, followed by five injections of 20 mg/kg (with a maximum of 1 g per injection) administered at intervals of 5–7 days. Melarsoprol is a powerful trypanocide able to cure both infections. Due to the high risk of complications during treatment the drug is only used in the late stage. The schedule consists of a daily injection for 10 consecutive days at 2.2 mg/kg per day.
The zoonotic protozoa Microsporidia was a rare human pathogen prior to 1985, when Enterocytozoon bieneusi was described in HIV-infected patients with chronic diarrhea (Banker, 2004). The organism enters the body through the gastrointestinal epithelium as well as through open wounds. In order to infect the host, the parasite emits a tubular filament that penetrates the host cell membrane, allowing the infective sporoplasm to be injected directly into the host cytoplasm. After multiple divisions, each resultant organism develops a thick membrane to become a sporant and, through further development, a spore. Accumulation of numerous spores results in rupture of the host cell, followed by elimination of the spores in the feces and their ingestion by another host. Polymyositis due to microsporidia has been documented in association with immunodeficiency, coursing with progressive generalized weakness. The parasites present as membrane enclosed clusters of spores, also found in macrophages and stain with PAS (Banker, 2004).
15.5.1.4. Sarcosporidiosis
15.5.1.6. Malaria
The disease is caused by a protozoa, Sarcocystis lindemanni, which is occasionally found encysted in skeletal and cardiac muscle fibers of various domestic and wild animals in many parts of the world (Southeast Asia, India, Central and South America, Africa, Europe, USA and China). Muscle involvement in man is uncommon (Pamphlett and O’Donoghue, 2000; Banker, 2004). Humans, the intermediate host, become infected by ingesting meat, vegetables and water contaminated with sporocysts, which liberate sporozoites in the intestine. These travel to endothelium, where they develop to schizonts and produce merozoites, which migrate to muscle, where they become encysted as sarcocysts. Grossly the muscle is often normal or contains small, pale intramuscular streaks or bodies, known as Miescher’s tubules, which microscopically reveal cylindrical compartmentalized cysts called sarcocysts varying in length and deeply embedded within the muscle fibers. The cysts are filled with many sporozoites, initially found in muscle fibers and subsequently enlarge to lengths of 1–2 mm, and 100–200 mm in diameter. Subacute or chronic inflammation may be inconspicuous and consists of myositis, often with eosinophils (Banker, 2004). The infection is usually asymptomatic and may be
Malaria is caused by protozoa of the genum Plasmodium, transmitted from person to person by infected anopheline mosquitoes. Only Plasmodium falciparum has been reported to damage skeletal muscle causing single muscle fiber necrosis in the acute stage (Banker, 2004). It seems that the degree of alteration depends upon the severity of the disease. The pathogenesis of this form of acute muscle fiber degeneration, whether the mechanism is the same as in other acute febrile illnesses, or whether there is active invasion of the muscle fiber by the parasite is uncertain, although muscle appears to be an important site for P. falciparum sequestration, which could contribute to metabolic and renal complications (Davis et al., 2000). Oral chloroquine phosphate at an initial dose of 1 g (600 mg base), followed by 500 mg (300 mg base) at 6 hours and again and 24 and 48 hours, is the best treatment.
an incidental biopsy or autopsy finding. When symptomatic the muscles show localized swelling and the patient complains of weakness preceded by local pain, tenderness and loss of tendon reflexes, usually accompanied by fever. 15.5.1.5. Microsporidiosis
15.5.2. Cestode infection 15.5.2.1. Cysticercosis Cysticercus cellulosae, the larval form of the pork tapeworm Taenia solium, which is encysted in subcutaneous tissue, skeletal and heart muscle, eye and brain, is the
INFECTIVE MYOPATHIES etiologic agent of cysticercosis. Humans acquire cysticercosis as intermediate hosts by ingesting water or food contaminated with T. solium ova from another human’s infected feces or by autoreinfection. As definitive hosts, humans develop the adult tapeworm after eating poorly cooked pork meat containing encysted larvae. Adult tapeworms eliminate gravid egg-laden proglottids into feces. The life cycle is completed when ova are eaten by the pig, the most common intermediate host (Turner and Scaravilli, 2002). The disease is endemic in several countries of Latin America, Africa and Asia as well as in some Eastern European countries, but not in Australia. It is also very frequent among Latin-American immigrants to the USA (Wadia and Katrak, 1999; White, 2000). Muscle biopsy disclosing encysted larvae may prove diagnostic, particularly in chronic cases. Cysticercus cellulosae cysts, ranging from 5 mm to almost 3–4 cm in diameter, consist of a thin translucent wall filled by clear fluid and a scolex with a spiral canal and a rostellum with four suckers and a double row of hooklets. The cyst wall has three layers: the external 3-mm thick folded eosinophilic cuticular layer, beneath which are bundles of muscle fibers, is covered with microtrichia; the middle layer is cellular; and the internal reticular layer consists of a fibrous network with a few calcareous bodies (Fig. 15.6). The parasite may remain viable for several years; inflammatory reaction mostly occurs after parasite degeneration due to cyst fluid permeation and includes lymphocytes, plasma cells and eosinophils, foreign body giant cells, at times surrounded by a fibrous capsule which may calcify (Wadia and Katrak, 1999). Clinical features vary according to cyst number and location, presenting one or more small subcutaneous nodules, which lie between muscle fibers. Myalgia, fever, headache and vomiting may be present during the acute phase. More rarely, disseminated cysticercosis may manifest with pseudohypertrophy of muscles without weakness, associated with seizures and dementia (Wadia and Katrak, 1999). For antibody detection, there is a specific immunoblot assay termed the enzymelinked immunotransfer blot, which employs parasitic glycoproteins. It is highly sensitive and nearly 100% specific for T. solium infection (White, 2000). Though unsuitable for serological diagnosis, PCR-based methods readily identify T. solium mitochondrial cytochrome oxidase I gene sequences (Mayta et al., 2000). Treatment is medical or surgical. Those with only calcified nodules do not require medical treatment, which consists of praziquantel (50–100 mg/kg/day in three divided doses for 30 days) and albendazole, given in a dosage of 400 mg orally twice daily for 10–28 days. Corticosteroid is usually given 1–2 days before
315
Fig. 15.6. For full color figure, see plate section. Cysticercosis. (A) A folded cyst wall. (B) Details of the wall with the three layers.
and during treatment with albendazole to minimize inflammation. 15.5.2.2. Echinococcosis or hydatidosis This is a human disease caused by the cystic larval stage of the dog tapeworm Echinococcus granulosus or E. multilocularis, responsible for cystic and the much rarer alveolar echinococcosis respectively. E. granulosus is widely distributed in parts of the world where sheep are raised and dogs are used to herd livestock (the Middle East, South America, Australia, New Zealand and parts of North America; Taratuto and Venturiello, 1997a). It is
316
L. CHIMELLI
usually acquired in childhood (Schantz et al., 1995). E. multilocularis is found in cold areas including Alaska, northern USA, central Europe, China, Russia and Turkey. The tapeworms parasite the gut of the dog, wild canines and other carnivorous definitive hosts involved as intermediate hosts, both domestic and wild animals harboring the larval form or hydatid cyst. Humans and sheep become accidental intermediate hosts by ingesting eggs eliminated in the feces of definitive hosts. A hexacanth embryo penetrates the intestinal wall and migrates by the portal system to the liver where hydatid cysts are formed and may metastasize to lung, brain, striated muscle, vertebrae, kidney and pericardium. The parasite evades host immune attack by diverse mechanisms including a barrier for host cells due to hydatid cyst laminated cuticle (Taratuto and Venturiello, 1997a). Muscle involvement has been reported in about 5% of humans with extra hepatic lesions and is the third most common site (Wadia and Katrak, 1999). The multilocular alveolar cyst has a thin outer membrane and a highly invasive germinal layer. The unilocular hydatid cyst is spherical and contains transparent fluid surrounded by a two-layer capsule. The outer cuticle is white, elastic, acellular, non-nucleated and PASpositive. The inner germinal layer is granular, syncytial and nucleated, generating scolices with suckers and double row of hooks, as well as small daughter vesicles. Host reaction is minimal, but when cysts degenerate, an epithelioid and giant cell reaction may take place to phagocytose the cuticle. Reabsorption occurs and amorphous necrotic debris is surrounded by reactive tissue and may become calcified (Taratuto and Venturiello, 1997a; Taratuto and Chimelli, 2002). Patients may remain asymptomatic for long periods. As the cyst slowly develops it appears as a muscle tumor mass on occasion affecting paravertebral, limb girdle, orbital and more rarely long limb muscles. Symptoms relate to both cyst location and size, requiring surgery for certain sites. Orbital cysts are usually manifested by proptosis and extra ocular muscle paresis (Taratuto and Venturiello, 1997a). Ultrasonography, computed tomography and magnetic resonance imaging are useful for diagnosis. Immunodiagnostic tests vary according to the form of disease (Lightowlers and Gottstein, 1995). For cystic hydatid disease indirect hemagglutination, indirect fluorescent antibody tests, and enzyme immunoassays (EIA), confirmed by immunoblot or gel diffusion assays are used. For alveolar hydatid disease, immunoaffinity-purified E. multilocularis antigens in EIA render positive serologic reactions in more than 95% of the cases. PCR followed by sequencing or restriction fragment length polymorphism (RFLP) is useful for strain identification from fine needle aspiration or
surgically removed cysts. Both nuclear and mitochondrial sequences have been used to characterize human E. granulosus isolates (Lightowlers and Gottstein, 1995; Scott et al., 1997; Rozenzvit et al., 1999). Treatment should be reserved for symptomatic lesions. Surgical excision may be preceded and supplemented by antihelminthic drugs, such as albendazole. It is given as a 400 mg dose twice a day for 28 days, often with additional 28-day courses given in subsequent months (usually 6 months), with each course separated by 14-day treatment-free periods. Control programs must include treatment of domestic dogs as well as incineration of parasitized viscera in abattoirs.
15.5.3. Nematode infection Trichinosis or trichinellosis is caused by a nematode Trichinella spp., which lacks a free-living stage. Human and lower animal infection with predominant muscle involvement is acquired through ingestion of undercooked meat, mainly of pork, containing infective encysted larvae. Although its incidence has declined over the last half century, it is still endemic worldwide sparing only Australia and certain Pacific Islands. Sporadic outbreaks have been reported in North and South America, Europe and Asia (Taratuto and Venturiello, 1997b). A complete life cycle develops in a single host harboring adult worms in the small intestine, from which newborn larvae migrate and encyst in striated muscle remaining viable for several years (Despommier et al., 1991). Muscles more frequently involved are diaphragm, intercostal, biceps, pectoral, gastrocnemius, back and lumbar region, extra ocular, masticator and tongue muscles to a widely variable degree. Muscle biopsy is highly diagnostic after the third week in clinically affected muscles and may disclose T. spiralis larvae with antigen-producing stichosomes and a central rudimentary digestive tube together with a thin muscular coat beneath a superficial cuticle, coiled within a muscle fiber host nurse cell surrounded by an eosinophilic, PAS-positive capsule. “Nurse cells” containing encysted larvae are multinucleated; their histochemical profile is suggestive of regeneration (Fig. 15.7). Cryostat sections incubated with human serum positive for T. spiralis and tested by indirect immunofluorescence may also clearly disclose the larvae. Inflammatory infiltration may be seen even at a distance from encysted larvae and includes plasma cells, eosinophils and T lymphocytes mainly of the suppressor/cytotoxic phenotype (Taratuto and Venturiello, 1997b).
INFECTIVE MYOPATHIES
317
References
Fig. 15.7. For full color figure, see plate section. Trichinosis. The parasite is seen inside a muscle fiber. (Courtesy of Dr Fernando Rosman.)
Clinical symptoms appear about 2 weeks after ingestion of contaminated food and include vomiting and diarrhea (enteric phase), followed by periorbital and facial edema, fever, myalgia and proximal weakness (acute systemic phase). Erythematous changes may mimic dermatomyositis. Contractures may develop and even affect jaw opening. Electromyography shows both myopathic changes and fibrillation potential as in idiopathic polymyositis. The ocular, lingual or pharyngeal weakness and/or hypereosinophilia suggest the diagnosis. Immunodiagnostic tests based on IgG antibodies are the most sensitive. Although PCR is unsuitable for serological diagnosis, as the larva is only found briefly in the bloodstream, it is useful for genotyping larvae from human muscle biopsies as well as of pigs and wild hosts (Rombout et al., 2001; Zarlenga et al., 1999). Since there are no pathognomonic signs or symptoms, clinical diagnosis may be difficult and the only reliable diagnostic methods are serodiagnosis and muscle biopsy (Taratuto and Chimelli, 2002). Most infections are not life threatening and are selflimited. Bed rest, analgesics and antipyretics suffice to alleviate myalgia and fever. Specific treatment is unsatisfactory; it consists of oral albendazole (400 mg twice daily for 8–14 days) and corticosteroid therapy with prednisone (40–60 mg daily), and is used particularly in severe cases. In order for these drugs to be effective they must be administered before the end of the acute stage; thus early diagnosis is fundamental (Kociecka, 2000; Pozio et al., 2003). 15.5.4. Other parasitic diseases Coenurosis, sparganosis, visceral larva migrans (Toxocara canis), cutaneous larva migrans (Ancylostoma caninum) and dracunculosis, have all been reported to involve muscle (Banker, 2004).
Agyeman P, Duppenthaler A, Heininger U, et al. (2004). Influenza-associated myositis in children. Infection 32: 199–203. Al-Matar MJ, Petty RE, Cabral DA, et al. (2002). Rheumatic manifestations of Bartonella infection in 2 children. J Rheumatol 29: 184–186. Al-Tawfiq JA, Sarosi GA, Cushing HE (2000). Pyomyositis in the acquired immunodeficiency syndrome. South Med J 93: 330–334. Attarian S, Azulay JP (2001). Infectious myopathies. Rev Prat 51: 284–288. Banker BQ (2004). Parasitic myositis. In: AJ Engel, C Franzini-Armstrong (Eds.), Myology, Vol. 2, McGraw-Hill, New York, pp. 1419–1443. Calore EE, Minkovski R, Khoury Z, et al. (2000). Skeletal muscle pathology in 2 siblings infected with Toxoplasma gondii. J Rheumatol 27: 1556–1559. Carpenter S, Karpati G (2001). Pathology of skeletal muscle, Oxford University Press, New York, pp. 542–606. Carvounis PE, Mehta AP, Geist CE (2004). Orbital myositis associated with Borrelia burgdorferi (Lyme disease) infection. Ophthalmology 111: 1023–1028. Chauhan S, Jain S, Varma S, et al. (2004). Tropical pyomyositis (myositis tropicans): current perspective. Postgrad Med J 80: 267–270. Chimelli L (2002). Bacterial myositis. In: G Karpati, (Ed.), Structural and molecular basis of skeletal muscle diseases. ISN Neuropath Press, Basel, pp. 236–237. Chimelli L, Mahler-Arau´jo MB (1997). Fungal infections. Brain Pathol 7: 613–627. Chimelli L, Scaravilli F (1997). Trypanosomiasis. Brain Pathol 7: 599–611. Chimelli L, Silva EF (2002). Viral myositis. In: G Karpati, (Ed.), Structural and molecular basis of skeletal muscle diseases. ISN Neuropath Press, Basel, pp. 231–235. Coffin JM (1996). Retroviridae: the viruses and their replication. In: BN Fields, DM Knipe, RM Chanock, et al. (Eds.), Fields Virology, Vol. 1, Lippincott-Raven, New York, pp. 655–712. Collazos J, Fernandez A, Martinez E, et al. (1996). Pneumococcal pyomyositis: case report, review of the literature, and comparison with classic pyomyositis caused by other bacteria. Arch Int Med 156: 1470–1474. Collazos J, Mayo J, Martinez E, et al. (1999). Muscle infections caused by Salmonella species: case report and review. Clin Infect Dis 29: 673–677. Dalakas MC (1995). Enterovirus and human neuromuscular diseases. In: HA Rotbart, (Ed.), Human Enterovirus Infections.ASM Press, Washington DC, pp. 387–398. Dalakas MC (2004). Virus-related muscle diseases. In: AJ Engel, C Franzini-Armstrong (Eds.), Myology, Vol. 2, Mc Graw-Hill, New York, pp. 1389–1417. Dalal M, Sterne G, Murray DS (2002). Streptococcal myositis: a lesson. Br J Plast Surg 55: 682–684. Davis TM, Supanaranond W, Pukrittayakamee S, et al. (2000). Progression of skeletal muscle damage during
318
L. CHIMELLI
treatment of severe falciparum malaria. Acta Trop 76: 271–276. Demir M, Cakir B, Vural O, et al. (2000). Staphylococcal pyomyositis in a patient with non-Hodgkin’s lymphoma. Ann Hematol 79: 279–282. Despommier D, Symmans WF, Dell R (1991). Changes in nurse cell nuclei during synchronous infection with Trichinella spiralis. J Parasitol 77: 290–295. Di Muzio A, Bonetti B, Capasso M, et al. (2003). Hepatitis C virus infection and myositis: a virus localization study. Neuromuscul Disord 13: 68–71. Flagg SD, Chang YJ, Masuell CP, et al. (2001). Myositis resulting from disseminated cryptococcosis in a patient with hepatitis C cirrhosis. Clin Infect Dis 32: 1104–1107. Fodili F, van Bommel EF (2003). Severe rhabdomyolysis and acute renal failure following recent Coxsackie B virus infection. Neth J Med 61: 177–179. Fox KA, Morgello S, Sympson DM (2005). Myopathies associated with HIV-1: clinical and pathological manifestation. In: HE Gendelman, I Grant, IP Everall, et al. (Eds.), The Neurology of AIDS. Oxford University Press, Oxford, pp. 449–459. Gherardi RK (1994). Skeletal muscle involvement in HIV infected patients. Neuropathol Appl Neurobiol 20: 232–237. Gherardi R, Baudrimont M, Lionnet F, et al. (1992). Skeletal muscle toxoplasmosis in patients with acquired immunodeficiency syndrome. A clinical and pathologic study. Ann Neurol 32: 535–542. Gilbert DT, Morgan O, Smikle MF, et al. (2001). HTLV-1 associated polymyositis in Jamaica. Acta Neurol Scand 104: 101–104. Gotuzzo E, Arango C, Queiroz-Campos A, et al. (2000). Human T-cell lymphotropic virus-I in Latin America. Infect Dis Clin North Am 14: 211–239. Greaves K, Oxford JS, Price CP, et al. (2003). The prevalence of myocarditis and skeletal muscle injury during acute viral infection in adults: measurement of cardiac troponins I and T in 152 patients with acute influenza infection. Arch Intern Med 163: 165–168. Hajjaji N, Cattier B, Lanotte P, et al. (2004). Mycobacterium chelonae myositis. Presse Med 33: 1519–1520. Hossain A, Reis ED, Soundararajan K, et al. (2000). Nontropical pyomyositis. Analysis of eight patients in an urban center. Am Surg 66: 1064–1066. Hu JJ, Kao CL, Lee PI, et al. (2004). Clinical features of influenza A and B in children and association with myositis. J Microbiol Immunol Infect 37: 95–98. Javier RM, Sibilia J, Lugger AS, et al. (2001). Fatal Aspergillus fumigatus myositis in an immunocompetent patient. Eur J Clin Microbiol Infect Dis 20: 810–813. Johnson RW, Williams FM, Kazi S, et al. (2003). Human immunodeficiency virus-associated polymyositis: a longitudinal study of outcome. Arthritis Rheum 49: 172–178. Kawasaki A, Borruat FX (2003). An unusual presentation of herpes zoster ophthalmicus: orbital myositis preceding vesicular eruption. Am J Ophthalmol 136: 574–575.
Keith BD, Bramwell VH (2000). Pyomyositis after chemotherapy for breast cancer. Am J Clin Oncol: Cancer Clin Trials 23: 42–44. Kociecka W (2000). Trichinellosis: human disease, diagnosis and treatment. Vet Parasitol 93: 365–383. Krasnianski M, Sievert M, Bau V, et al. (2004). External ophthalmoplegia due to ocular myositis in a patient with ophthalmic herpes zoster. Neuromuscul Disord 14: 438–441. Kupferschmidt O, Kruger D, Held TK, et al. (2001). Quantitative detection of Toxoplasma gondii DNA in human body fluids by TaqMan polymerase chain reaction. Clin Microbiol Infect 7: 120–124. Lightowlers MW, Gottstein B (1995). Echinococcosis/ hydatidosis: antigens, immunological and molecular diagnosis. In: RCA Thompson, AJ Lymbery (Eds.), Echinococcus and Hydatid Disease. CAB International, London, pp. 355–410. Littleton ET, Man WD, Holton JL, et al. (2002). Human T cell leukaemia virus type I associated neuromuscular disease causing respiratory failure. J Neurol Neurosurg Psychiatry 72: 650–652. Malheiros SM, Oliveira AS, Schmidt B, et al. (1993). Dengue: muscle findings in 15 patients. Arq Neuropsiquiatr 51: 159–164. Matsubara S, Takamori M, Adachi H, et al. (1990). Acute toxoplasma myositis: an immunohistochemical and ultrastructural study. Acta Neuropathol 81: 223–227. Mayta H, Talley A, Gilman RH, et al. (2000). Differentiating Taenia solium and Taenia saginata infections by simple hematoxylin-eosin staining and PCR- restriction enzyme analysis. J Clin Microbiol 38: 133–137. Melnick JL (1996). Enteroviruses: poliovirus, coxsackievirus, echovirus, and newer enteroviruses. In: BN Fields, DM Knipe, RM Chanock, et al. (Eds.), Fields Virology, Vol. 1, Lippincott-Raven, New York, pp. 655–712. Mujgan Sonmez F, Cakir M, Yayla S, et al. (2004). Benign acute childhood myositis. Med Princ Pract 13: 227–229. Nojima T, Hirakata M, Sato S, et al. (2000). A case of polymyositis associated with hepatitis B infection. Clin Exp Rheumatol 18: 86–88. O’Neill KM, Ormsby AH, Prayson RA (1998). Cryptococcal myositis. A case report and review of the literature. Pathology 30: 314–315. Pamphlett R, O’Donoghue P (2000). Sarcocystis infection of human muscle. Aust NZ J Med 20: 705–707. Plonquet A, Bassez G, Authier FJ, et al. (2003). Toxoplasmic myositis as a presenting manifestation of idiopathic CD4 lymphocytopenia. Muscle Nerve 27: 761–765. Pozio E, Gomez Morales MA, Dupouy-Camet J (2003). Clinical aspects, diagnosis and treatment of trichinellosis. Expert Rev Anti Infect Ther 1: 471–482. Puccioni-Sohler M, Chimelli L, Mercon M, et al. (2003). Pathological and virological assessment of acute HTLV-I associated myelopathy complicated with encephalitis and systemic inflammation. J Neurol Sci 207: 87–93.
INFECTIVE MYOPATHIES Rajajee S, Shankar J, Dhattatri L (2002). Pediatric presentations of leptospirosis. Indian J Pediatr 69: 851–853. Richardson SJ, Lopez F, Rojas S, et al. (2001). Multinodular polymyositis in a patient with human immunodeficiency and hepatitis C virus coinfection. Muscle Nerve 24: 433–437. Roberts JA (1986). Viral illnesses and sports performance. Sports Med 3: 298–303. Rombout YB, Bosch S, van der Giessen JW (2001). Detection and identification of eight Trichinella genotypes by reverse line blot hybridization. J Clin Microbiol 39: 642–646. Rozenzvit MC, Zhang LH, Kamenetzky L, et al. (1999). Genetic variation and epidemiology of Echinococcus granulosus in Argentina. Parasitology 118: 523–530. Salyers AA, Whitt DD (1994). Bacterial pathogenesis. A molecular approach, ASM Press, Washington. Schantz PM, Chai J, Craig PS, et al. (1995). Epidemiology and control. In: RCA Thompson, AJ Lymbery (Eds.), Echinococcus and Hydatid Disease.CAB International, London, pp. 234–331. Scott JC, Stefaniek J, Pawlowski ZS, et al. (1997). Molecular genetic analysis of human cystic hydatid cases from Poland: identification of a new genotypic group (G9) of Echinococcus granulosus. Parasitology 114: 37–43. Sharma M, Khatib R, Jones BA, et al. (2002). Cryptococcus neoformans myositis without dissemination. Scand J Infect Dis 34: 858–859. Smadja D, Bellance R, Cabre P, et al. (1995). Atteintes du syste`me nerveux pe´riphe´rique et du muscle squelettique au cours des paraple´gies associe´es au virus HTLV-1. E´tude de 70 cas observe´ en Martinique. Rev Neurol (Paris) 151: 190–195. Smith RD, Konoplev S, DeCourten-Myers G, et al. (2004). West Nile virus encephalitis with myositis and orchitis. Hum Pathol 35: 254–258. Subramanian KN, Lam KS (2003). Malignant necrotising streptococcal myositis: a rare and fatal condition. J Bone Joint Surg Br 85: 277–278. Tabbutt S, Leonard M, Godinez RI, et al. (2004). Severe influenza B myocarditis and myositis. Pediatr Crit Care Med 5: 403–406. Taratuto AL, Venturiello SM (1997a). Echinococcosis. Brain Pathol 7: 673–679. Taratuto AL, Venturiello SM (1997b). Trichinosis. Brain Pathol 7: 663–672.
319
Taratuto A, Chimelli L (2002). Parasitic myositis. In: G. Karpati, (Ed.), Structural and Molecular Basis of Skeletal Muscle Diseases. ISN Neuropath Press, Basel, pp. 238–244. Taratuto A, Pagano MA, Fumo T, et al. (1978). Histological and histochemical changes of the skeletal muscle in human chronic Chagas’ disease. Arq Neuropsiquiatr 36: 327–330. Turner G, Scaravilli F (2002). Parasitic and fungal infections. In: DI Graham, PL Lantos (Eds.), Greenfield’s Neuropathology, (Vol. 2), Arnold, London, pp. 107–150. Uchiyama T, Arai K, Yamamoto-Tabata T, et al. (2005). Generalized myositis mimicking polymyositis associated with chronic active Epstein–Barr virus infection. J Neurol 252: 519–525. Villanova M, Caudai C, Sabatelli P, et al. (2000). Hepatitis C virus infection and myositis: a polymerase chain reaction study. Acta Neuropathol (Berl) 99: 271–276. Wadia NH, Katrak SM (1999). Muscle infection: viral, parasitic, bacterial and spirochetal. In: AH Schapira, RC Griggs (Eds.), Muscle Diseases.Butterworth-Heinemmann, Woburn MA, pp. 339–362. Wang JY, Lee LN, Hsueh PR, et al. (2003). Tuberculous myositis: a rare but existing clinical entity. Rheumatology 42: 836–840. Weis W, Brown JH, Cusak S, et al. (1988). Structure of influenza virus hemagglutinin complexed with its receptor, sialic acid. Nature 333: 2079–2081. Werneck LC, Teive HA, Scola RH (1999). Muscle involvement in leprosy. Study of the anterior tibial muscle in 40 patients. Arq Neuropsiquiatr 57: 723–734. White CA (2000). Neurocysticercosis: updates and epidemiology, pathogenesis, diagnosis and management. Ann Rev Med 51: 187–206. Wlachovska B, Abraham B, Deux JF, et al. (2004). Proliferative myositis in a patient with AIDS. Skeletal Radiol 33: 237–240. Yoshino M, Suzuki S, Adachi K, et al. (2000). High incidence of acute myositis with type A influenza virus infection in the elderly. Intern Med 39: 431–432. Zarlenga DS, Chute MB, Martin A, et al. (1999). A multiplex PCR for unequivocal differentiation of all encapsulated and non-encapsulated genotypes of Trichinella. Int J Parasitol 29: 1859–1867. Zhang L, Tarleton RL (1999). Parasite persistence correlates with disease severity and localization in chronic Chagas’ disease. J Infect Dis 180: 480–486.
Handbook of Clinical Neurology, Vol. 86 (3rd series) Myopathies F. L. Mastaglia, D. Hilton-Jones, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 16
Toxic and iatrogenic myopathies FRANK L. MASTAGLIA1* AND ZOHAR ARGOV2 1
University of Western Australia, Perth, Australia and 2Hadassah-Hebrew University Medical Centre, Jerusalem, Israel
16.1. Introduction Many drugs used in various branches of medicine, as well as alcohol and other substances of addiction, may produce muscular symptoms, either through a direct effect on the skeletal muscles or by interfering with neuromuscular transmission or peripheral nerve function (Mastaglia, 2006). A variety of chemicals, biological toxins and venoms are also myotoxic. The possibility of a drug-induced myopathy should be considered in any patient who develops muscular symptoms while on drug therapy and in drug addicts. It is important to recognize the nature of these disorders as, in most instances, symptoms are reversible if the offending agent is withdrawn, whereas failure to do so will often lead to increasing disability and in some cases even a fatal outcome. It is particularly important that the possibility of such adverse effects should be considered in patients with a pre-existing neuromuscular disorder particularly if there is an unexpected deterioration or acceleration of their condition (Mastaglia, 2006).
16.2. Basic mechanisms The mechanisms of action of drugs and toxins on muscle are diverse and have been reviewed elsewhere (Table 16.1; Mastaglia, 1982; Max et al., 1986). Some have a direct toxic effect, either locally after intramuscular injection, or more widely after systemic administration or absorption of the agent. In the case of drugs which are not inherently myotoxic, muscle damage may be secondary to an immunological process, to hypokalaemia, or to muscle compression and ischemia during periods of unconsciousness and immobility following a drug overdose. In the case of drugs such
as tetrabenazine, phencyclidine and the cholinesterase inhibitors, muscle fiber necrosis may result from excessive neural driving and accumulation of acetylcholine at the neuromuscular junction, and can be prevented experimentally by prior denervation. Some drugs such as glucocorticoids have the potential to cause a myopathy in all individuals if given in sufficiently high doses for long enough, while others such as the statin group of drugs do so in only a small proportion of individuals, suggesting that there is an individual vulnerability. Such individual susceptibility may be genetically determined, as in the case of malignant hyperthermia (see chapter 5). Experimental studies have provided a better understanding of the basic cellular mechanisms of action of drugs and toxins. In the case of a number of drugs, venoms and other chemicals which cause muscle fiber necrosis, the plasma membrane is likely to be the primary site of action, being the outer boundary of the fiber which is exposed to the full extracellular concentration of the toxin, and therefore the most vulnerable component. Altered permeability of the plasma membrane allows increased entry of calcium ions into the sarcoplasm resulting in myofibrillar contracture, and initiating a chain of events leading to necrosis or activating the apoptotic cascade (Steer et al., 1986). The muscle fiber necrosis caused by cholinesterase inhibitors has been shown to be due to calcium influx at the endplate region, where the degenerative changes commence, and can be prevented by removing calcium from the incubating medium (Leonard and Salpeter, 1979). Increased sarcoplasmic calcium levels are also thought to be the basis for the myofibrillar contracture and necrosis that occurs in the malignant hyperpyrexia crisis when susceptible individuals are exposed to certain anesthetic agents and other drugs (see chapter 6).
*Correspondence to: F. L. Mastaglia MD FRCP FRACP, Consultant Neurologist, Queen Elizabeth II Medical Centre, Nedlands, WA 6009, Australia. E-mail:
[email protected], Tel: 618-9346-1611, Fax: 618-9346-1245.
322
F. L. MASTAGLIA AND Z. ARGOV
Table 16.1 Mechanisms of drug-induced muscle damage Direct toxic effects Local Diffuse Secondary effects Electrolyte disturbance Immunological reaction Compression (‘crush syndrome’) Ischemia Neural activation
A change in ionic conductance and excitability of the plasma membrane is the basis for the myotonia induced by a number of drugs and chemicals, and for the muscular weakness and hypotonia that occurs in patients who become severely hypokalaemic or hyperkalaemic while taking diuretics or certain other drugs. Changes in the electrical properties of the plasma membrane may also underlie the muscle cramps and myalgia that occur in patients treated with a variety of drugs (see below). A number of agents interfere with aerobic or anaerobic pathways of energy generation in muscle and have been used to induce experimental models of human metabolic myopathies. Uncoupling of oxidative phosphorylation with 2,4-dinitrophenol or other chemicals produces a myopathy comparable to mitochondrial myopathy in man (Hayes et al., 1985). Iodoacetate blocks glyceraldehyde-3-phosphate dehydrogenase and causes a condition resembling the disorders of muscle glycolysis and glycogenolysis in man (Brumback et al., 1983). Some drugs interfere with muscle protein synthesis and degradation. This occurs particularly with the natural and synthetic glucocorticoids which inhibit the synthesis of muscle specific proteins as well as increasing protein degradation (Karpati, 1984). Emetine also reduces protein synthesis, while bupivacaine has been shown to inhibit protein synthesis and increase protein degradation (Steer and Mastaglia, 1986). Chloroquine, amiodarone and a number of other amphiphilic cationic compounds cause a myopathy characterized by autophagic degeneration and phospholipid accumulation in muscle. These drugs are both water and lipid soluble and readily penetrate the cell membrane in the lipid phase to become adsorbed to intracellular membranes forming inert intralysosomal drug–phospholipid complexes which accumulate as membranous and crystalloid structures within autophagic vacuoles (Lullmann et al., 1978).
16.3. Drug-induced disorders The clinical spectrum of drug-induced myopathies is very broad and ranges from asymptomatic elevation of serum creatine kinase (CK) activity to severe forms of necrotizing myopathy and rhabdomyolysis (Table 16.2). 16.3.1. Myalgia and muscle cramps Muscle pain and cramps may occur in patients treated with a variety of drugs and are usually reversible once the drug is withdrawn. The drugs most commonly implicated are hypocholesterolemic agents (statins and fibrates), diuretics, antiarrhythmics, b-adrenergic agonists, chemotherapeutic agents, calcium channel blockers and depolarizing muscle relaxants (suxamethonium). In some patients there is an associated elevation of the serum CK level. Asymptomatic CK elevation may itself be the only sign of myotoxicity, as in the case of statin myopathy (in about 0.5% of individuals taking these drugs). Similar symptoms may also occur in patients with drug-induced myotonia and may also herald the onset of a more severe necrotizing myopathy (see below). Myalgia and fasciculations are common after administration of suxamethonium and can be prevented by the administration of D-tubocurarine, diazepam or calcium gluconate prior to anesthesia. Diffuse fasciculations and myokymia have been reported in some patients treated with D-penicillamine or gold compounds (Reeback et al., 1979; Mitsumoto et al., 1982; Pinals, 1983). 16.3.2. Myotonia A number of drugs may induce myotonia in man and in experimental animals (Kwiecinski, 1981). These include colchicine, chloroquine, clofibric acid, dichlorophenoxyacetate, 20,25-diazacholesterol and the 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins; Sonoda et al., 1994; Table 16.2 Clinicopathologic spectrum of drug-induced myopathy Asymptomatic hyperCKemia Myalgia and cramps Myotonia Malignant hyperthermia Acute necrotizing myopathy (rhabdomyolysis) Acute quadriplegic myopathy Mitochondrial myopathy Inflammatory myopathies Chronic progressive myopathy Focal myopathies
TOXIC AND IATROGENIC MYOPATHIES Rutkove et al., 1996). Other drugs may exacerbate myotonia or unmask previously undetected myotonia. These include the depolarizing muscle relaxants (e.g., suxamethonium) which can markedly exacerbate myotonia during general anesthesia. Non-depolarizing relaxants do not have this effect and are therefore preferable for use in patients with myotonia. The b2-adrenergic blockers propranolol and pindolol and the b2-adrenergic agonists fenoterol and ritodrine, can also aggravate myotonia (Sholl et al., 1985). A number of diuretics, including furosemide, ethacrynic acid, mersalyl and acetazolamide induce myotonia in animal muscles and should be used with caution in individuals with hereditary forms of myotonia (Bretag et al., 1980). 16.3.3. Necrotizing myopathies Many drugs can cause a myopathy characterized pathologically by muscle fiber necrosis without inflammation, and associated with elevation of the serum CK level. Symptoms in such cases usually evolve over a period of days or weeks and weakness involves mainly the proximal limb muscles, but may be more generalized and profound in some cases. Myalgia and muscle tenderness may be prominent in the more rapidly developing cases. The tendon reflexes are usually preserved, unless the myopathy is severe or is associated with a peripheral neuropathy. The condition varies greatly in severity from cases with only myalgia and hyperCKemia to the syndrome of acute rhabdomyolysis at the extreme end of the spectrum (see below). 16.3.3.1. Cholesterol-lowering agents 16.3.3.1.1. Statins These drugs have become the main lipid-lowering agents used in the current era, and are now prescribed for most patients with cardiovascular and cerebrovascular disease. Statins inhibit the function of HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis, causing a reduction in formation of mevalonate, which is an important intermediary metabolite in the synthesis of cholesterol. Since they were first introduced, statins were reported to be myotoxic and this caused concern because of their wide usage, however the magnitude of the risk, the exact syndromes and the mechanisms of this side effect are still unclear (for reviews see Ucar et al., 2000; Thompson et al., 2003; Rosenson, 2004) A recent advisory report (Pasternak et al., 2002) defined four clinical presentations of statin myotoxicity: (1) statin myopathy (any muscle complaint); (2) myalgia (pain without CK elevation); (3) myositis (muscle symptoms with raised CK); (4) rhabdomyolysis (marked CK elevation above 10 times the normal upper limit).
323
However, this subdivision is problematic as it gives emphasis to various non-specific complaints that may be unrelated to the statins (e.g., muscle pain), yet ignores cases with asymptomatic CK elevation (Thompson et al., 2003). In the neuromuscular clinic statin myotoxicity may present in the following ways: 1. Asymptomatic rise of serum CK which is usually mild and disappears after withdrawal of the statin. A subgroup of this category is exaggerated CK elevation after exercise in patients on statins (Thompson et al., 1990). 2. Myalgia or cramps, which are usually associated with CK elevation. There is a problem with the subgroup of patients who have myalgia with statin treatment without CK rise. Some studies suggested that the rate of this symptom is similar in patients who are on statin and in those who are on placebo (Thompson et al., 2003). However, this subgroup may include a large “dilutional” effect of patients on statins who have other non-specific complaints (see Franc et al., 2003). Both asymptomatic CK elevations and myalgia may persist after withdrawal of statins in some patients (Walravens et al., 1989; Argov, 2000). 3. Rhabdomyolysis, which may be severe and even fatal. More than 3500 cases have been recorded in which rhabdomyolysis appeared in patients on statins (Omar and Wilson, 2002) with an estimated mortality rate of 7.8% (Thompson et al., 2003). 4. Myositis, which is a very rare syndrome with statin treatment (Goldman et al., 1989). Initially myotoxicity was reported in 0.1% of patients on statin monotherapy, however this seems to be an underestimate. Serious side effects in the form of rhabdomyolysis are rare but may be life threatening, with an estimated mortality rate of 0.15 per 1 million prescriptions (Staffa et al., 2002). Interestingly, when the results of randomized studies were evaluated no significant difference was found in rates of myotoxicity and severe rhabdomyolysis between the control and the drug-treated groups; however this seems not to be the case after the introduction of wide usage of these medications (Thompson et al., 2003). Furthermore, some agents may be more hazardous, as was the case with cerivastatin, which was withdrawn from usage because of numerous cases of fatal rhabdomyolysis worldwide (Farmer, 2001), and more recently rosuvastatin (Alsheikh-Ali et al., 2005). There may also be an increased risk for the development of statin myopathy in certain subgroups of patients (Grundy, 2005). Some of the factors associated with this increased risk include advanced age (especially
324
F. L. MASTAGLIA AND Z. ARGOV
>80 years), female gender, high statin doses, the use of more than one cholesterol-lowering agent, renal insufficiency (especially if caused by diabetes), obstructive liver disease, and coadministration of drugs that inhibit or are metabolized by the CYP3A4 isoenzyme of the cytochrome P450 system (Rosenson, 2004; Grundy, 2005). These include gemfibrozil and other fibrates, nicotinic acid, ciclosporin, azole antifungal agents, macrolide antibiotics and niacin. Grapefruit juice, which contains the CYP3A4 inhibitor furano-coumarin, also increases the risk of developing myopathy (Dreier and Endres, 2004; Lilja et al., 2004). Most statins are metabolized by this enzyme system in the liver, and those that are not (e.g., pravastatin) are thought to carry a lower risk for myopathy, at least in animal experiments (Gadbut et al., 1995; Nakahara et al., 1998). It has also been postulated that those statins that are more lipophilic carry a higher risk for myotoxicity because of their increased penetrance into the cell. It is not known whether an elevated serum CK level before starting statin therapy increases the risk of myotoxicity. The exact mechanism by which statins produce muscle damage is unknown but several hypotheses have been suggested (for reviews see Ucar et al., 2000; Thompson et al., 2003). The prevailing theory is that all drugs that interfere with the production and metabolism of cholesterol deplete muscle membranes of some essential lipid component. Several other mechanisms have also been postulated to explain the statin-induced myopathy. The first is mitochondrial dysfunction due to reduced synthesis of ubiquinone or availability of another metabolite. Mevalonate is also a precursor of ubiquinone (coenzyme Q10, an important compound for mitochondrial function). Plasma ubiquinone levels were found to be reduced in patients on statins in some studies (Watts et al., 1993; Bargossi et al., 1994) but not in others (Laaksonen et al., 1996; Bleske et al., 2001) and have also been shown to be reduced in muscle in some patients with statin myopathy (Lamperti et al., 2005). Other possible mechanisms include induction of apoptosis (Johnson et al., 2004) and alteration of ionic conductance across membranes (Jamal et al., 2004). To reduce the risk of statin myopathy it is important to use the lowest drug dose to achieve the required level of cholesterol reduction, avoid using multiple cholesterol-lowering agents, and use non CYP3A4 metabolized statins (e.g., pravastatin), particularly when other medications that increase the risk of myopathy are being used (Baker et al., 2004). The use of supplementary ubiquinone (coenzyme Q10) has not been proven to be protective (Ucar et al., 2000). There is a controversy about the routine monitoring of CK levels before prescription of statins. We do recommend this in order to avoid having to stop the medication if any myalgic complaints appear and
the CK level is then found to be elevated. Another debate is whether to stop statins in asymptomatic patients if there is a rise in the CK level during treatment. It is not usually recommended to stop statin if the CK rise is less than 3–5 times the normal upper limit (Argov, 2000; Pasternak et al., 2002). Another major decision is whether to reintroduce a statin after an episode of rhabdomyolysis in patients who need it. The preferred options in this situation are to commence another statin such as pravastatin with a lower risk of myotoxicity or to use ezetimibe which inhibits intestinal absorption of cholesterol. However, recent reports indicate that ezetimibe may also cause myalgia and hyperCKemia when administered with a statin (Fux et al., 2004). 16.3.3.1.2. Fibrates A necrotizing myopathy also occurs in some patients treated with clofibrate or bezafibrate (Langer and Levy, 1968; Rumpf et al., 1984; Magarian et al., 1991), and in one survey elevated serum CK levels were found in 8–16% of patients taking a fibrate drug (Afifi et al., 1984). A recent population-based cohort study in Denmark concluded that the risk of developing a myopathy was six times greater in individuals taking a fibrate drug than in those taking a statin (Gaist et al., 2001). Symptomatic myopathy is uncommon when these drugs are taken in conventional doses but is more likely to occur when a fibrate is combined with a statin, and in patients with nephrotic syndrome, renal failure or hypothyroidism. Withdrawal of the drug or dose reduction is usually followed by gradual recovery but readministration may lead to a recurrence of symptoms (Magarian et al., 1991). 16.3.3.1.3. Nicotinic acid A reversible myopathy characterized by severe muscle pain, cramping and elevated enzyme levels can also occur in patients taking nicotinic acid (Litin and Anderson, 1989). Rhabdomyolysis has been reported in patients taking nicotinic acid in combination with lovastatin (Reaven and Witztum, 1988) and the combination of nicotinic acid and a statin should therefore be avoided. 16.3.3.2. S-aminocaproic acid A myopathy is a well-recognized but uncommon complication in patients with subarachnoid hemorrhage or hereditary angioneurotic oedema treated with this antifibrinolytic agent (Lane et al., 1979; Brown et al., 1982). The myopathy usually develops after 4–6 weeks of treatment with doses over 18 g per day and may vary in severity from a mild self-limiting condition to severe life-threatening rhabdomyolysis with myoglobinuria
TOXIC AND IATROGENIC MYOPATHIES and renal failure (Britt et al., 1980). Muscle biopsy shows disseminated myofiber necrosis and regeneration (Fig. 16.1) with selective involvement of type I fibers in some cases. As -aminocaproic acid is a lysine analogue, it may become incorporated into cell membranes in place of lysine, leading to altered membrane function, and may also compete with lysine in the synthesis of carnitine (Kane et al., 1988). An ischemic basis for the muscle damage is also possible as fibrinogen deposition and capillary occlusions are found in biopsies from some cases (Mastaglia, 1982). 16.3.3.3. Emetine A severe myopathy with weakness of the bulbar, neck and proximal limb and trunk muscles may develop in individuals taking emetine for the treatment of amoebiasis, or for alcohol aversion therapy, or using ipecac syrup as an emetic agent (Bennett et al., 1982; Friedman, 1984; Mateer et al., 1985; Palmer and Guay, 1985; Lacomis et al., 1996). Serum CK activity is elevated up to 15-fold but may be normal in some cases. Histological changes in biopsied muscles consist of scattered myofiber necrosis and regeneration, core-targetoid areas with loss of enzyme activity and cytoplasmic bodies (Lacomis et al., 1996). The drug also has cardiotoxic effects and can cause left ventricular dysfunction and cardiac failure in some cases. The condition is usually reversible, with gradual recovery over a period of weeks to months after the drug is stopped, but may be fatal in some cases (Friedman, 1984). Experimental studies have shown that emetine has a myotoxic action leading to mitochondrial and myofibrillar changes followed by myofiber necrosis and regeneration (Duane and Engel, 1970; Bradley et al., 1976).
Fig. 16.1. Necrotizing myopathy in a patient treated with E-aminocaproic acid (haematoxylin & eosin).
325
16.3.3.4. Cardiac glycosides There have been a number of reports in the Australian literature of the development of a proximal myopathy in opiate addicts consuming large quantities of the cough suppressant linctus codeine (Australian Pharmaceutical Formulary; Kennedy, 1981; Kilpatrick et al., 1982). One of the components of linctus codeine is squill (an extract of the bulb of Urginea maritama) which contains the cardiac glycosides scillarin A and B (Kennedy, 1981). Muscle pain and tenderness were prominent and myasthenic features were present in some cases. Serum CK levels were elevated up to 25-fold and muscle biopsy showed evidence of a necrotizing myopathy. Electrocardiographic changes of cardiac glycoside toxicity were also present in these cases. 16.3.4. Acute rhabdomyolysis This is the most serious and acute form of necrotizing myopathy encountered in clinical practice. It may occur following general anesthesia, alcohol intoxication, prolonged drug-induced coma, self-administration of heroin, cocaine and other narcotic drugs, or intoxication with one of a number of other drugs (Table 16.3; Gabow et al., 1982; Briner et al., 1986; Grob, 1990). The same syndrome may also occur following envenomation or other forms of poisoning. The condition is characterized by severe muscle pain, tenderness and areflexic weakness evolving over a period of 24–48 hours. Marked swelling of limb muscles may occur leading to the development of a compartment syndrome with secondary ischemia and peripheral nerve entrapment, and in some cases urgent fasciotomy is required. The serum CK level is markedly elevated and electromyography reveals florid myopathic motor unit changes and spontaneous potentials in multiple muscles. Myoglobinuria is an early feature and may lead to acute tubular necrosis and oliguric renal failure. Hyperkalemia, hyperphosphatemia and hypocalcemia are common in such patients, the latter being thought to be secondary to the deposition of calcium salts in damaged muscles, while hypercalcemia may develop during the recovery phase (Gabow et al., 1982; Knochel, 1982). Muscle biopsy shows widespread myofiber necrosis, and mild reactive inflammatory changes (Figs. 16.1 and 16.8). Regenerative changes are often also a feature but may be absent in cases dying at an early stage. Although the prognosis for recovery is generally good, some patients die as a result of multiple organ failure and other complications (Briner et al., 1986). Although a variety of drugs have been implicated in causing acute rhabdomyolysis (Table 16.3), few of these have been proven to be inherently myotoxic and in most
326
F. L. MASTAGLIA AND Z. ARGOV
Table 16.3
Table 16.3
Drugs and toxins that have been implicated in causing acute rhabdomyolysis and myoglobinuria
(Continued)
Therapeutic drugs Statins Fibrates E-aminocaproic acid Antidepressantsa Barbituratesa Opiatesa Salicylatesa Antihistaminesa Drugs of addiction Ethanol Amphetamines Heroin Cocaine Methadone Lysergic acid Hyperkinetic states Lithium Serotonin-specific reuptake inhibitors Phencyclidine Strychnine Chemical toxins Ethanol Isopropyl alcohol Ethylene glycol Carbon monoxide Mercuric chloride Copper sulphate Zinc phosphide Metaldehyde Chloralose Paraphenylenediamine Toluene (paint) Gasoline (sniffing) Lindane Carbon tetrachloride Metal fumes Malignant hyperthermia Suxamethonium Halothane Other anesthetics Neuroleptic malignant syndrome Phenothiazines Butyrophenones Thioxanthenes Metoclopramide Clozapine Lithium Dopaminergic drugs Hypokalaemia Diuretics Carbenoxolone Amphotericin
Licorice Laxative abuse Envenomations Snake venoms Hornet venom Wasp venom Brown spider venom Other Haff disease Quail ingestion a
Overdose
cases there are likely to be other contributory factors. In particular, in many cases of alcohol or drug overdose leading to prolonged periods of unconsciousness and immobility, muscle compression and ischemia, as well as hypoxia and hypotension are likely to play a major role. In another group of cases with drug-induced seizures (Tam et al., 1980; Jennings et al., 1983; Modi et al., 1985), dyskinesias (Lazarus and Toglia, 1985), acute dystonic reactions (Cogen et al., 1978) and neuroleptic malignant syndrome the common factor appears to be sustained or repetitive muscular activity. It is likely that a number of cases of post-anesthetic rhabdomyolysis attributed to suxamethonium were in fact incomplete forms of malignant hyperpyrexia. However there are some cases, particularly in children, who do not have malignant hyperpyrexia or a muscle enzyme defect, who develop rhabdomyolysis after the use of suxamethonium during anesthesia (Gibbs, 1978; Chaboche et al., 1982; Blumberg and Marti, 1984). The management of patients with acute rhabdomyolysis is primarily supportive and symptomatic with careful monitoring of fluid and electrolyte balance and renal function and early detection and treatment of any derangements that arise. Monitoring of intracompartment pressures is also important in patients with severe muscle swelling as a guide to when fasciotomy and decompression is required. 16.3.5. Mitochondrial myopathy A myopathy characterized by ragged red fibers, cytochrome C oxidase-negative fibers and abnormal mitochondria with paracrystalline inclusions (Fig. 16.2) was described in patients with the acquired immunodeficiency syndrome (AIDS) on long-term treatment with zidovudine (AZT; Dalakas et al., 1990; Panegyres et al., 1990; Mhiri et al., 1991; Chariot et al., 1993).
TOXIC AND IATROGENIC MYOPATHIES
Fig. 16.2. Electron micrograph showing enlarged pleomorphic mitochondria in a patient with AIDS with zidovudine myopathy. Bar ¼ 1 mm. (Courtesy of Dr. P. Panegyres.)
The myopathy is characterized clinically by myalgia, fatigue, proximal or generalized muscle weakness and atrophy and elevated serum CK levels, and usually improves when the drug is withdrawn (Chalmers et al., 1991). In some patients there is an associated inflammatory myopathy and it may be difficult to distinguish the two conditions. This myopathy has been shown to be due to inhibition of mtDNA replication and mtDNA depletion in muscle fibers (Arnaudo et al., 1991). A mitochondrial myopathy with ragged-red and cytochrome oxidase-negative fibers has been reported in some patients taking statins but is rare (England et al., 1995; Phillips et al., 2002). These cases differ from the more common form of statin myopathy in having normal serum CK levels. Mitochondrial abnormalities and reduced cytochrome C oxidase activity also occur in the myopathy induced by germanium which is a constituent of a number of dietary supplements and elixirs (Higuchi et al., 1991; Wu et al., 1992; Tao and Bolger, 1997). 16.3.6. Dyskalemic myopathy Hypokalemia of sufficient severity to cause muscular weakness and hypotonia may develop in patients treated with thiazide diuretics, amphotericin B, carbenoxolone, lithium and fluoroprednisolone-containing nasal sprays, or with laxative abuse (Vita et al., 1986; Chemali et al., 2001). Hypokalemic myopathy may also develop in individuals who consume large quantities of licorice or licorice extracts which are constituents of certain traditional Chinese drugs, or who use large quantities of snuff or chewing-tobacco (Valeriano et al., 1983; Mori et al. 1985). The common ingredient that causes hypokalemia is the powerful mineralocorticoid analogue glycyrrhizinic acid.
327
The weakness in such cases is often generalized and profound with hypotonia and depression of the tendon reflexes, and may resemble the Guillain–Barre´ syndrome. Although the condition is usually painless, myalgia may be present in more rapidly evolving cases. In some cases the weakness may be episodic and may resemble familial hypokalemic periodic paralysis. The serum CK level is usually markedly elevated and myoglobinuria and acute renal failure develops in some cases (Saito et al., 1994). Histological changes in muscle are relatively inconspicuous, scattered fibers being swollen and vacuolated, while in more severe cases, myofiber necrosis and regeneration is present (Comi et al., 1985). Complete recovery is the rule after potassium replacement. Less commonly, profound muscle weakness may develop in patients treated with potassium-retaining diuretics who become hyperkalemic (Udezue and Harrold, 1980). 16.3.7. Inflammatory myopathies 16.3.7.1. Polymyositis A number of drugs have been associated with the development of an inflammatory myopathy. The most frequent has been D-penicillamine (DPA) used in the treatment of patients with rheumatoid arthritis, progressive systemic sclerosis or Wilson’s disease. The average dose of DPA used in reported cases was 600 mg per day and the average duration of treatment before development of the inflammatory myopathy was 12 months (Takahashi et al., 1986; Carroll et al., 1987). However in some cases the myopathy developed even after a few weeks of treatment with doses as low as 50–100 mg per day. The myopathy may be indistinguishable clinically and pathologically from other forms of polymyositis or dermatomyositis. In most cases prompt improvement occurs after stopping DPA, but some cases require a course of prednisolone. The incidence of inflammatory myopathy appears to be higher than expected in patients with rheumatoid arthritis who are treated with DPA suggesting that the drug is causally involved in the development of the myopathy (Takahashi et al., 1986; Chappel and Willems, 1996). This is further supported by the observation that the myositis may reappear following a second course of DPA (Takahashi et al., 1986). Other patients fail to develop myositis during a second course of the drug, while some are able to continue taking a lower dose of DPA. D-penicillamine may also induce other autoimmune disorders and the development of myositis has been attributed to disturbed immunoregulation by the drug. An association with HLA-B18, B35 and DR4 was reported in one series of cases of DPA-induced myositis, suggesting that there is a genetic predisposition (Carroll et al., 1987).
328
F. L. MASTAGLIA AND Z. ARGOV
There have been a number of reports of polymyositis or dermatomyositis developing in patients treated with interferon-a (Kalkner et al., 1998; Cirigliano et al., 1999; Dietrich et al., 2000; Hengstman et al., 2000), which is used to treat chronic viral hepatitis as well as some forms of malignancy and resistant cases of chronic inflammatory demyelinating polyneuropathy. Interferon-a is also known to induce other autoimmune diseases such as myasthenia gravis and systemic lupus erythematosus. There are occasional reports of inflammatory myopathy developing in patients treated with a number of other drugs including: procainamide, cimetidine, leuprolide, propylthiouracil, carbimazole, hydralazine, phenytoin, mesantoin, penicillin and levodopa. However, the role of these drugs in causing inflammatory myopathy remains unproven. 16.3.7.2. Eosinophilia-myalgia syndrome An interstitial form of eosinophilic myositis and fasciitis was reported in the early 1990s in patients taking certain preparations containing the naturally occurring amino acid L-tryptophan (eosinophilia-myalgia syndrome; Eidson et al., 1990; Hertzman et al., 1990; Medsger, 1990; Silver et al., 1990; van Garsse and Boeykens, 1990). Over 1500 cases of this syndrome occurred in the United States (Kaufman, 1990). The syndrome was characterized by severe myalgia, muscle tenderness and hyperesthesia with edema and induration of the skin of the extremities resembling scleroderma, and a marked peripheral blood eosinophilia (Varga et al., 1990). In some cases there was an associated polyneuropathy and other systemic features (Kaufman, 1990). The bulk source of the tryptophan preparation in the American cases was traced to a single manufacturer and the syndrome is now thought to have been due to a chemical contaminant (Belongia et al., 1990). 16.3.7.3. Macrophagic myofasciitis This syndrome emerged in the 1990s, mainly in France (Gherardi et al., 1998), but also in other European countries, and consisted of diffuse myalgia and arthralgia associated with fatigue and the symptoms responded to steroid therapy. More than 130 cases were recorded (Gherardi et al., 2001). The syndrome was associated with other immune-mediated disorders in about one-third of the cases and is now thought to be caused by aluminium hydroxide which is a component of various intramuscularly injected vaccines (Gherardi and Authier, 2003). Deltoid muscle biopsies showed inflammatory cell infiltrates around the muscle tissue in the majority of patients. The inflammatory cells were mainly lymphocytes and macrophages, the latter containing inclusions that were shown to be composed of aluminium hydroxide. All 50
patients in one report (Gherardi et al., 2001) had been vaccinated for either hepatitis or tetanus. Symptoms appeared immediately after the vaccination or were delayed as much as a few months to a few years. The pathogenesis of this disorder is unclear and several questions remain unanswered: if the aluminum is to blame then why are the first symptoms in the legs and not closer to the site of injection of the vaccine? The long delay before the onset of symptoms is also unexplained. Are the macrophages sensitized in some way and then produce the syndrome (Gherardi and Authier, 2003)? Is it possible that only certain patients are susceptible to this condition as many more were immunized with the same preparations? Rats injected with aluminum-containing vaccines showed the same histological picture at the site of biopsy (Gherardi et al., 2001). Thus, focal muscle damage does occur with these preparations, as macrophages accumulate and contain intracytoplasmic inclusions of aluminum. However the mechanism by which it causes a more widespread syndrome remains to be proven. 16.3.8. b-adrenoreceptor blockers Patients treated with b-blockers commonly complain of muscle fatigue and reduced exercise tolerance. Physiological studies in normal subjects and hypertensive patients on long-term treatment have shown that these symptoms are due to a reduced cardiac output and the effects of the drug on muscle metabolism during exercise. Subjects on b-blockers show a greater than normal depletion of muscle ATP and creatine phosphate levels during exercise, which appears to be due to a reduction in the supply of free fatty acids, rather than to any substantial effect on glycogen utilization (Frisk-Holmberg et al., 1979; Kaiser et al., 1985). Endurance exercise capacity is reduced to a greater extent with non-selective b-blockers such as propranolol and more so in subjects with higher proportions of slow-twitch (type I) fibers in the lower limb muscles (Karlsson, 1983). Although b-blockers are not inherently myotoxic, there has been a report of a patient developing a severe painless proximal myopathy with elevated serum CK levels during treatment with propranolol and sotalol (Forfar et al., 1979). Muscle pain and raised serum CK levels have also been reported in a hypertensive patient being treated with labetalol (Teicher et al., 1981). The mechanism of the myopathy in these cases remains uncertain, although in both cases there was prompt improvement after withdrawal of the drugs, suggesting a causal relationship. The b-adrenergic blockers may also interfere with neuromuscular transmission and there are occasional reports of propranolol, oxprenolol and practolol unmasking myasthenia gravis or inducing a myasthenic syndrome
TOXIC AND IATROGENIC MYOPATHIES
329
de novo (Argov and Mastaglia, 1979a). Propranolol and pindolol have also been reported to exacerbate myotonia in some cases (Blessing and Walsh, 1977; Ricker et al., 1978). 16.3.9. Corticosteroid myopathy A myopathy is a common complication of prolonged treatment with glucocorticoids. There is a high risk of myopathy in patients taking daily doses of prednisone over 40 mg per day, but even lower doses (over 10 mg prednisone per day or its equivalent) may cause myopathy if taken for prolonged periods (Bowyer et al., 1985). The risk of myopathy is greater with the 9-a-fluorinated steroids triamcinolone, betamethasone and dexamethasone. Quantitative studies of muscle function in patients on long-term daily steroid therapy frequently show reductions in muscle performance (Khaleeli et al., 1983; Rothstein et al., 1983) and electromyographic studies also show a high incidence of subclinical myopathy. In a study of patients with brain tumors who were on daily dexamethasone therapy the risk of myopathy was found to be lower in patients who were also taking phenytoin which increases the hepatic metabolism of dexamethasone (Dropcho and Soong, 1991). Muscle weakness develops insidiously, in the quadriceps and pelvic girdle muscles initially, and may become profound and disabling in some cases. Muscles innervated by the cranial nerves are usually spared, but dysphonia due to myopathy of the laryngeal muscles may occur in patients who use inhaled corticosteroids (Williams et al., 1983). Diaphragmatic weakness may also develop in asthmatic patients on long-term corticosteroids (Bowyer et al., 1985). Serum CK levels are normal or reduced and if elevated should suggest the possibility of another necrotizing or inflammatory myopathy. Urinary excretion of creatine and 3-methylhistidine is increased but is not helpful diagnostically (Khaleeli et al., 1983). Electromyography shows typical myopathic changes in proximal limb muscles with reduction in motor unit duration and amplitude without spontaneous muscle fiber potentials. However, the EMG may be normal or only mildly abnormal in some cases. Muscle biopsy shows selective atrophy of type II fibers (Fig. 16.3), particularly of the type IIB fibers which are also selectively affected in experimental steroid myopathy (Braunstein and DeGirolami, 1981; Livingstone et al., 1981). Muscle fiber necrosis, regeneration and other degenerative changes are not a feature but may occur in the severe generalized form of myopathy which can occur in asthmatics after high doses of intravenous hydrocortisone (see below) and in some patients treated with high-doses of dexamethasone.
Fig. 16.3. Myosin ATPase (pH 9.4) preparation showing type II fibre atrophy in a patient with corticosteroid myopathy.
The biochemical and physiological effects of corticosteroids have been extensively investigated in experimental studies. These showed changes in aerobic and anaerobic metabolism (Shoji et al., 1974), lipid content (Wakata et al., 1983), calcium uptake by the sarcoplasmic reticulum (Shoji et al., 1976), muscle contractile proteins and myofibrillar ATPase activity (Clark and Vignos, 1979), protein synthesis and degradation (Santidrian et al., 1981; Clark et al., 1986), membrane excitability (Gruener and Stern, 1972) and muscle contractile properties (Gardiner and Edgerton, 1979). The basic cellular action of glucocorticoids appears to be an inhibition of mRNA synthesis which in turn interferes with the synthesis of muscle proteins (Rannels et al., 1978). The basis for the susceptibility of fast-twitch glycolytic (type IIB) fibers is uncertain. Studies of glucocorticoid receptor content in the slow-contracting soleus and fastcontracting extensor digitorum longus muscles of the rat showed a higher concentration of cytosol binding sites in the soleus than in the extensor digitorum longus (Shoji and Pennington, 1977; DuBois and Almon, 1984). An increase in receptor concentration occurs with disuse and denervation and it may therefore be that endogenous glucocorticoids play a part in causing the muscle fiber atrophy which occurs in these situations (DuBois and Almon, 1980; 1981). This would also account for the observation that the degree of atrophy induced by dexamethasone in denervated muscles is greater than that expected from either denervation or dexamethasone alone (Livingstone et al., 1981). Moreover, relative disuse of muscles due to physical inactivity may render them more susceptible to the effects of glucocorticoids. Corticosteroid myopathy is usually reversible if the drug is withdrawn or the dose reduced, or to some extent if an alternate day regimen is implemented. Anabolic steroids and B group vitamins have been shown to prevent the development of myopathy in the rat (Sakai et al., 1978) but not in man (Coomes, 1965). Recent
330
F. L. MASTAGLIA AND Z. ARGOV
studies in rats and in man have shown that glucocorticoid-induced muscle atrophy and weakness can be at least partially prevented or reversed by a regular program of physical training (Hickson and Davis, 1981; Horber et al., 1985). Growth hormone and insulin-like growth factor-1 have also been reported to be protective (Kanda et al., 1999). 16.3.10. Acute quadriplegic myopathy Acute quadriplegic myopathy (AQM) is the term used for the syndrome of severe skeletal muscle weakness that develops in patients treated in intensive care units (ICU), usually with a combination of corticosteroids and non-depolarizing neuromuscular blocking agents. Numerous such cases have been reported and various other terms were used for it: critical illness myopathy, acute steroid myopathy (Lacomis et al., 2000). The clinical picture is that of severe weakness of all voluntary limb muscles and neck flexors with paralysis of respiratory muscles leading to difficulties in weaning patients off the respirator. Facial weakness may infrequently be found. The tendon reflexes are either lost or markedly diminished. There is no sensory impairment, in contrast with the so-called intensive-care neuropathy, however, this may be difficult to assess in such patients. The serum CK level is usually elevated, but not to extreme levels, and some patients have a normal CK level. Muscle biopsy shows non-specific changes, such as atrophy of both fiber types, angulated fibers and fiber size variations; at times fiber necrosis may also be seen. ATPase staining may show reduced activity in the central part of the muscle fibers. However the diagnosis is confirmed only by the demonstration of selective loss of thick (myosin) filaments with preservation of Z bands on electron microscopy (Fig. 16.4). Electromyographic findings are heterogeneous: a mix of myopathic potentials and “neurogenic features” can be found and even spontaneous activity may be recorded. This may represent the combination of critical care neuropathy with the AQM syndrome. Nerve conduction is normal although the compound muscle action potentials may be reduced in amplitude. The electrophysiological hallmark of AQM is loss of membrane excitability. This is manifested by a reduced or absent response to direct muscle stimulation in vivo (Rich et al., 1996, 1997). It is usually found in patients with severe weakness and improves with clinical improvement. While most reported cases were treated with prolonged respiratory assistance, neuromuscular blockers and steroids (Lacomis et al., 1996), some patients had only one of these agents at times only in relatively low doses (Hoke et al., 1999).The first report of this syndrome was in patients with asthma, and some authors
Fig. 16.4. For full color figure, see plate section. Electron micrograph showing selective A-band and thick filament loss in a patient with acute quadriplegic myopathy. (Courtesy of Dr W Squires.)
have estimated that about one-third of patients with severe asthma who are treated in an ICU developed this complication (Douglass et al., 1992). AQM may also occur after liver transplantation at an estimated frequency of 7% (Campellone et al., 1998; Miro et al., 1999) or after heart transplantation (Perea et al., 2001). The differential diagnosis includes mainly critical care neuropathy, which may be associated with AQM, as it affects the same patient population, and may be hard to differentiate from the myopathy (Gutmann, 1999; Lacomis et al., 2000). The development of an acute neuromuscular disease such as Guillain–Barre´ syndrome or myasthenia gravis during the intensive care period, and metabolic conditions (hypokalemia, pseudocholinesterase deficiency) should also be considered in differential diagnosis (Argov, 2000). The causes of AQM and its pathophysiology are still unclear. The disorder may appear without exposure to either steroids or neuromuscular blockers (Showalter and Engel, 1997; Hoke et al., 1999), thus questioning whether it is purely a drug-induced condition. However the condition has been reported only in intensive care patients and should be regarded as iatrogenic. Contributing factors have been postulated to be protein malnutrition, muscle disuse and older age. An animal model in the rat has shown myosin loss in muscle only if it was denervated before the use of steroids (Massa et al., 1992), thus loss of neural activation rather than a toxic effect of neuromuscular-blocking agents may be an important factor. Such animals have also shown the feature of muscle fiber membrane inexcitability which was found to be due to impaired sodium channel activation (Rich and Pinter, 2001). It is not clear however that inexcitability occurs in all patients with AQM as this test was not performed in a large prospective study
TOXIC AND IATROGENIC MYOPATHIES
331
of patients with this condition as defined by the histological criteria. The mechanism by which all these factors combine to lead to disaggregation of myosin monomers is still speculative. The prognosis of AQM is usually good and better than that of critical care neuropathy, with most patients who survive the intensive care treatment, recovering within a period of a few months. 16.3.11. Autophagic myopathies A large group of drugs with amphiphilic cationic properties may interfere with lysosomal digestion and cause autophagic degeneration and accumulation of phospholipids in lysosomes (Drenckhahn and Lullmann-Rauch, 1979). Three of these drugs, chloroquine, amiodarone and perhexiline, as well as vincristine and colchicine, are known to cause a myopathy or neuromyopathy in man. 16.3.11.1. Chloroquine This antimalarial and antirheumatic drug has been reported to cause a myopathy or neuromyopathy after treatment with doses of 250–750 mg per day for periods ranging from several weeks to 4 years (Mastaglia et al., 1977). The condition is characterized by the insidious development of painless weakness, particularly of proximal muscle groups, often associated with atrophy which may be severe in advanced cases. Depression of tendon reflexes, mild sensory changes and abnormal nerve conduction studies are often also found, pointing to an associated peripheral neuropathy. Diplopia has been present in some cases. Serum enzyme levels are normal or slightly elevated, and electromyography may show spontaneous muscle fiber potentials in addition to the typical motor unit changes of myopathy (Eadie and Ferrier, 1966; Mastaglia et al., 1977). A cardiomyopathy is also present in some cases (Hughes et al., 1971; Estes et al., 1987). The myopathy is slowly reversible once the drug is withdrawn. Hydroxychloroquine may cause a similar but less severe condition (Richards, 1998; Stein et al., 2000). Histologically, the myopathy is characterized by vacuolar change in both major fiber types (Fig. 16.5). Electron microscopy shows that the vacuolation is due to autophagic degeneration (Fig. 16.6) with associated exocytosis and accumulation of lamellated membrane bodies (myeloid bodies) in muscle fibers and in interstitial cells, as well as curvilinear bodies (Mastaglia et al., 1977; Neville et al., 1979). Quantitative studies confirm that there is an accumulation of phospholipids and neutral lipids (Mastaglia et al., 1977). Experimental studies have shown early swelling of the sarcoplasmic
Fig. 16.5. Chloroquine myopathy. Myosin ATPase (pH 7.2) preparation showing vacuolar myopathy especially of type I muscle fibers.
Fig. 16.6. Electron micrograph showing autophagic degeneration in a muscle fibre in a case of chloroquine myopathy.
reticulum (Schmalbruch, 1980; Trout et al., 1981), and a marked increase in lysosomal enzyme activity (Stauber et al., 1981). 16.3.11.2. Perhexiline This drug causes a demyelinating peripheral neuropathy in a small proportion of treated patients (Argov and Mastaglia, 1979b). In some cases there are additional features of a myopathy with myalgia and weakness of proximal as well as distal limb muscle groups. Occasional cases of proximal myopathy without an associated peripheral neuropathy have also been reported (Tomlinson and Rosenthal, 1977). Ultrastructural studies in patients and in mice with an experimentally-induced form of perhexiline neuromyopathy have shown numerous membranous and granular inclusions of probable lysosomal origin in muscle fibers as well as endothelial cells and Schwann cells (Fardeau et al., 1979).
332
F. L. MASTAGLIA AND Z. ARGOV
16.3.11.3. Amiodarone There is a number of reports of a demyelinating peripheral neuropathy developing in patients treated with this antiarrhythmic drug (Mastaglia and Argov 1988). The drug may also cause a neuromyopathy in addition to its other adverse effects (Anderson et al., 1985; Fernando Roth et al., 1990). Histological changes in proximal limb muscles include fiber vacuolation, autophagic degeneration and membrane-bound dense bodies (Meier et al., 1979), and myofiber necrosis (Clouston and Donnelly, 1989). 16.3.11.4. Vincristine This alkaloid, which interferes with RNA and protein synthesis and with the polymerization of tubulin into microtubules, commonly causes an axonal peripheral neuropathy, and in some patients this is associated with a proximal myopathy (Bradley et al., 1970). Electron microscopic studies have shown that the drug has a profound effect on membrane systems leading to the formation of complex spheromembranous bodies, thought to be derived from the sarcoplasmic reticulum, and autophagic degeneration of muscle fibers (Anderson et al., 1967; Bradley et al., 1970). 16.3.11.5. Colchicine Like vincristine, this drug prevents the polymerization of tubulin into microtubules and may cause an axonal neuropathy or myopathy in man and in experimental animals (Riggs et al., 1986; Kuncl et al., 1987). Severe neuromyopathy has been reported with prolonged administration of high doses of the drug. It may also occur in patients taking conventional doses in the presence of renal insufficiency (Jagose and Bailey, 1997). Serum CK levels are usually elevated 10–20-fold. Prompt recovery occurs on withdrawal of the drug. Characteristic histological findings comprise excessive variation in fiber size, the presence of small vacuoles in muscle fibers, and central areas of altered staining on haematoxylin and eosin preparations with loss of enzyme activity resembling cores in histochemical preparations (Fig. 16.7). Muscle fiber necrosis and regeneration rarely occur but denervation changes may also be found in distal limb muscles. The major findings on electron microscopy are the presence of autophagic vacuoles and spheromembranous bodies. 16.3.12. Other drugs Other drugs rarely implicated in causing a myopathy include rifampicin (Jenkins and Emerson, 1981), mercaptoproprionyl glycine (Hales et al., 1982), tetracycline (Sinclair and Phillips, 1982), adenine arabinoside (Mak
Fig. 16.7. Myosin ATPase (pH 4.6) preparation showing central core formation in a case of colchicine myopathy.
et al., 1990), tretinoin (Miranda et al., 1994) and ethchlorvynol (Placidyl) which has been associated with the presence of tubular aggregates in muscle fibers (Petajan et al., 1986). 16.3.13. Alcoholic myopathy There is ample clinical and experimental evidence that ethanol is myotoxic. Acute, subacute and chronic forms of myopathy are well-documented in alcoholics (Urbano-Marquez and Fernandez-Sola, 2004). 16.3.13.1. Acute alcoholic myopathy This is a condition of variable severity ranging from transient asymptomatic elevation of serum CK activity to severe generalized rhabdomyolysis, which occurs predominantly in male alcoholics following binge drinking. It is probably more frequent than is generally appreciated judging from the finding of elevated CK levels in a high proportion of alcoholics admitted to hospital in an intoxicated state or with alcohol withdrawal (Haller and Knochel, 1984). Ethanol is considered to be the most important cause of non-traumatic acute rhabdomyolysis in hospitalized patients (Urbano-Marquez and Fernandez-Sola, 2004). The onset in such cases is usually abrupt with severe myalgia and tenderness of the proximal and calf muscles, generalized weakness, and myoglobinuria which often leads to acute tubular necrosis and renal failure (see above). Weakness of the pharyngeal and respiratory muscles may also occur. In less severe cases the onset is not as acute and there is a predominantly proximal pattern of muscle weakness. In others, there is focal involvement of the calf muscles and the clinical picture may resemble that of thrombophlebitis (Walsh and Conomy, 1977). In some alcoholics, several attacks of acute myopathy may occur following alcoholic
TOXIC AND IATROGENIC MYOPATHIES binges. The prognosis for recovery after an attack is usually good, with abstinence from drinking, but full recovery may take several months in severe cases. The pathological changes in muscle biopsies consist of scattered myofiber necrosis, which is more prominent in cases with the severe form of acute rhabdomyolysis, and evidence of regeneration. Other changes include a mild mononuclear cell infiltrate in some cases, and patchy loss of oxidative enzyme activity, especially in type I fibers (Kahn and Meyer, 1970; Martinez et al., 1973). 16.3.13.2. Chronic alcoholic myopathy This is the most common form of myopathy in chronic alcoholics and is often subclinical (Ekbom et al., 1964; Urbano-Marquez and Fernandez-Sola, 2004). The clinical picture is that of progressive weakness and atrophy of the pelvic and shoulder girdles muscles. Affected individuals often also have evidence of a peripheral neuropathy and other alcoholic complications such as cardiomyopathy and hepatic cirrhosis. The serum CK level is usually normal. Electromyography shows myopathic potentials, or mixed myopathic and neuropathic changes in proximal limb muscles. The typical histological finding in biopsies from proximal limb muscles such as the quadriceps femoris is type II fiber atrophy (Martin et al., 1985). There is also accumulation of triglyceride in muscle fibers (Sunnasy et al., 1983) and a reduction in glycolytic and glycogenolytic enzyme activity (Martin et al., 1984), accounting for the reduced lactic acid production during ischemic exercise in alcoholics (Perkoff et al., 1966). Type II fiber atrophy is also a frequent finding in biopsies from alcoholics without symptoms of muscle weakness suggesting that, as in the case of acute alcoholic myopathy, chronic alcoholic myopathy is frequently subclinical (Martin et al., 1982). In cases with an associated peripheral neuropathy, histological changes of denervation may also be found even in the proximal lower limb muscles. Tubular aggregates may be present in some cases (Chui et al., 1975). The proximal myopathy may improve gradually with abstinence, and the type II fiber atrophy has also been shown to be reversible (Slavin et al., 1983). 16.3.13.3. Pathogenesis There is considerable evidence that at least the acute necrotizing form of alcoholic myopathy is due to a direct toxic effect of ethanol itself or its metabolite acetaldehyde. Experimental observations in humans and in animals have shown acute elevations in serum CK activity after administration of ethanol, with a direct relationship
333
between the CK and blood alcohol levels (Haller and Drachman, 1980; Lane and Radoff, 1981; Schubert et al., 1981; Spargo, 1984; Haller, 1985). In addition, ultrastructural changes were found in muscle fibers in human volunteers after regular ingestion of large quantities of ethanol for a period of 1 month (Song and Rubin, 1972). Evidence from in-vitro studies indicates that ethanol alters the configuration, fluidity and Na,K-ATPase activity of cell membranes and inhibits calcium uptake by the sarcoplasmic reticulum (Haller and Knochel, 1984). Ethanol has also been shown to cause marked inhibition of oxidation of palmitic acid and glucose-6-phosphate, two of the major substrates for energy production in skeletal muscle (Anderson and Torrance, 1984). A number of contributory factors may also be involved. Food deprivation, which is a common accompaniment of binge drinking, retards the metabolism of ethanol, allowing the development of high blood levels which may be toxic to skeletal muscle. This was demonstrated in the rat model of experimental alcoholic myopathy, where rhabdomyolysis was triggered by a period of food deprivation (Haller, 1985). Hypokalemia is present in some cases of alcohol withdrawal and may be severe enough to cause a hypokalemic myopathy (Rubenstein and Wainapel, 1977). Phosphate depletion, which may develop with chronic alcohol ingestion, may also contribute to the development of acute myopathy in some chronically malnourished alcoholics. 16.3.14. Focal myopathy Localized areas of muscle damage occur after intramuscular injections as a result of needle insertion (needle myopathy) and local effects of the injected agent (Mastaglia, 1982). Certain drugs such as diazepam, digoxin and lidocaine cause more extensive muscle necrosis and elevated serum CK levels when injected in animals (Steinness et al., 1977; Yagiela et al., 1981). Other drugs which have a local myotoxic action include opiates, paraldehyde, cephalothin, chloroquine and chlorpromazine which may cause severe tissue damage and abscess formation (Saito et al., 1982; Mastaglia and Argov, 1988). Repeated intramuscular injections may lead to marked fibrosis and muscle contractures. This has been reported after prolonged courses of antibiotic injections into the quadriceps and deltoid muscles in children and in drug addicts who may develop multiple contractures following repeated injections of pethidine or pentazocine (Mastaglia et al., 1971; Hoefnagel et al., 1978; Rousseau et al., 1979; Mariani et al., 1981; Adams et al., 1983; Roberson and Dimon, 1983; Choucair and Ziter, 1984).
334
F. L. MASTAGLIA AND Z. ARGOV
16.4. Myopathies due to envenomation 16.4.1. Snake venoms The venoms of a number of Crotaline snakes, Elapine snakes and seasnakes have myotoxic properties and may cause rhabdomyolysis (Fig. 16.8) as well as inducing a postsynaptic neuromuscular blockade (Sunderland, 1983). Those that have been most fully investigated are the venoms of the Australian tiger snake (Notechis scutatus scutatus; Ng and Howard, 1980); the taipan (Oxyuranus scutellatus; Harris and Maltin, 1982); the mulga snake (Pseudechis australis; Papadimitriou and Mastaglia, 1973; Leonard and Salpeter, 1979); the seasnake (Enhydrina schistose; Fohlman and Eaker, 1977); the coral snake (Micrurus nigrocinctus; Gutierrez et al., 1986); the prairie rattlesnake (Crotalus viridis viridis); the Western diamondback rattlesnake (Crotalus atrox) and the South American rattlesnake (Crotalus durissus terrificus; Huang and Perez, 1982; Azevedo-Marques et al., 1985); and the Costa Rican vipers (Bothrops nummifer and Bothrops asper; Gutierrez et al., 1984, 1989). The major myotoxic components of snake venoms have been shown to be phospholipases and single chain peptides (Mebs and Ownby, 1990). 16.4.2. Spider venoms The venoms of a number of spiders, including the Arkansas and Honduran tarantulas (Dugesiella hentzi and Aphonophelma spp.), are intensely myotoxic and cardiotoxic (Ori M. Ikeda, 1998). Both the crude venom and purified necrotoxin (6.7-kDa protein) cause rapid irreversible injury to the muscle fiber plasma membrane leading to necrosis and marked accumulation of calcium and phosphate in muscle fibers (Ownby and Odell,
1983). Rhabdomyolysis has also been reported following envenomation by the brown spider (Gabow et al., 1982) and redback spider (Gala and Katelaris, 1992). 16.4.3. Wasp venoms There have been reports of severe rhabdomyolysis with associated renal failure following envenomation by the wasp Vespa cincta and the hornet Vespa affinis (Sitprija and Boonpucknavig, 1972). The venom of Vespa affinis is known to contain polypeptides and phospholipases but the myotoxic components have not been identified. Rhabdomyolysis may also occur following envenomation by the Africanized honey bee (Franca et al., 1994).
16.5. Haff disease This condition occurred in epidemic form in East Prussia, Russia and Sweden between 1923 and 1943 (Berlin, 1948). It is estimated that over 1000 cases occurred in two major epidemics in the Koenigsberg Haff in East Prussia. In each epidemic individuals who had eaten fish from nearby waters were mainly affected. Low grade muscle discomfort for a few days was followed by the sudden onset of severe widespread muscle pain and tenderness, particularly in the calves, back and neck and dark-brown discoloration of the urine presumed to be due to myoglobinuria. Rapid recovery over a period of 24–72 hours was the rule. The condition was presumed to be toxic in origin but the nature of the toxic agent has never been identified. There have been more recent reports of similar outbreaks in the United States (Buchholz et al., 2000).
16.6. Quail myopathy This is a form of rhabdomyolysis which has been reported in a number of Mediterranean countries and is characterized by the onset of severe myalgia , myoglobinuria and acute renal failure after ingestion of quail (Billis et al., 1971; Papadimitriou et al., 1996). The toxic agent is thought to be derived from seeds containing hemlock (Conium maculatum), which is myotoxic (Scatizzi et al., 1993), or hellebore (a veratrine alkaloid) ingested by the quail. The occurrence of repeated attacks in some individuals suggests that they may have an underlying enzymic deficiency that predisposes them to develop rhabdomyolysis.
16.7. Clostridial toxins Fig. 16.8. Extensive rhabdomyolysis in a patient after envenomation by the Australian mulga brown snake (Pseudechis Australis).
Clostridial toxins may have profound effects on the neuromuscular system. Clostridium. welchii and
TOXIC AND IATROGENIC MYOPATHIES C. perfringens, which cause gas gangrene, produce a number of toxins. That which is thought to be primarily responsible for the muscle damage is the a-toxin (lecithinase C) that has been shown experimentally to cause focal lysis of the muscle fiber plasma membrane and necrosis (Strunk et al., 1967). Botulinum toxin causes neuromuscular block by preventing ACh release from motor nerve terminals. Experimental studies have shown that the toxin induces degenerative changes in muscle fibers and motor endplates with prominent sprouting of nerve terminals (Duchen, 1971a, 1971b). In addition to its central action on inhibitory spinal cord interneurones, tetanus toxin also acts on motor nerve terminals interfering with transmitter release and causing prolonged weakness or paralysis (Duchen, 1973). Degenerative changes were found in muscle fibers but not in motor nerve terminals or endplates in biopsies from patients with tetanus (Agostini and Noetzel, 1970). In an experimental study, intramuscular injection of tetanus toxin was found to cause sprouting of motor nerve terminals in slow-twitch but not in fast-twitch muscle fibers (Duchen, 1973).
16.8. Organophosphates There have been reports of myopathy developing in individuals exposed to organophosphate insecticides but this is less frequent than the polyneuropathy that occurs following acute or chronic exposure to these agents (Ahlgren et al., 1979; Karalliedde and Henry, 1993). Experimental studies have shown that organophosphates, which are irreversible cholinesterase inhibitors, cause dose-related muscle fiber necrosis which begins in the motor endplate region and can be prevented by prior denervation or administration of pyridine-2-aldoxime methiodide (Wecker et al., 1978).
16.9. Gasoline sniffing There has been a number of reports of an acute necrotizing myopathy with myoglobinuria or of marked serum CK elevations in gasoline sniffers (Kovanen et al., 1983; Fortenberry, 1985). In some cases the myopathy is also associated with signs of an encephalopathy (Kovanen et al., 1983). It is not known which of the various organic solvents and other components of gasoline are myotoxic.
16.10. Solvents Rhabdomyolysis has been reported in a number of cases of intoxication with the organic solvent toluene
335
which is used in paint sprays, lacquer thinners and household glues (Streicher et al., 1981). Hypokalemic periodic paralysis secondary to renal tubular acidosis has also been reported following chronic toluene exposure (Bennett and Forman, 1980).
References Adams EM, Horowitz HW, Sundstrom WR (1983). Fibrous myopathy in association with pentazocine. Arch Intern Med 143: 2203–2204. Afifi AK, Hajj GA, Saad S, et al. (1984). Clofibrate-induced myotoxicity in rats. Temporal profile of myopathology. Eur Neurol 23: 182–197. Agostini B, Noetzel H (1970). Morphological study of muscle fibres and motor end-plates in tetanus. In: JN Walton, N Canal, G Scarlato (Eds.), Muscle Diseases. Excerpta Medica, Amsterdam, pp. 123–127. Ahlgren JD, Manz HJ, Harvey JC (1979). Myopathy of chronic organophosphate poisoning: a clinical entity? South Med J 72: 555–558, 563. Alsheikh-Ali AA, Ambrose MS, Kuvin JT, et al. (2005). The safety of rosuvastatin as used in common clinical practice. A postmarketing analysis. Circulation 111: 3051–3057. Anderson TL, Torrance CA (1984). Metabolic mechanisms of acute alcoholic myopathy. Neurology 34: 81. Anderson PJ, Song SK, Slotwiner P (1967). The fine structure of spheromembranous degeneration of skeletal muscle induced by vincristine. J Neuropathol Exp Neurol 26: 15–24. Anderson NE, Lynch NM, O’Brien KP (1985). Disabling neurological complications of amiodarone. Aust N Z J Med 15: 300–304. Argov Z (2000). Drug-induced myopathies. Curr Opin Neurol 13: 541–545. Argov Z, Mastaglia FL (1979a). Drug therapy: disorders of neuromuscular transmission caused by drugs. N Engl J Med 301: 409–413. Argov Z, Mastaglia FL (1979b). Drug-induced peripheral neuropathies. Br Med J 1: 663–666. Arnaudo E, Dalakas M, Shanske S, et al. (1991). Depletion of muscle mitochondrial DNA in AIDS patients with zidovudine-induced myopathy. Lancet 337: 508–510. Azevedo-Marques MM, Cupo P, Coimbra TM, et al. (1985). Myonecrosis, myoglobinuria and acute renal failure induced by South American rattlesnake (Crotalus durissus terrificus) envenomation in Brazil. Toxicon 23: 631–636. Baker SK, Goodwin S, Sur M, et al. (2004). Cytoskeletal myotoxicity from simvastatin and colchicine. Muscle Nerve 30: 799–802. Bargossi AM, Battino M, Gaddi A, et al. (1994). Exogenous CoQ10 preserves plasma ubiquinone levels in patients treated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Int J Clin Lab Res 24: 171–176. Belongia EA, Hedberg CW, Gleich GJ, et al. (1990). An investigation of the cause of the eosinophilia-myalgia syndrome associated with tryptophan use. N Engl J Med 323: 357–365.
336
F. L. MASTAGLIA AND Z. ARGOV
Bennett HS, Spiro AJ, Pollack MA, et al. (1982). Ipecacinduced myopathy simulating dermatomyositis. Neurology 32: 91–94. Bennett RH, Forman HR (1980). Hypokalemic periodic paralysis in chronic toluene exposure. Arch Neurol 37: 673. Berlin R (1948). Haff disease in Sweden. Acta Med Scand 129: 560–572. Billis AG, Kastanakis S, Giamarellou H, et al. (1971). Acute renal failure after a meal of quail. Lancet 2: 702. Bleske BE, Willis RA, Anthony M, et al. (2001). The effect of pravastatin and atorvastatin on coenzyme Q10. Am Heart J 142: E2. Blessing W, Walsh JC (1977). Myotonia precipitated by propranolol therapy. Lancet 1: 73–74. Blumberg A, Marti HR (1984). Acute rhabdomyolysis following administration of succinylcholine. Schweiz Med Wochenschr 114: 1068–1071. Bowyer SL, LaMothe MP, Hollister JR (1985). Steroid myopathy: incidence and detection in a population with asthma. J Allergy Clin Immunol 76: 234–242. Bradley WG, Lassman LP, Pearce GW, et al. (1970). The neuromyopathy of vincristine in man. Clinical, electrophysiological and pathological studies. J Neurol Sci 10: 107–131. Bradley WG, Fewings JD, Harris JB, et al. (1976). Emetine myopathy in the rat. Br J Pharmacol 57: 29–31. Braunstein PW Jr., DeGirolami U (1981). Experimental corticosteroid myopathy. Acta Neuropathol (Berl) 55: 167–172. Bretag AH, Dawe SR, Moskwa AG (1980). Chemically induced myotonia in amphibia. Nature 286: 625–626. Briner V, Colombi A, Brunner W, et al. (1986). Acute rhabdomyolysis. Schweiz Med Wochenschr 116: 198–208. Britt CW Jr, Light RR, Peters BH, et al. (1980). Rhabdomyolysis during treatment with epsilon-aminocaproic acid. Arch Neurol 37: 187–188. Brown JA, Wollmann RL, Mullan S (1982). Myopathy induced by epsilon-aminocaproic acid. Case report. J Neurosurg 57: 130–134. Brumback RA, Gerst JW, Knull HR (1983). High energy phosphate depletion in a model of defective muscle glycolysis. Muscle Nerve 6: 52–55. Buchholz U, Mouzin E, Dickey R, et al. (2000). Haff disease: from the Baltic Sea to the U.S. shore. Emerg Infect Dis 6: 192–195. Campellone JV, Lacomis D, Kramer DJ, et al. (1998). Acute myopathy after liver transplantation. Neurology 50: 46–53. Carroll GJ, Will RK, Peter JB, et al. (1987). Penicillamine induced polymyositis and dermatomyositis. J Rheumatol 14: 995–1001. Chaboche C, Nordmann Y, Fontaine JL, et al. (1982). Myoglobinuria following anesthesia [author’s translation]. Arch Fr Pediatr 39: 169–171. Chalmers AC, Greco CM, Miller RG (1991). Prognosis in AZT myopathy. Neurology 41: 1181–1184. Chappel R, Willems J (1996). D-penicillamine–induced myositis in rheumatoid arthritis. Clin Rheumatol 15: 86–87.
Chariot P, Monnet I, Gherardi R (1993). Cytochrome c oxidase reaction improves histopathological assessment of zidovudine myopathy. Ann Neurol 34: 561–565. Chemali KR, Suarez JI, Katirji B (2001). Acute hypokalemic paralysis associated with long-term lithium therapy. Muscle Nerve 24: 297–298. Choucair AK, Ziter FA (1984). Pentazocine abuse masquerading as familial myopathy. Neurology 34: 524–527. Chui LA, Neustein H, Munsat TL (1975). Tubular aggregates in subclinical alcoholic myopathy. Neurology 25: 405–412. Cirigliano G, Della Rossa A, Tavoni A, et al. (1999). Polymyositis occurring during alpha-interferon treatment for malignant melanoma: a case report and review of the literature. Rheumatol Int 19: 65–67. Clark AF, DeMartino GN, Wildenthal K (1986). Effects of glucocorticoid treatment on cardiac protein synthesis and degradation. Am J Physiol 250: C821–C827. Clark AF, Vignos PJ, Jr. (1979). Experimental corticosteroid myopathy: effect on myofibrillar ATPase activity and protein degradation. Muscle Nerve 2: 265–273. Clouston PD, Donnelly PE (1989). Acute necrotising myopathy associated with amiodarone therapy. Aust N Z J Med 19: 483–485. Cogen FC, Rigg G, Simmons JL, et al. (1978). Phencyclidine-associated acute rhabdomyolysis. Ann Intern Med 88: 210–212. Comi G, Testa D, Cornelio F, et al. (1985). Potassium depletion myopathy: a clinical and morphological study of six cases. Muscle Nerve 8: 17–21. Coomes EN (1965). The rate of recovery of reversible myopathies and the effects of anabolic agents in steroid myopathy. Neurology 15: 523–530. Dalakas MC, Illa I, Pezeshkpour GH, et al. (1990). Mitochondrial myopathy caused by long-term zidovudine therapy. N Engl J Med 322: 1098–1105. Dietrich LL, Bridges AJ, Albertini MR (2000). Dermatomyositis after interferon alpha treatment. Med Oncol 17: 64–69. Douglass JA, Tuxen DV, Horne M, et al. (1992). Myopathy in severe asthma. Am Rev Respir Dis 146: 517–519. Dreier JP, Endres M (2004). Statin-associated rhabdomyolysis triggered by grapefruit consumption. Neurology 62: 670. Drenckhahn D, Lullmann-Rauch R (1979). Experimental myopathy induced by amphiphilic cationic compounds including several psychotropic drugs. Neuroscience 4: 549–562. Dropcho EJ, Soong SJ (1991). Steroid-induced weakness in patients with primary brain tumors. Neurology 41: 1235–1239. Duane DD, Engel AG (1970). Emetine myopathy. Neurology 20: 733–739. DuBois DC, Almon RR (1980). Disuse atrophy of skeletal muscle is associated with an increase in number of glucocorticoid receptors. Endocrinology 107: 1649–1651. DuBois DC, Almon RR (1981). A possible role for glucocorticoids in denervation atrophy. Muscle Nerve 4: 370–373.
TOXIC AND IATROGENIC MYOPATHIES DuBois DC, Almon RR (1984). Glucocorticoid sites in skeletal muscle: adrenalectomy, maturation, fiber type, and sex. Am J Physiol 247: E118–E125. Duchen LW (1971a). Changes in the electron microscopic structure of slow and fast skeletal muscle fibres of the mouse after the local injection of botulinum toxin. J Neurol Sci 14: 61–74. Duchen LW (1971b). An electron microscopic study of the changes induced by botulinum toxin in the motor endplates of slow and fast skeletal muscle fibres of the mouse. J Neurol Sci 14: 47–60. Duchen LW (1973). The effects of tetanus toxin on the motor end-plates of the mouse. An electron microscopic study. J Neurol Sci 19: 153–167. Eadie MJ, Ferrier TM (1966). Chloroquine myopathy. J Neurol Neurosurg Psychiatry 29: 331–337. Eidson M, Philen RM, Sewell CM, et al. (1990). L-tryptophan and eosinophilia-myalgia syndrome in New Mexico. Lancet 335: 645–648. Ekbom K, Hed R, Kirstein L, et al. (1964). Muscular affections in chronic alcoholism. Arch Neurol 10: 449–458. England JD, Walsh JC, Stewart P, et al. (1995). Mitochondrial myopathy developing on treatment with the HMG CoA reductase inhibitors — simvastatin and pravastatin. Aust N Z J Med 25: 374–375. Estes ML, Ewing-Wilson D, Chou SM, et al. (1987). Chloroquine neuromyotoxicity. Clinical and pathologic perspective. Am J Med 82: 447–455. Fardeau M, Tome FM, Simon P (1979). Muscle and nerve changes induced by perhexiline maleate in man and mice. Muscle Nerve 2: 24–36. Farmer JA (2001). Learning from the cerivastatin experience. Lancet 358: 1383–1385. Fernando Roth R, Itabashi H, Louie J, et al. (1990). Amiodarone toxicity: myopathy and neuropathy. Am Heart J 119: 1223–1225. Fohlman J, Eaker D (1977). Isolation and characterization of a lethal myotoxic phospholipase A from the venom of the common sea snake Enhydrina schistosa causing myoglobinuria in mice. Toxicon 15: 385–393. Forfar JC, Brown GJ, Cull RE (1979). Proximal myopathy during beta-blockade. Br Med J 2: 1331–1332. Fortenberry JD (1985). Gasoline sniffing. Am J Med 79: 740–744. Franc S, Dejager S, Bruckert E, et al. (2003). A comprehensive description of muscle symptoms associated with lipid-lowering drugs. Cardiovasc Drugs Ther 17: 459–465. Franca FO, Benvenuti LA, Fan HW, et al. (1994). Severe and fatal mass attacks by ‘killer’ bees (Africanized honey bees — Apis mellifera scutellata) in Brazil: clinicopathological studies with measurement of serum venom concentrations. Q J Med 87: 269–282. Friedman EJ (1984). Death from ipecac intoxication in a patient with anorexia nervosa. Am J Psychiatry 141: 702–703. Frisk-Holmberg M, Jorfeldt L, Juhlin-Dannfelt A, et al. (1979). Metabolic changes in muscle on long-term alprenolol therapy. Clin Pharmacol Ther 26: 566–571.
337
Fux R, Morike K, Gundel UF, et al. (2004). Ezetimibe and statin-associated myopathy. Ann Intern Med 140: 671–672. Gabow PA, Kaehny WD, Kelleher SP (1982). The spectrum of rhabdomyolysis. Medicine (Baltimore) 61: 141–152. Gadbut AP, Caruso AP, Galper JB (1995). Differential sensitivity of C2–C12 striated muscle cells to lovastatin and pravastatin. J Mol Cell Cardiol 27: 2397–2402. Gaist D, Rodriguez LA, Huerta C, et al. (2001). Lipid-lowering drugs and risk of myopathy: a population-based followup study. Epidemiology 12: 565–569. Gala S, Katelaris CH (1992). Rhabdomyolysis due to redback spider envenomation. Med J Aust 157: 66. Gardiner PF, Edgerton VR (1979). Contractile responses of rat fast-twitch and slow-twitch muscles to glucocorticoid treatment. Muscle Nerve 2: 274–281. Gherardi RK, Authier FJ (2003). Aluminum inclusion macrophagic myofasciitis: a recently identified condition. Immunol Allergy Clin North Am 23: 699–712. Gherardi RK, Coquet M, Cherin P, et al. (1998). Macrophagic myofasciitis: an emerging entity. Groupe d’Etudes et Recherche sur les Maladies Musculaires Acquises et Dysimmunitaires (GERMMAD) de l’Association Francaise contre les Myopathies (AFM). Lancet 352: 347–352. Gherardi RK, Coquet M, Cherin P, et al. (2001). Macrophagic myofasciitis lesions assess long-term persistence of vaccine-derived aluminium hydroxide in muscle. Brain 124: 1821–1831. Gibbs JM (1978). A case of rhabdomyolysis associated with suxamethonium. Anaesth Intensive Care 6: 141–145. Goldman JA, Fishman AB, Lee JE, et al. (1989). The role of cholesterol-lowering agents in drug-induced rhabdomyolysis and polymyositis. Arthritis Rheum 32: 358–359. Grob D (1990). Rhabdomyolysis and drug-related myopathies. Curr Opin Rheumatol 2: 908–915. Gruener R, Stern LZ (1972). Corticosteroids. Effects on muscle membrane excitability. Arch Neurol 26: 181–185. Grundy SM (2005). The issue of statin safety. Where do we stand? Circulation 111: 3016–3019. Gutierrez JM, Arroyo O, Chaves F, et al. (1986). Pathogenesis of myonecrosis induced by coral snake (Micrurus nigrocinctus) venom in mice. Br J Exp Pathol 67: 1–12. Gutierrez JM, Chaves F, Gene JA, et al. (1989). Myonecrosis induced in mice by a basic myotoxin isolated from the venom of the snake Bothrops nummifer (jumping viper) from Costa Rica. Toxicon 27: 735–745. Gutierrez JM, Ownby CL, Odell GV (1984). Isolation of a myotoxin from Bothrops asper venom: partial characterization and action on skeletal muscle. Toxicon 22: 115–128. Gutmann L (1999). Critical illness neuropathy and myopathy. Arch Neurol 56: 527–528. Hales DS, Scott R, Lewi HJ (1982). Myopathy due to mercaptopropionyl glycine. Br Med J (Clin Res Ed) 285: 939. Haller RG (1985). Experimental acute alcoholic myopathy — a histochemical study. Muscle Nerve 8: 195–203. Haller RG, Drachman DB (1980). Alcoholic rhabdomyolysis: an experimental model in the rat. Science 208: 412–415.
338
F. L. MASTAGLIA AND Z. ARGOV
Haller RG, Knochel JP (1984). Skeletal muscle disease in alcoholism. Med Clin North Am 68: 91–103. Harris JB, Maltin CA (1982). Myotoxic activity of the crude venom and the principal neurotoxin, taipoxin, of the Australian taipan, Oxyuranus scutellatus. Br J Pharmacol 76: 61–75. Hayes DJ, Byrne E, Shoubridge EA, et al. (1985). Experimentally induced defects of mitochondrial metabolism in rat skeletal muscle. Biological effects of the NADH: coenzyme Q reductase inhibitor diphenyleneiodonium. Biochem J 229: 109–117. Hengstman GJ, Vogels OJ, ter Laak HJ, et al. (2000). Myositis during long-term interferon-alpha treatment. Neurology 54: 2186. Hertzman PA, Blevins WL, Mayer J, et al. (1990). Association of the eosinophilia-myalgia syndrome with the ingestion of tryptophan. N Engl J Med 322: 869–873. Hickson RC, Davis JR (1981). Partial prevention of glucocorticoid-induced muscle atrophy by endurance training. Am J Physiol 241: E226–E232. Higuchi I, Takahashi K, Nakahara K, et al. (1991). Experimental germanium myopathy. Acta Neuropathol (Berl) 82: 55–59. Hoefnagel D, Jalbert EO, Publow DG, et al. (1978). Progressive fibrosis of the deltoid muscles. J Pediatr 92: 79–81. Hoke A, Rewcastle NB, Zochodne DW (1999). Acute quadriplegic myopathy unrelated to steroids or paralyzing agents: quantitative EMG studies. Can J Neurol Sci 26: 325–329. Horber FF, Scheidegger JR, Grunig BE, et al. (1985). Thigh muscle mass and function in patients treated with glucocorticoids. Eur J Clin Invest 15: 302–307. Huang SY, Perez JC (1982). A comparative electron microscopic study of myonecrosis induced by Crotalus atrox (Western diamondback rattlesnake) in gray woodrats and mice. Toxicon 20: 443–449. Hughes JT, Esiri M, Oxbury JM, et al. (1971). Chloroquine myopathy. Q J Med 40: 85–93. Jagose JT, Bailey RR (1997). Muscle weakness due to colchicine in a renal transplant recipient. N Z Med J 110: 343. Jamal SM, Eisenberg MJ, Christopoulos S (2004). Rhabdomyolysis associated with hydroxymethylglutaryl-coenzyme A reductase inhibitors. Am Heart J 147: 956–965. Jenkins P, Emerson PA (1981). Myopathy induced by rifampicin. Br Med J (Clin Res Ed) 283: 105–106. Jennings AE, Levey AS, Harrington JT (1983). Amoxapineassociated acute renal failure. Arch Intern Med 143: 1525–1527. Johnson TE, Zhang X, Bleicher KB, et al. (2004). Statins induce apoptosis in rat and human myotube cultures by inhibiting protein geranylgeranylation but not ubiquinone. Toxicol Appl Pharmacol 200: 237–250. Kahn LB, Meyer JS (1970). Acute myopathy in chronic alcoholism: a study of 22 autopsy cases, with ultrastructural observations. Am J Clin Pathol 53: 516–530. Kaiser P, Tesch PA, Thorsson A, et al. (1985). Skeletal muscle glycolysis during submaximal exercise following acute beta-adrenergic blockade in man. Acta Physiol Scand 123: 285–291.
Kalkner KM, Ronnblom L, Karlsson Parra AK, et al. (1998). Antibodies against double-stranded DNA and development of polymyositis during treatment with interferon. Q J Med 91: 393–399. Kanda F, Takatani K, Okuda S, et al. (1999). Preventive effects of insulin-like growth factor-I on steroid-induced muscle atrophy. Muscle Nerve 22: 213–217. Kane MJ, Silverman LR, Rand JH, et al. (1988). Myonecrosis as a complication of the use of epsilon amino-caproic acid: a case report and review of the literature. Am J Med 85: 861–863. Karalliedde L, Henry JA (1993). Effects of organophosphates on skeletal muscle. Hum Exp Toxicol 12: 289–296. Karlsson J (1983). Muscle fibre composition, short term 1- þ 2- and 1-blockade and endurance exercise performance in healthy young men. Drugs 25: 241–246. Karpati G (1984). Denervation and disuse atrophy of skeletal muscles: involvement of endogenous glucocorticoid hormones? Trends Neurosci 7: 61–62. Kaufman LD (1990). Neuromuscular manifestations of the L-tryptophan-associated eosinophilia-myalgia syndrome. Curr Opin Rheumatol 2: 896–900. Kennedy M (1981). Cardiac glycoside toxicity. An unusual manifestation of drug addiction. Med J Aust 2: 686, 688–689. Khaleeli AA, Edwards RH, Gohil K, et al. (1983). Corticosteroid myopathy: a clinical and pathological study. Clin Endocrinol (Oxf) 18: 155–166. Kilpatrick C, Braund W, Burns R (1982). Myopathy with myasthenia features possibly induced by codeine linctus. Med J Aust 2: 410. Knochel JP (1982). Rhabdomyolysis and myoglobinuria. Ann Rev Med 33: 435–443. Kovanen J, Somer H, Schroeder P (1983). Acute myopathy associated with gasoline sniffing. Neurology 33: 629–631. Kuncl RW, Duncan G, Watson D, et al. (1987). Colchicine myopathy and neuropathy. N Engl J Med 316: 1562–1568. Kwiecinski H (1981). Myotonia induced by chemical agents. Crit Rev Toxicol 8: 279–310. Laaksonen R, Jokelainen K, Laakso J, et al. (1996). The effect of simvastatin treatment on natural antioxidants in low-density lipoproteins and high-energy phosphates and ubiquinone in skeletal muscle. Am J Cardiol 77: 851–854. Lacomis D, Giuliani MJ, Van Cott A, et al. (1996). Acute myopathy of intensive care: clinical, electromyographic, and pathological aspects. Ann Neurol 40: 645–654. Lacomis D, Zochodne DW, Bird SJ (2000). Critical illness myopathy. Muscle Nerve 23: 1785–1788. Lamperti C, Naini AB, Lucchini V, et al. (2005). Muscle coenzyme Q10 level in statin-related myopathy. Arch Neurol 62: 1709–1712. Lane RJ, McLelland NJ, Martin AM, et al. (1979). Epsilon aminocaproic acid (EACA) myopathy. Postgrad Med J 55: 282–285. Lane RJ, Radoff FM (1981). Alcohol and serum creatinine kinase levels. Ann Neurol 10: 581–583. Langer T, Levy RI (1968). Acute muscular syndrome associated with administration of clofibrate. N Engl J Med 279: 856–858.
TOXIC AND IATROGENIC MYOPATHIES Lazarus AL, Toglia JU (1985). Fatal myoglobinuric renal failure in a patient with tardive dyskinesia. Neurology 35: 1055–1057. Leonard JP, Salpeter MM (1979). Agonist-induced myopathy at the neuromuscular junction is mediated by calcium. J Cell Biol 82: 811–819. Lilja JJ, Neuvonen M, Neuvonen PJ (2004). Effects of regular consumption of grapefruit juice on the pharmacokinetics of simvastatin. Br J Clin Pharmacol 58: 56–60. Litin SC, Anderson CF (1989). Nicotinic acid-associated myopathy: a report of three cases. Am J Med 86: 481–483. Livingstone I, Johnson MA, Mastaglia FL (1981). Effects of dexamethasone on fibre subtypes in rat muscle. Neuropathol Appl Neurobiol 7: 381–398. Lullmann H, Lullmann-Rauch R, Wassermann O (1978). Lipidosis induced by amphiphilic cationic drugs. Biochem Pharmacol 27: 1103–1108. Magarian GJ, Lucas LM, Colley C (1991). Gemfibrozilinduced myopathy. Arch Intern Med 151: 1873–1874. Mak KH, Boey ML, Wan SH, et al. (1990). Myocardial and skeletal muscle injuries following adenine arabinoside therapy. Aust N Z J Med 20: 811–813. Mariani C, Meola G, Meroni PL, et al. (1981). Pentazocineinduced neuromuscular syndromes: clinical, immunological and histopathological studies in two cases. Acta Neuropathol Suppl (Berl) 7: 246–248. Martin FC, Slavin G, Levi AJ (1982). Alcoholic muscle disease. Br Med Bull 38: 53–56. Martin FC, Levi AJ, Slavin G, et al. (1984). Glycogen content and activities of key glycolytic enzymes in muscle biopsies from control subjects and patients with chronic alcoholic skeletal myopathy. Clin Sci (Lond) 66: 69–78. Martin F, Ward K, Slavin G, et al. (1985). Alcoholic skeletal myopathy, a clinical and pathological study. Q J Med 55: 233–251. Martinez AJ, Hooshmand H, Faris AA (1973). Acute alcoholic myopathy. Enzyme histochemistry and electron microscopic findings. J Neurol Sci 20: 245–252. Massa R, Carpenter S, Holland P, et al. (1992). Loss and renewal of thick myofilaments in glucocorticoid-treated rat soleus after denervation and reinnervation. Muscle Nerve 15: 1290–1298. Mastaglia FL (1982). Adverse effects of drugs on muscle. Drugs 24: 304–321. Mastaglia FL (2006). Drug-induced myopathies. Practical Neurology 6: 4–13. Mastaglia FL, Argov Z (1988). Drug-induced neuromuscular disorders in man. In: JN Walton, (Ed.), Disorders of Voluntary Muscle. Churchill Livingstone, Edinburgh, pp. 873–906. Mastaglia FL, Gardner-Medwin D, Hudgson P (1971). Muscle fibrosis and contractures in a pethidine addict. Br Med J 4: 532–533. Mastaglia FL, Papadimitriou JM, Dawkins RL, et al. (1977). Vacuolar myopathy associated with chloroquine, lupus erythematosus and thymoma. Report of a case with unusual mitochondrial changes and lipid accumulation in muscle. J Neurol Sci 34: 315–328.
339
Mateer JE, Farrell BJ, Chou SS, et al. (1985). Reversible ipecac myopathy. Arch Neurol 42: 188–190. Max SR, Konagaya M, Konagaya Y (1986). Drug-induced myopathies: examples of cellular mechanisms. Muscle Nerve 9: 33. Mebs D, Ownby CL (1990). Myotoxic components of snake venoms: their biochemical and biological activities. Pharmacol Ther 48: 223–236. Medsger TA, Jr. (1990). Tryptophan-induced eosinophiliamyalgia syndrome. N Engl J Med 322: 926–928. Meier C, Kauer B, Muller U, et al. (1979). Neuromyopathy during chronic amiodarone treatment. A case report. J Neurol 220: 231–239. Mhiri C, Baudrimont M, Bonne G, et al. (1991). Zidovudine myopathy: a distinctive disorder associated with mitochondrial dysfunction. Ann Neurol 29: 606–614. Miranda N, Oliveira P, Frade MJ, et al. (1994). Myositis with tretinoin. Lancet 344: 1096. Miro O, Salmeron JM, Masanes F, et al. (1999). Acute quadriplegic myopathy with myosin-deficient muscle fibres after liver transplantation: defining the clinical picture and delimiting the risk factors. Transplantation 67: 1144–1151. Mitsumoto H, Wilbourn AJ, Subramony SH (1982). Generalized myokymia and gold therapy. Arch Neurol 39: 449–450. Modi KB, Horn EH, Bryson SM (1985). Theophylline poisoning and rhabdomyolysis. Lancet 2: 160–161. Mori M, Satoh A, Tsujihata M, et al. (1985). Myotonic discharges in a case of licorice-induced hypokalemic myopathy. Rinsho Shinkeigaku 25: 560–564. Nakahara K, Kuriyama M, Sonoda Y, et al. (1998). Myopathy induced by HMG-CoA reductase inhibitors in rabbits: a pathological, electrophysiological, and biochemical study. Toxicol Appl Pharmacol 152: 99–106. Neville HE, Maunder-Sewry CA, McDougall J, et al. (1979). Chloroquine-induced cytosomes with curvilinear profiles in muscle. Muscle Nerve 2: 376–381. Ng RH, Howard BD (1980). Mitochondria and sarcoplasmic reticulum as model targets for neurotoxic and myotoxic phospholipases A2. Proc Natl Acad Sci U S A 77: 1346–1350. Omar MA, Wilson JP (2002). FDA adverse event reports on statin-associated rhabdomyolysis. Ann Pharmacother 36: 288–295. Ori M, Ikeda H (1998). Spider venoms and spider toxins. J Toxicol Toxin Rev 17: 405–426. Ownby CL, Odell GV (1983). Pathogenesis of skeletal muscle necrosis induced by tarantula venom. Exp Mol Pathol 38: 283–296. Palmer EP, Guay AT (1985). Reversible myopathy secondary to abuse of ipecac in patients with major eating disorders. N Engl J Med 313: 1457–1459. Panegyres PK, Papadimitriou JM, Hollingsworth PN, et al. (1990). Vesicular changes in the myopathies of AIDS. Ultrastructural observations and their relationship to zidovudine treatment. J Neurol Neurosurg Psychiatry 53: 649–655. Papadimitriou A, Hadjigeorgiou GM, Tsairis P, et al. (1996). Myoglobinuria due to quail poisoning. Eur Neurol 36: 142–145.
340
F. L. MASTAGLIA AND Z. ARGOV
Papadimitriou JM, Mastaglia FL (1973). Myopathy induced by mulga snake venom: a model for the study of muscle degeneration and regeneration. In: ICSN 294, Basic Research in Myology, Proceedings of the Second International Congress on Muscle Disease, Excerpta Medica, Amsterdam, pp. 426–437. Pasternak RC, Smith SC Jr., Bairey-Merz CN, et al. (2002). ACC/AHA/NHLBI clinical advisory on the use and safety of statins. J Am Coll Cardiol 40: 567–572. Perea M, Picon M, Miro O, et al. (2001). Acute quadriplegic myopathy with loss of thick (myosin) filaments following heart transplantation. J Heart Lung Transplant 20: 1136–1141. Perkoff GT, Hardy P, Velez-Garcia E (1966). Reversible acute muscular syndrome in chronic alcoholism. N Engl J Med 274: 1277–1285. Petajan JH, Townsend J, Currey KM (1986). Ethchlorvynol (Placidyl) may produce tubular aggregates in skeletal muscle. Electroencephalogr Clin Neurophysiol 64: 54. Phillips PS, Haas RH, Bannykh S, et al. (2002). Statin-associated myopathy with normal creatine kinase levels. Ann Intern Med 137: 581–585. Pinals RS (1983). Diffuse fasciculations induced by D-penicillamine. J Rheumatol 10: 809–810. Rannels SR, Rannels DE, Pegg AE, et al. (1978). Glucocorticoid effects on peptide-chain initiation in skeletal muscle and heart. Am J Physiol 235: E134–E139. Reaven P, Witztum JL (1988). Lovastatin, nicotinic acid, and rhabdomyolysis. Ann Intern Med 109: 597–598. Reeback J, Benton S, Swash M, et al. (1979). Penicillamineinduced neuromyotonia. Br Med J 1: 1464–1465. Rich MM, Pinter MJ (2001). Sodium channel inactivation in an animal model of acute quadriplegic myopathy. Ann Neurol 50: 26–33. Rich MM, Teener JW, Raps EC, et al. (1996). Muscle is electrically inexcitable in acute quadriplegic myopathy. Neurology 46: 731–736. Rich MM, Bird SJ, Raps EC, et al. (1997). Direct muscle stimulation in acute quadriplegic myopathy. Muscle Nerve 20: 665–673. Richards AJ (1998). Hydroxychloroquine myopathy. J Rheumatol 25: 1642–1643. Ricker K, Haass A, Glotzner F (1978). Fenoterol precipitating myotonia in a minimally affected case of recessive myotonia congenita. J Neurol 219: 279–282. Riggs JE, Schochet SS Jr., Gutmann L, et al. (1986). Chronic human colchicine neuropathy and myopathy. Arch Neurol 43: 521–523. Roberson JR, Dimon JH, 3rd (1983). Myofibrosis and joint contractures caused by injections of pentazocine. A case report. J Bone Joint Surg Am 65: 1007–1009. Rosenson RS (2004). Current overview of statin-induced myopathy. Am J Med 116: 408–416. Rothstein JM, Delitto A, Sinacore DR, et al. (1983). Muscle function in rheumatic disease patients treated with corticosteroids. Muscle Nerve 6: 128–135. Rousseau JJ, Reznik M, LeJeune GN, et al. (1979). Sciatic nerve entrapment by pentazocine-induced muscle fibrosis: a case report. Arch Neurol 36: 723–724.
Rubenstein AE, Wainapel SF (1977). Acute hypokalemic myopathy in alcoholism. A clinical entity. Arch Neurol 34: 553–555. Rumpf KW, Barth M, Blech M, et al. (1984). Bezafibrateinduced myolysis and myoglobinuria in patients with impaired renal function. Klin Wochenschr 62: 346–348. Rutkove SB, De Girolami U, Preston DC, et al. (1996). Myotonia in colchicine myoneuropathy. Muscle Nerve 19: 870–875. Saito K, Kakei M, Uchimura S, et al. (1982). Toxic effects of chlorpromazine on red and white muscles in rats: an ultrastructural study. Toxicol Appl Pharmacol 65: 347–353. Saito T, Tsuboi Y, Fujisawa G, et al. (1994). An autopsy case of licorice-induced hypokalemic rhabdomyolysis associated with acute renal failure: special reference to profound calcium deposition in skeletal and cardiac muscle. Nippon Jinzo Gakkai Shi 36: 1308–1314. Sakai Y, Kobayashi K, Iwata N (1978). Effects of an anabolic steroid and vitamin B complex upon myopathy induced by corticosteroids. Eur J Pharmacol 52: 353–359. Santidrian S, Moreyra M, Munro HN, et al. (1981). Effect of corticosterone and its route of administration on muscle protein breakdown, measured in vivo by urinary excretion of N tau-methylhistidine in rats: response to different levels of dietary protein and energy. Metabolism 30: 798–804. Scatizzi A, Di Maggio A, Rizzi D, et al. (1993). Acute renal failure due to tubular necrosis caused by wildfowlmediated hemlock poisoning. Ren Fail 15: 93–96. Schmalbruch H (1980). The early changes in experimental myopathy induced by chloroquine and chlorphentermine. J Neuropathol Exp Neurol 39: 65–81. Schubert DS, Brocco K, Miller F, et al. (1981). Brief and mild alcohol intake can increase serum creatine phosphokinase. Ann Neurol 9: 200–201. Shoji S, Pennington RJ (1977). Binding of dexamethasone and cortisol to cytosol receptors in rat extensor digitorum longus and soleus muscles. Exp Neurol 57: 342–348. Shoji S, Takagi A, Sugita H, et al. (1974). Muscle glycogen metabolism in steroid-induced myopathy of rabbits. Exp Neurol 45: 1–7. Shoji S, Takagi A, Sugita H, et al. (1976). Dysfunction of sarcoplasmic reticulum in rabbit and human steroid myopathy. Exp Neurol 51: 304–309. Sholl JS, Hughey MJ, Hirschmann RA (1985). Myotonic muscular dystrophy associated with ritodrine tocolysis. Am J Obstet Gynecol 151: 83–86. Showalter CJ, Engel AG (1997). Acute quadriplegic myopathy: analysis of myosin isoforms and evidence for calpainmediated proteolysis. Muscle Nerve 20: 316–322. Silver RM, Heyes MP, Maize JC, et al. (1990). Scleroderma, fasciitis, and eosinophilia associated with the ingestion of tryptophan. N Engl J Med 322: 874–881. Sinclair D, Phillips C (1982). Transient myopathy apparently due to tetracycline. N Engl J Med 307: 821–822. Sitprija V, Boonpucknavig V (1972). Renal failure and myonecrosis following wasp-stings. Lancet 1: 749–750. Slavin G, Martin F, Ward P, Levi J, et al. (1983). Chronic alcohol excess is associated with selective but reversible injury to type 2B muscle fibres. J Clin Pathol 36: 772–777.
TOXIC AND IATROGENIC MYOPATHIES Song SK, Rubin E (1972). Ethanol produces muscle damage in human volunteers. Science 175: 327–328. Sonoda Y, Gotow T, Kuriyama M, et al. (1994). Electrical myotonia of rabbit skeletal muscles by HMG-CoA reductase inhibitors. Muscle Nerve 17: 891–897. Spargo E (1984). The acute effects of alcohol on plasma creatine kinase (CK) activity in the rat. J Neurol Sci 63: 307–316. Staffa JA, Chang J, Green L (2002). Cerivastatin and reports of fatal rhabdomyolysis. N Engl J Med 346: 539–540. Stauber WT, Hedge AM, Trout JJ, et al. (1981). Inhibition of lysosomal function in red and white skeletal muscles by chloroquine. Exp Neurol 71: 295–306. Steer JH, Mastaglia FL (1986). Protein degradation in bupivacaine-treated muscles. The role of extracellular calcium. J Neurol Sci 75: 343–351. Steer JH, Mastaglia FL, Papadimitriou JM, et al. (1986). Bupivacaine-induced muscle injury. The role of extracellular calcium. J Neurol Sci 73: 205–217. Stein M, Bell MJ, Ang LC (2000). Hydroxychloroquine neuromyotoxicity. J Rheumatol 27: 2927–2931. Steinness E, Rasmussen F, Svendsen O, et al. (1977). A comparative study of serum creatine phosphokinase (CPK) activity in rabbits, pigs and humans after intramuscular injection of local damaging drugs. Acta Pharmacol Toxicol 42: 357–364. Streicher HZ, Gabow PA, Moss AH, et al. (1981). Syndromes of toluene sniffing in adults. Ann Intern Med 94: 758–762. Strunk SW, Smith CW, Blumberg JM (1967). Ultrastructural studies on the lesion produced in skeletal muscle fibers by crude type A Clostridium perfringens toxin and its purified alpha fraction. Am J Pathol 50: 89–107. Sunderland SK (1983). Australian Animal Toxins, Oxford University Press, Melbourne. Sunnasy D, Cairns SR, Martin F, et al. (1983). Chronic alcoholic skeletal muscle myopathy: a clinical, histological and biochemical assessment of muscle lipid. J Clin Pathol 36: 778–784. Takahashi K, Ogita T, Okudaira H, et al. (1986). D-penicillamine-induced polymyositis in patients with rheumatoid arthritis. Arthritis Rheum 29: 560–564. Tam CW, Olin BR, 3rd, Ruiz AE (1980). Loxapine-associated rhabdomyolysis and acute renal failure. Arch Intern Med 140: 975–976. Tao SH, Bolger PM (1997). Hazard assessment of germanium supplements. Regul Toxicol Pharmacol 25: 211–219. Teicher A, Rosenthal T, Kissin E, et al. (1981). Labetalolinduced toxic myopathy. Br Med J (Clin Res Ed) 282: 1824–1825. Thompson PD, Nugent AM, Herbert PN (1990). Increases in creatine kinase after exercise in patients treated with HMG Co-A reductase inhibitors. JAMA 264: 2992.
341
Thompson PD, Clarkson P, Karas RH (2003). Statin-associated myopathy. JAMA 289: 1681–1690. Tomlinson IW, Rosenthal FD (1977). Proximal myopathy after perhexiline maleate treatment. Br Med J 1: 1319–1320. Trout JJ, Stauber WT, Schottelius BA (1981). Chloroquineinduced alterations in phasic muscles. II. Sarcoplasmic reticulum. Exp Mol Pathol 34: 237–243. Ucar M, Mjorndal T, Dahlqvist R (2000). HMG-CoA reductase inhibitors and myotoxicity. Drug Saf 22: 441–457. Udezue EO, Harrold BP (1980). Hyperkalaemic paralysis due to spironolactone. Postgrad Med J 56: 254–255. Urbano-Marquez A, Fernandez-Sola J (2004). Effects of alcohol on skeletal and cardiac muscle. Muscle Nerve 30: 689–707. Valeriano J, Tucker P, Kattah J (1983). An unusual cause of hypokalemic muscle weakness. Neurology 33: 1242–1243. van Garsse LG, Boeykens PP (1990). Two patients with eosinophilia myalgia syndrome associated with tryptophan. Br Med J 301: 21. Varga J, Peltonen J, Uitto J, et al. (1990). Development of diffuse fasciitis with eosinophilia during L-tryptophan treatment: demonstration of elevated type I collagen gene expression in affected tissues. A clinicopathologic study of four patients. Ann Intern Med 112: 344–351. Vita G, Bartolone S, Santoro M, et al. (1986). Hypokalemic myopathy induced by fluroprednizolone-containing nasal spray. Acta Neurol (Napoli) 8: 108–109. Wakata N, Kawamura Y, Araki Y, et al. (1983). Study on steroid-induced muscular change. Rinsho Shinkeigaku 23: 430–435. Walravens PA, Greene C, Frerman FE (1989). Lovastatin, isoprenes, and myopathy. Lancet 2: 1097–1098. Walsh JC, Conomy AB (1977). The effect of ethyl alcohol on striated muscle: some clinical and pathological observations. Aust N Z J Med 7: 485–490. Watts GF, Castelluccio C, Rice-Evans C, et al. (1993). Plasma coenzyme Q (ubiquinone) concentrations in patients treated with simvastatin. J Clin Pathol 46: 1055–1057. Wecker L, Laskowski B, Dettbarn WD (1978). Neuromuscular dysfunction induced by acetylcholinesterase inhibition. Fed Proc 37: 2818–2822. Williams AJ, Baghat MS, Stableforth DE, et al. (1983). Dysphonia caused by inhaled steroids: recognition of a characteristic laryngeal abnormality. Thorax 38: 813–821. Wu CM, Matsuoka T, Takemitsu M, et al. (1992). An experimental model of mitochondrial myopathy: germaniuminduced myopathy and coenzyme Q10 administration. Muscle Nerve 15: 1258–1264. Yagiela JA, Benoit PW, Buoncristiani RD, et al. (1981). Comparison of myotoxic effects of lidocaine with epinephrine in rats and humans. Anesth Analg 60: 471–480.
Handbook of Clinical Neurology, Vol. 86 (3rd series) Myopathies F. L. Mastaglia, D. Hilton-Jones, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 17
Endocrine myopathies RICHARD W. ORRELL* Royal Free and University College Medical School, University College London, London, UK
17.1. Introduction Muscle is one of the largest tissues in the body, and is susceptible to the metabolic and trophic effects of the endocrine system. The commonest endocrine disorders, and associated myopathies, are of the thyroid and corticosteroid hormones. Rarer myopathies are associated with growth hormone, insulin, parathormone, epinephrine, insulin and testosterone. These are dealt with in turn in this chapter. Much of the descriptive and epidemiological literature is relatively old. To some extent this reflects changes in emphasis in interest and research in muscle disorders. In earlier decades the muscle abnormalities were probably more prominent, as endocrine disorders were more difficult to diagnose at an early stage, and more difficult to manage. Most endocrine disorders are now detected and treated at an early stage, and muscle abnormalities more rarely are troublesome or severe. Nevertheless patients continue to be troubled by muscle symptoms and signs as manifestations of endocrine disease. Recognition of the association is important, as diagnosis is relatively straightforward, and treatment is often effective. The pathophysiology of the endocrine myopathies is still relatively uncertain. Many of the explanations rely on animal studies. A particular feature of many of the endocrine myopathies is the disproportionate degree of weakness or fatigue for extent of muscle wasting, emphasizing the energetic component to the symptoms. It is possible that our understanding of pathophysiology will improve as a result of development of therapeutic agents for muscle and nerve growth and repair, including growth
factors, which act on signaling pathways common to the endocrine disorders described.
17.2. Thyroxine 17.2.1. Hyperthyroid myopathy Muscle weakness in hyperthyroidism is well recognized, with clinical evidence of weakness in up to around 75% of patients (although these figures are historical, probably reflecting later diagnosis and treatment). However, the symptoms are of clinical significance in less than 5% (Swanson et al., 1981). The clinical presentation is of a proximal myopathy, with wasting and weakness (Fig. 17.1). It is more common in females than males. Distal weakness may also be present. Respiratory muscle weakness may occur, with breathlessness, sometimes requiring respiratory support (McElvaney et al., 1990). Bulbar muscles may also be affected. The weakness may be out of proportion to the degree of muscle wasting. Prominent shoulder girdle weakness, with scapular winging, may be a feature (Fig. 17.1B; Ramsay, 1966). Reflexes are usually normal or brisk. Cramps, myalgia and fasciculation may be present (McComas et al., 1974; Feibel and Campa, 1976), and may occasionally lead to confusion with amyotrophic lateral sclerosis (Serradell et al., 1990). Serum creatine kinase (CK) is usually within the normal range (Docherty et al., 1984), although occasionally very high in a thyroid storm (Bennett and Huston, 1984). Electromyography (EMG) shows features of a myopathy (Ramsay, 1965; Puvandendran et al., 1979).
*Correspondence to: Richard W. Orrell, BSc MD FRCP, University Department of Clinical Neurosciences Royal Free and University College Medical School, University College London, Rowland Hill Street, London NW3 2PF, UK. E-mail: r.orrell@medsch. ucl.ac.uk, Tel: þ44-(0)20-7830-2387, Fax: þ44-(0)20-7472-6829.
344
R. W. ORRELL
Fig. 17.1(A,B). Muscle wasting in patients with hyperthyroidism. (Acknowledgement Professor Pierre Bouloux.)
Almost all thyrotoxic patients will have some EMG features of myopathy in the proximal muscles. Muscle histology is usually non-specific, including features of type 1 and type 2 fiber atrophy (Wiles et al., 1979; KorenyiBoth et al., 1981). Experimental studies in hyperthyroid rats demonstrated conversion of type 1 to type 2 fibers (Ianuzzo et al., 1977). The pathogenesis probably relates to the metabolic effects of thyroxine. Thyroxine has a catabolic effect on muscle protein. There is evidence of a reduced efficiency of muscle contraction (Wiles et al., 1979; Zurcher et al., 1989). This may explain the relative preservation of muscle bulk in the presence of weakness. In humans, hyperthyroidism shortens the ankle reflex relaxation time (Wiles et al., 1979). In thyrotoxic rats, time to peak tension and twitch tension of type 1 and type 2 muscle is reduced. Underlying changes include a shift in expression of myosin heavy and light chains to those typical of fast-twitch muscle, an increase in calcium sensitivity of the contractile proteins, and increased calcium uptake by the sarcoplasmic reticulum (Dulhunty, 1990). Reduced muscle fiber membrane excitability in patients and animals probably results from depolarization-induced sodium-channel inactivation (Ruff et al., 1988). There may be systemic and skeletal muscle potassium depletion in patients with thyrotoxicosis, leading to weakness (Satoyoshi et al., 1963a). There may also be a relationship between zinc depletion found in thyrotoxicosis and muscle weakness (Ubogu et al., 2004).
Muscle power usually improves on correction of the excess thyroxine, in advance of reversal of muscle wasting (Kissel and Mendell, 1992). Response to treatment may take several months, but propranolol may reverse muscle weakness more rapidly (Pimstone et al., 1968). Myasthenia gravis should be considered as a possible concomitant illness in hyperthyroid patients with sudden generalized weakness and bulbar palsy. There is an increased frequency of thyroid disorders in association with myasthenia gravis, around 6% being hyperthyroid (and 5% hypothyroid) (Kaminski and Ruff, 1994). 17.2.2. Hypothyroid myopathy Up to 40% of patients with hypothyroidism have been claimed to have clinical evidence of muscle weakness (Kissel and Mendell, 1992). Typical symptoms include muscle stiffness, pain and cramps, especially related to exercise or cold weather (Wilson and Walton, 1959). Delayed muscle relaxation, or pseudomyotonia, is present in around 25% of patients. A clinical triad of proximal muscle weakness with raised serum creatine kinase, slurring dysarthria and slow relaxing reflexes is recognized as a presenting feature of hypothyroidism (Wise et al., 1995). Hypothyroidism may present with respiratory muscle weakness (Martinez et al., 1989) or rhabdomyolysis (Riggs, 1990). In adults, an extreme presentation of hypothyroidism is Hoffmann’s syndrome (Fig. 17.2; Kocher, 1892;
ENDOCRINE MYOPATHIES
345
Banerjee, 1978), and may be related to the impaired ischemic lactate production, weakness and fatigue seen in hypothyroidism (Argov et al., 1988). There also effects of hypothyroidism on the Naþ–Kþ pump in rat muscle (Everts et al., 1990). There is a prolongation of ankle reflex relaxation time in hypothyroidism (Khaleeli and Edwards, 1984). Animal studies suggest this relates to altered myosin ATPase activity, with myosin light chains in fast-twitch muscle converting to those of slow muscle (Kirschbaum et al., 1990). There is a slowing of calcium sequestration by the sarcolplasmic reticulum. Muscle symptoms and signs usually recover completely when the hypothyroidism is corrected. 17.2.3. Thyrotoxic periodic paralysis
Fig. 17.2. Muscle hypertrophy in a patient with hypothyroidism (Hoffman’s syndrome).
Hoffmann, 1897; Klein, 1981). Hoffmann’s original patient was an adult with muscle hypertrophy, weakness, slow movements, painful spasms and delayed relaxation, which did not improve with repetition (distinguishing this from true myotonia). A clinical sign of myoedema is recognized. This is a sustained, electrically silent, focal muscle contraction elicited by tapping the muscle with a tendon hammer. In children with congenital hypothyroidism a similar syndrome of muscle hypertrophy (but without cramps) is termed Kocher–Debre´–Se´me´laigne syndrome (Kocher and Se´me´laigne, 1892; Debre´, 1935). There are no consistent findings on muscle biopsy to explain the muscle hypertrophy. Serum creatine kinase may be raised, often to around 10 times normal (Docherty et al., 1984). EMG may show myopathic features and sometimes fibrillations, positive sharp waves, and other spontaneous activity (Scarpalezos et al., 1973; Venables et al., 1978). The pathogenesis of hypothyroid muscle disease is uncertain. Hypothyroidism has a wide range of metabolic effects. This includes a reduction in mitochondrial oxidation, muscle oxidative enzyme activity, and glucose uptake. Impaired glycogenolysis may contribute to muscle cramps and fatigue. Reduced acid maltase activity, corrected by thyroxine, has been demonstrated in some patients (McDaniel et al., 1977). In rats, hypothyroidism impairs growth and decreases protein synthesis and degradation (d’Albis et al., 1990). Hypothyroidism in rats reduces the number of b-adrenergic receptors on muscle cells, reducing glycogenolysis (Sharma and
The periodic paralysis of thyrotoxicosis is clinically similar to hypokalemic periodic paralysis (Swanson et al., 1981). In thyrotoxicosis the condition is usually sporadic, and most common in patients from China and Japan (Satoyoshi et al., 1963b). For example, in China 13% of men (and 0.2% of women) with hyperthyroidism had thyrotoxic periodic paralysis, usually with onset between 20 and 39 years of age (McFadzean and Yeung, 1967). There has been association with a number of human leukocyte antigen (HLA) haplotypes (Tamai et al., 1987). Males are more commonly affected than females. Weakness of the proximal limb and trunk muscles may be precipitated by exercise, cold or high carbohydrate intake. The paralysis lasts from hours to a week, and may occur several times in a week (McFadzean and Yeung, 1967). Serum potassium may be low during an attack, and the attack may be precipitated by infusion of insulin and glucose (McFadzean and Yeung, 1967). Serum phosphate may be low, together with serum magnesium (Manoukian et al., 1999). Thyrotoxic periodic paralysis may be the presenting feature of thyrotoxicosis, often occurring at disease onset (Magsino and Ryan, 2000). The cause of paralysis is uncertain, but may relate to an increase in the number of muscle Naþ–Kþ pumps and altered membrane excitability (Kaminski and Ruff, 1994), or sodium channel inactivation as a result of sarcolemmal depolarization, with loss of membrane excitability (Ruff et al., 1988). On electron microscopy, vacuolar dilatation of the sarcoplasmic reticulum may be seen (Satoyoshi et al., 1963b; Engel, 1966a). The occurrence of paralysis is not clearly related to the severity or duration of thyrotoxicosis. Correction of the thyroid hormone disturbance prevents the paralytic attacks, and thyroid hormone replacement may precipitate attacks. Propranolol may also prevent paralytic attacks. Acetazolamide is not effective (Kufs et al., 1989). In the acute attack of paralysis potassium replacement may prevent potential
346
R. W. ORRELL
life-threatening cardiac arrhythmias (Magsino and Ryan, 2000). 17.2.4. Thyroid-associated ophthalmopathy (exophthalmic Graves’ disease] Swelling or enlargement of the extraocular muscles in autoimmune thyroid disease may lead to exophthalmos and ocular myopathy. Most patients affected are biochemically hyperthyroid, but may be hypothyroid or euthyroid (Salvi et al., 1990). The patients usually present with exophthalmos (Figs 17.3 and 17.4), which may be painful, or diplopia. Enlargement of the extraocular muscles may lead to optic nerve compression and loss of vision (Hallin and Feldon, 1988). The swelling of the
Fig. 17.3. Thyroid associated ophthalmopathy, with exophthalmos on the left, in a patient with Graves’ disease. (Acknowledgement Professor Pierre Bouloux.)
Fig. 17.4. Magnetic resonance imaging of brain and orbits demonstrating enlargement of the extraocular muscles in a patient with Graves’ disease. (Acknowledgement Professor Pierre Bouloux.)
muscles is due to edema of the orbital contents and extraocular muscles as a result of glycoprotein accumulation and inflammatory changes (Riley, 1972; Kaminski and Ruff, 1994; Bartalena et al., 2004). The autoimmune process involves antibodies specific for extraocular muscles (Ahman et al., 1987; Hiromatsu et al., 1988). An alternative suggestion is that the extraocular muscles may be exposed to a high level of thyroid antibodies as a result of selective delivery through lymphatic channels (Kriss, 1975). The ocular muscles have features distinguishing them from other muscles (Porter et al., 2001). The antibodies react with extraocular muscle, and also with retro-orbital connective tissue (Schifferdecker et al., 1989). The pathology appears to be largely T-cell mediated (Pappa et al., 1997), and potential target antigens include the thyrotropin receptor (Paschke et al., 1995; Bartalena et al., 2004). Any biochemical disturbance of thyroid function should be treated. Lid retraction (as a result of b-adrenergic hyperactivity) may respond to adrenergic blocking eye drops (guanethidine), and taping of the eyelids at night. Local injection of steroids may be needed for more severe edema. Systemic corticosteroids, oral and intravenous, are often effective (Wiersinga, 1996; Wiersinga and Prummel, 2000). Orbital radiotherapy also has a role (Prummel et al., 1993), and may be combined with corticosteroids (Marcocci et al., 1987). There is a risk of radiation retinopathy. Intravenous immunoglobulin has been demonstrated to have similar effects to oral corticosteroids (Kahaly et al., 1996). Cyclosporine may be used as a corticosteroid-sparing agent (Prummel, 1989; Wiersinga and Prummel, 2000), but azathioprine appears not to be helpful (Perros et al., 1990). Sometimes surgical decompression of the orbit may be necessary to prevent compressive optic neuropathy and exposure keratitis (Bahn and Gorman, 1987). Other conditions to be differentiated include orbital myositis, which includes orbital pseudotumor and some forms of Tolosa–Hunt syndrome (Banker, 1994). Other causes of extraocular muscle enlargement include tumor infiltration, for example lymphoma, and local vascular malformations or venous congestion (Harris et al., 1994). Computerized tomography or magnetic resonance imaging of the orbit usually demonstrates symmetrical bilateral extraocular muscle enlargement in thyroid disease. In orbital myositis, the features are more often unilateral, and may involve only a single muscle, or be asymmetrical in other ways. In orbital myositis the clinical presentation is with acute orbital pain, and responds to corticosteroid (Slavin and Glaser, 1982). In addition, the erythrocyte sedimentation rate is often raised, and there may be eosinophilia, but no abnormality of thyroid function.
ENDOCRINE MYOPATHIES
17.3. Corticosteroids 17.3.1. Cushing’s syndrome and steroid myopathy Cushing’s disease, ectopic production of adrenocorticotrophic hormone (ACTH), and corticosteroid administration, all produced similar myopathic features in patients (Fig. 17.5). The clinical features are typically a painless symmetrical proximal myopathy. This usually affects the legs more than the arms. There may be additional marked muscle wasting, and the more general systemic features of glucocorticoid excess (Muller and Kugelberg, 1959). Myopathy may be present in up to 80% of patients with Cushing’s disease (Urbanic and George, 1981). Patients on chronic corticosteroid treatment may also develop a chronic painless proximal myopathy (Lane and Mastaglia, 1978), usually developing within a few weeks of commencing treatment (Rothstein et al., 1983). A particular clinical problem may be the difficulty in distinguishing the weakness due to the underlying disorder being treated (for example polymyositis) and that due to the corticosteroid treatment. Electromyography may show many myopathic features (Muller and Kugelberg, 1959). Serum creatine kinase is usually normal (Lacomis et al., 1993). Muscle biopsy may show selective type 2 fiber atrophy, with increased muscle glycogen (Fig. 17.6; Harriman and Reed, 1972; Rebuffe-Scrive et al., 1988). Electron microscopy may show mitochondrial aggregates and vacuolation (Engel, 1966b).
347
The structural features do not appear to account fully for the degree of muscle weakness, and there are probably additional metabolic or energetic effects. In particular glucocorticoids affect muscle carbohydrate and protein metabolism. As in thyrotoxicosis, the muscle wasting may be disproportionately severe with relative preservation of muscle strength, and this may reflect potentiation of excitation-contraction coupling (Kaminski and Ruff, 1994). Glucocorticoids lead to skeletal muscle catabolism, and stimulate muscle protein degradation (Shoji, 1989). Glucocorticoids also lead to an insulin-resistant state, and have a range of other potential metabolic effects on muscle (Ubogu, 2004). Following treatment of Cushing’s syndrome by hypophysectomy, recovery in muscle strength may occur, but may be slow and incomplete (Khaleeli et al., 1983). Treatment of iatrogenic corticosteroid-induced myopathy is limited by the need to treat the underlying disease, but steroid-sparing agents may be added. The corticosteroid should be given at the lowest dose possible, and alternate day administration may help. A nonfluorinated corticosteroid should be given if possible, as the fluorinated corticosteroids (triamcinolone, betamethasone and dexamethasone) are more likely to produce weakness. Starvation or protein deprivation may exacerbate a corticosteroid myopathy, and adequate nutrition should be given. Physical inactivity may also potentiate muscle wasting, and intensive physical therapy may partially prevent this (Falduto et al., 1990). In the intensive-care situation, administration of high doses of corticosteroids, especially intravenous, may
Fig. 17.5. Patients with Cushing’s disease demonstrating (A) abdominal enlargement and striae, (B) buffalo hump. (Acknowledgement Professor Pierre Bouloux.)
348
R. W. ORRELL
Fig. 17.6. Quadriceps femoris muscle biopsy from a patient with corticosteroid induced myopathy. There is a wide varation in fiber diameters, with small atrophic and often angulated fibers. There is an excess of type I fibers, with atrophy predominantly of type II fibers. (A) For full color figure, see plate section. Haematoxylin and eosin; (B) ATPase pH 4.3; (C) ATPase pH 9.4.
precipitate within days an acute severe myopathy (Ramsay et al., 1993). In patients with sepsis this may be an acute necrotizing myopathy, and in patients with asthma this may be a less severe myopathy (Shee, 1990). Commonly called critical illness myopathy (Bolton, 2005; Latronico et al., 2005), other terms include acute quadriplegic myopathy, acute necrotizing myopathy of intensive care, acute myopathy in severe asthma, acute corticosteroid myopathy, thick-filament myopathy, acute corticosteroid and pancuronium associated myopathy and critical care myopathy. The critical illness myopathy of intensive care may be precipitated by other factors including immobility, neuromuscular blockade for mechanical ventilation, and sepsis (Ramsay et al., 1993). The corticosteroids may have a priming effect on the muscle, with other factors such as non-depolarizing blocking medication acting as a trigger for muscle necrosis. Critical illness myopathy may coexist with critical illness polyneuropathy, and may confuse electrodiagnostic examination. Muscle biopsy demonstrates a range of fea-
tures including muscle fiber atrophy, angulated fibers, internal nuclei, rimmed vacuoles, fatty degeneration, fibrosis and single fiber necrosis and regeneration (Latronico et al., 1996; Lacomis et al., 2000). There may be a disrupted intermyofibrillar network, with reduction in myosin ATPase activity in non-necrotic fibers due to loss of thick filaments (Lacomis et al., 1996). Electron microscopy shows diffuse loss of myosin filaments (AlLozi et al., 1994; Showalter and Engel, 1997; Lacomis et al., 2000). The pathogenesis is uncertain, but is probably a combination of factors mentioned above, including the acute inflammatory response, sepsis and glucocorticoids, stimulating muscle proteoloysis, and exacerbated by muscle inactivity, neuromuscular blockade and membrane instability (Ruff, 1998; Ubogu et al., 2004). Withdrawal of the trigger may accelerate recovery (Ramsay et al., 1993), and if the critical illness is survived, muscle power usually returns. Isolated ACTH excess may produce a proximal myopathy, as in patients with Nelson’s syndrome following
ENDOCRINE MYOPATHIES adrenalectomy (and corticosteroid replacement therapy) who subsequently develop a myopathy (Phineas et al., 1968). The myopathy is especially prevalent in patients who develop excessive pigmentation. Primary hyperaldosteronism (Conn’s syndrome) may present with muscle weakness, which is often found in this condition (Conn et al., 1964). The weakness may be due to hypokalemia, and is often episodic. Muscle symptoms resolve with treatment of the underlying disorder. 17.3.2. Glucocorticoid deficiency Up to 50% of patients with adrenal insufficiency have symptoms of generalized weakness, muscle cramps and fatigue (Mor et al., 1987). The myopathy is independent of the cause of adrenal insufficiency, the common causes including malignant or infectious destruction of the adrenal gland, autoimmune adrenal failure, adrenal hemorrhage, or ACTH deficiency. Addison’s disease (Fig. 17.7) may cause additional weakness of the respiratory muscles (Mier et al., 1988) or precipitate myasthenia gravis (Dumas et al., 1985). Creatine kinase and EMG are usually normal, and muscle biopsy shows no specific features (Mor et al., 1987; Kaminski and Ruff, 1994). The myopathic features result from impaired muscle carbohydrate metabolism, disturbance of water and electrolyte imbalance, and impaired blood flow with exercise-induced hypotension (Kaminski and Ruff, 1994). The muscle symptoms improve when the glucocorticoid deficiency is corrected. A form of hyperkalemic periodic paralysis may be seen in adrenal insufficiency. Potassium or exercise may precipitate a flaccid quadriplegia. This is reversed when the serum potassium is lowered (Vilchez et al., 1980). Treatment is by correction of the endocrine deficiency, with glucocorticoid, and sometimes mineralcorticoid.
Fig. 17.7. Buccal hyperpigmentation in a patient with Addison’s disease. (Acknowledgement Professor Pierre Bouloux.)
349
17.4. Growth hormone 17.4.1. Acromegaly Around 50% of patients with increased growth hormone and acromegaly have proximal muscle weakness with pain and reduced exercise tolerance (Fig. 17.8; Khaleeli et al., 1984). The muscle weakness is slowly progressive, with minimal muscle wasting. EMG may show myopathic features. Muscle biopsy features include hypertrophy or atrophy of type 1 and type 2 fibers, with excess lipofuscin and glycogen deposition, loss of myofibrils, and increase in satellite cells (Mastaglia, 1973; Khaleeli et al., 1984). The weakness and fatigability are out of proportion to the degree of muscle wasting observed. Possible mechanisms for the reduced power of muscle contraction include decreased sarcolemmal excitability, and reduced myofibrillar ATPase activity. Fatigability may be due to impaired carbohydrate metabolism, or reduced muscle blood flow (Kaminski and Ruff, 1994). Human growth hormone acts by stimulating formation of insulin-like growth factor (IGF). IGF-1 is synthesized primarily by the liver. There are a number of other isoforms. IGF-1 binds to a cell surface tyrosine kinase receptor, leading to modulation of cAMP and a range of other signaling and metabolic effects (Werner and Le Roith, 2000). The myopathy responds to correction of the growth hormone excess, usually by surgical removal of a pituitary adenoma, local irradiation, or bromocriptine. 17.4.2. Hypopituitarism Growth hormone deficiency is usually associated with pituitary failure. In adults causes include infarction, local tumor, head injury and meningitis. There may be a more
Fig. 17.8. Enlargement of the hands and fingers in a patient with acromegaly. (Acknowledgement Professor Pierre Bouloux.)
350
R. W. ORRELL
generalized disturbance of pituitary function, and many of the symptoms may be attributed to loss of thyroid and adrenocortical hormones. Growth hormone deficiency may contribute to the symptoms, with significant weakness and fatigue, which is out of proportion to any muscle wasting (Kaminski and Ruff, 1994). In children, before puberty, the hypopituitarism is usually idiopathic or due to a craniopharyngioma. Growth hormone replacement is required to achieve normal muscle development and growth (Raben, 1962). Decreased levels of growth hormone in elderly individuals may contribute to the loss of muscle mass. This may be mediated through a reduction of splicing of IGF-I to MGF (mechano growth factor). MGF is a local tissue repair factor produced by exercise or damaged muscle, and may have pathogenic and therapeutic implications for improvement of muscle growth in a range of muscle diseases and the aging process (Goldspink, 2006).
17.5. Insulin Insulin resistance may be associated with a number of endocrine disorders, including hyperthyroidism and hypothyroidism. The lack of the anabolic effect of insulin may contribute to muscle atrophy in some of these conditions.
lipodystrophy affects mainly women, usually commencing in the first or second decade, with loss of facial fat, and sometimes additional loss of fat over the arms, chest, and abdomen, but with normal or increased fat deposition over the legs (Senior and Gellis, 1964). The lack or excess of subcutaneous fat may be misinterpreted as muscle wasting or hypertrophy. Clinical, electrophysiological and histological features of myopathy have been reported in patients with lipodystrophy (Afifi et al., 1985, Orrell et al., 1995a). Muscle symptoms include aching and fatigue of the legs with marked proximal leg weakness, and may be associated with insulin resistance (Orrell et al., 1995a). Clinical and metabolic studies suggest that partial lipodystrophy may be an incomplete variant of acquired generalized lipodystrophy. Insulin resistance, with diabetes mellitus, may be associated with acquired generalized lipodystrophy, and has been reported with muscle weakness (Sasaki et al., 1992). Insulin resistance in lipodystrophy has been attributed to an insulin receptor defect (Oseid et al., 1977) and also to a prereceptor abnormality (Golden et al., 1985). Abnormal muscle histology, including hypertrophy of type 1 and type 2 fibers, with accumulation of lipid droplets between the myofibrils has been described in acquired partial lipodystrophy (Orrell et al., 1995a). The pathogenesis of the myopathy in lipodystrophy remains uncertain.
17.5.1. Lipodystrophy There is a reduction, or loss, of subcutaneous fat in the lipodystrophies (Fig. 17.9). There may be associated insulin resistance and myopathy. Acquired partial
17.5.2. Diabetic neuromyopathy Diabetic amyotrophy is primarily a neuropathy (Chokroverty, 1977; Barohn et al., 1991). However, ischemic infarction of the thigh muscles may occur in poorly controlled diabetes mellitus (Barohn and Kissel, 1992). The acute onset of pain, tenderness and edema of the thigh is associated with a palpable mass, usually in the quadriceps or hamstring muscles. Muscle biopsy demonstrates widespread muscle infarction with necrosis, and evidence of arteriolar occlusion. The symptoms resolve spontaneously and treatment is symptomatic, avoiding surgical exploration if possible (Banker and Chester, 1973). The symptoms may recur, in the same or opposite thigh.
17.6. Parathormone 17.6.1. Hyperparathyroidism
Fig. 17.9. Loss of subcutaneous adipose tissue in a patient with lipodystrophy. (Acknowledgement Professor Pierre Bouloux.)
Generalized muscle weakness and stiffness may be a symptom in patients with hyperparathyroidism due to parathyroid adenoma (Patten et al., 1974). There may be proximal muscle weakness and wasting, especially of the lower limbs, tongue fasciculation and sometimes hyperreflexia. Serum creatine kinase is usually normal
ENDOCRINE MYOPATHIES (Patten et al., 1974; Turken et al., 1989). EMG may show myopathic features (Frame, 1968; Patten et al., 1974). Muscle biopsy may be normal or show non-specific features (Patten et al., 1974; Ljunghall et al., 1984). Parathyroidectomy corrects the hormonal disturbance and relieves the symptoms (Patten et al., 1974; Delbridge et al., 1988). As a result of earlier biochemical diagnosis and treatment, a significant myopathy is now very rare. Patients with chronic renal failure may have secondary hyperparathyroidism. They may develop a myopathy, predominantly affecting the legs (Floyd et al., 1974). Other metabolic abnormalities associated with chronic renal failure, including carnitine deficiency, may contribute to the myopathy (Savica et al., 1983). 17.6.2. Osteomalacia Approximately 30% of patients with osteomalacia have proximal weakness or myalgia. The myopathy may present before the bone features of osteomalacia (Glerup et al., 2000). The myopathy of osteomalacia is caused by dietary deficiency or malabsorption of vitamin D, or abnormal vitamin D metabolism associated with renal tubular acidosis or anticonvulsant use (Ritz et al., 1980). For example, a proximal myopathy with osteomalacia caused by celiac disease has been described (Kozanoglu et al., 2005). In osteomalacia, there is elevated serum calcium and phosphate. Parathormone levels may be normal or increased. EMG shows myopathic features. Muscle biopsy findings are non-specific. In children, vitamin D deficiency manifests as rickets, and may be associated with proximal myopathy (Alyaarubi and Rodd, 2005). 17.6.3. Hypoparathyroidism and pseudohypoparathyroidism Hypoparathyroidism, usually results from surgical excision of the parathyroid glands or other local disease, with deficiency of parathormone. In pseudohypoparathyroidism the parathormone level is normal or increased, but there is a defect in the cellular response to parathormone. The most common muscle symptoms and signs are of tetany, due to neural hyperexcitability, as a result of hypocalcemia and hypomagnesemia. Acute treatment is with intravenous calcium, and sometimes magnesium. Chronic treatment includes oral supplements of calcium, vitamin D, and magnesium if indicated. Myopathy is rarely associated with parathormone deficiency, but has been described in both hypoparathyroidism (Yamaguchi et al., 1987) and pseudohypoparathyroidism (Cape, 1969). In hypoparathyroidism the muscle weakness may be mild, creatine kinase mildly elevated, and the muscle biopsy shows normal
351
or atrophic fibers. The symptoms resolve with calcium and vitamin D supplements.
17.7. Epinephrine 17.7.1. Phaeochromocytoma Around 25% of patients with phaeochromocytoma complain of weakness, but this generally appears to be nonspecific, and is not necessarily due to primary muscle pathology (Thomas et al., 1966; Ross and Griffith, 1989). A focal myositis of skeletal muscle has been described in a patient with phaeochromocytoma (Bhatnagar et al., 1986). There was acute onset of muscle tenderness and weakness in the arms and legs. The myositis was proposed to be the result of catecholamine release from the tumor. Serum creatine kinase was markedly raised, and the patient died of renal failure. There was no evidence of the myocarditis that may be associated with phaeochromocytoma (Van Vilet et al., 1966).
17.8. Calcitonin A myopathy has been associated with medullary carcinoma of the thyroid with hypercalcitoninemia (Cunliffe et al., 1970). The clinical features of a 19-year-old girl with a medullary carcinoma of the thyroid secreting calcitonin were described. She had been “floppy” since birth, with features of proximal limb weakness. Serum creatine kinase was normal. EMG showed myopathic features. Muscle biopsy showed histological features similar to a nemaline myopathy, with most fibers demonstrating a high level of oxidative activity, correlated with large numbers of mitochondria, and increased sarcoplasmic glycogen. There were additional dysmorphic features and developmental abnormalities, and it is not clear whether there was any causal relationship between the calcitonin excess and the myopathy.
17.9. Testosterone The effect of androgens on muscle size and function is well recognized in animals, where administration may cause increased muscle bulk, and castration or pituitary lesions lead to muscle wasting and weakness. Males generally have an increased muscle mass and strength compared to females, and the increase in circulating androgens at puberty accounts in part for the increase in muscle mass. Men with primary and secondary hypogonadism may have generalized muscle weakness (Chauhan et al., 1986). A proximal symmetrical weakness is typical of severe disease. The presenting features are usually impotence and loss of libido, although in one study 9
352
R. W. ORRELL
of 28 patients presented with generalized weakness, 19 of 28 having symptoms of muscle weakness on direct questioning (Chauhan et al., 1986). Secondary testosterone deficiency may occur as a result of pituitary or testicular disease, and as a result of aging (Vermeulen, 1991). A myopathy may be associated with this deficiency, and testosterone replacement may produce significant functional improvement (Orrell et al., 1995b). This may be given as a monthly intramuscular injection of a depot preparation. Significant risks of testosterone administration include prostatic cancer, benign prostatic hypertrophy and sleep apnea (Bardin et al., 1991). Using conventional replacement levels of androgens, there appears to be little long-term gain in muscle mass in injured, undernourished, or elderly patients without testosterone deficiency (Wilson and Griffin, 1980). It is not clear whether androgen use by athletes has a positive benefit on muscle function (Wilson, 1988).
References Afifi AK, Bergman RA, Zaynoun ST, et al. (1985). Partial (localised) lipodystrophy. J Am Acad Dermatol 12: 198–203. Ahman A, Banker JR, Weetman AP, et al. (1987). Antibodies to porcine eye muscle in patients with Graves’ ophthalmopathy: identification of serum immunoglobulins directed against unique determinants by immunoblotting and enzyme-linked immunosorbent assay. J Clin Endocrinol Metab 64: 454–460. Al-Lozi MT, Pestronk A, Yee WC, et al. (1994). Rapidly evolving myopathy with myosin-deficient muscle fibers. Ann Neurol 35: 273–279. Alyaarubi S, Rodd C (2005). Treatment of malabsorption vitamin D deficiency myopathy with intramuscular vitamin D. K Pediatr Endocrinol Metab 18: 719–722. Argov Z, Renshaw P, Boden B, et al. (1988). Effects of thyroid hormones on skeletal muscle bioenergetics. In vivo phosphorous-31 magnetic resonance spectroscopy study of humans and rats. J Clin Invest 81: 1695–1701. Bahn RS, Gorman GA (1987). Choice of therapy and criteria for assessing treatment outcome in thyroid associated ophthalmology. Endocrinol Metab Clin North Am 16: 391–407. Banker BQ (1994). Other inflammatory myopathies. In: AG Engel, C Frazini-Armstrong (Eds.), Myology, 2nd edn. New York: McGraw-Hill, pp. 1461–1486. Banker BQ, Chester CS (1973). Infarction of thigh muscle in the diabetic patient. Neurology 23: 667–677. Bardin CW, Swerdloff RS, Santen RJ (1991). Androgens: risks and benefits. J Clin Endocrinol Metab 73: 4–7. Barohn RJ, Kissel JT (1992). Painful thigh mass in a young woman: diabetic muscle infarction. Muscle Nerve 15: 850–855. Barohn RJ, Sahenk Z, Warmolts JR, et al. (1991). The Bruns– Garland syndrome (“diabetic amyotrophy”): revisited 100 years later. Arch Neruol 48: 1130–1135.
Bartalena L, Wiersinga WM, Pinchera A (2004). Graves’ ophthalmopathy: state of the art and perspectives. J Endocrinol Invest 27: 295–301. Bennett WR, Huston DP (1984). Rhabdomyolysis in thyroid storm. Am J Med 77: 733–735. Bhatnagar D, Carey P, Pollard A (1986). Focal myocarditis and elevated creatine kinase levels in a patient with phaeochromoctyoma. Postgrad Med J 62: 197–198. Bolton CF (2005). Neuromuscular manifestations of critical illness. Muscle Nerve 32: 140–163. Cape CA (1969). Phosphorylase A deficiency in pseudohypoparathyroidism. Neurology 19: 167–172. Chauhan AK, Katiyar BC, Misra S, et al. (1986). Muscle dysfunction in male hypogonadism. Acta Neurol Scand 73: 466–471. Chokroverty S, Reyes MG, Rubino FA, et al. (1977). The syndrome of diabetic amyotrophy. Ann Neurol 2: 181–194. Conn JW, Knopf RF, Nesbit RM (1964). Clinical characteristics of primary aldosteronism from analysis of 145 cases. Am J Surg 107: 159–172. Cunliffe WJ, Hudgson P, Fulthorpe JJ, et al. (1970). A calcitonin-secreting medullary thyroid carcinoma associated with mucosal neuromas, marfanoid features, myopathy and pigmentation. Am J Med 48: 120–126. D’Albis A, Chanoine C, Janmot C, et al. (1990). Musclespecific response to thyroid hormone of myosin isoform transitions during rat postnatal development. Eur J Biochem 193: 155–161. Debre´ F, Se´me´laigne G (1935). Syndrome of diffuse muscular hypertrophy in infants causing athletic appearance: its connection with congenital myxoedema. Am J Dis Child 50: 1351–1361. Delbridge LW, Marshman D, Reeve JS, et al. (1988). Neuromuscular symptoms in elderly patients with hyperparathyroidism: improvement with parathyroid surgery. Med J Aust 149: 74–76. Docherty I, Harrop JS, Hine KR, et al. (1984). Myoglobin concentration, creatine kinase activity, and creatine kinase B subunit concentration in serum during thyroid disease. Clin Chem 30: 42–45. Dulhunty AF (1990). The rate of tetanic relaxation is correlated with the density of calcium ATPase in the terminal cisternae of thyrotoxic skeletal muscle. Pflugers Arch 415: 433–439. Dumas P, Archambeaud–Mouveroux F, Vallat JM, et al. (1985). Myasthenia gravis associated with adrenocortical insufficiency: report of two cases. J Neurol 232: 354–356. Engel AG (1966a). Electron microscopic observations in primary hypokalemic and thyrotoxic periodic paralysis. Mayo Clin Proc 41: 797–808. Engel AG (1966b). Electron microscopic observations in thyrotoxic and corticosteroid myopathies. Mayo Clin Proc 41: 785–796. Everts M, Dorup I, Flyvbjerg A, et al. (1990). Naþ–Kþ pump in rat muscle: effects of hypophysectomy, growth hormone, and thyroid hormone. Am J Physiol 259: E278–E283. Falduto MT, Czerwinski SM, Hickson RC (1990). Glucocorticoid-induced muscle atrophy prevention by exercise in fast-twitch fibers. J Appl Physiol 69: 1058–1062.
ENDOCRINE MYOPATHIES Feibel JH, Campa JF (1976). Thyrotoxic neuropathy (Basedow’s paraplegia). J Neurol Neurosurg Psychiatry 39: 491–497. Floyd M, Ayyar DR, Barwick DD, et al. (1974). Myopathy in chronic renal failure. Q J Med 43: 509–524. Frame B, Heinze EG, Block MA, et al. (1968). Myopathy in primary hyperthyroidism. Ann Intern Med 68: 1022–1027. Glerup H, Mikkelsen K, Poulsen L, et al. (2000). Hypovitaminosis D myopathy without biochemical signs of osteomalacic bone involvement. Calcif Tissue Int 66: 419–424. Golden MP, Charles MA, Arquilla ER, et al. (1985). Insulin resistance in total lipodystrophy: evidence for a pre-receptor defect in insulin action. Metabolism 34: 330–335. Goldspink G (2006). Impairment of IGF-I gene splicing and MGF expression associated with muscle wasting. Int J Biochem Cell Biol 38: 481–489. Hallin E, Feldon SSE (1988). Graves’ ophthalmolopathy. II. Correlation of clinical signs with measures derived from computed tomography. Br J Ophthalmol 72: 678–682. Harriman DGF, Reed R (1972). The incidence of lipid droplets in human skeletal muscle in neuromuscular disorders. J Pathol 106: 1–24. Harris GJ, Murphy ML, Schmidt EW, et al. (1994). Orbital myositis as a paraneoplastic syndrome. Arch Ophthalmol 112: 380–386. Hiromatsu Y, Fukazawa H, Guinard F, et al. (1988). A thyroid cytotoxic antibody that cross-reacts with an eye muscle surface antigen may be the cause of thyroid associated ophthalmolopathy. J Clin Endocrinol Metab 67: 565–570. Hoffmann J (1897). Weiter Beitrag zur Lehre von der Tetaine. Deutsche Z Nervenheilk 9: 278–290. Ianuzzo D, Patel P, Chen V, et al. (1977). Thyroidal trophic influence on skeletal muscle myosin. Nature 270: 74–76. Kahaly G, Pitz S, Muller-Forell W, et al. (1996). Randomized trial of intravenous immunoglobulins versus prednisolone in Graves’ ophthalmopathy. Clin Exp Immunol 106: 197–202. Kaminski HJ, Ruff RL (1994). Endocrine myopathies (hyperand hypofunction of adrenal, thyroid, pituitary, and parathyroid glands and iatrogenic corticosteroid myopathy). In: AG Engel, C Frazini-Armstrong (Eds.), Myology, 2nd edn. McGraw-Hill, New York, pp. 1726–1753. Khaleeli AA, Edwards RH (1984). Effect of treatment on skeletal muscle dysfunction in hypothyroidism. Clin Sci 66: 63–68. Khaleeli AA, Betteridge DJ, Edwards RH, et al. (1983). Effect of treatment of Cushing’s syndrome on skeletal muscle structure and function. Clin Endocrinol 19: 547–556. Khaleeli AA, Levy RD, Edwards RHT, et al. (1984). The neuromuscular features of acromegaly: a clinical and pathological study. J Neurol Neurosurg Psychiatry 47: 1009–1015. Kirschbaum B, Kucher H, Termin A, et al. (1990). Antagonistic effects of chronic low frequency stimulation and thyroid hormone on myosin expression in rat fast-twitch muscle. J Biol Chem 265: 13974–13980. Kissel JT, Mendell JR (1992). The endocrine myopathies. In: LP Rowland, S DiMauro (Eds.), Handbook of Clinical Neurology, Vol. 18 (62): Myopathies. Elsevier, Amsterdam, pp. 527–551.
353
Klein I, Parker M, Sherbert R, et al. (1981). Hypothyroidism presenting as muscle stiffness and pseudohypertrophy. Hoffmann’s syndrome. Am J Med 70: 891–894. Kocher T (1892). Zur Verhu¨tung der Creatinismus und cretinoider Zusta¨nde nach neuen Forschungen. Deutsche Z Chir 34: 556–626. Korenyi-Both A, Korenyi-Both I, Kayes BC (1981). Thyrotoxic myopathy: pathomorphological observations of human material and experimentally induced thyrotoxicosis in rats. Acta Neuropathol (Berlin) 53: 237–248. Kozanoglu E, Basaran S, Goncu MK (2005). Proximal myopathy as an unusual presenting feature of celiac disease. Clin Rheumatol 24: 76–78. Kriss JP (1975). Studies on the pathogenesis of Graves’ ophthalmopathy (with some related observations regarding therapy). Recent Prog Horm Res 31: 533–566. Kufs WM, McBiles M, Jurney T (1989). Familial thyrotoxic periodic paralysis. West J Med 150: 461–463. Lacomis D, Chad DA, Aronin N, et al. (1993). The myopathy of Cushing’s syndrome. Muscle Nerve 16: 880–881. Lacomis D, Giuliani MJ, Van Cott A, et al. (1996). Acute myopathy of intensive care: clinical, electromyographic, and pathological aspects. Ann Neurol 40: 645–654. Lacomis D, Zochodne D, Bird M (2000). Critical illness myopathy. Muscle Nerve 23: 1785–1788. Lane RJM, Mastaglia FL (1978). Drug induced myopathies in man. Lancet 2: 562–566. Latronico N, Fenzi F, Recupero D, et al. (1996). Critical illness myopathy and neuropathy. Lancet 347: 1579–1582. Latronico N, Peli E, Botteri M (2005). Critical illness myopathy and neuropathy. Curr Opin Crit Care 11: 126–132. Ljunghall S, Akerstrom G, Johansson G, et al. (1984). Neuromuscular involvement in primary hyperparathyroidism. J Neurol 231: 263–265. Magsino CH, Ryan AJ (2000). Thyrotoxic periodic paralysis. South Med J 93: 996–1003. Manoukian MA, Fote JA, Crapo LM (1999). Clinical and metabolic features of thyrotoxic periodic paralysis in 24 epidsodes. Arch Intern Med 159: 601–606. Marcocci C, Bartalena L, Panicucci M, et al. (1987). Oribital cobalt irradiation combined with retrobulbar or systemic corticosteroids for Graves’ ophthalmopathy: a comparative study. Clin Endocrinol (Oxf) 27: 33–42. Martinez F, Berumudez-Gomez M, Celli B (1989). Hypothyroidism. A reversible cause of diaphragmatic dysfunction. Chest 96: 1059–1063. Mastaglia FL (1973). Pathological changes in skeletal muscle in acromegaly. Acta Neuropathol 24: 273–286. McComas AJ, Sica REP, McNabb AR, et al. (1974). Evidence for reversible motoneurone dysfunction in thyrotoxicosis. J Neurol Neurosurg Psychiatry 37: 548–558. McDaniel H, Pitman C, Oh S, et al. (1977). Carbohydrate metabolism in hypothyroid myopathy. Metabolism 26: 867–873. McElvaney G, Wilcox P, Fairbarn M, et al. (1990). Respiratory muscle weakness and dyspnea in thyrotoxic patients. Am Rev Respir Dis 141: 1221–1227. McFadzean AJ, Yeung R (1967). Periodic paralysis complicating thyrotoxicosis in Chinese. Br Med J 1: 451–455.
354
R. W. ORRELL
Mier A, Larcoche C, Wass J, et al. (1988). Respiratory muscle weakness in Addison’s disease. Br Med J 297: 457–458. Mor F, Green P, Wysenbeek AJ (1987). Myopathy in Addison’s disease. Ann Rheum Dis 46: 81–83. Muller R, Kugelberg E (1959). Myopathy in Cushing’s syndrome. J Neurol Neurosurg Psychiatry 22: 314–319. Orrell RW, Peatfield RC, Collins CE, et al. (1995a). Myopathy in acquired partial lipodystrophy. Clin Neurol Neurosurg 97: 181–186. Orrell RW, Woodrow DF, Barrett MC, et al. (1995b). Testosterone deficiency myopathy. J R Soc Med 88: 454–456. Oseid S, Beck-Nielsen H, Pederson O, et al. (1977). Decreased binding of insulin to its receptor in patients with congenital generalized lipodystrophy. N Engl J Med 296: 245–248. Pappa A, Calder V, Ajjan R, et al. (1997). Analysis of extraocular muscle-infiltrating T cells in thyroid-associated ophthalmopathy (TAO). Clin Exp Immunol 109: 362–369. Paschke R, Vassart G, Ludgate M (1995). Current evidence for and against the TSH receptor being the common antigen in Graves’ disease and thyroid-associated ophthalmopathy. Clin Endocrinol (Oxf) 42: 565–569. Patten BM, Bilezidian JP, Mallette LE, et al. (1974). Neuromuscular involvement in primary hyperparathyroidism. Ann Intern Med 80: 182–193. Perros P, Weightman DR, Crombie AL, et al. (1990). Azathioprine in the treatment of thyroid-associated ophthalmopathy. Acta Endorinol (Copenh) 122: 8–12. Phineas J, Hall R, Barwick DD, et al. (1968). Myopathy associated with pigmentation following adrenalectomy for Cushing’s syndrome. Q J Med 37: 63–77. Pimstone N, Marine N, Pimstone B (1968). Beta-adrenergic blockade in thyrotoxic myopathy. Lancet 2: 1219–1220. Porter JD, Khanna S, Kaminski HJ, et al. (2001). Extraocular muscle is defined by a fundamentally distinct gene expression profile. Proc Natl Acad Sci U S A 98: 12062–12067. Prummel MF, Mourits MP, Berghout A, et al. (1989). Prednisone and cyclosporine in the treatment of severe Graves’ disease. N Engl J Med 321: 1353–1359. Prummel MF, Mourits MP, Blank L, et al. (1993). Randomized double-blind trial of prednisone versus radiotherapy in Graves’ ophthalmopathy. Lancet 342: 949–954. Puvandendran K, Cheah JS, Naganthan N, et al. (1979). Thyrotoxic myopathy: a clinical and quantitative analytic electromyographic study. J Neurol Sci 42: 441–451. Raben MS (1962). Growth hormone 2. Clinical use of growth hormone. N Engl J Med 266: 82–86. Ramsay DA, Zochodne DW, Robertson DM, et al. (1993). A syndrome of acute severe muscle necrosis in intensive care unit patients. J Neuropathol Exp Neurol 52: 387–398. Ramsay JD (1965). Electromyography in thyrotoxicosis. Q J Med 34: 255–267. Ramsay JD (1966). Muscle dysfunction in hyperthryoidism. Lancet 2: 931–934. Rebuffe-Scrive M, Krotkiewski M, Elfverson J, et al. (1988). Muscle adipose tissue morphology and metabolism in Cushing’s syndrome. J Clin Endocrinol Metab 67: 1122–1128.
Riggs J (1990). Acute exertional rhabdomyolysis in hypothyroidism: the result of a reversible defect in glycogenolysis? Mil Med 155: 171–172. Riley FC (1972). Orbital pathology in Graves’s disease. Mayo Clin Proc 47: 975. Ritz E, Boland R, Kreusser W (1980). Effects of vitamin D and parathormone on muscle: potential role in uremic myopathy. Am J Clin Nutr 33: 1522–1529. Ross EJ, Griffith DNW (1989). The clinical presentations of phaeochromocytoma. Q J Med 71: 485–496. Rothstein JM, Delitto A, Sinacore DR, et al. (1983). Muscle function in rheumatic disease patients treated with corticosteroids. Muscle Nerve 6: 128–135. Ruff RL (1998). Why do ICU patients become paralyzed? Ann Neurol 43: 154–155. Ruff RL, Simonicini L, Stuhmer W (1988). Slow sodium channel inactivation in mammalian muscle: a possible role in regulating excitability. Muscle Nerve 11: 502–510. Salvi M, Zhang ZG, Halgert D (1990). Patients with endocrine ophthalmopathy not associated with overt thyroid disease have multiple thyroid immunologic abnormalities. J Clin Endocrinol Metab 70: 89–94. Sasaki T, Ono H, Nakajima H, et al. (1992). Lipoatrophic diabetes. J Dermatol 19: 246–249. Satoyoshi E, Murakami K, Koine H, et al. (1963a). Periodic paralysis in hyperthyroidism. Neurology 13: 746–752. Satoyoshi E, Murakami K, Kowa H, et al. (1963b). Myopathy in thryotoxicosis: with special emphasis on an effect of potassium ingestion on serum and urinary creatine. Neurology 13: 645–658. Savica V, Bellinghier G, Di Stefano C, et al. (1983). Plasma and muscle carnitine levels in haemodialysis patients with morphological-ultrastructural examination of muscle samples. Nephron 35: 232–236. Scarpalezos S, Lygidakis C, Papageorgiou C, et al. (1973). Neural and muscular manifestatations of hypothyroidism. Arch Neurol 29: 140–144. Schifferdecker E, Ketzler-Sasse U, Boehm O, et al. (1989). Re-evaluation of eye muscle autoantibody determination in Graves’ ophthalmopathy: failure to detect a specific antigen by use of enzyme-linked immunosorbent assay, indirect immunofluorescence, and immunoblotting techniques. Acta Endocrinol (Copenh) 121: 643–650. Senior B, Gellis SS (1964). The syndromes of total lipodystrophy and of partial lipodystrophy. Paediatrics 33: 593–612. Serradell AP, Gonzalez JR, Torres JMC, et al. (1990). Syndrome de sclerose laterale amyotrophique et hyperthyroidie: gue´rison sous antithyroidiens. Rev Neurol 146: 219– 220. Sharma V, Banerjee S (1978). Beta-adrenergic receptors in rat skeletal muscle. Effects of thyroidectomy. Biochim Biophys Acta 539: 538–542. Shee CD (1990). Risk factors for hydrocortisone myopathy in acute severe asthma. Respir Med 84: 229–233. Shoji S (1989). Myofibrillar protein catabolism in rat steroid myopathy measured by 3-methylhistidine excretion in the urine. J Neurol Sci 93: 333–340.
ENDOCRINE MYOPATHIES Showalter C, Engel AG (1997). Acute quadriplegic myopathy: analysis of myosin isoforms and evidence for calpain-mediated proteolysis. Muscle Nerve 20: 316–322. Slavin ML, Glaser JS (1982). Idiopathic orbital myositis. Arch Ophthalmol 100: 1261–1265. Swanson JW, Kelly JJ, McConahey WM (1981). Neurologic aspects of thyroid dysfunction. Mayo Clin Proc 56: 504–512. Tamai H, Tanaka K, Komaki G, et al. (1987). HLA and thyrotoxic periodic paralysis in Japanese patients. J Clin Endocrinol Metab 64: 1075–1078. Thomas JE, Rooke ED, Kvale WF (1966). The neurologists experience with phaeochromocytoma. JAMA 197: 754–758. Turken SA, Cafferty M, Silverberg SJ, et al. (1989). Neuromuscular involvement in mild, asymptomatic primary hyperparathyroidism. Am J Med 87: 553–557. Ubogu EE, Ruff RL, Kaminski HJ (2004). Endocrine myopathies. In: AG Engel, C Franzini-Armstrong (Eds.), Myology, 3rd edn. McGraw-Hill, New York, pp. 1713–1738. Urbanic RC, George JM (1981). Cushing’s disease — 18 years’ experience. Medicine 60: 14–24. Van Vilet PD, Burchell HB, Titus JC (1966). Focal myocarditis associated with phaeochromocytoma. N Engl J Med 274: 1102–1108. Venables GS, Bates D, Shaw DA (1978). Hypothyroidism with true myotonia. J Neurol Neuorsurg Psychiatry 41: 1013–1015. Vermeulen A (1991). Androgens in the aging male. J Clin Endocrinol Metab 73: 221–224. Vilchez JJ, Cabello A, Bendito J, et al. (1980). Hyperkalaemic paralysis, neuropathy, and persistent motor neuron
355
discharges at rest in Addison’s disease. J Neurol Neurosurg Psychiatry 43: 818–822. Werner H, Le Roith D (2000). New concepts in regulation and function of the insulin growth factors: implications for understanding normal growth and neoplasia. Cell Mol Life Sci 57: 932–942. Wiersinga W (1996). Advances in medical therapy of thyroid-associated ophthalmopathy. Orbit 15: 177. Wiersinga WM, Prummel MF (2000). An evidence-based approach to the treatment of Graves’ ophthalmopathy. Endocrinol Metab Clin North Am 29: 297–319. Wiles CM, Young A, Jones DA, et al. (1979). Muscle relaxation rate, fibre-type composition and energy turnover in hyper- and hypothyroid patients. Clin Sci 57: 375–384. Wilson JD (1988). Androgen abuse by athletes. Endocr Rev 9: 181–199. Wilson JD, Griffin JE (1980). The use and misuse of androgens. Metabolism 29: 1278–1295. Wilson J, Walton JN (1959). Some muscular manifestations of hypothyroidism. J Neurol Neurosurg Psychiatry 22: 320–324. Wise MP, Blunt S, Lane RJM (1995). Neurological presentations of hypothyroidism: the importance of slow relaxing reflexes. J Roy Soc Med 88: 272–274. Yamaguchi H, Okamoto K, Shooji M, et al. (1987). Muscle histology of hypocalcemic myopathy in hypoparathyroidism. J Neurol Neurosurg Psychiatry 50: 817–818. Zurcher RM, Harber FF, Grunig BE, et al. (1989). Effect of thyroid dysfunction on thigh muscle efficiency. J Clin Endocrinol Metab 69: 1082–1086.
Handbook of Clinical Neurology, Vol. 86 (3rd series) Myopathies F. L. Mastaglia, D. Hilton-Jones, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 18
Muscle diseases and aging PIRAYE SERDAROGLU* Istanbul University, Istanbul, Turkey
18.1. Introduction Alterations in biological and functional properties of skeletal muscle occur with aging, leading to the loss of muscle mass and force generating capacity, which is one of the most common causes of frailty and health problems in the elderly.
18.2. Aging-related changes in healthy human muscle (Sarcopenia) Almost half of the body mass is composed of skeletal muscles which are connected to the skeleton by tendons. It is only through this connection that the forces and movements which are produced by muscle contractions can be transmitted to the skeleton. Preservation of all these structures is therefore essential for the overall stability of the body. As an integral part of skeletal mobility, muscle contraction acts as a generator of stability and power for all body movements at the cellular level and impairment of this function will lead to instability and diminished mobility. Muscle function can be impaired as a result of different external and internal conditions such as trauma, disuse, disease states or as a result of old age. No matter how it happens, impaired muscle function will affect quality of life at all ages. As a result of the aging process, the elderly are more susceptible and vulnerable to any of these influences. The term sarcopenia refers to aging-related changes in skeletal muscle and is defined as the progressive loss of muscle mass associated with reduced motor function (Roubenoff, 2000a; Roubenoff and Hughes, 2000; Morley et al., 2001). As the definition implies, both the quality and the quantity of skeletal muscle is affected by the aging process (Greenlund and Nair, 2003). Sarcopenia is not a disease but is a universal condition, even in
otherwise healthy individuals, and does not refer to weight loss associated with inadequate food intake as in starvation, or in the advanced stages of cancer or the acquired immunodeficiency syndrome. It also differs from cachexia which is a cytokine-driven loss of lean body mass despite the maintenance of body weight, as occurs in congestive cardiac failure, renal failure, rheumatoid arthritis and other conditions (Roubenoff, 2001). The term sarcopenia was first introduced by Rosenberg in 1988 and has since been used to define aging-related loss of muscle mass and quality associated with decline in strength as a cause of frailty (Rosenberg, 1997; Roubenoff and Hughes, 2000). The word “sarcopenia” originates from two Greek words; sarx which means “flesh” and penia which means deficiency or poverty of something (Rosenberg, 1997). In fact, according to the Encyclopedia Mythica, penia is the personification of poverty and was worshipped among the poor (Rosenberg, 1997). Hence, sarcopenia literally means “poverty of flesh” (Rosenberg, 1997). Although the term sarcopenia has been used in the literature to refer to loss of skeletal muscle mass, what is of more importance to the elderly individual is the associated loss of strength and resulting reduction in functional capacity (Doherty, 2003). Sarcopenia, particularly of the lower limbs, eventually becomes an important factor in causing frailty, impaired balance and reduced functional capacity in the aging population, accounting for the more frequent falls and higher probability of having to use walking implements in old age (Kamel, 2003; Kinney, 2004). This was illustrated in a study in New Mexico which showed that sarcopenic women and men had 3.6 and 4.1 times higher rates of disability respectively when compared with study participants with normal muscle mass (Baumgartner et al., 1998; Roubenoff and Hughes, 2000). The resulting economic burden which is created, and which is likely to
*Correspondence to: Piraye Serdaroglu, MD, Professor of Neurology, Department of Neurology, Istanbul University, Istanbul Faculty of Medicine, Capa 34390, Istanbul, Turkey. E-mail:
[email protected], Tel: þ90-212-414-2000/ Ext: 32571, Fax: þ90-212-533-8575.
358
P. SERDAROGLU
escalate in the coming years, was well documented in the study by Janssen and colleagues which showed that each sarcopenic man and woman in the United States added $860 and $933 respectively per year in healthcare expenditure, accounting for 1.5% of the total healthcare expenditure in the year 2000. This expenditure was estimated to be reduced by $1.1 billion if the prevalence of sarcopenia was reduced by 10% (Janssen et al., 2004). Sarcopenia affects all individuals who live long enough. As in some previous studies, the Rancho Bernardo study of individuals between 55 and 98 years of age also showed that sarcopenia increases with age (Castillo et al., 2003). In the Rosetta Study, a large cross-sectional study of body composition in Caucasians, the prevalence of sarcopenia which was defined as a muscle mass >2 SD below the mean for young healthy participants, was found to increase from 13% to 24% in individuals of 65–70 years of age, and to over 50% in those older than 80 years of age. The prevalence of sarcopenia among the Chinese population was found to be lower than in Caucassians (Lau et al., 2005). In general, the biological process of sarcopenia occurs in both men and women, being more prevalent in men (Baumgartner et al., 1998; Roubenoff and Hughes, 2000; Janssen et al., 2002; Lau et al., 2005,), but is more disabling in women (Baumgartner et al., 1999). It is well documented that muscle bulk is reduced in the elderly when compared with adult non-aged populations (Melton et al., 2000). Reductions in lean body mass, total body potassium and urinary creatinine excretion all indicate decline in skeletal muscle mass with aging (Fleg and Lakatta, 1988; Flynn et al., 1989, 1992). As muscle tissue accounts for about 40% of the total body mass and 75% of the body’s cell mass, muscle loss also accounts for most of the loss of body protein with aging. However, these losses do not typically result in weight loss since there is a corresponding accumulation of body fat (Nair, 2000; Phillips and Leeuwenburgh, 2005). Measurements of cross-sectional areas of limb muscles by ultrasound, computed tomographic scanning, magnetic resonance imaging (MRI), and direct measurement of whole muscle cross-sections from cadaveric specimens have all shown reductions in muscle cross-sectional area of about 40% between the ages of 20 and 60 years (Doherty et al., 1993a; Brooks and Faulkner, 1994; Porter et al., 1995; Vandervoort, 2002; Doherty, 2003; Morse et al., 2005). The average reported age-related reductions in strength range from 20% to 40%, with even greater losses of 50% or more in individuals in the ninth decade and beyond (Larsson et al., 1979; Murray et al., 1980; Young et al., 1984, 1985; Doherty, 2003). In a study on 468 individuals between 18 and 88 years of age the relative muscle mass was found to start to decrease in the third decade
and the most noticeable decline occurred after the end of the fifth decade. The decrease in skeletal muscle approximated 1.9 and 1.1 kg/decade in men and women respectively in this study (Janssen et al., 2000). In another study which included 284 individuals of both sexes of African-American and Caucasian origins who were ambulant and who did not undertake previous vigorous exercise, it was found that older men and women had less appendicular skeletal muscle than their younger counterparts after adjusting for stature and weight, being greater in men than in women (Gallagher et al., 1997). Although physical activity is quite an important factor in both sexes, in women sarcopenia is closely associated with inactivity and total fat mass (Baumgartner et al., 1999). As shown by these various studies, loss of muscle mass is therefore a universal phenomenon which affects all of us with aging. Whether it reaches the point of becoming a cause of frailty and a healthcare problem depends on additional factors including the previous and current levels of physical activity in any given individual (Roubenoff and Hughes, 2000). In general, similar losses are present in proximal and distal muscles in the upper and lower extremities, and the distribution of muscle loss is similar in men and women on a relative basis (Doherty, 2003). A study of muscle mass in the upper extremities showed that although there was a relative reduction with increasing age, women had less upper extremity muscle mass as compared to men (Gallagher and Heymsfield, 1998). When Nikolic and coworkers compared the deltoid, vastus lateralis and external intercostal muscles they found that the proportion of type I fibers increased with age whereas the proportion of type IIA fibers decreased, with the vastus lateralis being the most affected. They therefore suggested that age-related muscle atrophy has a preferential effect on certain muscles (Nikolic et al., 2001). Frontera et al. (2000a) found sex-related differences at the whole muscle and single fiber level, while in a study by Janssen et al. (2000) the decrease in muscle mass, although widespread, was more prominent in the lower extremities, in keeping with the findings in other studies (Larsson et al., 1978; Holloszy et al., 1991; Phillips and Leeuwenburgh, 2005). It is well known that muscle conditioning by regular resistance training helps maintain the physical status of the individual (de los Reyes et al., 2003; Greenlund and Nair, 2003; Kamel, 2003; Jespersen et al., 2003; Marcell, 2003). This would lead us to assume that sarcopenia may be related to decreased levels of physical activity, and that it would not occur in the individuals who are physically active (Brooks, 2003). However, it has been shown in many studies that maintaining physical activity may lessen but does not prevent the development of sarcopenia (Marcell, 2003). While it has been demonstrated
MUSCLE DISEASES AND AGING that physically active older people maintain higher levels of muscle mass and function than sedentary individuals of similar age, there is also evidence that muscle mass decreases with age even in individuals who exercise actively (Proctor et al., 1995; Tseng et al., 1995; Proctor et al., 1998) and even in previously well-trained world class athletes (Klitgaard et al., 1990). Furthermore, although record-setting performances have improved by 20% to 90% over a century of Olympic competition, it is noteworthy that such performances have consistently been in early adulthood and not by the elderly (Faulkner and Brooks, 1995; Brooks, 2003). Similarly, aerobic capacity and strength also decline with age, even in active runners and swimmers, reflecting a decline both in muscle and cardiopulmonary reserves (Pollock et al., 1997; Hughes et al., 2001). Nevertheless, exercise training should be considered as one approach to reducing sarcopenia and physical frailty with aging (Evans and Cyr-Campbell, 1997; Foster-Burns, 1999). Although it is apparent that alterations solely due to aging do occur in muscle tissue, the causal links between the different cellular changes leading to muscle weakness and atrophy in aging or disease still remains unresolved. This is in part due to the fact that aging-related alterations that occur in skeletal muscles are more complicated than in most other tissues, as skeletal muscles show structural, functional and biochemical adaptations when exposed to conditioning programs. These adaptations allow muscle to confront new exposures which would have previously been potentially damaging.
18.2.1. Hallmarks of sarcopenia at the cellular level The determinants of reduced muscle mass and quality of muscle with aging are atrophy, fiber loss and reduced force generating capacity of muscle fibers. 18.2.1.1. Sarcopenic atrophy Whole-muscle atrophy with aging results from the combined effects of loss of muscle fibers and atrophy of the residual fibers (Fig. 18.1) (Brooks, 2003). The number of fibers in a muscle is determined at birth and changes very little throughout the lifespan of the individual, except in the case of injury or disease. This is not the case with regard to the size of muscle fibers. The number of myofibrils and muscle fiber cross-sectional area increase with normal growth or as a result of exercise-induced hypertrophy and decrease with atrophy resulting from inactivity, immobilization, injury, disease or aging (Brooks, 2003). Most of the morphological data on atrophy in aging muscles come from histologic studies of needle biopsy samples from the vastus lateralis muscle which is known
359
to display substantial signs of atrophy with age (Larsson et al., 1978; Lexell, 1995; Phillips and Leeuwenburgh, 2005). Atrophy of different degrees has also been shown to occur in other muscles (Gallagher et al., 1997; Gallagher and Heymsfield, 1998; Doherty, 2003). Histomorphometric observations in the masseter and vastus lateralis muscles from the young and very old individuals showed that these muscles were affected in different ways by aging (Monemi et al., 1998; Kirkeby and Garbarsch, 2000). In another study comparing the degree of atrophy in the deltoid, vastus lateralis and external intercostal muscles from 30 healthy males aged between 20 and 80 years, all muscle fiber types were found to be reduced in size in each of these muscles whereas the proportion of type I fibers increased and the proportion of type IIA fibers decreased with increasing age. The changes were most marked in the vastus lateralis muscle suggesting that age-related muscle atrophy does not affect all muscles to the same extent (Nikolic et al., 2001). Similar differential changes have also been found in animal studies (Yarovaya et al., 2002; McKiernan et al., 2004). Although the underlying mechanism is still not well understood, the size of type II muscle fibers has consistently been found to diminish to a greater extent than that of type I fibers with aging (Larsson et al., 1978; Lexell et al., 1988; Lexell and Downham, 1992; Lexell, 1993, 1995; Roos et al., 1997; Vandervoort, 2002; Doherty, 2003). One suggested explanation for the selective atrophy and loss of type II muscle fibers is the lower mitochondrial content of such fibers in comparison to type I fibers, making them more vulnerable to the accumulation of mitochondrial DNA mutations with aging (Bua et al., 2002; Phillips and Leeuwenburgh, 2005). Fiber type-specific differences in TNF-a signaling may provide another possible explanation as to why different fiber types atrophy to different degrees with aging. A study in male Fischer rats demonstrated that aging was accompanied by elevated TNF-a signaling to NF-aB to a much greater extent in type II muscle fibers in the superficial vastus lateralis than in the soleus muscle (Phillips and Leeuwenburgh, 2005). 18.2.1.2. Loss of muscle fibers The mechanisms underlying loss of muscle fibers due to aging are still not well understood. However, there is evidence that fiber loss may be due to differences in susceptibility to contraction-induced injury, in repair mechanisms and in motor neuron remodeling in the elderly. 18.2.1.2.1. Contraction induced injury and repair Animal studies show that the muscles of older animals are more easily injured and regenerate less efficiently
360
P. SERDAROGLU
than the muscles of younger adults. Furthermore, the structural and functional recovery after severe muscle injuries is incomplete (Faulkner et al., 1995). Regardless of the age of the individual, muscle fibers are subjected to contraction-induced injury throughout their lifespan. This occurs during muscle contraction, even in healthy individuals, and may also occur in many pathological conditions (Brooks, 2003). However, the adaptive capacity of muscle cells prevents muscle tissue from catastrophic changes occurring (Close et al., 2005). Contraction-related injury is mechanically induced and occurs most likely during activities associated with lengthening of the muscles during contractions (Brooks, 2003). As a result, sarcomeres are excessively stretched, inducing lengthening, and the relationship with other organelles in the muscle fibers is disrupted. As observed in electron microscopic studies, this type of injury may involve sarcomeres focally, or the entire length of a muscle fiber, or many fibers in a particular muscle (Brooks, 2003). It has been hypothesized that this type of injury occurs when the weaker sarcomeres are stretched by nearby stronger ones, and it is assumed that aged muscles have a higher proportion of weaker sarcomeres making them more susceptible to this type of damage (Brooks, 2003). When only minor disruptions of single sarcomeres are involved in the injury, the damaged molecules can be replaced by newly synthesized molecules within the neighboring cytoplasm (Russell et al., 1992). However, after more severe injuries regeneration of the damaged portion of the muscle fiber has to take place (Brooks, 2003). Regeneration is a vital process as it not only repairs the damaged portion of the muscle fiber but also replenishes the progenitor satellite cells (Bischoff and Franzini-Armstrong, 2004). In adults muscle activation of satellite cells is one of the key events in regeneration and is brought about by factors from the damaged muscle fiber itself, or from infiltrating neutrophils and macrophages. Once activated, satellite cells undergo mitotic division and transform into myoblasts that undergo fusion to form multinucleated myotubes which eventually differentiate into new muscle fibers within the remaining basal lamina of the degenerated fibers (Zammit and Beauchamp, 2001; Bischoff and FranziniArmstrong, 2004; Zammit et al., 2004). This process of muscle fiber regeneration from satellite cells therefore resembles closely the embryonic development of muscle cells, and embryonic isoforms of some muscle proteins are expressed in the regenerating fibers. Activation of satellite cells and their fate are shown to be determined and controlled by the Notch signaling pathway in both humans and drosophila (Conboy and Rando, 2002; Miller and Emerson, 2003). A rapid increase in expression of the Notch ligand, Delta,
occurs after injury and initiates the pathway by activating the previously inactivated Notch-1. Activation of Notch-1 leads satellite cells to gain the properties of myogenic precursor cells and to proliferate (Conboy and Rando, 2002; Conboy et al., 2003). Numb, on the other hand, is thought to have a role in the specification of cell fate. The attenuation of Notch-mediated cell proliferation and the differentiation into a myogenic lineage are all possible through the functions of Numb (Conboy and Rando, 2002). The newly formed myoblasts provide muscle fibers with new myonuclei which increase in size during growth or hypertrophy. Myoblasts are defined by the expression of certain myogenic regulatory factors and lineage markers, such as Myf-5, MyoD, M-cadherin, myogenin, MRF4, a7-integrin and desmin (Creuzet et al., 1998; Beauchamp et al., 2000; Conboy and Rando, 2002; Buckingham et al., 2003) These myogenic regulatory factors interact to regulate the transcription of muscle specific genes (Seale et al., 2004; Zammit et al., 2004). Myf-5 and MyoD are primary factors which are required for the determination of myoblasts, therefore they determine the myogenic lineage (Rudnicki et al., 1993). Myf-5 locus is already active in quiescent satellite cells but MyoD appears as the activation starts after injury. Myogenin and MRF4 function as secondary yet essential factors. Myogenin appears following the determination of myoblasts and contributes to their differentiation into myotubes (Fuchtbauer and Westphal, 1992; Grounds et al., 1992; Yablonka-Reuveni and Rivera, 1994; Beauchamp et al., 2000; Brooks, 2003; Zammit et al., 2004). Pax3 and Pax7, members of the paired box transcription factor family, have also been shown to be integral to muscle biology. Pax3 is essential for the migration of muscle precursors from the somites during development and is expressed in a small population of satellite cells, whereas Pax7 is required for satellite cell specification (Tajbakhsh et al., 1996; Seale et al., 2000, 2004; Buckingham et al., 2003). However, the role of Pax7 during satellite cell activation and muscle regeneration has not yet been fully investigated (Zammit et al., 2004). The myoblasts are able to fuse with each other and to form multinucleated myotubes which act locally in repairing the injured section of the fiber or propagate a completely new fiber within the remaining basal lamina of a degenerated fiber. The myotubes eventually differentiate completely into adult muscle fibers (Bischoff and Franzini-Armstrong, 2004). In a way, this new adult muscle fiber formation from satellite cells carries a resemblance to embryonic muscle cell development as embryonic isoforms of some muscle proteins are expressed in these regenerating muscle cells. It has been suggested that there is a decreased regenerative capacity of muscle with aging and that this may be
MUSCLE DISEASES AND AGING due in part to reduced availability of satellite cells (Sajko et al., 2004). It has been shown that the number of satellite cells present in muscle decreases with age although their ability to proliferate and differentiate seems to be preserved (Allbrook et al., 1971; Bonavaud et al., 1997; Renault et al., 2000; Gallegly et al., 2004). Some properties of satellite cells also change with aging. In some studies, satellite cells from aged rats were shown to display an additional delay before entering the cell cycle when compared with cells from young animals (Dodson and Allen, 1987; Johnson and Allen, 1995). Moreover, Conboy et al. (2003) recently demonstrated that satellite cells from older mice showed a striking impairment in their ability to proliferate and produce myoblasts which was shown to be due to impaired upregulation of the Notch ligand in regenerating muscles of aged animals. The same workers also showed that inhibition of Notch in young animals impaired regeneration and, conversely, that forced activation of Notch in older muscles restored their regenerative potential. They therefore concluded that Notch signaling is a key determinant of the regenerative potential of muscle and that it declines with age as a consequence of impaired activation by the Notch ligand Delta. These studies all indicate that certain properties of satellite cells are indeed altered during the aging process and that this may be one of the factors that contributes to controlling muscle size in the elderly. Various growth factors including fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), transforming growth factor-b (TGF-b) and the insulin-like growth factors (IGFs) are all known to have a regulatory effect on satellite cell function and the effects of these factors on satellite cell proliferation and differentiation have been studied extensively in cell culture (Florini and Magri, 1989; Brooks, 2003). Age-dependent changes in these factors probably also have a negative effect on satellite cell activation shifting the balance towards a reduced muscle regenerative capacity with aging. However, some recent reports have argued against the role of impaired regeneration in muscle fiber loss with aging in humans and animals (Edstrom and Ulfhake, 2005; Grounds, 2002). 18.2.1.2.2. Motor unit remodeling Muscle fiber atrophy and loss due to denervation is one of the important contributory factors to the reduction in muscle mass with aging. Histological changes suggestive of denervation and reinnervation including angulated fibers, fiber type grouping and a decrease in total number of muscle fibers have been demonstrated in aged rats and humans in various studies (Kanda and Hashizume, 1989; Doherty et al., 1993b; Larsson et al., 2001). Studies in animals as well as in humans have also shown that there is reduction in motor unit numbers with
361
aging (Brooks and Faulkner, 1994; Kadhiresan et al., 1996; Liu et al., 1996; Larsson et al., 2001; McNeil et al., 2005,). This decrease involves all components of the motor unit including myelinated motor axons as well as a reduction in the size and numbers of spinal motor neurons (Hashizume et al., 1988; Einsiedel and Luff, 1992; Doherty et al., 1993a, 1993b; Liu et al., 1996; Zhang et al., 1996; McNeil et al., 2005). There is good evidence from some studies that the type of motor neuron and consequent muscle fiber loss is preferential and involves mainly the fast firing larger motor neurons and type II muscle fibers (Hashizume et al., 1988; Doherty et al., 1993a; Kadhiresan et al., 1996). This is partially compensated for by collateral reinnervation by surviving motor neurons (Doherty et al., 1993b). The final result of this process in muscle is that some motor units disappear whereas others acquire an increased fiber load, particularly in slowfiring motor units. As a result of this spatial remodeling the motor units become fewer, larger and slower in their contractile properties in the elderly (Doherty et al., 1993b). However, due to the limited innervation capacity of motor neurons, it is not easy to cope with the ongoing process of denervation or to contain the decline in the muscle fiber numbers (Einsiedel and Luff, 1992). Furthermore, observations in humans and animals indicate that the process of collateral sprouting is also reduced during aging, thereby contributing to the further loss of muscle fibers (Einsiedel and Luff, 1992; Verdu et al., 2000). Probably, muscle fibers that are not reinnervated undergo denervation atrophy and eventually disappear entirely. The atrophy and loss of individual muscle fibers and the loss of fast motor units with expansion of the slow motor units are factors which contribute to the reduced maximal force and power, slower force generation and loss of fine motor control even in otherwise healthy aged individuals (Doherty et al., 1993b; Erim et al., 1999). 18.2.1.3. Reduced force-generating capacity of sarcopenic muscle Various factors contribute to the reduced force-generating capacity of aged muscles (Brooks and Faulkner, 1994; Hakkinen et al., 1997; Proctor and Joyner, 1997; Proctor et al., 1998; Lynch et al., 1999). The maximum unloaded shortening velocity, which is dependent on the MyHC isoform, as well as the specific tension of muscle fibers (maximum force normalized to cross-sectional area) were both found to be significantly lower in the MyHC-I- and IIAcontaining fibers of old versus young humans (Larsson et al., 1997). In another study slowing in both type I and type II fibers was found in the elderly (Hook et al., 2001). Also, isolated fibers expressing the same MyHC
362
P. SERDAROGLU
isoform from older men were shown to generate less force than fibers from younger men (Frontera et al., 2000b). Extrinsic factors affecting the capacity and speed of force generation in aging muscles include incomplete central activation of motor units, motor neuron remodeling, peripheral nerve dysfunction and hormonal changes (Frontera et al., 2000b). At the cellular level alterations in excitation-contraction coupling, energy supply, and changes in contractile proteins are also likely to be contributory factors (Frontera et al., 2000b). The main focus has been on changes in the properties of contractile proteins, in particular in the structure and function of myosin which can be considered as the molecular motor that generates force and consequently movement (Hook et al., 2001; Brooks, 2003). The slowing in maximum force production has been attributed to the reduced concentration of MyHC-I in type I muscle fibers (Proctor et al., 1998) and there is evidence that the rate of synthesis of MyHC is reduced in aged muscles (Balagopal et al., 1997; Lowe et al., 2002; Piec et al., 2005). In addition, the ability of myosin to interact with actin during the contractile process has been shown to be reduced in older rodents and humans (Hook et al., 1999, 2001). The reduced forcegenerating capacity with aging was not found to be associated with a reduction in myosin ATPase activity in rats (Lowe et al., 2002). In contrast, paramagnetic resonance experiments have demonstrated that during a maximal isometric contraction a lower number of myosin heads were in the strong-binding state in elderly subjects (Lowe et al., 2001, 2002, 2004). Aging-related changes in the functional properties of the contractile proteins still require further investigation. It is well established that conditioning exercise can improve the force-generating capacity of muscles in the elderly. One approach to improving force generation would be to attempt to reverse the changes in muscle contractile protein properties which occur with aging (Evans, 2004). Thus, in the study by Lowe et al. (2004) the reduction in myosin strong-binding state in rat muscles was shown to be reversed to normal by exercise. A magnetic resonance imaging study in older humans showed that there was more than a twofold non-contractile content ratio when compared to younger adults and that this was positively affected by habituated exercise (KentBraun et al., 2000).
18.2.2. Factors affecting sarcopenic changes Although it is not well understood which factor plays the most important role, the loss of muscle mass and function during aging is affected by different factors. It is likely that a combination of these factors is responsible (Fig. 18.1).
18.2.2.1. Loss of muscle fibers by apoptosis A number of studies have indicated that apoptosis may have a role in the loss of muscle fibers and myonuclei during aging (Dirks and Leeuwenburgh, 2002; Leeuwenburgh, 2003; Dirks and Leeuwenburgh, 2004; DupontVersteegden, 2005). Two studies from the same group demonstrated that apoptotic changes were 50% more frequent in aged male Fischer rats when compared with adult rats (Dirks and Leeuwenburgh, 2002) and have been associated with significant increases in caspase-3, pro-caspase-12 and a reduction in “apoptosis repressor with a caspase recruitment domain” (ARC), which were reversed with calorie restriction (Dirks and Leeuwenburgh, 2004). In the tibialis anterior muscle, which is composed primarily of type II fibers, the extent of apoptosis was correlated with the degree of muscle atrophy and increase in circulating TNF-a levels (Vescovo et al., 1998). In another study less apoptosis and no muscle atrophy was found in the type I fiber-predominant soleus muscle when compared with other type II-predominant muscles (Libera et al., 1999). These findings suggest that apoptotic changes are also fiber type specific and that apoptosis occurs to a greater extent in type II muscle fibers than in type I muscles. 18.2.2.2. Changes in protein metabolism In skeletal muscle, as in any mammalian tissue, protein levels are determined by relative rates of protein synthesis and breakdown (Taillandier et al., 2004). The daily turnover of all cellular proteins is equivalent to the amount of protein contained in 1–1.5 kg of muscle tissue. Consequently, even a small but persistent decrease in protein synthesis or increase in protein degradation may result in marked loss of muscle mass, as occurs in patients with trauma, sepsis or renal failure (Mitch and Price, 2003). With regard to aging, considerable emphasis has been placed on relating sarcopenia to a reduction in protein synthesis, an increase in protein degradation or to a combination of these processes (Attaix et al., 2005). Besides this logical framework, the importance of muscle proteins for the whole body places these alterations among the factors which could have an impact on other tissues during aging. First of all, muscle protein stores are in use as contractile proteins in muscle and this contributes to mobility as well as being a reserve for times of starvation. Second, muscle is the major source of protein for functions such as antibody production, wound healing and white blood cell production during illness. When the body’s protein reserves are already depleted by sarcopenia, there is less to utilize during periods of illness in old age (Roubenoff, 2004; Bechet et al., 2005).
MUSCLE DISEASES AND AGING
Exercise
−
Muscle
+
synthesis
363 Hormonal changes
protein Sex hormones
Nutrition +
+
Growth hormone
+
Protein +
degradation (especially
Muscle fiber
proteasomal )
atrophy (type II fibers)
+ Mitochodrial
+
Muscle fiber loss
+
Insulin and IGF-I Cytokines(TNF-a)
+ +
Apoptosis
dysfunction and oxidative stress
Specific force+
generating capacity
+ Vascular supply
? Gene up-and downregulation
Sarcopenia
Fig. 18.1. Factors contributing to sarcopenia.
18.2.2.2.1. Alterations in protein synthesis The proposition that basal muscle protein synthesis is downregulated with age remains controversial (Welle et al., 1993; Balagopal et al., 1997; Volpi et al., 2001; Paddon-Jones et al., 2004). However, it is reported that at least the catabolic states make these changes apparent (Attaix et al., 2005). It has been shown that myofibrillar protein synthesis is reduced in elderly humans (Welle et al., 1993; Balagopal et al., 1997; Nair, 2005). Reduced ATP production could be the basis for the reductions in protein turnover (Nair, 2005). However, studies in rats have shown that biomarkers related to protein synthesis remain unchanged up until 21 months of age but, surprisingly, increase between 21 and 24 months of age although muscle mass decreases markedly. The conclusion reached from this finding was that the increase in protein synthesis was an unsuccessful attempt to maintain muscle mass during the aging process (Kimball et al., 2004). In their interesting study, Rooyackers and colleagues were unable to show any decline also in fractional mitochondrial protein synthesis rate in their elderly group, although a slight decrease did occur in middle age (Rooyackers et al., 1996).
Similarly, it was shown in humans that muscle protein synthesis was slightly higher in elderly than in young active men, while the basal muscle catabolism did not differ in the two groups, indicating that the muscle loss associated with aging could not be explained on the basis of increased basal protein turnover (Volpi et al., 2001). A previous study by the same group on the effects of amino acid intake showed that the anabolic response to a mixed glucose–amino acid diet was reduced in elderly individuals (Volpi et al., 2003). This was supported by other studies, suggesting that it is not protein synthesis but the response to anabolic stimuli from fasting that fails in the elderly (Volpi et al., 2000, 2001; Roubenoff and Castaneda, 2001; Paddon-Jones et al., 2003; Cuthbertson et al., 2005). One of the ways to build up body proteins is through the intake of external dietary amino acids. As it has been suggested that protein requirements increase with aging, and because of their ready accessibility and safety, nutritional interventions aimed at increasing muscle mass and strength have been attractive but have proved unsuccessful (Fiatarone et al., 1994; Campbell et al., 1995; Pannemans et al., 1998; Volpi et al., 2001).
364
P. SERDAROGLU
However, it still remains a reasonable objective to try to find ways of increasing muscle mass in the elderly, not only to increase muscle strength and function, but also to provide additional protein stores for use in disease states, or to increase glucose tolerance and the capacity to oxidize fats (Rennie, 2001a). Besides nutrition, exercise may play a major role in building up protein stores in muscle. Muscle hypertrophy due to resistance training results principally from the synthesis of contractile muscle proteins. The mechanisms whereby mechanical events associated with such training increase RNA and protein synthesis are not well understood. It has been shown that even short bouts of resistance exercise can increase protein synthesis (Chesley et al., 1992; Esmarck et al., 2001). As opposed to endurance exercise, resistance training results in reduced nitrogen excretion and lowers dietary protein needs which in turn may be important in sarcopenia. Furthermore, increased dietary protein intake has been shown to enhance the hypertrophic response to resistance exercise (Wolfe, 2002; Evans, 2004). Oral supplementation with amino acids acts synergistically with the effects of exercise, especially immediately after a strenuous exercise session (Esmarck et al., 2001; Rennie, 2001b). 18.2.2.2.2. Alterations in protein degradation Little is known about the role of muscle protein degradation in the loss of muscle mass that occurs with aging (Trappe et al., 2003). The two main proteins of muscle, myosin and actin, have been shown to be degraded at a higher rate in older than in younger individuals both in the resting and fasting states. Recent studies have shown that the ubiquitinproteasome-dependent proteolytic pathway is mainly responsible for the breakdown of myofibrillar proteins (Taillandier et al., 2004). Myosin and actin are degraded separately through ubiquitination whereas the actomyosin complex has to undergo initial degradation by recombinant caspase-3 cleavage prior to degradation by the ubiquitin pathway (Du et al., 2005). To be degraded through the ubiquitin-proteasome pathway proteins first have to be tagged with a polyubiquitin degradation signal through the ubiquitin-activating and ubiquitin-conjugating enzymes and ubiquitin-protein ligases. Polyubiquitinated protein substrates are then specifically recognized and degraded by the 26S proteasome (Ciechanover and Brundin, 2003). It has been suggested that hyperactivity of the ubiquitin-proteasome pathway is involved in the aging process of fast-twitch muscles (Cai et al., 2004). However, many studies have indicated that there is a general decline in proteasomal activity with aging, suggesting that there is an inhibition rather than an activation of
the ubiquitin-proteasomal system (Shringarpure and Davies, 2002). Inhibition of the ubiquitin-proteasomal system could favor the accumulation of oxidized proteins as a result of oxidative stress and the accumulation of such proteins has been reported in many experimental aging models. The accumulation of oxidized, misfolded, unfolded or cross-linked proteins over a lifetime, exceeding the degradative capacity of the proteasomal system may be an important contributory factor to aging of skeletal muscle. Studies in aged rats have shown a remarkable decrease in proteasomal activity in both slow- and fast-twitch muscle fibers (Husom et al., 2004; Ferrington et al., 2005). In addition, a decrease in heat shock proteins, which closely interact with the proteasomal system and have been shown to maintain catalytic activity and are responsible for the prevention of protein aggregation, has also been observed in aged rats and can be reversed by lifelong calorie restriction (Selsby et al., 2005). Among heat shock proteins, HSP70 is found to have beneficial effects on the maintenance of muscle content in old age (McArdle et al., 2004a). Aging probably involves both an increase in the generation of reactive oxygen species and a progressive decline in proteasomal activity, resulting in the progressive accumulation of oxidatively damaged protein aggregates that eventually lead to cellular dysfunction in the elderly (Shringarpure and Davies, 2002). Accordingly, a milieu develops which allows the development of degenerative muscle diseases as well as other neurodegenerative diseases of late onset. The ubiquitin proteolytic system and its implications in disease are excellently reviewed by Ciechanover (2006). There is also some evidence that calcium-dependent proteolysis may decline with aging (Viner et al., 1997). It has been proposed that the failure of cellular homeostasis which occurs during aging is due to impaired function of all of the major cellular proteolytic mechanisms, namely the proteasomal, lysosomal and calpain-dependent systems (Chondrogianni et al., 2002). 18.2.2.3. Mitochondrial changes and oxidative damage The theory of oxidative damage has been one of the most attractive concepts in aging research and there is now good evidence that oxidative damage shortens the lifespan of humans and animals (Katic and Kahn, 2005). In Caenorhabditis elegans it has been demonstrated that gene mutations which increase oxidative damage shorten lifespan. For example, mutations in a cytosolic catalase (ctl-1) gene cause earlier accumulation of lipofuscin and more rapid aging, while the sod3 and mev-1 genes accelerate aging by producing
MUSCLE DISEASES AND AGING mutant forms of superoxide dismutase and succinic dehydrogenase. On the other hand, all mutant forms of C. elegans and drosophila with an extended lifespan were also found to have oxidative stress resistance. The same resistance was also found in mice and rats whose lifespans were extended by caloric restriction (Guarente and Kenyon, 2000). Oxidative stress mainly occurs through the formation of highly reactive oxygen (ROS) and nitrogen species (NO) and lead to irreversible damage in cells (Sohal and Sohal, 1991; Afanas’ev, 2004a, 2004b). The ground-O2 is not reactive but on absorbing energy and losing an electron through a series of reductions it produces O2 and H2O2, then the extremely reactive hydroxyl radical (OH) in the presence of iron or copper. All of these intermediate or end products are called free radicals or ROS (Katic and Kahn, 2005). The ROS cascade is generated mainly from the mitochondrial respiratory chain (electron transport system), but also from peroxisomal lipid metabolism, the P450 enzyme system and phagocytic cell “respiratory burst”. They target and damage lipids, nucleic acids and proteins (Katic and Kahn, 2005). NO is produced by NO synthetase isoforms. ROS and NO derivatives are produced continually and are detectable in both the cytosolic and extracellular compartments (Reid and Durham, 2002). To neutralize and combat these free radicals, long-lived mammalian species have developed scavenger systems such as enzyme systems (superoxide dismutase, catalase and glutathione), molecular scavengers (urate, glutathione, thioreductin), and a reducing environment of cells (glucose-6-phosphate dehydrogenase). Exogenous scavengers include ascorbate, tocopherols, flavenoids and carotenoids (Katic and Kahn, 2005). However, a certain proportion of ROS are not controlled by these defenses and will result in continuous oxidative damage to DNA, proteins and lipids (Spiers et al., 2000; DiMauro et al., 2002; Hoehn and Renner, 2003). The final outcome of the damage depends on the balance between these factors. As mitochondria consume over 90% of total cellular oxygen and are the main source of ROS, oxidative damage and mitochondrial abnormalities have come to be regarded as twin causative factors in aging and a vast amount of literature has accumulated on the very attractive catastrophic mitochondrial theory of aging. It has been shown that mutations in the mitochondrial genome accumulate with aging in humans and in animals, with a predilection for certain cell types such as neurons and muscle cells (Muller-Hocker, 1992; Chung et al., 1994; Schwarze et al., 1995; Cortopassi and Wong, 1999; DiMauro et al., 2002; Sastre et al., 2003; Drew and Leeuwenburgh, 2004; Trifunovic et al., 2004). The cumulative effect of these mutations is to improve
365
oxidative phosphorylation (Oxphos) in the respiratory enzyme chain, which in turn accelerates the production of ROS which induce further deletions in the mitochondrial genome, thereby constituting a vicious circle. The mitochondria themselves are both a target and source within this vicious circle since they are present in multiple copies in all cells, are naked and do not have protective histones, have a higher spontaneous mutation rate with less efficient repair systems than in nuclear DNA, and are in closest proximity to the main source of ROS generation (Cortopassi and Wong, 1999; DiMauro et al., 2002; McKenzie et al., 2002). It is now well established that cytochrome oxidase (COX)-negative cells appear and increase in frequency with age and that this is associated with the accumulation of mitochondrial DNA mutations and deficiency in one or more of the respiratory enzyme chain complexes (Zhang et al., 1992; Luft and Luthman, 1993; Hsieh et al., 1994; Cortopassi and Wong, 1999; Sastre et al., 2000; Wang et al., 2001; Drew and Leeuwenburgh, 2003; Sastre et al., 2003; Oldfors et al., 2005). The mutations do not consist only of deletions. In a recent study in experimentally created homozygous knock-in mice with PolgA deficiency there was a threeto fivefold increase in point mutations as well as increased amounts of deleted mtDNA. This increase in somatic mtDNA mutations was associated with reduced lifespan and the premature onset of aging-related phenotypes pointing to a causal link between mitochondrial mutations and aging (Trifunovic et al., 2004). All of these changes occur mainly in postmitotic, terminally differentiated tissues such as brain or muscle given that in mitochondrial diseases there is a threshold level for a particular mutation beyond which pathological changes become overt. This threshold is quite high, approaching 70–80% in the Kearns–Sayre syndrome (DiMauro et al., 2002). However, as shown in the study by Simonetti and colleagues 1992) the “common deletion” (mtDNA deletion 4977) accumulated in muscle by a factor of 10 000 over the course of the normal lifespan reaching a level of only 0.1% of the total mitochondrial DNA by the age of 84 years, which is much slower than the amount needed for pathological changes to become overt in the tissue. Similar results have also been shown in other studies (Soong et al., 1992). It has therefore been suggested that this threshold would never be reached during normal aging and that it is therefore unlikely that mitochondrial mutations alone are responsible for aging-related changes in muscle. However, it may also be possible that the damaging effects could become overt even with very low levels of mtDNA deletions (DiMauro et al., 2002). In addition, it has been shown that caloric restriction does not abolish but only reduces mitochondrial DNA accumulation
366
P. SERDAROGLU
lending further support to the conclusion that mtDNA deletions are not the starting point of oxidative damage during aging (Lass et al., 1998; Bua et al., 2004). Muscle is one of the most energy-demanding tissues and is affected in many primary mitochondrial diseases. It has thus been the focus for the investigation of agerelated mitochondrial changes. Despite undeniable evidence supporting the oxidative mitochondrial theory of aging in some tissues, existing data regarding its contribution to sarcopenia are inconsistent (Barogi et al., 1995; Zucchini et al., 1995; Brierly et al., 1997; Lee et al., 1998; Barazzoni et al., 2000; Sastre et al., 2000; Rasmussen et al., 2003; Terman and Brunk, 2004). This mainly arises from technical differences in oxidative enzyme assays and the use of whole-muscle extracts that provide sum-total results of genetic and enzymatic features of all the fibers within that given extract. In a recent study significantly increased levels of a marker for oxidative damage (8-OHdG), and of protein carbonyls, Mn-superoxide dismutase and catalase were found in the vastus lateralis muscle and urine in elderly as compared to young men supporting the hypothesis that healthy aging is associated with oxidative damage to proteins and DNA, and that antioxidant enzymes are upregulated to cope with this process (Gianni et al., 2004). The expression of Lon protease and the accumulation of damaged proteins such as aconitase in mitochondria of murine skeletal muscle, together with increased ROS production in aged rat muscles, also indicate that oxidative damage is associated with the development of sarcopenia (Bota et al., 2002; Pansarasa et al., 2002; Capel et al., 2004; Mansouri et al., 2006), but in different ways in different muscles (Marzani et al., 2005). A study on healthy young and elderly human subjects demonstrated reduction in the abundance of mtDNA and mRNA which was well correlated with the reduction in ATP production and consequently with the reduced aerobic capacity in the elderly (Short et al., 2005). Due to the uneven distribution of mtDNA mutations and their clonal expansion in muscle fibers histochemical enzyme reactions on muscle sections may show a mosaic pattern (Johnston et al., 1995; Schwarze et al., 1995; Wanagat et al., 2001; Fayet et al., 2002; Wanagat et al., 2002; Pak et al., 2003). As shown in the study by Fayet and colleagues (2002), mtDNA mutations can accumulate focally within single muscle fibers with associated reductions in cytochrome c oxidase activity even when the overall levels of mtDNA point mutations and deletions in whole muscle are low. In this study, single muscle fibers deficient in cytochrome c oxidase were shown to have high levels of clonally expanded point mutations and deletions in mtDNA. Focal accumulation of mtDNA mutations and deficiencies in com-
ponents of the electron transport system have also been demonstrated at the single fiber level in the rat and rhesus monkey using laser capture microdissection (Aiken et al., 2002; McKenzie et al., 2002). Segmental abnormalities of the electron transport system were found to be closely associated with mtDNA mutations within the same areas in aged muscle fibers and could be associated with fiber atrophy and breakage. A number of hypotheses have been proposed for the mechanisms whereby oxidative damage and mtDNA deletion mutations may contribute to sarcopenia (Aiken et al., 2002; McKenzie et al., 2002; Terman et al., 2003; Afanas’ev, 2004b) and to the preferential involvement of type II muscle fibers which is a hallmark of muscle aging (Proctor et al., 1995; Pansarasa et al., 2002; Capel et al., 2004). 18.2.2.4. Hormonal influences The differences in muscle changes with aging between the two sexes and the profound muscle wasting which occurs in elderly patients with diabetes, especially in the preinsulin era, suggests that hormonal factors may play an important role in the development of sarcopenia and that hormonal therapy may be a rational approach to its management (Phillips et al., 1993; Frontera et al., 2000a; Roubenoff and Hughes, 2000). 18.2.2.4.1. Sex hormones Deficiency of estrogen associated with the menopause triggers changes in body composition that affect skeletal muscle mass and force production which can be prevented by the use of hormone replacement therapy (HRT; Dionne et al., 2000). Following the administration of HRT the decline in these parameters is more gradual and only commences after the age of 60 years, reaching the level seen in postmenopausal women after the age of 75 years. As both estrogen and testosterone have notable anabolic effects on skeletal muscle, decline in either will cause similar effects at later stages of life in males and females. The effect of estrogen may be mediated through its conversion to testosterone (Phillips et al., 1993; Frontera et al., 2000b; Roubenoff and Hughes, 2000). Exercise is thought to have a positive impact on the production of these anabolic hormones (Bonnefoy et al., 2002). Testosterone has been shown to increase the number of muscle satellite cells and myoblast formation, leading to hypertrophy and increase in muscle strength. As testosterone results in an increase in lean body mass and a reduction in fat mass in young as well as old men, it has been suggested that it may be promoting differentiation of mesenchymal pluripotent cells into the
MUSCLE DISEASES AND AGING myogenic lineage rather than the adipogenic lineage through an androgen receptor mediated pathway (Herbst and Bhasin, 2004). Observations in animals also support this conclusion (Inoue et al., 1994; Brandstetter et al., 2000). There is some indication that older men may be less sensitive to testosterone as many older men have testosterone levels which are still within the normal range (Bhasin et al., 2001; Bhasin et al., 2005). In addition, both estrogen and testosterone may also act by inhibiting the production of catabolic cytokines such as IL-1 and IL-6 (Roubenoff and Hughes, 2000). Other factors in addition to sex hormone levels may contribute to sarcopenia in postmenopausal women. For example, it is known that sarcopenia is as common in non-obese women on long-term estrogen replacement therapy as in untreated women. In addition, in some studies sarcopenia has been found to correlate with the levels of testosterone but not of estradiol and HRT did not protect against the development of sarcopenia (Kenny et al., 2003). In line with this, in elderly men decrease in muscle strength has been shown to outweigh the loss of muscle mass and may be due to a decrease in muscle contractile proteins or in their force-generating properties with aging (Gallagher et al., 1997; Pollock et al., 1997; Roubenoff and Hughes, 2000; Szulc et al., 2004). 18.2.2.4.2. Growth hormone Growth hormone (GH) plays an important role in muscle development. It is an important mediator of muscle mass by promoting protein synthesis and increases the number of muscle fibers, both of which decline with age (Marcell et al., 2001; Ubogu et al., 2004). Growth hormone acts via a single transmembrane domain receptor which modifies gene expression through several steps (Ubogu et al., 2004). It stimulates the production of mRNA for insulin-like growth factor (IGF)-I and II, and exerts its effects through them. Growth hormone levels begin to decline in the fourth decade. It has been shown that GH secretion is highest among postmenopausal women with the lowest body cell mass indicating that a decline in GH levels may not be an important cause of sarcopenia with aging (Roubenoff et al., 1998). The levels of GH and myostatin are inversely correlated and it has been suggested that an increase in myostatin expression as a result of a decline in GH levels related to aging may be a contributory factor in the development of sarcopenia (Marcell et al., 2001). 18.2.2.4.3. Insulin/IGF-1 signaling Insulin and the insulin-like growth factors (IGF-I and IGF-II) are major anabolic stimulants in muscle tissue, and represent a family of hormones/growth factors that
367
regulate the metabolism, growth, cell differentiation and survival of most tissues in mammals. While insulin is primarily involved in metabolism and glucose homeostasis, the primary role of IGF-I is to mediate the effects of GH on somatic growth (Katic and Kahn, 2005). The role of insulin in sarcopenia is not clear, but insulin resistance may play a part in its development (Roubenoff and Hughes, 2000). Insulin resistance increases with age, increasing fat mass and physical inactivity. New methods have shown that one of the effects of insulin is to increase muscle blood flow by recruiting nutritive capillaries and insulin may act to switch blood flow from the non-nutritive to the nutritive route (Roubenoff and Hughes, 2000; Clark et al., 2003; Pattison et al., 2003a). Exercise training has been shown to improve insulin-mediated capillary recruitment and glucose uptake by muscle (Clark et al., 2003). Insulin-like growth factors are mitogenic for muscle and IGF-I has effects on myoblast proliferation, differentiation and growth as well as increasing the protein content of muscle fibers, in turn leading to hypertrophy (Florini and Magri, 1989; Marcell et al., 2001; Grounds, 2002; Spangenburg et al., 2003). It is of interest that aging-related muscle atrophy did not develop in a muscle specific IGF-I transgenic animal model with markedly hypertrophied muscles, and that the proliferative response to muscle injury was preserved with aging (Musaro et al., 2001). A decline in IGF-I and its receptor levels during aging has been shown to be associated with atrophy of muscle fibers in animal models and it has been shown that IGF-I has a rescue effect on aged muscle satellite cell proliferation by inhibiting the cell-cycle inhibitor p27Kip1 (Dodson and Allen, 1987; Chakravarthy et al., 2001). In addition to effects on muscle growth, IGF-I also affects age-dependent contractile properties of muscle. Animal studies have shown that IGF-I prevents the aging-related decline in peak intracellular calcium levels and specific force in a muscle and regulates the charge movement and the level of L-type Ca2þ channel a-1 subunits through activation of gene expression in skeletal muscle cells (Wang et al., 1999). Dihydropyridine receptor (DHPR) expression is also regulated by IGF-I (Zheng et al., 2001). In transgenic mice overexpressing muscle-specific IGF-I the number of DHPRs and the DHPR/RyR1 ratio were higher than in wildtype mice at all ages and did not change with aging. In addition, the muscles of older transgenic animals developed higher twitch and tetanic muscle force (Renganathan et al., 1997). IGF-1 has been shown to act at different levels of the motor unit including the motor neuron, axons and myelin, neuromuscular junction, muscle fibers and satellite cells (Lewis et al., 1993; Festoff et al., 1995;
368
P. SERDAROGLU
Dobrowolny et al., 2005). Thus, IGF-1 may have aging-related effects at more than one level. 18.2.2.4.4. Cytokines Cytokines are also known to affect muscle mass. For example tumor necrosis factor-a (TNF-a) is well known to induce proteolysis and cachexia. TNF-a directly induces skeletal muscle protein loss and rapidly activates NF-kB in differentiated skeletal muscle cells. The TNF-a/NF-kB signaling in skeletal muscle is regulated by endogenous ROS (Li et al., 1998, 1999; Li and Reid, 2001). This may therefore have a role in the development of aging-related muscle atrophy since the production of ROS increases over the years during aging and the serum levels of TNF-a are also known to increase during aging. Both TNF-a mRNA and protein levels have been shown to be increased in elderly women and men and were reversed by exercise. This reversal was associated with a rise in the rate of protein synthesis showing that changes in protein synthesis in the elderly may be mediated through TNF-a (Greiwe et al., 2001). In cell culture studies TNF-a were shown to exert its effect on muscle protein synthesis through an interleukin (IL)-6 mediated pathway, whereas its effect on murine skeletal myoblasts were IL-6 independent (Alvarez et al., 2002). Other cytokines such as IL-I and interferon-g also cause cachexia and could contribute to sarcopenia, whereas IL-12 and IL-15 have the opposite effect and are considered to be anabolic in muscle tissue (Argiles et al., 2001; Carbo et al., 2001; Pedersen et al., 2004). Transforming growth factor-b (TGF-b) inhibits myogenic cell differentiation in vitro and is present in increased amounts in atrophic muscle fibers in some myopathies. However, it is not known whether TGF-b has a role in sarcopenia and the role of other proinflammatory cytokines is not well understood. 18.2.2.4.5. Other The results of a prospective, population-based study showed that lower 25-hydroxyvitamin D (25-OHD) and higher parathormone (PTH) levels increased the risk of sarcopenia in older men and women (Visser et al., 2003). 18.2.2.5. Changes in gene expression with aging It is only during the past few years that changes in gene expression with aging have attracted attention as a possible cause of sarcopenia. The first report on the gene expression profile of mammalian skeletal muscle was that of (Lee and colleagues 1999) describing expression patterns indicating an increased stress response and
decreased expression of metabolic and biosynthetic genes, and the finding that these changes were prevented by calorie restriction. Further reports on the genetic profiles in various mammalian species including humans followed this report (Roth et al., 2000; Kayo et al., 2001; Welle et al., 2001; Roth et al., 2004; Bortoli et al., 2005; Giresi et al., 2005). When considered together, most studies showed a decrease in levels of genes which are linked to energy metabolism but an increase in genes related to oxidative stress response with aging both in humans and animals (Kayo et al., 2001; Welle et al., 2001). Differential expression of genes involved in DNA damage repair, RNA binding/splicing, proteasomal degradation and immune-inflammatory regulation have also been reported (Welle et al., 2003; Giresi et al., 2005). Whereas serum levels of myostatin have previously been reported to increase with age, in the study by Welle and colleagues (2003) myostatin gene expression was not found to be reduced in the elderly. Interestingly, there was a significant increase in the expression of the gene encoding foliostatin, a protein which binds to myostatin and inhibits its activity (Yarasheski et al., 2002; Welle et al., 2003). This may represent a protective mechanism to inhibit the suppressive effect of myostatin on muscle cells with aging. Another interesting finding in the same study was of an increase in metallothionein gene expression in elderly men. As metallothionein is a protein which binds heavy metals and reduces their toxicity, this may represent an adaptive defense mechanism against environmental factors such as heavy metals (Welle et al., 2003). Despite the lack of specific changes in the expression of genes encoding proteins involved in muscle structure and/or function, an age-related induction of genes involved in the stress response and a downregulation of genes involved both in mitochondrial electron transport/ATP synthase and in glycolysis/TCA cycle was demonstrated in myotubes in an in-vitro study (Bortoli et al., 2005). However in another study all members of the myogenic regulatory factor family were substantially expressed and seemed to be active in aged muscle. These changes might well be functioning as a compensatory mechanism in maintaining the aged muscle at a steady state (Musaro et al., 1995). Aging also was found to contribute to strength-related large-scale gene expression patterns, particularly in the structural, metabolic and regulatory gene classes (Roth et al., 2002). The study of Pattison and colleagues (2003b) identified 64 new candidate genes, the inappropriate expression of which could play some role in the failure of old skeletal muscle to regrow. These include elfin and clusterin, proteins which have been associated with increased cell death (Pattison et al., 2003b).
MUSCLE DISEASES AND AGING
369
Giresi and colleagues (2005) have looked at gene expression from a different point of view, seeking a molecular signature for sarcopenia and a reference point that can be used to identify aged muscle, and found changes in 45 genes. The genes which were upregulated include C1Q-a and FOXO3A that are involved in clearance of debris from damaged cells and apoptotic nuclei respectively, genes involved in pre-mRNA splicing, localization and modification of RNA, MS4A4A gene that is involved in membrane-based signaling, PER2 gene which has a role in dampening circadian rhythm as well as in tumor suppression and the DNA damage response, and the SLIT2 gene which is involved in axon guidance and neuronal migration. In contrast, the glutamine uptake system, which is normally upregulated in amino acid starvation and a gene involved in TNFinduced inflammatory or cell death response was found to be downregulated in this study (Giresi et al., 2005).
large and small arteries, in inducing capillary recruitment, and in switching local flow from the non-nutritive to the nutritive route.
18.2.2.6. Alterations in vascular properties of muscle
18.3.1. Camptocormia
Tolerance to both maximal and submaximal exercise as well as maximal oxygen uptake are reduced in aged humans and animals (Irion et al., 1987; Proctor and Joyner, 1997; Musch et al., 2004). Delivery of oxygen to the muscles is determined collectively by cardiac output and local vascular properties (Murrant and Sarelius, 2002; Clark et al., 2003; Delorey et al., 2004; Spier et al., 2004). A number of studies have shown that the ability to increase muscle blood flow during exercise, which requires timely and sufficient vasomotor activity, is reduced with aging both in animals and humans (Irion et al., 1987; Proctor et al., 1998). The vasodilator responses, and the ability to conduct vasodilatation along the muscle arterioles, have been found to be reduced in older animals (Bearden et al., 2004; Hepple and Vogell, 2004). Similarly, old rats showed transient reduction in microvascular pO2 while switching from rest to contraction. This could explain the premature fatigue in the older animals as compared to their younger counterparts (Behnke et al., 2005). Other studies have demonstrated changes in the myogenic responses of blood vessels to transmural pressure in resistance arteries and in hemodynamic blood–myocyte interactions in muscle in elderly animals (Russell et al., 2003). Several angiogenesis-related factors were also shown to have downregulated in aged mouse muscles, suggesting that maintenance and repair of muscular vessels were reduced in these aged animals (Wagatsuma, 2006). Insulin resistance, which is hypothesized to develop during aging, may also play a part in the changes in muscle blood flow as insulin is known to have an important role in mediating vasodilatation in
18.3. Muscular conditions and diseases associated with aging In general, the diagnosis and treatment of muscle diseases in elderly individuals is prone to be more complicated because of the greater probability of concomitant systemic or other neuromuscular diseases and the use of multiple medications. In addition, the treatment of more common muscle diseases such as polymyositis, dermatomyositis and myasthenia gravis requires special attention as they may be more severe in the elderly who are also more likely to develop adverse drug effects. In this section only the possible effects of those conditions which occur exclusively in aged individuals are considered.
Camptocormia (bent spine) is the term given to pronounced anterior flexion of the trunk which appears in the vertical posture, increases while walking, and is abolished in the supine position (Fig. 18.2) (Hilliquin et al., 1992; Delisle et al., 1993; Laroche et al., 1995; Karbowski, 1999; Delcey et al., 2002). It is a thoracolumbar kyphosis resulting from inability to immobilize or stabilize the lumbar spine in relation to pelvis (Delisle et al., 1993; Karbowski, 1999). Camptocormia was first described by Brodie in 1818 but the term camptocormia was first proposed by Souquess and Rosanoff-Saloff in 1915 (Karbowski, 1999). Until a decade ago it was considered to be a disabling psychiatric condition that was frequently encountered among soldiers during war times and among young women (Kosbab, 1961; Ballenger, 1976; Soreff, 1983; Gomez and Drooby, 1987; Miller and Forbes, 1990; Perez-Sales, 1990; Karbowski, 1999). However, over the past 15 years it has come to be recognized in other clinical settings such as Parkinson’s disease, segmental dystonia, multiple system atrophy, paraneoplastic syndromes, myopathies including proximal myotonic myopathy (PROMM), neurogenic conditions and as an adverse effect of drugs (Kiuru and Iivanainen, 1987; Hilliquin et al., 1992; Zwecker et al., 1998; Djaldetti et al., 1999; Serratrice et al., 2000; Friedman, 2001; Reichel et al., 2001; Delcey et al., 2002; Holler et al., 2003; Feriha et al., 2004; Skidmore et al., 2005; Slawek et al., 2006) . In the literature, reports on camptocormia associated with Parkinson’s disease or paraspinal myopathy outnumber other causes and is sometimes called Pisa syndrome or antecollis, all of which are probably the continuum of a spectrum (Slawek et al., 2006). The observation that in some
370
P. SERDAROGLU
Fig. 18.2. (A, B) Camptocormia in a 67-year-old male who had Parkinson’s disease. Note that the anterior flexion of the trunk upon standing worsens while walking (courtesy of Dr F. Ozer). Paraspinal muscle biopsy of the same patient. Rod formation in many fibers is the most prominent finding (C) (400).
patients with Parkinson’s disease the camptocormia did not respond to levodopa therapy, and that myopathic changes were present in the paraspinal muscles, led to the suggestion that the condition may be myopathic in origin (Djaldetti et al., 1999; Linazasoro and Suarez, 2002; Slawek et al., 2003). The most convincing evidence that camptocormia is myopathic in origin was the description of two patients with multiple system atrophy, who also clearly showed pronounced focal myositis (Diederich et al., 2006). Camptocormia has also come to be accepted as a condition that may occur in isolation in the elderly (Hilliquin et al., 1992; Laroche et al., 1995; Karbowski, 1999; Delcey et al., 2002; Schabitz et al., 2003). The symptom of camptocormia is a result of paraspinal muscle weakness in most of the cases with organic causes (Laroche et al., 1995). In this group of patients pathological changes are usually found exclusively in the paraspinal muscles and biopsies from limb muscles are usually normal. Atrophy and fatty replacement is usually prominent in paraspinal muscle biopsies and is also well demonstrated by imaging techniques such as computed tomography and magnetic resonance imaging (Hilliquin et al., 1992; Legaye and Dimboiu, 1995; Jimenez-Gonzalez et al., 2002; Delcey et al., 2002; Schabitz et al., 2003). Other histopathological changes that have been recorded include features of mitochondrial, inflammatory and amyloid myopathy, and non-specific myopathic changes such as autophagic vacuoles (Hilliquin et al., 1992; Laroche et al., 1995; Delcey et al., 2002; Wunderlich et al., 2002; Schabitz
et al., 2003). It is not yet known whether these are features of a specific myopathy or purely non-specific changes occurring in the paraspinal muscles with aging. Genetic factors have been hypothesized to play a part in some reports (Laroche et al., 1995; Delcey et al., 2002; Schabitz et al., 2003). Although camptocormia is likely to be heterogeneous, it is regarded as a steroid-responsive condition (Karbowski, 1999). Most patients with inflammatory changes have been reported to respond to corticosteroid therapy, but even patients without inflammatory changes may have a good response (Hilliquin et al., 1992; Delcey et al., 2002). All aspects of camptocormia are excellently reviewed by Azher and Jankovic (2005). 18.3.2. Late-onset mitochondrial myopathy (LOMM) As discussed above, the accumulation of mtDNA mutations and reduced mitochondrial enzyme activity occur during normal aging and are one of the accepted causes of sarcopenia. Although muscle performance is reduced in sarcopenia, overt myopathic weakness is not a feature of this condition. Mitochondrial abnormalities are also found in some late-on set muscle diseases such as inclution body myositis (s-IBM) and oculopharyngeal muscular dystrophy (OPMD). However, an insidious onset proximal limb myopathy or progressive external ophthalmoplegia with prominent mitochondrial abnormalities is recognized as one of the myopathies
MUSCLE DISEASES AND AGING of later life (Fig. 18.3) (Kamieniecka and Sjo, 1984; Johnston et al., 1995; Motta et al., 1997; Silvestri et al., 1998). The occurrence of fatigue, which is a common symptom in mitochondrial myopathies, may cause diagnostic problems especially when associated with ptosis and ophthalmoplegia, and needs to be differentiated from myasthenia gravis (Motta et al., 1997). A detailed study by Johnston and colleagues (1995) of nine patients with late-onset mitochondrial myopathy demonstrated a significantly increased proportion of fibers with abnormal mitochondria and COX-negative fibers when compared with normal control muscles. Clonally expanded mtDNA deletion mutations were found in all patients in this study and these changes have been interpreted as an exaggerated aging phenomenon (Johnston et al., 1995). The conclusion was in agreement with another report (Mendell, 1995). The most convincing evidence that there is a late-onset mitochondrial myopathy came from a family in which the index patient developed late-onset ptosis, dysphonia, mild proximal weakness and generalized fatigue, while the mother and two brothers also had an onset after the age of 50 years. A tRNA mutation in the mtDNA was demonstrated in muscle extracts (Silvestri et al., 1998). The finding of a G7497A mutation in the mitochondrial tRNA (Ser(UCN)) gene in two siblings with late-onset limb myopathy provided further convincing evidence for the existence of LOMM, as the fibers harbored more than 97% mutated mitochondria. The interesting aspect of these cases was that they also showed dystrophic histopathological changes (Muller et al., 2005). In another study, postmenopausal women comprised almost half of a total group of 27 patients with ptosis, ophthalmoplegia and mitochondrial abnormalities suggesting that this
371
mitochondrial myopathy should be regarded as a separate late-onset entity (Kamieniecka and Sjo, 1984). 18.3.3. Oculopharyngeal muscular dystrophy Oculopharyngeal muscular dystrophy (OPMD) is one of the myopathies that become manifest in late life. It is characterized by progressive eyelid drooping, swallowing difficulties and proximal limb weakness, and the pathological hallmark of the disease is the presence of unique intranuclear inclusions in skeletal muscle fibers (Tome and Fardeau, 1980; Bouchard et al., 1989; Tome et al., 1989; Calado et al., 2000; Shanmugam et al., 2000). (Ruegg et al., 2005). The autosomal dominant form of this disease is caused by the GCA or GCG expansions of a 10-alanine stretch to 12/17 alanine residues in the poly(A)-binding protein, nuclear 1 (PABPN1; PABP2) on chromosome 14 (Brais et al., 1995, 1998; Robinson et al., 2005). It has similarities to a number of other late-onset degenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, dentatorubral-pallidoluysian atrophy, bulbospinal muscular atrophy and some spinocerebellar ataxias in which neuronal inclusion body formation also occurs (Michalik and Van Broeckhoven, 2003). PABPN1 is an RNA-processing protein which is found abundantly in the nucleus. It binds to the poly(A) tail of mRNA with high affinity, polyadenylates mRNA and controls the length of the poly(A) tails. The mechanism by which the inclusions cause cell death is still unknown. One hypothesis is that the polyalanine stretches adopt a b-sheet structure with the formation of fibrils which are resistant to chemical denaturation and enzymatic degradation (Forood et al., 1995;
Fig. 18.3. (A) A single ragged red fiber (RRF) was seen in sections of this normal biceps biopsy from a 53-year-old male (200). (B) Four of many RRFs in the biceps biopsy from a 65-year-old male who had ophthalmoplegia and distal weakness since 40 years of age (200).
372
P. SERDAROGLU
Perez-Paya et al., 1996; Bao et al., 2002). The expanded poly(A) stretch in the mutant PABPN1 may also destabilize the native conformation of the protein causing it to misfold and aggregate (Abu-Baker et al., 2003). It has recently been shown that an attempt to reproduce mutation in PABPN1 gene resulted in upregulation of other genes, 60% of which encode nuclear proteins. These proteins are sequestered in OPMD intranuclear inclusions (Corbeil-Girard et al., 2005). The OPMD intranuclear inclusions may also sequester mRNA or other nuclear components and interfere with its processing or exportation from the nucleus to the cytoplasm. Unlike the poly(Q) stretch associated diseases in which the pathological changes occur in the presence of a much higher number of repeats, OPMD is caused by a short expansion of poly(A) stretch in PABPN1. The poly(A) stretch expansion from 10 to 12 is sufficient to cause the dominant OPMD disorder, although some wild-type transcription factors contain a nonpathological stretch of around 15 alanines (Fan et al., 2001). Depending on the likely possibility that the toxicity of this short polyalanine stretch is, at least in part, dependent on the host protein itself, Fan et al proposed a model for the pathogenesis of inclusion formation in OPMD. According to this proposal, expansion of poly (A) stretch in PABPN1 causes misfolding and exposes its hydrophobic alanine stretch which would otherwise be buried inside in the wild-type form. The size exposed in the hydrophobic region directly correlates with the length of the expanded poly(A) stretch. A gain of function is acquired by this misfolded mutant PABPN1 and self-association of the protein is weakened through these exposed hydrophobic regions. As the oligomerization is not affected due to the N-terminus location of poly(A) stretches, this weak self-association is facilitated by linking mutated PABPN1 molecules together leading to inclusion formation. Concurrently, mutant PABPN1 is detected and bound by chaperones, components of the UPS, and by some other critical proteins. Binding of these proteins to mutant PABPN1 normally aims at promoting refolding, increased solubility and/or degradation of the protein, depending on the balance between elimination and aggregation. When the oligomerization of mutated PABPN1 is activated, the formation of aggregates slows down and allows the UPS to degrade the abnormal proteins more efficiently, therefore preventing the formation of protein aggregation (Fan et al., 2001). However, it has also been shown that the HSP-UPS interaction does not result in degradation of PABPN1 itself but in increasing its solubility or correcting its conformation without causing any reduction in the amount of PABPN1 (Abu-Baker et al., 2003).
The poly(A) inclusions of OPMD and the polyglutamine inclusions associated with diseases such as Huntington’s disease seem to arise through common mechanisms and to elicit similar host responses (Fan et al., 2001; Ravikumar et al., 2002). For example, these inclusions all contain components of the ubiquitin-proteasome system (UPS) and molecular chaperones which represent the two main protective cellular pathways against the accumulation of misfolded or unfolded polypeptides. The overexpression of these components in the inclusions implies that there is an ongoing but ineffective effort to eliminate these aggregated proteins (Cummings et al., 1998; Chai et al., 1999; Wyttenbach et al., 2000). The UPS catalyzes selective and targeted degradation of misfolded, unassembled or damaged proteins in the nucleus and cytosol that could otherwise form toxic aggregates. However, it has been shown that the activity of the UPS is inhibited when it is overloaded by such proteins even before there are detectable aggregates (Bennett et al., 2005). Proteasome inhibitors have been shown to increase the formation of inclusions (Bence et al., 2001; Ravikumar et al., 2002; Verhoef et al., 2002). Abu-Baker and co-workers (2003) have demonstrated that the ubiquitin-proteasome pathway is inhibited by the mutant PABPN1-ala17 in vitro and that the proteasome inhibitor lactacystin increased protein aggregation whereas overexpression of the molecular chaperones HSP40 and HSP70 suppressed protein aggregation and toxicity (Abu-Baker et al., 2003). One interesting possibility is that parkin, which is an E3 ligase that targets specific proteins for degradation by the UPS, and which is mutated in autosomal-recessive Parkinson’s disease (Bonifati et al., 2004), may be involved in the accumulation of abnormal proteins. It has been reported that parkin reduces the aggregation and cytotoxicity of expanded poly(Q) ataxin-3 fragment by forming a complex with the expansion, HSP70 and proteasome, and by reducing the proteasome impairment as well as the endoplasmic stress marker caspase 12 (Tsai et al., 2003). It has recently been demonstrated that parkin is also expressed in normal human muscle fibers, forming more organized arrays in advanced age, thus suggesting that it may also have a function in human muscle tissue (Serdaroglu et al., 2005a, 2005b). Whether parkin also plays a role in late onset degenerative muscle diseases such as OPMD, the hallmark of which is intranuclear inclusions composed of protein aggregates, is of interest. As the ability to deal with abnormal proteins decreases in the aging cell, the balance between the elimination or refolding and aggregation of mutated PAPBN1 becomes impaired and favors aggregation. Because PAPBN1 envelops the poly(A) stretch of
MUSCLE DISEASES AND AGING mRNA in the nucleus, the intranuclear OPMD protein aggregates may sequester mRNA itself and interfere with its export from the nucleus which is detrimental to cells and may cause cell death (Fan et al., 2001, 2003). This is supported with the finding that when mutant PABPN1 is targeted to cytoplasm both intranuclear aggregate formation and cellular toxicity, two histological consequences in OPMD, were suppressed showing that the nuclear environment is vital for these consequences (Abu-Baker et al., 2005). In keeping with these scenarios, it has also been shown that HSP40 and HSP70 are overexpressed at the sites of inclusions (Bao et al., 2002). It is well known that different types of heat shock proteins (HSPs) are upregulated under conditions of cellular stress, and act as chaperones for misfolded proteins destined to undergo proteolysis. They bind to hydrophobic segments of the proteins and, in the case of OPMD, to the expanded stretches of poly(A) which are hydrophobic. It seems that the affected muscles can successfully cope with the mutant PAPBN1 for many years until these mechanisms are overwhelmed by the amount of accumulated mutant proteins. One possible explanation for this is that HSPs and the stress response are known to decrease with age (McArdle et al., 2004b). As the poly(A) containing PAPBN accumulates and with an age-related reduction in the HSP response, a vicious cycle results in the formation of insoluble inclusions which may lead to cell death (Abu-Baker et al., 2003). Support for the age dependency of the disease also comes from findings in the transgenic mouse model described by Hino et al. (2004) in which animals developed a myopathy with a 13-alanine stretch which became more apparent with advancing age and nuclear inclusions appeared late in the course of the disease (Hino et al., 2004). An alternative pathway which has been suggested as being involved in the elimination of aggregated proteins, both in poly(A) and poly(Q) diseases, is the autophagic pathway. The study of Ravikumar et al (2002), in two different cell lines, showed that autophagy is involved in the degradation of poly(A) and poly(Q) since both accumulated when cells were treated with different lysosomal inhibitors but were more efficiently cleared from the cells when they were treated with rapamycin which stimulates autophagy (Ravikumar et al., 2002). A very recent report has suggested a mechanism other than protein processing that may shed light on the pathogenesis of inclusion body formation and impairment of cell function in OPMD. Microarray analysis of an adenoviral model of PAPBN1 expression associated with intranuclear inclusions revealed that PAPBN1 overexpression unregulated many genes encoding nuclear proteins, including RNA and DNA
373
binding proteins. All nuclear proteins tested encoded by eight upregulated genes were found to colocalize with PAPBN1 within the inclusions by immunofluorescence. It was concluded that these sequestred nuclear proteins may contribute to the impairment of cellular function in this model (Corbeil-Girard et al., 2005). Another interesting aspect of OPMD is the reported presence of mitochondrial abnormalities in muscle (Pratt and Meyers, 1986; Pauzner et al., 1991; Schroder et al., 1995; Wong et al., 1996; de Seze et al., 1997; Lezza et al., 1997; Gambelli et al., 2004). In all these studies the finding of abnormal mitochondria attracted attention as they were more abundant than usually seen in the elderly. Two patients showed different types of deletion mutations in different fibers, including the “common deletion” which is commonly found in aged muscle (Lezza et al., 1997). The patient reported by Gambelli et al. (2004), had increased numbers of ragged-red and COX-negative fibers but there was no detectable deletion mutation in the mtDNA (Gambelli et al., 2004). It has been suggested that PABPN1 may interfere with the post-transcription or regulation and export of nuclear-encoded mitochondrial proteins (Andersson et al., 2000; Gambelli et al., 2004). 18.3.4. Sporadic inclusion body myositis (s-IBM) Sporadic inclusion body myositis is one of the most important muscle diseases manifesting in late life. The clinical picture usually becomes overt after the age of 50 years and s-IBM is currently considered to be the most prevalent muscle disease of the elderly (Phillips et al., 2000; Askanas and Engel, 2002a; Mastaglia et al., 2003a; Engel and Askanas, 2003). Invasion of non-necrotic muscle fibers by mononuclear cells, and the presence of rimmed vacuoles and intracytoplasmic inclusions are the pathological hallmarks of the condition (Mikol and Engel, 2004). It is not clear yet if the inflammatory and degenerative features of the disease progress parallel with or independently from each other (Dalakas, 2006). Although it is classified in the group of inflammatory myopathies, the response to various types of immunosuppressive treatment is usually poor and at best temporary (Cronin et al., 1989; Mastaglia et al., 2003a; Dalakas, 2004). Although s-IBM is probably a multifactorial disease, its most consistent feature is the age-dependency of its clinical, morphological and molecular manifestations. In a broader sense, the presence of intracytoplasmic inclusions in muscle may be regarded as the counterpart of the inclusions which are present in the nervous system in other age-related neurodegenerative diseases such as Alzheimer’s disease (AD) and amyotrophic
374
P. SERDAROGLU
lateral sclerosis (ALS). Furthermore, AD and s-IBM have in common the accumulation of a number of proteins including b-amyloid, apolipoprotein E, presenilin, prion protein, and a-synuclein, suggesting that a common or similar pathobiological pathway may be involved in the degenerative process in these conditions (Askanas and Engel, 1998; Sugarman et al., 2002). The first attempt to demonstrate ubiquitination of the intracytoplasmic inclusions of s-IBM in 1991 (Askanas et al., 1991), which was soon after the ubiquitin positivity had been demonstrated in neurons in AD and ALS, created enormous controversy (Askanas et al., 1992). The demonstration of amyloid deposits in vacuolated muscle fibers in s-IBM further emphasized the similarities in the histopathological features of these two lateonset diseases (Askanas et al., 1994; Askanas and Engel, 2002a). Many other proteins have since been investigated in s-IBM (Askanas and Engel, 2001). Whatever the primary insult, any proposed hypothesis for the mechanisms of the disease must include changes in cellular environment associated with aging as a contributory factor (Askanas and Engel, 2002a). However, the nature of this is still not well understood. Most of the AD-related proteins are upregulated in vacuolated muscle fibers in s-IBM, and most of these colocalize with the paired helical filaments (PHFs) (Askanas and Engel 1998; Oldfors and Fyhr, 2001; Wojcik et al., 2005). Among the accumulated proteins amyloid-b42 (Ab42), together with its Ab precursor protein (AbPP) is thought to have a central role in the pathogenetic cascade (Askanas and Engel 2003). The Ab, AbPP and the mRNA of an alternatively spliced variant of AbPP (AbPP751) are all present in vacuolated and non-vacuolated areas of muscle fibers (Askanas and Engel, 2002b). It is known that Ab42 components appear and/or increase in quantity in brain tissue in the elderly. For example, Ab42 protein, which is found in the brain in AD, may also be present in the brains of non-demented elderly individuals (Vinters and Gilbert, 1983; Mastaglia et al., 2003b). Furthermore, Ab40 and Ab42 components have been shown to be present in the temporalis muscle of non-demented elderly individuals as well as AD patients using mass spectrometric analysis (Kuo et al., 2000). Studies in AbPP transgenic mouse models have also shown overexpression of AbPP and its proteolytic derivatives in older animals (Jin et al., 1998; Sugarman et al., 2002) which display some of the muscle pathological changes of s-IBM. Interestingly, in one of these studies, although the C-terminal fragments of AbPP were expressed in young animals, the pathological changes were only observed in older animals, leading to the suggestion that upregulation of C-terminal fragments
rendered these animals more susceptible to the effects of oxidative stress with increasing age. As in the case of s-IBM, other neurodegenerative disorders such as AD, Parkinson’s disease (PD) and ALS are all associated with the accumulation of ubiquitinated proteins within neuronal inclusions (Li et al., 2003). The main function of the ubiquitin-proteasome system is to degrade short-lived self proteins as well as abnormal and foreign proteins and when this proteolytic machinery is disrupted due to various causes such as oxidative damage, genetic mutations or aginginduced decline in proteasome function, oxidized, misfolded, unfolded or cross-linked proteins accumulate and may eventually overwhelm the proteasome system (Carrard et al., 2002; Shringarpure and Davies, 2002; Fratta et al., 2004). Studies of the proteasome have shown a decline in activity with aging (Shringarpure and Davies, 2002; Davies and Shringarpure, 2006). Despite a three- to fourfold increase in the 20S catalytic core, there is a remarkable decrease in the specific activity, as shown by a reduction of the ubiquitin-activating PA28 and PA700 components and the proteolysis of oxidized calmodulin in F344BN rats indicating that the ubiquitin-proteasome system is functionally inhibited rather than being upregulated during the aging process (Husom et al., 2004; Ferrington et al., 2005). With aging there is probably both an increase in the generation of reactive oxygen species and a progressive decline in proteasome activity, resulting in the progressive accumulation of oxidatively damaged protein aggregates that eventually contribute to cellular dysfunction and senescence (Shringarpure and Davies, 2002). Accordingly, the resulting milieu favors the development of late-onset degenerative muscle and other neurodegenerative diseases. As shown in neurons undergoing degeneration in AD and ALS, the inability of some cells to degrade ubiquitinated proteins may also result from structural or conformational changes in the proteins themselves rendering them inaccessible to degradation (Sherman and Goldberg, 2001). They may also undergo erroneous degradation or misprocessing, hence producing non-self proteins that may act as antigenic stimuli (Vigneron et al., 2004). The resulting aggregation of different proteins lead to the formation of intracellular inclusions which may represent a form of compartmentalization aimed at protecting the cell from toxic effects of the aberrant protein (Li et al., 2003). In neurodegenerative disorders, the neurons which show ubiquitinated inclusions also exhibit signs of inflammation (Finch, 2006). For example, damaged neurons in AD brains which contain neurofibrillary tangles show high expression of cyclo-oxygenase (COX-2; Oka and Takashima, 1997; Ho et al., 1999). It has been postulated that the abnormal protein aggregates may
MUSCLE DISEASES AND AGING themselves trigger the expression of COX-2, the products of which can in turn increase the levels of ubiquitinated proteins and also cause COX-2 upregulation, thereby creating a self-destructive feedback mechanism (Li et al., 2003). The abundance of COX-2 RNA signal was found to correlate with increased nuclear factor kb (NF-kb)DNA binding in one study (Lukiw and Bazan, 1998). NFkb, which is upregulated in s-IBM, is also activated by the ubiquitin system. In addition to ubiquitin, other heat shock proteins such as Hsp70 and aB-crystallin (aBC) have been shown to be upregulated in muscle fibers in s-IBM (Banwell and Engel, 2000; Karpati and Hohlfeld, 2000). Of interest was the finding that marked accumulation of aBC occurred not only in pathological but more commonly in normal-appearing muscle fibers, pointing to a preinflammatory stress response which might lead to downstream events including inflammation. It has also been postulated that aBC, or its combination with some other molecules, may target antigens (Karpati and Hohlfeld, 2000), but this has yet to be confirmed. As a number of transcriptional factors have been found to be upregulated in the muscles of s-IBM patients, it has been suggested that bAPP production and/or its transcription may be the result of upregulation of these factors (Askanas and Engel, 2002a). One such transcriptional factor, NF-kb, which is increased in s-IBM, can induce bAPP and may also be induced by kbAPP. The NF-kb transcription factor complex is one of the cellular sensors that regulates expression of genes involved in the immune response, inflammation and oxidative stress (Helenius et al., 1996a; Roy et al., 1996). There is no clear evidence that NF-kb is upregulated in normal aged human muscles. However, it has been shown that the gene encoding tumor necrosis factor receptor-associated factor (TRAF)-6-inhibitory zinc finger protein (TIZ) is downregulated in human muscle. It is know that TRAF activates NF-kb while TIZ is capable of inhibiting this TRAF-induced activation of NF-kb (Giresi et al., 2005). Inhibition of TRAFinduced activation of NF-kb in aged muscle could therefore lead to a relative increase in levels of NF-kb which in turn may contribute to bAPP production. It has also been shown that the NF-kb transcription factor pathway is activated during aging in mouse cardiac muscle (Helenius et al., 1996b). Besides an increased stress response and possible production of bAPP, the upregulation of NF-kb may also contribute to the proinflammatory state in aging and to the inflammation in s-IBM in combination with other causative factors. Another hallmark of s-IBM is the presence of inflammatory changes which are the basis for its classification as an inflammatory myopathy. However, s-IBM differs from the other inflammatory myopathies as the
375
inflammatory changes are associated with vacuole and inclusion body formation and upregulation of many proteins in the muscle fibers. Its features other than inflammation led some authors to propose that mechanisms other than the inflammation play the main role in s-IBM and that in patients over the age of 50 years, pure polymyositis was rare and that virtually all such older patients with lymphocytic myositis had s-IBM (Askanas and Engel, 2002a, 2005). A subclinical inflammatory state may also exist in normal aging muscle and may contribute to sarcopenia (Roubenoff and Hughes, 2000). Expression profiles of muscle samples from monkeys have shown that inflammatory pathways are more active in older animals as compared to their younger counterparts (Kayo et al., 2001). It has been postulated that the cellular defense mechanisms may be diminished within the aged cellular environment resulting in the underexpression of “youthful” genes encoding beneficial cellular components, or overexpression of yet unknown genes encoding toxic cellular factors (Askanas and Engel, 2001). Few genes involved in inflammatory pathways have been shown to be expressed at high levels in aged muscle, while others are expressed at lower levels (Welle et al., 2003). Also, attempts to find an aging-specific signature for skeletal muscle have led to the recognition of gene expression patterns consistent with an inflammatory response. Several genes that were found to be upregulated in such studies were the ones involved in clearance of damaged cells, protection from inflammation and apoptosis (Giresi et al., 2005). This could account for a low-grade inflammatory state in the elderly which might be considered as a protective mechanism to cope with possible deleterious effects of inflammation or contraction-induced injury in aged muscle. It would be expected that increased inflammation with aging would involve increased expression of many of the genes that are also activated in patients with inflammatory myopathies although giving rise to quantitatively smaller effects during normal aging (Greenberg et al., 2002). However, the inflammation in s-IBM muscle does not seem to be simply an enhanced form of the general inflammatory status associated with the aging organism (Finch, 2006). The MHC-1 restricted and T-cell mediated inflammation in s-IBM is associated with specifically selected and clonally expanded CD8þ T-cell populations (Dalakas, 2006). These features, together with the persistence of the clonal restriction of T-cell receptor (TCR) expression over time, suggests a response to a persisting antigenic stimulation in muscle, although to date no antigen has yet been identified (Oldfors and Lindberg, 1999; Amemiya et al., 2000; Oldfors and Fyhr, 2001). The strong association of the disease with HLA-DR3 and its ancestral haplotypes 8.1AH and 35.2AH provide further
376
P. SERDAROGLU
evidence for autoimmunity and an immunogenetic basis for s-IBM (Kok et al., 1999; Price et al., 2004). Although s-IBM seems to have a totally different type of inflammation to that seen in normal aging, in view of the unique nature of the inflammation with associated vacuole and inclusion body formation, it is possible that the inflammatory changes are induced by the antigenic properties of the proteins that accumulate in elderly muscle over time in genetically predisposed individuals. In support of this, a recent report demonstrated that some vacuolated or non-vacuolated s-IBM fibers contained PABP1 stress deposits and also poly-A containing RNA (poly-Aþ RNA), which suggested an inhibition of degradation of RNA. The authors speculated that an autoantibody to poly-Aþ RNA after the first insult with cytotoxic T cells, could cause this inhibition within the s-IBM fiber (Nakano et al., 2005). It has also been speculated that the inflammatory response may be secondary to a degenerative process in the muscle and declines as the immune system becomes tolerant, or perhaps that the degenerative phenomena and the inflammatory changes are independently provoked by some other factor such as an occult viral agent or by one of the “foreign” accumulated proteins (Askanas and Engel, 2001, 2005). The expression of many proinflammatory cytokines, such as IL-1a, IL-1b, TNF-a as well as the inhibitory cytokines TGF-b and IL-6, has been demonstrated in muscle tissue in s-IBM as well as in other idiopathic inflammatory myopathies, although the results of studies on enhanced expression of the catabolic cytokine TNF-a in s-IBM muscles are somewhat conflicting (Lundberg et al., 1995; De Bleecker et al., 1999; Lundberg, 2000; Baron et al., 2001). On the other hand, studies in normal elderly individuals have shown that TNF-a is increased in plasma or in muscle tissue of ambulatory or frail individuals and may contribute to sarcopenic muscle atrophy (Roubenoff, 2000b; Greiwe et al., 2001; Roubenoff, 2003; Roubenoff et al., 2003). More interestingly, class-I MHC expression in normal myoblasts can be induced by prestimulation with TNF-a and to a lesser extent IL-1b (Chevrel et al., 2005). However, no changes in MHC-I expression have been reported in aging muscle. It is now well accepted that the gene encoding IL-6 is present in muscle tissue and is induced by muscle contraction and by insulin. The production of IL-6 is activated by intracellular calcium levels, mitogenactivated protein kinases, reduced glycogen availability and IL-1b. The IL-6 is then released by muscle fibers into the circulation even in the absence of inflammation (Febbraio, 2003). The reduced availability of glycogen due to insulin resistance and increased levels of IL-1b are known to be factors contributing to the activation of IL-6 production in normal aged muscles. A correlation between increased levels of IL-6 and
muscle atrophy were found in the Framingham Heart Study and it was suggested that the increase in IL-6 may have been an attempt to downregulate an upstream inflammatory stimulus that would be catabolic to muscle rather than being a direct cause of sarcopenia (Roubenoff et al., 2003). It is possible that the age-related increase in these cytokines, which normally cause an insidious subclinical inflammatory state in the elderly organism, may be partially responsible for the inflammation in s-IBM. The viral hypothesis, as a triggering factor in s-IBM, is still considered of possible importance (Askanas and Engel, 2001; Oldfors and Fyhr, 2001; Walter et al., 2001; Warabi et al., 2004). It has been postulated that the aging milieu in muscle may create a preferential susceptibility to a newly invading virus and may allow cytopathic manifestations of the virus. This could be supported by the evolution of mechanisms by viruses allowing them to cope with the proteasomal activity and to survive within the cell (Ciechanover and Schwartz, 2004). It is possible that viral DNA which has remained dormant for years may start to be transcribed within the aged cellular environment because of the age-dependent up- or downregulation of activation or inhibition factors. The viral hypothesis of s-IBM has been supported by the occurrence of the disease in some patients with HTVL-I or HCV infection (Askanas and Engel, 2001; Warabi et al., 2004). Oxidative stress and mitochondrial alterations are well known features of s-IBM muscle and are evidenced by the presence of ragged red and COXnegative fibers, mtDNA mutations and increased aBC content in some muscle fibers (Banwell and Engel, 2000; Karpati and Hohlfeld, 2000; Askanas and Engel, 2001; Oldfors and Fyhr, 2001). As stated above, mitochondrial oxidative stress is one of the most important causes of age-related muscular atrophy. The occurrence of mitochondrial abnormalities and the finding of oxidative stress indicators in s-IBM therefore points more than any other aspect of the disease to the importance of the aged muscle fiber environment. The significance of the mitochondrial changes is still under debate and these findings are considered by some authors to be age related. However, the extent of the ragged red and COX-negative fibers, mtDNA deletion mutations and oxidative stress response is still more than would be expected in the normal aged population (Oldfors et al., 1995; Rifai et al., 1995; Santorelli et al., 1996; Oldfors et al., 2005). Muscle biopsies from 98% of patients with s-IBM show COX-negative fibers in a segmental distribution (Oldfors et al., 2005). The degree of these mitochondrial changes in s-IBM is comparable to many mitochondrial myopathies. It is possible that only when age-dependent mitochondrial alterations and oxidative
MUSCLE DISEASES AND AGING stress reach a certain critical point that other pathogenetic factors come into action. It is also possible that the increase in mtDNA mutations as compared to normal aged individuals is secondary to the disease process itself. An observation which supports this concept is the ability of b amyloid to induce oxidative stress and cell death in cultured hippocampal neurons and in C. elegans (Harris et al., 1995; Askanas and Engel, 2001, 2002a; Drake et al., 2003). Another possibility is that there are specific s-IBM mtDNA mutations which, like all mutant mtDNAs, have greater replicative capacity and ability to accumulate and clonally expand in segments of cells until the cell’s protective mechanisms are exceeded and pathological changes are triggered. When considered together, most studies have shown a decrease in the levels of genes linked to energy metabolism with an associated increase in genes related to the oxidative stress response with aging both in humans and animals (Welle et al., 2001). A phylogenetic analysis of the mtDNA D-loop region in 38 s-IBM and 142 AD patients and in 169 normal control subjects showed a clustering of the 4580A variant, in addition to the previously shown clustering of the 4336G variant (Kok et al., 2000). Interestingly, 35% of the s-IBM patients but only 11.4% of the AD patients and 15.4% of control subjects carried the 16311C variant. Ten of the s-IBM patients in the study were HLA-DR3-positive pointing to the possibility of an interaction between these genetic factors in the development of the disease (Kok et al., 2000). As stated above, the proposed mechanism of mitochondrial oxidative stress in the pathogenesis of sarcopenia involves muscle fiber atrophy and fiber breakages at sites of extreme amounts of accumulated mutant mitochondria (Aiken et al., 2002; McKenzie et al., 2002). These observations may therefore be pertinent also to the atrophy of muscle fibers in s-IBM. The data outlined above point to a number of similarities between s-IBM and exaggerated aging-related changes in relation to the accumulation of certain proteins and deviations in other cellular mechanisms. However, to attempt to explain the pathological changes in s-IBM purely on the basis of an exaggerated aging process per se would be an oversimplification. While aging does appear to be a strong contributory factor in the pathogenesis of the disease, other factors such as the immunogenetic background of the individual, viral infection or other as yet unidentified factors must also be involved.
18.4. Summary Skeletal muscle mass and force-generating capacity are reduced with aging even in normal individuals resulting in frailty in the elderly. This natural condition is called
377
sarcopenia. The correlates of sarcopenia at the cellular level are muscle fiber atrophy and loss, together with functional impairment in the intracellular contractile mechanisms of the muscle fibers. These changes are determined by alterations in the rate of protein synthesis and degradation, and by oxidative stress, hormonal influences, genetic alterations and changes in vascular supply all of which are affected during aging. Combination of these changes produces a unique milieu in the senescent muscle cell which favors the development of late-onset diseases such as s-IBM. Although they do not prevent sarcopenia, aerobic strength training and calorie restrictions have been shown to have a positive impact on the qualitative and quantitative decline in muscle associated with aging. The most frequent muscular conditions and diseases of the elderly organism are camptocormia, late onset mitochondrial myopathy, oculopharyngeal muscular dystrophy and sporadic inclusion body myositis. Although not proven yet, the effects of aging in muscle tissue may contribute to or determine the onset or course of these conditions.
References Abu-Baker A, Messaed C, Laganiere J, et al. (2003). Involvement of the ubiquitin-proteasome pathway and molecular chaperones in oculopharyngeal muscular dystrophy. Hum Mol Genet 12: 2609–2623. Abu-Baker A, Laganiere S, Fan X, et al. (2005). Cytoplasmic targeting of mutant poly(A)-binding protein nuclear 1 suppresses protein aggregation and toxicity in oculopharyngeal muscular dystrophy. Traffic 6: 766–779. Afanas’ev I (2004a). Interplay between superoxide and nitric oxide in aging and diseases. Biogerontology 5: 267–270. Afanas’ev IB (2004b). Mechanism of superoxide-mediated damage relevance to mitochondrial aging. Ann N Y Acad Sci 1019: 343–345. Aiken J, Bua E, Cao Z, et al. (2002). Mitochondrial DNA deletion mutations and sarcopenia. Ann N Y Acad Sci 959: 412–423. Allbrook DB, Han MF, Hellmuth AE (1971). Population of muscle satellite cells in relation to age and mitotic activity. Pathology 3: 223–243. Alvarez B, Quinn LS, Busquets S, et al. (2002). Tumor necrosis factor-alpha exerts interleukin-6-dependent and -independent effects on cultured skeletal muscle cells. Biochim Biophys Acta 1542: 66–72. Amemiya K, Granger RP, Dalakas MC (2000). Clonal restriction of T-cell receptor expression by infiltrating lymphocytes in inclusion body myositis persists over time. Studies in repeated muscle biopsies. Brain 123 (10): 2030–2039. Andersson U, Antonicka H, Houstek J, et al. (2000). A novel principle for conferring selectivity to poly(A)-binding proteins: interdependence of two ATP synthase beta-subunit mRNA-binding proteins. Biochem J 346: 33–39.
378
P. SERDAROGLU
Argiles JM, Meijsing SH, Pallares-Trujillo J, et al. (2001). Cancer cachexia: a therapeutic approach. Med Res Rev 21: 83–101. Askanas V, Engel WK (1998). Sporadic inclusion-body myositis and its similarities to Alzheimer disease brain. Recent approaches to diagnosis and pathogenesis, and relation to aging. Scand J Rheumatol 27: 389–405. Askanas V, Engel WK (2001). Inclusion-body myositis: newest concepts of pathogenesis and relation to aging and Alzheimer disease. J Neuropathol Exp Neurol 60: 1–14. Askanas V, Engel WK (2002a). Newest pathogenetic considerations in inclusion-body myositis: possible role of amyloid-beta, cholesterol, relation to aging and to Alzheimer’s disease. Curr Rheumatol Rep 4: 427–433. Askanas V, Engel WK (2003). Proposed pathogenetic cascade of inclusion-body myositis: importance of amyloidbeta, misfolded proteins, predisposing genes, and aging. Curr Opin Rheumatol 15: 737–44. Askanas V, Engel WK (2002b). Inclusion-body myositis and myopathies: different etiologies, possibly similar pathogenic mechanisms. Curr Opin Neurol 15: 525–531. Askanas V, Engel WK (2005). Sporadic inclusion-body myositis: a proposed key pathogenetic role of the abnormalities of the ubiquitin-proteasome system, and protein misfolding and aggregation. Acta Myol 24: 17–24. Askanas V, Serdaroglu P, Engel WK, et al. (1991). Immunolocalization of ubiquitin in muscle biopsies of patients with inclusion body myositis and oculopharyngeal muscular dystrophy. Neurosci Lett 130: 73–76. Askanas V, Serdaroglu P, Engel WK, et al. (1992). Immunocytochemical localization of ubiquitin in inclusion body myositis allows its light-microscopic distinction from polymyositis. Neurology 42: 460–461. Askanas V, Engel WK, Bilak M, et al. (1994). Twisted tubulofilaments of inclusion body myositis muscle resemble paired helical filaments of Alzheimer brain and contain hyperphosphorylated tau. Am J Pathol 144: 177–187. Attaix D, Mosoni L, Dardevet D, et al. (2005). Altered responses in skeletal muscle protein turnover during aging in anabolic and catabolic periods. Int J Biochem Cell Biol 37: 1962–1973. Azher SN, Jankovic J (2005). Camptocormia: pathogenesis, classification, and response to therapy. Neurology 65: 355–359. Balagopal P, Proctor D, Nair KS (1997). Sarcopenia and hormonal changes. Endocrine 7: 57–60. Ballenger JC (1976). A case of camptocormia occurring in psychotherapy. J Nerv Ment Dis 162: 291–294. Banwell BL, Engel AG (2000). AlphaB-crystallin immunolocalization yields new insights into inclusion body myositis. Neurology 54: 1033–1041. Bao YP, Cook LJ, O’Donovan D, et al. (2002). Mammalian, yeast, bacterial, and chemical chaperones reduce aggregate formation and death in a cell model of oculopharyngeal muscular dystrophy. J Biol Chem 277: 12263–12269. Barazzoni R, Short KR, Nair KS (2000). Effects of aging on mitochondrial DNA copy number and cytochrome c oxidase gene expression in rat skeletal muscle, liver, and heart. J Biol Chem 275: 3343–3347.
Barogi S, Baracca A, Parenti Castelli G, et al. (1995). Lack of major changes in ATPase activity in mitochondria from liver, heart, and skeletal muscle of rats upon ageing. Mech Ageing Dev 84: 139–150. Baron P, Galimberti D, Meda L, et al. (2001). Production of IL–6 by human myoblasts stimulated with Abeta: relevance in the pathogenesis of IBM. Neurology 57: 1561–1565. Baumgartner RN, Koehler KM, Gallagher D, et al. (1998). Epidemiology of sarcopenia among the elderly in New Mexico. Am J Epidemiol 147: 755–763. Baumgartner RN, Waters DL, Gallagher D, et al. (1999). Predictors of skeletal muscle mass in elderly men and women. Mech Ageing Dev 107: 123–136. Bearden SE, Payne GW, Chisty A, et al. (2004). Arteriolar network architecture and vasomotor function with ageing in mouse gluteus maximus muscle. J Physiol 561: 535–545. Beauchamp JR, Heslop L, Yu DS, et al. (2000). Expression of CD34 and Myf5 defines the majority of quiescent adult skeletal muscle satellite cells. J Cell Biol 151: 1221–1234. Bechet D, Tassa A, Combaret L, et al. (2005). Regulation of skeletal muscle proteolysis by amino acids. J Ren Nutr 15: 18–22. Behnke BJ, Delp MD, Dougherty PJ, et al. (2005). Effects of aging on microvascular oxygen pressures in rat skeletal muscle. Respir Physiol Neurobiol 146: 259–268. Bence NF, Sampat RM, Kopito RR (2001). Impairment of the ubiquitin-proteasome system by protein aggregation. Science 292: 1552–1555. Bennett EJ, Bence NF, Jayakumar R, et al. (2005). Global impairment of the ubiquitin-proteasome system by nuclear or cytoplasmic protein aggregates precedes inclusion body formation. Mol Cell 17: 351–365. Bhasin S, Woodhouse L, Storer TW (2001). Proof of the effect of testosterone on skeletal muscle. J Endocrinol 170: 27–38. Bhasin S, Woodhouse L, Casaburi R, et al. (2005). Older men are as responsive as young men to the anabolic effects of graded doses of testosterone on the skeletal muscle. J Clin Endocrinol Metab 90: 678–688. Bischoff R, Franzini-Armstrong C (2004). Satellite and stem cells in muscle regeneration. In: AG Engel, C FranziniArmstrong (Eds.), Myology. McGraw-Hill, New York, pp. 66–87. Bonavaud S, Thibert P, Gherardi RK, et al. (1997). Primary human muscle satellite cell culture: variations of cell yield, proliferation and differentiation rates according to age and sex of donors, site of muscle biopsy, and delay before processing. Biol Cell 89: 233–240. Bonifati V, Oostra BA, Heutink P (2004). Unraveling the pathogenesis of Parkinson’s disease — the contribution of monogenic forms. Cell Mol Life Sci 61: 1729–1750. Bonnefoy M, Patricot MC, Lacour JR, et al. (2002). Relation between physical activity, muscle function and IGF-1, testosterone and DHEAS concentrations in the elderly. Rev Med Interne 23: 819–27. Bortoli S, Renault V, Mariage-Samson R, et al. (2005). Modifications in the myogenic program induced by in vivo and in vitro aging. Gene 347: 65–72.
MUSCLE DISEASES AND AGING Bota DA, Van Remmen H, Davies KJ (2002). Modulation of Lon protease activity and aconitase turnover during aging and oxidative stress. FEBS Lett 532: 103–106. Bouchard JP, Gagne F, Tome FM, et al. (1989). Nuclear inclusions in oculopharyngeal muscular dystrophy in Quebec. Can J Neurol Sci 16: 446–450. Brais B, Xie YG, Sanson M, et al. (1995). The oculopharyngeal muscular dystrophy locus maps to the region of the cardiac alpha and beta myosin heavy chain genes on chromosome 14q11.2-q13. Hum Mol Genet 4: 429–434. Brais B, Bouchard JP, Xie YG, et al. (1998). Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy. Nat Genet 18: 164–167. Brandstetter AM, Pfaffl MW, Hocquette JF, et al. (2000). Effects of muscle type, castration, age, and compensatory growth rate on androgen receptor mRNA expression in bovine skeletal muscle. J Anim Sci 78: 629–637. Brierly EJ, Johnson MA, Bowman A, et al. (1997). Mitochondrial function in muscle from elderly athletes. Ann Neurol 41: 114–116. Brooks SV (2003). Current topics for teaching skeletal muscle physiology. Adv Physiol Educ 27: 171–182. Brooks SV, Faulkner JA (1994). Skeletal muscle weakness in old age: underlying mechanisms. Med Sci Sports Exerc 26: 432–439. Bua EA, McKiernan SH, Wanagat J, et al. (2002). Mitochondrial abnormalities are more frequent in muscles undergoing sarcopenia. J Appl Physiol 92: 2617–2624. Bua E, McKiernan SH, Aiken JM (2004). Calorie restriction limits the generation but not the progression of mitochondrial abnormalities in aging skeletal muscle. FASEB J 18: 582–584. Buckingham M, Bajard L, Chang T, et al. (2003). The formation of skeletal muscle: from somite to limb. J Anat 202: 59–68. Cai D, Lee KK, Li M, et al. (2004). Ubiquitin expression is up-regulated in human and rat skeletal muscles during aging. Arch Biochem Biophys 425: 42–50. Calado A, Tome FM, Brais B, et al. (2000). Nuclear inclusions in oculopharyngeal muscular dystrophy consist of poly(A) binding protein 2 aggregates which sequester poly(A) RNA. Hum Mol Genet 9: 2321–2328. Campbell WW, Crim MC, Young VR, et al. (1995). Effects of resistance training and dietary protein intake on protein metabolism in older adults. Am J Physiol 268: E1143–E1153. Capel F, Buffiere C, Patureau Mirand P, et al. (2004). Differential variation of mitochondrial H2O2 release during aging in oxidative and glycolytic muscles in rats. Mech Ageing Dev 125: 367–373. Carbo N, Lopez-Soriano J, Costelli P, et al. (2001). Interleukin-15 mediates reciprocal regulation of adipose and muscle mass: a potential role in body weight control. Biochim Biophys Acta 1526: 17–24. Carrard G, Bulteau AL, Petropoulos I, et al. (2002). Impairment of proteasome structure and function in aging. Int J Biochem Cell Biol 34: 1461–1474. Castillo EM, Goodman-Gruen D, Kritz-Silverstein D, et al. (2003). Sarcopenia in elderly men and women: the Rancho Bernardo study. Am J Prev Med 25: 226–231.
379
Chai Y, Koppenhafer SL, Shoesmith SJ, et al. (1999). Evidence for proteasome involvement in polyglutamine disease: localization to nuclear inclusions in SCA3/MJD and suppression of polyglutamine aggregation in vitro. Hum Mol Genet 8: 673–682. Chakravarthy MV, Booth FW, Spangenburg EE (2001). The molecular responses of skeletal muscle satellite cells to continuous expression of IGF-1: implications for the rescue of induced muscular atrophy in aged rats. Int J Sport Nutr Exerc Metab 11: S44–S48. Chesley A, MacDougall JD, Tarnopolsky MA, et al. (1992). Changes in human muscle protein synthesis after resistance exercise. J Appl Physiol 73: 1383–1388. Chevrel G, Granet C, Miossec P (2005). Contribution of tumour necrosis factor alpha and interleukin (IL) 1beta to IL6 production, NF-kappaB nuclear translocation, and class I MHC expression in muscle cells: in vitro regulation with specific cytokine inhibitors. Ann Rheum Dis 64: 1257–1262. Chondrogianni N, Fragoulis EG, Gonos ES (2002). Protein degradation during aging: the lysosome-, the calpainand the proteasome-dependent cellular proteolytic systems. Biogerontology 3: 121–123. Chung SS, Weindruch R, Schwarze SR, et al. (1994). Multiple age-associated mitochondrial DNA deletions in skeletal muscle of mice. Aging (Milano) 6: 193–200. Ciechanover A (2006). The ubiquitin proteolytic system: from a vague idea, through basic mechanisms, and onto human diseases and drug targeting. Neurology 66: S7–S19. Ciechanover A, Brundin P (2003). The ubiquitin proteasome system in neurodegenerative diseases: sometimes the chicken, sometimes the egg. Neuron 40: 427–446. Ciechanover A, Schwartz AL (2004). The ubiquitin system: pathogenesis of human diseases and drug targeting. Biochim Biophys Acta 1695: 3–17. Clark MG, Wallis MG, Barrett EJ, et al. (2003). Blood flow and muscle metabolism: a focus on insulin action. Am J Physiol Endocrinol Metab 284: E241–E258. Close GL, Kayani A, Vasilaki A, et al. (2005). Skeletal muscle damage with exercise and aging. Sports Med 35: 413–427. Conboy IM, Rando TA (2002). The regulation of Notch signaling controls satellite cell activation and cell fate determination in postnatal myogenesis. Dev Cell 3: 397–409. Conboy IM, Conboy MJ, Smythe GM, et al. (2003). Notchmediated restoration of regenerative potential to aged muscle. Science 302: 1575–1577. Corbeil-Girard LP, Klein AF, Sasseville AM, et al. (2005). PABPN1 overexpression leads to upregulation of genes encoding nuclear proteins that are sequestered in oculopharyngeal muscular dystrophy nuclear inclusions. Neurobiol Dis 18: 551–567. Cortopassi GA, Wong A (1999). Mitochondria in organismal aging and degeneration. Biochim Biophys Acta 1410: 183–193. Creuzet S, Lescaudron L, Li Z, et al. (1998). MyoD, myogenin, and desmin-nls-lacZ transgene emphasize the distinct patterns of satellite cell activation in growth and regeneration. Exp Cell Res 243: 241–253.
380
P. SERDAROGLU
Cronin ME, Miller FW, Hicks JE, et al. (1989). The failure of intravenous cyclophosphamide therapy in refractory idiopathic inflammatory myopathy. J Rheumatol 16: 1225–1228. Cummings CJ, Mancini MA, Antalffy B, et al. (1998). Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1. Nat Genet 19: 148–154. Cuthbertson D, Smith K, Babraj J, et al. (2005). Anabolic signaling deficits underlie amino acid resistance of wasting, aging muscle. FASEB J 19: 422–424. Dalakas MC (2004). Inflammatory disorders of muscle: progress in polymyositis, dermatomyositis and inclusion body myositis. Curr Opin Neurol 17: 561–567. Dalakas MC (2006). Inflammatory, immune, and viral aspects of inclusion-body myositis. Neurology 66: S33–S38. Davies KJ, Shringarpure R (2006). Preferential degradation of oxidized proteins by the 20S proteasome may be inhibited in aging and in inflammatory neuromuscular diseases. Neurology 66: S93–S96. De Bleecker JL, Meire VI, Declercq W, et al. (1999). Immunolocalization of tumor necrosis factor-alpha and its receptors in inflammatory myopathies. Neuromuscul Disord 9: 239–246. De Los Reyes AD, Bagchi D, Preuss HG (2003). Overview of resistance training, diet, hormone replacement and nutritional supplements on age-related sarcopenia — a minireview. Res Commun Mol Pathol Pharmacol 113/114: 159–170. De Seze J, Pasquier F, Ruchoux MM, et al. (1997). [Mitochondrial anomalies in oculopharyngeal muscular dystrophy]. Rev Neurol (Paris) 153: 335–338. Delcey V, Hachulla E, Michon-Pasturel U, et al. (2002). [Camptocormia: a sign of axial myopathy. Report of 7 cases]. Rev Med Interne 23: 144–154. Delisle MB, Laroche M, Dupont H, et al. (1993). Morphological analyses of paraspinal muscles: comparison of progressive lumbar kyphosis (camptocormia) and narrowing of lumbar canal by disc protrusions. Neuromuscul Disord 3: 579–582. Delorey DS, Kowalchuk JM, Paterson DH (2004). Effect of age on O(2) uptake kinetics and the adaptation of muscle deoxygenation at the onset of moderate-intensity cycling exercise. J Appl Physiol 97: 165–172. Diederich NJ, Goebel HH, Dooms G, et al. (2006). Camptocormia associated with focal myositis in multiple-system atrophy. Mov Disord 21: 390–394. DiMauro S, Tanji K, Bonilla E, et al. (2002). Mitochondrial abnormalities in muscle and other aging cells: classification, causes, and effects. Muscle Nerve 26: 597–607. Dionne IJ, Kinaman KA, Poehlman ET (2000). Sarcopenia and muscle function during menopause and hormonereplacement therapy. J Nutr Health Aging 4: 156–161. Dirks A, Leeuwenburgh C (2002). Apoptosis in skeletal muscle with aging. Am J Physiol Regul Integr Comp Physiol 282: R519–R527. Dirks AJ, Leeuwenburgh C (2004). Aging and lifelong calorie restriction result in adaptations of skeletal muscle apoptosis repressor, apoptosis-inducing factor, X-linked
inhibitor of apoptosis, caspase-3, and caspase-12. Free Radic Biol Med 36: 27–39. Djaldetti R, Mosberg-Galili R, Sroka H, et al. (1999). Camptocormia (bent spine) in patients with Parkinson’s disease — characterization and possible pathogenesis of an unusual phenomenon. Mov Disord 14: 443–447. Dobrowolny G, Giacinti C, Pelosi L, et al. (2005). Muscle expression of a local Igf-1 isoform protects motor neurons in an ALS mouse model. J Cell Biol 168: 193–199. Dodson MV, Allen RE (1987). Interaction of multiplication stimulating activity/rat insulin-like growth factor II with skeletal muscle satellite cells during aging. Mech Ageing Dev 39: 121–128. Doherty TJ (2003). Invited review: Aging and sarcopenia. J Appl Physiol 95: 1717–1727. Doherty TJ, Vandervoort AA, Taylor AW, et al. (1993a). Effects of motor unit losses on strength in older men and women. J Appl Physiol 74: 868–874. Doherty TJ, Vandervoort AA, Brown WF (1993b). Effects of ageing on the motor unit: a brief review. Can J Appl Physiol 18: 331–358. Drake J, Link CD, Butterfield DA (2003). Oxidative stress precedes fibrillar deposition of Alzheimer’s disease amyloid beta-peptide (1-42) in a transgenic Caenorhabditis elegans model. Neurobiol Aging 24: 415–420. Drew B, Leeuwenburgh C (2003). Method for measuring ATP production in isolated mitochondria: ATP production in brain and liver mitochondria of Fischer-344 rats with age and caloric restriction. Am J Physiol Regul Integr Comp Physiol 285: R1259–R1267. Drew B, Leeuwenburgh C (2004). Ageing and subcellular distribution of mitochondria: role of mitochondrial DNA deletions and energy production. Acta Physiol Scand 182: 333–341. Du J, Hu Z, Mitch WE (2005). Molecular mechanisms activating muscle protein degradation in chronic kidney disease and other catabolic conditions. Eur J Clin Invest 35: 157–163. Dupont-Versteegden EE (2005). Apoptosis in muscle atrophy: relevance to sarcopenia. Exp Gerontol 40: 473–481. Edstrom E, Ulfhake B (2005). Sarcopenia is not due to lack of regenerative drive in senescent skeletal muscle. Aging Cell 4: 65–77. Einsiedel LJ, Luff AR (1992). Effect of partial denervation on motor units in the ageing rat medial gastrocnemius. J Neurol Sci 112: 178–184. Engel WK, Askanas V (2006). Inclusion-body myositis. Clinical, diagnostic, and pathologic aspects. Neurology 66: S20–S29. Erim Z, Beg MF, Burke DT, et al. (1999). Effects of aging on motor-unit control properties. J Neurophysiol 82: 2081–2091. Esmarck B, Andersen JL, Olsen S, et al. (2001). Timing of postexercise protein intake is important for muscle hypertrophy with resistance training in elderly humans. J Physiol 535: 301–311. Evans WJ (2004). Protein nutrition, exercise and aging. J Am Coll Nutr 23: 601S–609S.
MUSCLE DISEASES AND AGING Evans WJ, Cyr-Campbell D (1997). Nutrition, exercise, and healthy aging. J Am Diet Assoc 97: 632–638. Fan X, Dion P, Laganiere J, et al. (2001). Oligomerization of polyalanine expanded PABPN1 facilitates nuclear protein aggregation that is associated with cell death. Hum Mol Genet 10: 2341–2351. Fan X, Messaed C, Dion P, et al. (2003). HnRNP A1 and A/ B interaction with PABPN1 in oculopharyngeal muscular dystrophy. Can J Neurol Sci 30: 244–251. Faulkner JA, Brooks SV (1995). Muscle fatigue in old animals. Unique aspects of fatigue in elderly humans. Adv Exp Med Biol 384: 471–480. Faulkner JA, Brooks SV, Zerba E (1995). Muscle atrophy and weakness with aging: contraction-induced injury as an underlying mechanism. J Gerontol A Biol Sci Med Sci 50: 124–129. Fayet G, Jansson M, Sternberg D, et al. (2002). Ageing muscle: clonal expansions of mitochondrial DNA point mutations and deletions cause focal impairment of mitochondrial function. Neuromuscul Disord 12: 484–493. Febbraio MA (2003). Signaling pathways for IL-6 within skeletal muscle. Exerc Immunol Rev 9: 34–39. Feriha O, Aytul M, Hasan M (2004). A case of camptocormia (bent spine) secondary to early motor neuron disease. Behav Neurol 15: 51–54. Ferrington DA, Husom AD, Thompson LV (2005). Altered proteasome structure, function, and oxidation in aged muscle. FASEB J 19: 644–646. Festoff BW, Yang SX, Vaught J, et al. (1995). The insulinlike growth factor signaling system and ALS neurotrophic factor treatment strategies. J Neurol Sci 129 (Suppl.): 114–121. Fiatarone MA, O’Neill EF, Ryan ND, et al. (1994). Exercise training and nutritional supplementation for physical frailty in very elderly people. N Engl J Med 330: 1769–1775. Finch CE (2006). A perspective on sporadic inclusion-body myositis. The role of aging and inflammatory processes. Neurology 66 (Suppl. 1): S1–S6. Fleg JL, Lakatta EG (1988). Role of muscle loss in the age-associated reduction in VO2 max. J Appl Physiol 65: 1147–1151. Florini JR, Magri KA (1989). Effects of growth factors on myogenic differentiation. Am J Physiol 256: C701–C711. Flynn MA, Nolph GB, Baker AS, et al. (1989). Total body potassium in aging humans: a longitudinal study. Am J Clin Nutr 50: 713–717. Flynn MA, Nolph GB, Baker AS, et al. (1992). Aging in humans: a continuous 20-year study of physiologic and dietary parameters. J Am Coll Nutr 11: 660–672. Forood B, Perez-Paya E, Houghten RA, et al. (1995). Formation of an extremely stable polyalanine beta-sheet macromolecule. Biochem Biophys Res Commun 211: 7–13. Foster-Burns SB (1999). Sarcopenia and decreased muscle strength in the elderly woman: resistance training as a safe and effective intervention. J Women Aging 11: 75–85. Fratta P, Engel WK, Van Leeuwen FW, et al. (2004). Mutant ubiquitin UBBþ1 is accumulated in sporadic inclusionbody myositis muscle fibers. Neurology 63: 1114–1117.
381
Friedman JH (2001). Episodic camptocormia in PD. Mov Disord 16: 1201. Frontera WR, Hughes VA, Fielding RA, et al. (2000a). Aging of skeletal muscle: a 12-yr longitudinal study. J Appl Physiol 88: 1321–1326. Frontera WR, Suh D, Krivickas LS, et al. (2000b). Skeletal muscle fiber quality in older men and women. Am J Physiol Cell Physiol 279: C611–C618. Fuchtbauer EM, Westphal H (1992). MyoD and myogenin are coexpressed in regenerating skeletal muscle of the mouse. Dev Dyn 193: 34–39. Gallagher D, Heymsfield SB (1998). Muscle distribution: variations with body weight, gender, and age. Appl Radiat Isot 49: 733–734. Gallagher D, Visser M, De Meersman RE, et al. (1997). Appendicular skeletal muscle mass: effects of age, gender, and ethnicity. J Appl Physiol 83: 229–239. Gallegly JC, Turesky NA, Strotman BA, et al. (2004). Satellite cell regulation of muscle mass is altered at old age. J Appl Physiol 97: 1082–1090. Gambelli S, Malandrini A, Ginanneschi F, et al. (2004). Mitochondrial abnormalities in genetically assessed oculopharyngeal muscular dystrophy. Eur Neurol 51: 144–147. Gianni P, Jan KJ, Douglas MJ, et al. (2004). Oxidative stress and the mitochondrial theory of aging in human skeletal muscle. Exp Gerontol 39: 1391–1400. Giresi PG, Stevenson EJ, Theilhaber J, et al. (2005). Identification of a molecular signature of sarcopenia. Physiol Genomics 21: 253–263. Gomez EA, Drooby AS (1987). Camptocormia in a case of manic-depressive disorder. Psychosomatics 28: 592, 594–595. Greenberg SA, Sanoudou D, Haslett JN, et al. (2002). Molecular profiles of inflammatory myopathies. Neurology 59: 1170–1182. Greenlund LJ, Nair KS (2003). Sarcopenia — consequences, mechanisms, and potential therapies. Mech Ageing Dev 124: 287–299. Greiwe JS, Cheng B, Rubin DC, et al. (2001). Resistance exercise decreases skeletal muscle tumor necrosis factor alpha in frail elderly humans. FASEB J 15: 475–482. Grounds MD (2002). Reasons for the degeneration of ageing skeletal muscle: a central role for IGF-1 signalling. Biogerontology 3: 19–24. Grounds MD, Garrett KL, Lai MC, et al. (1992). Identification of skeletal muscle precursor cells in vivo by use of MyoD1 and myogenin probes. Cell Tissue Res 267: 99–104. Guarente L, Kenyon C (2000). Genetic pathways that regulate ageing in model organisms. Nature 408: 255–262. Hakkinen K, Kraemer WJ, Newton RU (1997). Muscle activation and force production during bilateral and unilateral concentric and isometric contractions of the knee extensors in men and women at different ages. Electromyogr Clin Neurophysiol 37: 131–142. Harris ME, Hensley K, Butterfield DA, et al. (1995). Direct evidence of oxidative injury produced by the Alzheimer’s beta-amyloid peptide (1–40) in cultured hippocampal neurons. Exp Neurol 131: 193–202.
382
P. SERDAROGLU
Hashizume K, Kanda K, Burke RE (1988). Medial gastrocnemius motor nucleus in the rat: age-related changes in the number and size of motoneurons. J Comp Neurol 269: 425–430. Helenius M, Hanninen M, Lehtinen SK, et al. (1996a). Changes associated with aging and replicative senescence in the regulation of transcription factor nuclear factorkappa B. Biochem J 318 (Pt 2): 603–608. Helenius M, Hanninen M, Lehtinen SK, et al. (1996b). Aging-induced up-regulation of nuclear binding activities of oxidative stress responsive NF-kB transcription factor in mouse cardiac muscle. J Mol Cell Cardiol 28: 487–498. Hepple RT, Vogell JE (2004). Anatomic capillarization is maintained in relative excess of fiber oxidative capacity in some skeletal muscles of late middle-aged rats. J Appl Physiol 96: 2257–2264. Herbst KL, Bhasin S (2004). Testosterone action on skeletal muscle. Curr Opin Clin Nutr Metab Care 7: 271–277. Hilliquin P, Menkes CJ, Laoussadi S, et al. (1992). [Camptocormia in the elderly. A new entity by paravertebral muscle involvement?]. Rev Rhum Mal Osteoartic 59: 169–175. Hino H, Araki K, Uyama E, et al. (2004). Myopathy phenotype in transgenic mice expressing mutated PABPN1 as a model of oculopharyngeal muscular dystrophy. Hum Mol Genet 13: 181–190. Ho L, Pieroni C, Winger D, et al. (1999). Regional distribution of cyclooxygenase-2 in the hippocampal formation in Alzheimer’s disease. J Neurosci Res 57: 295–303. Hoehn H, Renner A (2003). Human aging and longevity: genetic aspects. In HD Osiewacz (Ed.), Aging of Organisms, 1st edn. Kluwer Academic Publishers, Dodrecht pp. 247–269. Holler I, Dirnberger G, Pirker W, et al. (2003). Camptocormia in idiopathic Parkinson’s disease: [(123)I]beta-CIT SPECT and clinical characteristics. Eur Neurol 50: 118–120. Holloszy JO, Chen M, Cartee GD, et al. (1991). Skeletal muscle atrophy in old rats: differential changes in the three fiber types. Mech Ageing Dev 60: 199–213. Hook P, Li X, Sleep J, et al. (1999). In vitro motility speed of slow myosin extracted from single soleus fibres from young and old rats. J Physiol 520: 463–471. Hook P, Sriramoju V, Larsson L (2001). Effects of aging on actin sliding speed on myosin from single skeletal muscle cells of mice, rats, and humans. Am J Physiol Cell Physiol 280: C782–C788. Hsieh RH, Hou JH, Hsu HS, et al. (1994). Age-dependent respiratory function decline and DNA deletions in human muscle mitochondria. Biochem Mol Biol Int 32: 1009–1022. Hughes VA, Frontera WR, Wood M, et al. (2001). Longitudinal muscle strength changes in older adults: influence of muscle mass, physical activity, and health. J Gerontol A Biol Sci Med Sci 56: B209–B217. Husom AD, Peters EA, Kolling EA, et al. (2004). Altered proteasome function and subunit composition in aged muscle. Arch Biochem Biophys 421: 67–76. Inoue K, Yamasaki S, Fushiki T, et al. (1994). Androgen receptor antagonist suppresses exercise-induced hypertro-
phy of skeletal muscle. Eur J Appl Physiol Occup Physiol 69: 88–91. Irion GL, Vasthare US, Tuma RF (1987). Age-related change in skeletal muscle blood flow in the rat. J Gerontol 42: 660–665. Janssen I, Heymsfield SB, Wang ZM, et al. (2000). Skeletal muscle mass and distribution in 468 men and women aged 18–88 yr. J Appl Physiol 89: 81–88. Janssen I, Heymsfield SB, Ross R (2002). Low relative skeletal muscle mass (sarcopenia) in older persons is associated with functional impairment and physical disability. J Am Geriatr Soc 50: 889–896. Janssen I, Baumgartner RN, Ross R, et al. (2004). Skeletal muscle cutpoints associated with elevated physical disability risk in older men and women. Am J Epidemiol 159: 413–421. Jespersen J, Pedersen TG, Beyer N (2003). [Sarcopenia and strength training. Age-related changes: effect of strength training]. Ugeskr Laeger 165: 3307–3311. Jimenez-Gonzalez MM, Pons-Serra M, Castano-Moreno C, et al. (2002). [Camptocormia: an infrequent muscular disease]. An Med Interna 19: 470–472. Jin LW, Hearn MG, Ogburn CE, et al. (1998). Transgenic mice over-expressing the C-99 fragment of betaPP with an alpha-secretase site mutation develop a myopathy similar to human inclusion body myositis. Am J Pathol 153: 1679–1686. Johnson SE, Allen RE (1995). Activation of skeletal muscle satellite cells and the role of fibroblast growth factor receptors. Exp Cell Res 219: 449–453. Johnston W, Karpati G, Carpenter S, et al. (1995). Late-onset mitochondrial myopathy. Ann Neurol 37: 16–23. Kadhiresan VA, Hassett CA, Faulkner JA (1996). Properties of single motor units in medial gastrocnemius muscles of adult and old rats. J Physiol 493 (2): 543–552. Kamel HK (2003). Sarcopenia and aging. Nutr Rev 61: 157–167. Kamieniecka Z, Sjo O (1984). Mitochondrial myopathy as a cause of ptosis and ophthalmoplegia in elderly females. Acta Ophthalmol (Copenh) 62: 401–412. Kanda K, Hashizume K (1989). Changes in properties of the medial gastrocnemius motor units in aging rats. J Neurophysiol 61: 737–746. Karbowski K (1999). The old and the new camptocormia. Spine 24: 1494–1498. Karpati G, Hohlfeld R (2000). Biologically stressed muscle fibers in sporadic IBM: a clue for the enigmatic etiology? Neurology 54: 1020–1021. Katic M, Kahn CR (2005). The role of insulin and IGF-1 signaling in longevity. Cell Mol Life Sci 62: 320–343. Kayo T, Allison DB, Weindruch R, et al. (2001). Influences of aging and caloric restriction on the transcriptional profile of skeletal muscle from rhesus monkeys. Proc Natl Acad Sci U S A 98: 5093–5098. Kenny AM, Dawson L, Kleppinger A, et al. (2003). Prevalence of sarcopenia and predictors of skeletal muscle mass in nonobese women who are long-term users of estrogen-
MUSCLE DISEASES AND AGING replacement therapy. J Gerontol A Biol Sci Med Sci 58: M436–M440. Kent-Braun JA, Ng AV, Young K (2000). Skeletal muscle contractile and noncontractile components in young and older women and men. J Appl Physiol 88: 662–668. Kimball SR, O’Malley JP, Anthony JC, et al. (2004). Assessment of biomarkers of protein anabolism in skeletal muscle during the life span of the rat: sarcopenia despite elevated protein synthesis. Am J Physiol Endocrinol Metab 287: E772–E780. Kinney JM (2004). Nutritional frailty, sarcopenia and falls in the elderly. Curr Opin Clin Nutr Metab Care 7: 15–20. Kirkeby S, Garbarsch C (2000). Aging affects different human muscles in various ways. An image analysis of the histomorphometric characteristics of fiber types in human masseter and vastus lateralis muscles from young adults and the very old. Histol Histopathol 15: 61–71. Kiuru S, Iivanainen M (1987). Camptocormia, a new side effect of sodium valproate. Epilepsy Res 1: 254–257. Klitgaard H, Mantoni M, Schiaffino S, et al. (1990). Function, morphology and protein expression of ageing skeletal muscle: a cross-sectional study of elderly men with different training backgrounds. Acta Physiol Scand 140: 41–54. Kok CC, Croager EJ, Witt CS, et al. (1999). Mapping of a candidate region for susceptibility to inclusion body myositis in the human major histocompatibility complex. Immunogenetics 49: 508–516. Kok CC, Boyt A, Gaudieri S, et al. (2000). Mitochondrial DNA variants in inclusion body myositis. Neuromuscul Disord 10: 604–611. Kosbab FP (1961). Camptocormia — a rare case in the female. Am J Psychiatry 117: 839–840. Kuo YM, Kokjohn TA, Watson MD, et al. (2000). Elevated abeta42 in skeletal muscle of Alzheimer disease patients suggests peripheral alterations of AbetaPP metabolism. Am J Pathol 156: 797–805. Laroche M, Delisle MB, Aziza R, et al. (1995). Is camptocormia a primary muscular disease? Spine 20: 1011–1016. Larsson L, Sjodin B, Karlsson J (1978). Histochemical and biochemical changes in human skeletal muscle with age in sedentary males, age 22–65 years. Acta Physiol Scand 103: 31–39. Larsson L, Grimby G, Karlsson J (1979). Muscle strength and speed of movement in relation to age and muscle morphology. J Appl Physiol 46: 451–456. Larsson L, Li X, Yu F, et al. (1997). Age-related changes in contractile properties and expression of myosin isoforms in single skeletal muscle cells. Muscle Nerve 5: S74–S78. Larsson L, Yu F, Hook P, et al. (2001). Effects of aging on regulation of muscle contraction at the motor unit, muscle cell, and molecular levels. Int J Sport Nutr Exerc Metab 11 (Suppl.): S28–S43. Lass A, Sohal BH, Weindruch R, et al. (1998). Caloric restriction prevents age-associated accrual of oxidative damage to mouse skeletal muscle mitochondria. Free Radic Biol Med 25: 1089–1097.
383
Lau EM, Lynn HS, Woo JW, et al. (2005). Prevalence of and risk factors for sarcopenia in elderly Chinese men and women. J Gerontol A Biol Sci Med Sci 60: 213–216. Lee CM, Lopez ME, Weindruch R, et al. (1998). Association of age-related mitochondrial abnormalities with skeletal muscle fiber atrophy. Free Radic Biol Med 25: 964–972. Lee CK, Klopp RG, Weindruch R, et al. (1999). Gene expression profile of aging and its retardation by caloric restriction. Science 285: 1390–1393. Leeuwenburgh C (2003). Role of apoptosis in sarcopenia. J Gerontol A Biol Sci Med Sci 58: 999–1001. Legaye J, Dimboiu D (1995). [Camptocormia or reducible lumbar kyphosis in elderly subjects. Apropos of 2 cases of lipoid degeneration of the paravertebral muscles]. Acta Orthop Belg 61: 278–281. Lewis Me NN, Contreras PC, Stong DB, et al. (1993). Insulin-like growth factor-I: potential for treatment of motor neuronal disorders. Exp Neurol 124: 73–88. Lexell J (1993). Ageing and human muscle: observations from Sweden. Can J Appl Physiol 18: 2–18. Lexell J (1995). Human aging, muscle mass, and fiber type composition. J Gerontol A Biol Sci Med Sci 50 (Spec No): 11–16. Lexell J, Downham D (1992). What determines the muscle cross-sectional area? J Neurol Sci 111: 113–114. Lexell J, Taylor CC, Sjostrom M (1988). What is the cause of the ageing atrophy? Total number, size and proportion of different fiber types studied in whole vastus lateralis muscle from 15- to 83-year-old men. J Neurol Sci 84: 275–294. Lezza AM, Cormio A, Gerardi P, et al. (1997). Mitochondrial DNA deletions in oculopharyngeal muscular dystrophy. FEBS Lett 418: 167–170. Li YP, Reid MB (2001). Effect of tumor necrosis factoralpha on skeletal muscle metabolism. Curr Opin Rheumatol 13: 483–487. Li YP, Schwartz RJ, Waddell ID, et al. (1998). Skeletal muscle myocytes undergo protein loss and reactive oxygenmediated NF-kappaB activation in response to tumor necrosis factor alpha. FASEB J 12: 871–880. Li YP, Atkins CM, Sweatt JD, et al. (1999). Mitochondria mediate tumor necrosis factor-alpha/NF-kappaB signaling in skeletal muscle myotubes. Antioxid Redox Signal 1: 97–104. Li Z, Jansen M, Pierre SR, et al. (2003). Neurodegeneration: linking ubiquitin/proteasome pathway impairment with inflammation. Int J Biochem Cell Biol 35: 547–552. Libera LD, Zennaro R, Sandri M, et al. (1999). Apoptosis and atrophy in rat slow skeletal muscles in chronic heart failure. Am J Physiol 277: C982–C986. Linazasoro G, Suarez JA (2002). Myopathic camptocormia in a patient with levodopa unresponsive parkinsonism. Neurologia 17: 162–164. Liu RH, Bertolotto C, Engelhardt JK, et al. (1996). Agerelated changes in soma size of neurons in the spinal cord motor column of the cat. Neurosci Lett 211: 163–166. Lowe DA, Surek JT, Thomas DD, et al. (2001). Electron paramagnetic resonance reveals age-related myosin
384
P. SERDAROGLU
structural changes in rat skeletal muscle fibers. Am J Physiol Cell Physiol 280: C540–C547. Lowe DA, Thomas DD, Thompson LV (2002). Force generation, but not myosin ATPase activity, declines with age in rat muscle fibers. Am J Physiol Cell Physiol 283: C187–C192. Lowe DA, Warren GL, Snow LM, et al. (2004). Muscle activity and aging affect myosin structural distribution and force generation in rat fibers. J Appl Physiol 96: 498–506. Luft R, Luthman H (1993). [Physiopathology of mitochondria. From Luft’s disease to aging and diabetes]. Lakartidningen 90: 2770–2775. Lukiw WJ, Bazan NG (1998). Strong nuclear factor-kappaBDNA binding parallels cyclooxygenase-2 gene transcription in aging and in sporadic Alzheimer’s disease superior temporal lobe neocortex. J Neurosci Res 53: 583–592. Lundberg IE (2000). The role of cytokines, chemokines, and adhesion molecules in the pathogenesis of idiopathic inflammatory myopathies. Curr Rheumatol Rep 2: 216–224. Lundberg I, Brengman JM, Engel AG (1995). Analysis of cytokine expression in muscle in inflammatory myopathies, Duchenne dystrophy, and non-weak controls. J Neuroimmunol 63: 9–16. Lynch NA, Metter EJ, Lindle RS, et al. (1999). Muscle quality. I. Age-associated differences between arm and leg muscle groups. J Appl Physiol 86: 188–194. Mansouri A, Muller FL, Liu Y, et al. (2006). Alterations in mitochondrial function, hydrogen peroxide release and oxidative damage in mouse hind-limb skeletal muscle during aging. Mech Ageing Dev 127: 298–306. Marcell TJ (2003). Sarcopenia: causes, consequences, and preventions. J Gerontol A Biol Sci Med Sci 58: M911–M916. Marcell TJ, Harman SM, Urban RJ, et al. (2001). Comparison of GH, IGF-I, and testosterone with mRNA of receptors and myostatin in skeletal muscle in older men. Am J Physiol Endocrinol Metab 281: E1159–E1164. Marzani B, Felzani G, Bellomo RG, et al. (2005). Human muscle aging: ROS-mediated alterations in rectus abdominis and vastus lateralis muscles. Exp Gerontol 40: 959–965. Mastaglia FL, Garlepp MJ, Phillips BA, et al. (2003a). Inflammatory myopathies: clinical, diagnostic and therapeutic aspects. Muscle Nerve 27: 407–425. Mastaglia FL, Byrnes ML, Johnsen RD, et al. (2003b). Prevalence of cerebral vascular amyloid-beta deposition and stroke in an aging Australian population: a postmortem study. J Clin Neurosci 10: 186–189. McArdle F, Spiers S, Aldemir H, et al. (2004a). Preconditioning of skeletal muscle against contraction-induced damage: the role of adaptations to oxidants in mice. J Physiol 561: 233–244. McArdle A, Dillmann WH, Mestril R, et al. (2004b). Overexpression of HSP70 in mouse skeletal muscle protects against muscle damage and age-related muscle dysfunction. FASEB J 18: 355–357. McKenzie D, Bua E, McKiernan S, et al. (2002). Mitochondrial DNA deletion mutations: a causal role in sarcopenia. Eur J Biochem 269: 2010–2015.
McKiernan SH, Bua E, McGorray J, et al. (2004). Earlyonset calorie restriction conserves fiber number in aging rat skeletal muscle. FASEB J 18: 580–581. McNeil CJ, Doherty TJ, Stashuk DW, et al. (2005). Motor unit number estimates in the tibialis anterior muscle of young, old, and very old men. Muscle Nerve 31: 461–467. Melton LJ 3rd, Khosla S, Crowson CS, et al. (2000). Epidemiology of sarcopenia. J Am Geriatr Soc 48: 625–630. Mendell JR (1995). Mitochondrial myopathy in the elderly: exaggerated aging in the pathogenesis of disease. Ann Neurol 37: 3–4. Michalik A, Van Broeckhoven C (2003). Pathogenesis of polyglutamine disorders: aggregation revisited. Hum Mol Genet 12(2): R173–R186. Mikol J, Engel A (2004). Inclusion body myositis. In: A Engel, C Franzini-Armstrong (Eds.), Myology. McGrawHill, New York, pp. 1367–1389. Miller JB, Emerson CP Jr (2003). Does the road to muscle rejuvenation go through Notch? Sci Aging Knowledge Environ 48: 34. Miller RW, Forbes JF (1990). Camptocormia. Mil Med 155: 561–565. Mitch WE, Price SR (2003). Mechanisms activating proteolysis to cause muscle atrophy in catabolic conditions. J Ren Nutr 13: 149–152. Monemi M, Eriksson PO, Eriksson A, et al. (1998). Adverse changes in fibre type composition of the human masseter versus biceps brachii muscle during aging. J Neurol Sci 154: 35–48. Morley JE, Baumgartner RN, Roubenoff R, et al. (2001). Sarcopenia. J Lab Clin Med 137: 231–243. Morse CI, Thom JM, Birch KM, et al. (2005). Changes in triceps surae muscle architecture with sarcopenia. Acta Physiol Scand 183: 291–298. Motta E, Strugalska H, Miller K (1997). [Diagnostic difficulties in a case of mitochondrial myopathy in a 51-year-old woman]. Neurol Neurochir Pol 31: 1033–1040. Muller T, Deschauer M, Neudecker S, et al. (2005). Lateonset mitochondrial myopathy with dystrophic changes due to a G7497A mutation in the mitochondrial tRNA (Ser (UCN)) gene. Acta Neuropathol (Berl) 110: 426–430. Muller-Hocker J (1992). Mitochondria and ageing. Brain Pathol 2: 149–158. Murrant CL, Sarelius IH (2002). Multiple dilator pathways in skeletal muscle contraction-induced arteriolar dilations. Am J Physiol Regul Integr Comp Physiol 282: R969–R978. Murray MP, Gardner GM, Mollinger LA, et al. (1980). Strength of isometric and isokinetic contractions: knee muscles of men aged 20 to 86. Phys Ther 60: 412–419. Musaro A, Cusella De Angelis MG, Germani A, et al. (1995). Enhanced expression of myogenic regulatory genes in aging skeletal muscle. Exp Cell Res 221: 241–248. Musaro A, McCullagh K, Paul A, et al. (2001). Localized IGF-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle. Nat Genet 27: 195–200. Musch TI, Eklund KE, Hageman KS, et al. (2004). Altered regional blood flow responses to submaximal exercise in older rats. J Appl Physiol 96: 81–88.
MUSCLE DISEASES AND AGING Nair KS (2000). Age-related changes in muscle. Mayo Clin Proc 75: S14–S18. Nair KS (2005). Aging muscle. Am J Clin Nutr 81: 953–963. Nakano S, Shinde A, Ito H, et al. (2005). Messenger RNA degradation may be inhibited in sporadic inclusion body myositis. Neurology 65: 420–425. Nikolic M, Malnar-Dragojevic D, Bobinac D, et al. (2001). Age-related skeletal muscle atrophy in humans: an immunohistochemical and morphometric study. Coll Antropol 25: 545–553. Oka A, Takashima S (1997). Induction of cyclo-oxygenase 2 in brains of patients with Down’s syndrome and dementia of Alzheimer type: specific localization in affected neurones and axons. Neuroreport 8: 1161–1164. Oldfors A, Fyhr IM (2001). Inclusion body myositis: genetic factors, aberrant protein expression, and autoimmunity. Curr Opin Rheumatol 13: 469–475. Oldfors A, Lindberg C (1999). Inclusion body myositis. Curr Opin Neurol 12: 527–533. Oldfors A, Moslemi AR, Fyhr IM, et al. (1995). Mitochondrial DNA deletions in muscle fibers in inclusion body myositis. J Neuropathol Exp Neurol 54: 581–587. Oldfors A, Moslemi AR, Jonasson L, et al. (2005). Mitochondrial abnormalities in inclusion-body myositis. Neurology 66: S49–S55. Paddon-Jones D, Sheffield-Moore M, Creson DL, et al. (2003). Hypercortisolemia alters muscle protein anabolism following ingestion of essential amino acids. Am J Physiol Endocrinol Metab 284: E946–E953. Paddon-Jones D, Sheffield-Moore M, Zhang XJ, et al. (2004). Amino acid ingestion improves muscle protein synthesis in the young and elderly. Am J Physiol Endocrinol Metab 286: E321–E328. Pak JW, Herbst A, Bua E, et al. (2003). Mitochondrial DNA mutations as a fundamental mechanism in physiological declines associated with aging. Aging Cell 2: 1–7. Pannemans DL, Wagenmakers AJ, Westerterp KR, et al. (1998). Effect of protein source and quantity on protein metabolism in elderly women. Am J Clin Nutr 68: 1228–1235. Pansarasa O, Felzani G, Vecchiet J, et al. (2002). Antioxidant pathways in human aged skeletal muscle: relationship with the distribution of type II fibers. Exp Gerontol 37: 1069–1075. Pattison JS, Folk LC, Madsen RW, et al. (2003a). Expression profiling identifies dysregulation of myosin heavy chains IIb and IIx during limb immobilization in the soleus muscles of old rats. J Physiol 553: 357–368. Pattison JS, Folk LC, Madsen RW, et al. (2003b). Selected contribution: identification of differentially expressed genes between young and old rat soleus muscle during recovery from immobilization-induced atrophy. J Appl Physiol 95: 2171–2179. Pauzner R, Blatt I, Mouallem M, et al. (1991). Mitochondrial abnormalities in oculopharyngeal muscular dystrophy. Muscle Nerve 14: 947–952. Pedersen M, Steensberg A, Keller C, et al. (2004). Does the aging skeletal muscle maintain its endocrine function? Exerc Immunol Rev 10: 42–55.
385
Perez-Paya E, Forood B, Houghten RA, et al. (1996). Structural characterization and 50-mononucleotide binding of polyalanine beta-sheet complexes. J Mol Recognit 9: 488–493. Perez-Sales P (1990). Camptocormia. Br J Psychiatry 157: 765–767. Phillips T, Leeuwenburgh C (2005). Muscle fiber-specific apoptosis and TNF-alpha signaling in sarcopenia are attenuated by life-long calorie restriction. FASEB J 19: 668–670. Phillips SK, Rook KM, Siddle NC, et al. (1993). Muscle weakness in women occurs at an earlier age than in men, but strength is preserved by hormone replacement therapy. Clin Sci (Lond) 84: 95–98. Phillips BA, Zilko PJ, Mastaglia FL (2000). Prevalence of sporadic inclusion body myositis in Western Australia. Muscle Nerve 23: 970–972. Piec I, Listrat A, Alliot J, et al. (2005). Differential proteome analysis of aging in rat skeletal muscle. FASEB J 19: 1143–1145. Pollock ML, Mengelkoch LJ, Graves JE, et al. (1997). Twenty-year follow-up of aerobic power and body composition of older track athletes. J Appl Physiol 82: 1508–1516. Porter MM, Vandervoort AA, Lexell J (1995). Aging of human muscle: structure, function and adaptability. Scand J Med Sci Sports 5: 129–142. Pratt MF, Meyers PK (1986). Oculopharyngeal muscular dystrophy: recent ultrastructural evidence for mitochondrial abnormalities. Laryngoscope 96: 368–373. Price P, Santoso L, Mastaglia F, et al. (2004). Two major histocompatibility complex haplotypes influence susceptibility to sporadic inclusion body myositis: critical evaluation of an association with HLA-DR3. Tissue Antigens 64: 575–580. Proctor DN, Joyner MJ (1997). Skeletal muscle mass and the reduction of VO2max in trained older subjects. J Appl Physiol 82: 1411–1415. Proctor DN, Sinning WE, Walro JM, et al. (1995). Oxidative capacity of human muscle fiber types: effects of age and training status. J Appl Physiol 78: 2033–2038. Proctor DN, Balagopal P, Nair KS (1998). Age-related sarcopenia in humans is associated with reduced synthetic rates of specific muscle proteins. J Nutr 128: 351S–355S. Rasmussen UF, Krustrup P, Kjaer M, et al. (2003). Experimental evidence against the mitochondrial theory of aging. A study of isolated human skeletal muscle mitochondria. Exp Gerontol 38: 877–886. Ravikumar B, Duden R, Rubinsztein DC (2002). Aggregateprone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum Mol Genet 11: 1107–1117. Reichel G, Kirchhofer U, Stenner A (2001). [Camptocormia—-segmental dystonia. Proposal of a new definition for an old disease]. Nervenarzt 72: 281–285. Reid MB, Durham WJ (2002). Generation of reactive oxygen and nitrogen species in contracting skeletal muscle: potential impact on aging. Ann N Y Acad Sci 959: 108–116. Renault V, Piron-Hamelin G, Forestier C, et al. (2000). Skeletal muscle regeneration and the mitotic clock. Exp Gerontol 35: 711–719.
386
P. SERDAROGLU
Renganathan M, Messi ML, Schwartz R, et al. (1997). Overexpression of hIGF-1 exclusively in skeletal muscle increases the number of dihydropyridine receptors in adult transgenic mice. FEBS Lett 417: 13–16. Rennie MJ (2001a). Control of muscle protein synthesis as a result of contractile activity and amino acid availability: implications for protein requirements. Int J Sport Nutr Exerc Metab 11: S170–S176. Rennie MJ (2001b). Grandad, it ain’t what you eat, it depends when you eat it — that’s how muscles grow! J Physiol 535: 2. Rifai Z, Welle S, Kamp C, et al. (1995). Ragged red fibers in normal aging and inflammatory myopathy. Ann Neurol 37: 24–29. Robinson DO, Hammans SR, Read SP, et al. (2005). Oculopharyngeal muscular dystrophy (OPMD): analysis of the PABPN1 gene expansion sequence in 86 patients reveals 13 different expansion types and further evidence for unequal recombination as the mutational mechanism. Hum Genet 116: 267–271. Roos MR, Rice CL, Vandervoort AA (1997). Age-related changes in motor unit function. Muscle Nerve 20: 679–690. Rooyackers OE, Adey DB, Ades PA, et al. (1996). Effect of age on in vivo rates of mitochondrial protein synthesis in human skeletal muscle. Proc Natl Acad Sci U S A 93: 15364–15369. Rosenberg IH (1997). Sarcopenia: origins and clinical relevance. J Nutr 127: 990S–991S. Roth SM, Ferrell RF, Hurley BF (2000). Strength training for the prevention and treatment of sarcopenia. J Nutr Health Aging 4: 143–155. Roth SM, Ferrell RE, Peters DG, et al. (2002). Influence of age, sex, and strength training on human muscle gene expression determined by microarray. Physiol Genomics 10: 181–190. Roth SM, Zmuda JM, Cauley JA, et al. (2004). Vitamin D receptor genotype is associated with fat-free mass and sarcopenia in elderly men. J Gerontol A Biol Sci Med Sci 59: 10–15. Roubenoff R (2000a). Sarcopenia and its implications for the elderly. Eur J Clin Nutr 54 (Suppl. 3): S40–S47. Roubenoff R (2000b). Sarcopenia: a major modifiable cause of frailty in the elderly. J Nutr Health Aging 4: 140–142. Roubenoff R (2001). Origins and clinical relevance of sarcopenia. Can J Appl Physiol 26: 78–89. Roubenoff R (2003). Sarcopenia: effects on body composition and function. J Gerontol A Biol Sci Med Sci 58: 1012–1017. Roubenoff R (2004). Sarcopenic obesity: the confluence of two epidemics. Obes Res 12: 887–888. Roubenoff R, Castaneda C (2001). Sarcopenia — understanding the dynamics of aging muscle. JAMA 286: 1230–1231. Roubenoff R, Hughes VA (2000). Sarcopenia: current concepts. J Gerontol A Biol Sci Med Sci 55: M716–M724. Roubenoff R, Rall LC, Veldhuis JD, et al. (1998). The relationship between growth hormone kinetics and sarcopenia in postmenopausal women: the role of fat mass and leptin. J Clin Endocrinol Metab 83: 1502–1506.
Roubenoff R, Parise H, Payette HA, et al. (2003). Cytokines, insulin-like growth factor 1, sarcopenia, and mortality in very old community-dwelling men and women: the Framingham Heart Study. Am J Med 115: 429–435. Roy AK, Vellanoweth RL, Chen S, et al. (1996). The evolutionary tangle of aging, sex, and reproduction and an experimental approach to its molecular dissection. Exp Gerontol 31: 83–94. Rudnicki MA, Schnegelsberg PN, Stead RH, et al. (1993). MyoD or Myf-5 is required for the formation of skeletal muscle. Cell 75: 1351–1359. Ruegg S, Lehky Hagen M, Hohl U, et al. (2005). Oculopharyngeal muscular dystrophy — an under-diagnosed disorder? Swiss Med Wkly 135: 574–586. Russell B, Dix DJ, Haller DL, et al. (1992). Repair of injured skeletal muscle: a molecular approach. Med Sci Sports Exerc 24: 189–196. Russell JA, Kindig CA, Behnke BJ, et al. (2003). Effects of aging on capillary geometry and hemodynamics in rat spinotrapezius muscle. Am J Physiol Heart Circ Physiol 285: H251–H258. Sajko S, Kubinova L, Cvetko E, et al. (2004). Frequency of M-cadherin-stained satellite cells declines in human muscles during aging. J Histochem Cytochem 52: 179–185. Santorelli FM, Sciacco M, Tanji K, et al. (1996). Multiple mitochondrial DNA deletions in sporadic inclusion body myositis: a study of 56 patients. Ann Neurol 39: 789–795. Sastre J, Pallardo FV, Garcia De La Asuncion J, et al. (2000). Mitochondria, oxidative stress and aging. Free Radic Res 32: 189–198. Sastre J, Pallardo FV, Vina J (2003). The role of mitochondrial oxidative stress in aging. Free Radic Biol Med 35: 1–8. Schabitz WR, Glatz K, Schuhan C, et al. (2003). Severe forward flexion of the trunk in Parkinson’s disease: focal myopathy of the paraspinal muscles mimicking camptocormia. Mov Disord 18: 408–414. Schroder JM, Krabbe B, Weis J (1995). Oculopharyngeal muscular dystrophy: clinical and morphological followup study reveals mitochondrial alterations and unique nuclear inclusions in a severe autosomal recessive type. Neuropathol Appl Neurobiol 21: 68–73. Schwarze SR, Lee CM, Chung SS, et al. (1995). High levels of mitochondrial DNA deletions in skeletal muscle of old rhesus monkeys. Mech Ageing Dev 83: 91–101. Seale P, Sabourin LA, Girgis-Gabardo A, et al. (2000). Pax7 is required for the specification of myogenic satellite cells. Cell 102: 777–786. Seale P, Ishibashi J, Holterman C, et al. (2004). Muscle satellite cell-specific genes identified by genetic profiling of MyoD-deficient myogenic cell. Dev Biol 275: 287–300. Selsby JT, Judge AR, Yimlamai T, et al. (2005). Life long calorie restriction increases heat shock proteins and proteasome activity in soleus muscles of Fisher 344 rats. Exp Gerontol 40: 37–42. Serdaroglu P (2004). Myopathies in the elderly. Acta Myol 23: 16. Serdaroglu P, Hanagasi H, Tasli H, et al. (2005a). Parkin expression in muscle from three patients with autosomal
MUSCLE DISEASES AND AGING recessive Parkinson’s disease carrying parkin mutation. Acta Myol 24: 2–5. Serdaroglu P, Tasli H, Hanagasi H, et al. (2005b). Parkin expression in human skeletal muscle. J Clin Neurosci 12: 928–930. Serratrice J, Weiller PJ, Pouget J, et al. (2000). [An unrecognized cause of camptocormia: proximal myotonic myopathy]. Presse Med 29: 1121–1123. Shanmugam V, Dion P, Rochefort D, et al. (2000). PABP2 polyalanine tract expansion causes intranuclear inclusions in oculopharyngeal muscular dystrophy. Ann Neurol 48: 798–802. Sherman MY, Goldberg AL (2001). Cellular defenses against unfolded proteins: a cell biologist thinks about neurodegenerative diseases. Neuron 29: 15–32. Short KR, Bigelow ML, Kahl J, et al. (2005). Decline in skeletal muscle mitochondrial function with aging in humans. Proc Natl Acad Sci U S A 102: 5618–5623. Shringarpure R, Davies KJ (2002). Protein turnover by the proteasome in aging and disease. Free Radic Biol Med 32: 1084–1089. Silvestri G, Rana M, Dimuzio A, et al. (1998). A late-onset mitochondrial myopathy is associated with a novel mitochondrial DNA (mtDNA) point mutation in the tRNA (Trp) gene. Neuromuscul Disord 8: 291–295. Simonetti S, Chen X, DiMauro S, et al. (1992). Accumulation of deletions in human mitochondrial DNA during normal aging: analysis by quantitative PCR. Biochim Biophys Acta 1180: 113–122. Skidmore F, Mikolenko I, Weiss H, et al. (2005). Camptocormia in a patient with multiple system atrophy. Mov Disord 20: 1063–1064. Slawek J, Derejko M, Lass P (2003). Camptocormia as a form of dystonia in Parkinson’s disease. Eur J Neurol 10: 107–108. Slawek J, Derejko M, Lass P, et al. (2006). Camptocormia or Pisa syndrome in multiple system atrophy. Clin Neurol Neurosurg 108: 699–704. Sohal RS, Sohal BH (1991). Hydrogen peroxide release by mitochondria increases during aging. Mech Ageing Dev 57: 187–202. Soong NW, Hinton DR, Cortopassi G, et al. (1992). Mosaicism for a specific somatic mitochondrial DNA mutation in adult human brain. Nat Genet 2: 318–323. Soreff J (1983). Camptocormia. Arch Orthop Trauma Surg 101: 151–152. Spangenburg EE, Abraha T, Childs TE, et al. (2003). Skeletal muscle IGF-binding protein-3 and -5 expressions are age, muscle, and load dependent. Am J Physiol Endocrinol Metab 284: E340–E350. Spier SA, Delp MD, Meininger CJ, et al. (2004). Effects of ageing and exercise training on endothelium-dependent vasodilatation and structure of rat skeletal muscle arterioles. J Physiol 556: 947–958. Spiers S, McArdle F, Jackson MJ (2000). Aging-related muscle dysfunction. Failure of adaptation to oxidative stress? Ann N Y Acad Sci 908: 341–343. Sugarman MC, Yamasaki TR, Oddo S, et al. (2002). Inclusion body myositis-like phenotype induced by transgenic
387
overexpression of beta APP in skeletal muscle. Proc Natl Acad Sci U S A 99: 6334–6339. Szulc P, Duboeuf F, Marchand F, et al. (2004). Hormonal and lifestyle determinants of appendicular skeletal muscle mass in men: the MINOS study. Am J Clin Nutr 80: 496–503. Taillandier D, Combaret L, Pouch MN, et al. (2004). The role of ubiquitin-proteasome-dependent proteolysis in the remodelling of skeletal muscle. Proc Nutr Soc 63: 357–361. Tajbakhsh S, Rocancourt D, et al. (1996). Muscle progenitor cells failing to respond to positional cues adopt non-myogenic fates in myf-5 null mice. Nature 384: 266–270. Terman A, Brunk UT (2004). Myocyte aging and mitochondrial turnover. Exp Gerontol 39: 701–705. Terman A, Dalen H, Eaton JW, et al. (2003). Mitochondrial recycling and aging of cardiac myocytes: the role of autophagocytosis. Exp Gerontol 38: 863–876. Tome FM, Fardeau M (1980). Nuclear inclusions in oculopharyngeal dystrophy. Acta Neuropathol (Berl) 49: 85–87. Tome FM, Askanas V, Engel WK, et al. (1989). Nuclear inclusions in innervated cultured muscle fibers from patients with oculopharyngeal muscular dystrophy. Neurology 39: 926–932. Trappe T, Williams R, Carrithers J, et al. (2003). Influence of age and resistance exercise on human skeletal muscle proteolysis: a microdialysis approach. J Physiol 554: 803–813. Trifunovic A, Wredenberg A, Falkenberg M, et al. (2004). Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429: 417–423. Tsai YC, Fishman PS, Thakor NV, et al. (2003). Parkin facilitates the elimination of expanded polyglutamine proteins and leads to preservation of proteasome function. J Biol Chem 278: 22044–22055. Tseng BS, Marsh DR, Hamilton MT, et al. (1995). Strength and aerobic training attenuate muscle wasting and improve resistance to the development of disability with aging. J Gerontol A Biol Sci Med Sci 50: 113–119. Ubogu EE, Ruff RL, Kaminski HJ (2004). Endocrine myopathies. In: AG Engel, C Franzini-Armstrong (Eds.), Myology.3rd edn.,McGraw-Hill, New York, pp. 1713–1739. Vandervoort AA (2002). Aging of the human neuromuscular system. Muscle Nerve 25: 17–25. Verdu E, Ceballos D, Vilches JJ, et al. (2000). Influence of aging on peripheral nerve function and regeneration. J Peripher Nerv Syst 5: 191–208. Verhoef LG, Lindsten K, Masucci MG, et al. (2002). Aggregate formation inhibits proteasomal degradation of polyglutamine proteins. Hum Mol Genet 11: 2689–2700. Vescovo G, Zennaro R, Sandri M, et al. (1998). Apoptosis of skeletal muscle myofibers and interstitial cells in experimental heart failure. J Mol Cell Cardiol 30: 2449–2459. Vigneron N, Stroobant V, Chapiro J, et al. (2004). An antigenic peptide produced by peptide splicing in the proteasome. Science 304: 587–590. Viner RI, Ferrington DA, Aced GI, et al. (1997). In vivo aging of rat skeletal muscle sarcoplasmic reticulum
388
P. SERDAROGLU
Ca-ATPase. Chemical analysis and quantitative simulation by exposure to low levels of peroxyl radicals. Biochim Biophys Acta 1329: 321–335. Vinters HV, Gilbert JJ (1983). Cerebral amyloid angiopathy: incidence and complications in the aging brain. II. The distribution of amyloid vascular changes. Stroke 14: 924–928. Visser M, Deeg DJ, Lips P (2003). Low vitamin D and high parathyroid hormone levels as determinants of loss of muscle strength and muscle mass (sarcopenia): the Longitudinal Aging Study Amsterdam. J Clin Endocrinol Metab 88: 5766–5772. Volpi E, Mittendorfer B, Rasmussen BB, et al. (2000). The response of muscle protein anabolism to combined hyperaminoacidemia and glucose-induced hyperinsulinemia is impaired in the elderly. J Clin Endocrinol Metab 85: 4481–4490. Volpi E, Sheffield-Moore M, Rasmussen BB, et al. (2001). Basal muscle amino acid kinetics and protein synthesis in healthy young and older men. JAMA 286: 1206–1212. Volpi E, Kobayashi H, Sheffield-Moore M, et al. (2003). Essential amino acids are primarily responsible for the amino acid stimulation of muscle protein anabolism in healthy elderly adults. Am J Clin Nutr 78: 250–258. Wagatsuma A (2006). Effect of aging on expression of angiogenesis-related factors in mouse skeletal muscle. Exp Gerontol 41: 49–54. Walter MC, Lochmuller H, Schlotter B, et al. (2001). [New insights in pathogenesis and therapy of sporadic inclusion body myositis (s-IBM)]. Nervenarzt 72: 117–121. Wanagat J, Cao Z, Pathare P, et al. (2001). Mitochondrial DNA deletion mutations colocalize with segmental electron transport system abnormalities, muscle fiber atrophy, fiber splitting, and oxidative damage in sarcopenia. FASEB J 15: 322–332. Wanagat J, Wolff MR, Aiken JM (2002). Age-associated changes in function, structure and mitochondrial genetic and enzymatic abnormalities in the Fischer 344 x Brown Norway F(1) hybrid rat heart. J Mol Cell Cardiol 34: 17–28. Wang ZM, Messi ML, Delbono O (1999). Patch-clamp recording of charge movement, Ca(2þ) current, and Ca (2þ) transients in adult skeletal muscle fibers. Biophys J 77: 2709–2716. Wang Y, Michikawa Y, Mallidis C, et al. (2001). Musclespecific mutations accumulate with aging in critical human mtDNA control sites for replication. Proc Natl Acad Sci USA 98: 4022–4027. Warabi Y, Matsubara S, Mizutani T, et al. (2004). [Inclusion body myositis after interferon-alpha treatment in a patient with HCV and HTLV-1 infection]. Rinsho Shinkeigaku 44: 609–614. Welle S, Thornton C, Jozefowicz R, et al. (1993). Myofibrillar protein synthesis in young and old men. Am J Physiol 264: E693–E698. Welle S, Brooks A, Thornton CA (2001). Senescence-related changes in gene expression in muscle: similarities and differences between mice and men. Physiol Genomics 5: 67–73. Welle S, Brooks AI, Delehanty JM, et al. (2003). Gene expression profile of aging in human muscle. Physiol Genomics 14: 149–159.
Wojcik S, Engel WK, McFerrin J, et al. (2005). Myostatin is increased and complexes with amyloid-beta within sporadic inclusion-body myositis muscle fibers. Acta Neuropathol (Berl) 110: 173–177. Wolfe RR (2002). Regulation of muscle protein by amino acids. J Nutr 132: 3219S–3224S. Wong KT, Dick D, Anderson JR (1996). Mitochondrial abnormalities in oculopharyngeal muscular dystrophy. Neuromuscul Disord 6: 163–166. Wunderlich S, Csoti I, Reiners K, et al. (2002). Camptocormia in Parkinson’s disease mimicked by focal myositis of the paraspinal muscles. Mov Disord 17: 598–600. Wyttenbach A, Carmichael J, Swartz J, et al. (2000). Effects of heat shock, heat shock protein 40 (HDJ-2), and proteasome inhibition on protein aggregation in cellular models of Huntington’s disease. Proc Natl Acad Sci USA 97: 2898–2903. Yablonka-Reuveni Z, Rivera AJ (1994). Temporal expression of regulatory and structural muscle proteins during myogenesis of satellite cells on isolated adult rat fibers. Dev Biol 164: 588–603. Yarasheski KE, Bhasin S, Sinha-Hikim I, et al. (2002). Serum myostatin-immunoreactive protein is increased in 60–92 year old women and men with muscle wasting. J Nutr Health Aging 6: 343–348. Yarovaya NO, Kramarova L, Borg J, et al. (2002). Agerelated atrophy of rat soleus muscle is accompanied by changes in fibre type composition, bioenergy decline and mtDNA rearrangements. Biogerontology 3: 25–27. Young A, Stokes M, Crowe M (1984). Size and strength of the quadriceps muscles of old and young women. Eur J Clin Invest 14: 282–287. Young A, Stokes M, Crowe M (1985). The size and strength of the quadriceps muscles of old and young men. Clin Physiol 5: 145–154. Zammit P, Beauchamp J (2001). The skeletal muscle satellite cell: stem cell or son of stem cell? Differentiation 68: 193–204. Zammit PS, Golding JP, Nagata Y, et al. (2004). Muscle satellite cells adopt divergent fates: a mechanism for self-renewal? J Cell Biol 166: 347–357. Zhang C, Baumer A, Maxwell RJ, et al. (1992). Multiple mitochondrial DNA deletions in an elderly human individual. FEBS Lett 297: 34–38. Zhang C, Goto N, Suzuki M, et al. (1996). Age-related reductions in number and size of anterior horn cells at C6 level of the human spinal cord. Okajimas Folia Anat Jpn 73: 171–177. Zheng Z, Messi ML, Delbono O (2001). Age-dependent IGF-1 regulation of gene transcription of Ca2þ channels in skeletal muscle. Mech Ageing Dev 122: 373–384. Zucchini C, Pugnaloni A, Pallotti F, et al. (1995). Human skeletal muscle mitochondria in aging: lack of detectable morphological and enzymic defects. Biochem Mol Biol Int 37: 607–616. Zwecker M, Iancu I, Zeilig G, et al. (1998). Camptocormia: a case of possible paraneoplastic aetiology. Clin Rehabil 12: 157–160.
Handbook of Clinical Neurology, Vol. 86 (3rd series) Myopathies F. L. Mastaglia, D. Hilton-Jones, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 19
Muscle cramp syndromes PHILIP D. THOMPSON* University of Adelaide, Royal Adelaide Hospital, Adelaide, Australia
Muscle cramps are a common complaint and may be caused by many diseases of muscle, peripheral nerve and the central nervous system. Accordingly, the differential diagnosis is large. A careful history and physical examination is vital in the diagnostic evaluation of cramps. It is helpful to distinguish between the localized stereotyped occurrence of benign physiological cramps (the commonest cause of muscle cramps) and multifocal or generalized muscle cramps that indicate a systemic disorder or an underlying neuromuscular cause. In the latter case, other physical signs will be present to provide further clues to a neuropathic or myopathic origin. Cramps should be distinguished from muscle spasm and contracture. Muscle spasms are fluctuating contractions of groups of muscles, typically affecting one region or segment of the body. The widespread recruitment of muscles in a spasm usually suggests an origin within the central nervous system, although the term “spasm” is frequently used interchangeably with cramps. The term contracture is used to describe the electrically silent shortening of muscle, without accompanying electromyographic potentials of active muscle contraction. A contracture may be fixed and permanent because of fibrotic change within the muscle, or transient due to failure of muscle fiber relaxation after contraction as occurs in some metabolic myopathies. Muscle cramps are frequently painful. A distinction should also be made between symptoms of muscle cramps and muscle pain or myalgia and muscle stiffness. A classification of muscle cramp according to the site of origin of the cramp is listed in Table 19.1.
19.1. Cramps of peripheral nerve origin 19.1.1. Benign (physiological) cramps Benign, physiological cramps are common in healthy people. They are typically localized to part of a muscle or one muscle. The calf, hamstrings and intrinsic foot muscles are most commonly affected. Occasionally cramps occur in muscles of the upper limb and trunk. Benign cramps occur at rest or during sleep but may interrupt exercise, particularly after forceful contraction of a shortened muscle. Cramps begin abruptly and last seconds to minutes. The cramp is accompanied by intense localized muscle pain that may be of sufficient intensity to stop activity or wake the subject from sleep. The muscle contraction of a cramp forces the affected limb into an abnormal posture. “Breaking” the cramp by stretching the affected muscle (and correcting the posture) terminates the cramp rapidly with relief of pain although a lingering discomfort often persists. Breaking the cramp in this way is a useful diagnostic sign of benign muscle cramps. Cramps develop in healthy people without apparent predisposing factors, but occurrence after vigorous exercise is common. Dehydration, salt depletion, other electrolyte disturbances, pregnancy and denervation are recognized predisposing factors. Cramps are more common in people with systemic illness and multiple medical or surgical comorbidities, particularly the elderly. Benign muscle cramps are believed to originate in the peripheral nervous system from spontaneous activity in terminal motor nerve fibers (Bertolasi et al., 1993). Electromyography during cramp discloses normal motor units discharging at very high frequency but with variable
*Correspondence to: Philip D. Thompson, University Department of Medicine, Level 6 Eleanor Harrald Building, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia. E-mail:
[email protected], Tel: þ61-8-8222-5502, Fax: þ61-8-8223-3870.
390
P. D. THOMPSON
Table 19.1 Muscle cramp syndromes according to site of origin Muscle disease Glycogen-storage diseases (electrically silent contracture) Ca2þ ATPase reuptake deficiency (electrically silent contracture) Myopathy with tubular aggregates Mitochondrial diseasea Myoadenylate deaminase deficiencya Fatty acid oxidation defectsa Myotonias Neuromuscular junction Schwarz–Jampel syndrome Peripheral nerve Benign physiological cramps Lower motor neuron syndromes (with denervation) Peripheral nerve hyperexcitability syndromes Tetany Central nervous system (tend to produce spasms rather than cramps) Stiff-person syndrome Tonic spasms of multiple sclerosis Paroxysmal dyskinesias Tonic seizures Basal ganglia diseases (rigidity and spasms) Upper motor neuron syndromes (spasticity) a Myalgia and exercise intolerance more prominent than muscle cramps.
pattern of recruitment (Norris et al., 1957). The activity may begin at one site and spread to a larger area of muscle or begin in multiple sites at once. The length of muscle is a major determinant in the generation of muscle cramps. Cramps with similar characteristics can be evoked in muscles shortened by voluntary contraction or high frequency peripheral nerve stimulation, but not when the muscle is prevented from shortening (Bertolasi et al., 1993). As mentioned above, lengthening the shortened cramping muscle by stretching, characteristically interrupts cramps. Treatment with quinine is widely regarded as effective for benign cramps, though there is no firm evidence to support this and concerns have been raised about the adverse effects of quinine. Other treatments that have been used without demonstrated efficacy include membrane stabilizers (phenytoin, carbamazepine), baclofen, dantrolene, verapamil and vitamin E. 19.2.2. Peripheral nerve hyperexcitability syndromes These syndromes are characterized by continuous muscle activity driven by ectopic discharges originating within peripheral (motor) nerves. The clinical picture is distinc-
tive with muscle twitching, rippling, stiffness, cramps and delayed muscle relaxation. All muscle groups are affected. Continuous motor unit and muscle fiber discharge manifest clinically as fasciculation and myokymia (undulating, vermicular rippling of muscle). Electromyography reveals fasciculations, semirhythmic grouped motor unit discharges in doublets or triplets, and highfrequency muscle fiber discharges (Fig. 19.1). Afterdischarges follow voluntary contraction (Fig. 19.2) and are the physiological basis for the delay in muscle relaxation (after voluntary contraction) and the symptoms of muscle stiffness and cramp. Peripheral nerve stimulation and percussion of peripheral nerves also evoke afterdischarges (Fig. 19.2). Continuous muscle activity persists during sleep, spinal and general anesthesia but is abolished by peripheral neuromuscular blockade. The ectopic discharges are generated at various sites throughout the length of the peripheral motor axons from proximal segments (Wallis et al., 1968; Hahn et al., 1991) to the distal terminal motor arborization. There may be evidence of generalized axon hyperexcitability (Maddison et al., 1999) but this cannot always be demonstrated suggesting that the disorder may be focal or multifocal (Kiernan et al., 2001). The generalized distribution and continuous nature of symptoms along with the characteristic electromyographic findings and response to treatment differentiate peripheral nerve hyperexcitability syndromes from other causes of muscle stiffness and cramp.
400 uV
100 ms
Fig. 19.1. Concentric needle electromyographic recording of spontaneous motor unit discharges in doublets and triplets and smaller muscle fiber discharges from medial gastrocnemius in a patient with continuous motor activity and delayed muscle relaxation (modified from Thompson, 2001).
MUSCLE CRAMP SYNDROMES
391
Table 19.2 Voluntary contraction
Peroneal nerve stimulation
0.25 mV 250 ms
B
250 ms
A
Fig. 19.2. After-discharges in tibialis anterior following (A) peroneal nerve stimulation and (B) voluntary dorsiflexion of the foot in a patient with acquired neuromyotonia and delayed muscle relaxation (modified from Thompson, 2001).
A variety of terms have been used to describe this clinical syndrome. Isaacs’ syndrome (Isaacs, 1964) is well known though there were earlier descriptions (Denny-Brown and Foley, 1948). The term neuromyotonia was introduced to distinguish the syndrome from myotonia and emphasize a neural origin (Mertens and Zschocke, 1965). Neuromyotonia is also used in an electromyographic sense to describe grouped and complex discharges of motor units. Similarly, myokymia refers to the visible undulations of continuous muscle contraction and the grouped discharges recorded on electromyography. The syndrome has been described in a variety of acquired and inherited axonopathies and demyelinating neuropathies, but in many cases there is little or no evidence of an underlying neuropathy (Table 19.2). Newsom-Davis and colleagues (Newsom-Davis and Mills, 1993; Hart et al., 2002) have demonstrated an autoimmune etiology involving antibodies to voltage-gated potassium channels in more than 50% of such cases. Neuromyotonia is also found in association with mutations in the genes coding for voltage-gated potassium channel in episodic ataxia type 1 (Brunt and van Weerden, 1990). Neuromyotonia is abolished by agents that reduce conductance in sodium channels such as carbamazepine and tocainide. Immunological therapies have also been used in cases with a demonstrated autoimmune etiology (Hart et al., 2002). 19.2.2.1. Schwartz–Jampel syndrome The Schwartz–Jampel syndrome is a rare condition in which continuous muscle activity with high frequency discharges occurs along with skeletal deformity (Schwartz and Jampel, 1962). The condition begins at an early age. Limb, axial and facial muscles contract continuously producing generalized muscle rippling. The typical facial appearance of blepharophimosis and
Peripheral nerve hyperexcitablity syndromes defined by continuous muscle activity, myokymia, fasciculations and delayed muscle relaxation (adapted from Hart et al., 2002) Inherited Isolated (without neuropathy) Associated with hereditary neuropathy Associated with spinal muscular atrophy Antibody-mediated (voltage-gated K channel antibodies) Isolated Associated with central nervous system features (Morvan’s syndrome) Paraneoplastic Thymoma (myasthenia gravis) Small-cell lung carcinoma (neuropathy) Adenocarcinoma Associated with “idiopathic” peripheral neuropathy Associated with autoimmune disorders Myasthenia gravis (without thymoma) Systemic lupus erythematosus, scleroderma Guillain–Barre´ syndrome Mutations in voltage-gated K channel (KCNA1) Familial episodic ataxia type 1 Acquired Associated with neuropathy Thyroid disease Drugs (penicillamine, gold) Radiation Toxins
dimpling of the chin is caused by the continuous contraction of facial muscles. Limb muscles appear prominent and well developed because of ongoing contraction. Movements are effortful and the gait is stiff and awkward. Muscle relaxation after contraction is delayed. The muscle activity in this condition is often referred to as “myotonia” but the discharge characteristics are those of neuromyotonia. Electromyography reveals continuous motor unit discharges with spontaneous high frequency discharges and after-discharges following nerve stimulation or muscle percussion (Fig. 19.3). The Schwartz–Jampel syndrome has been shown to be due to a mutation in the genes encoding perlecan, a basement membrane proteoglycan which plays a role in localizing acetylcholinesterase within synapses at the neuromuscular junction (Nicole et al., 2000). Reduced synaptic acetylcholinesterase allows persistent cholinergic activation of terminal neuromuscular synapses. This explanation suggests the continuous muscle activity in the Schwartz–Jampel syndrome is generated from within the neuromuscular junction and is therefore distinct from the muscle membrane disorder of myotonia and the peripheral nerve hyperexcitability syndromes.
392
P. D. THOMPSON
Stimulate facial nerve
Mentalis
1 mV 50 ms
Fig. 19.3. Concentric needle electromyograph recordings from mentalis muscle following stimulation of the facial nerve in a patient with Schwartz–Jampel syndrome. Afterdischarges with complex repetitive morphology follow for several hundred milliseconds.
19.2.2.2. Tetany Tetany refers to the twitching and cramp caused by spontaneous repetitive muscle discharges in the setting of hypocalcaemia (also hypomagnesaemia) and alkalosis. This is typically evident in the face and distal limbs (carpopedal spasm). The biochemical changes render terminal motor fibers hyperexcitable. Hyperventilation may precipitate tetany and percussion of the nerve may induce a brief muscle cramp. Motor unit potentials discharge in repetitive trains of doublets, triplets and multiplets. Sensory fibers are also involved and symptoms of perioral and distal paresthesiae commonly precede the spontaneous muscle activity. 19.2.2.3. Generalized muscle cramps Severe systemic illness with organ failure, particularly renal or liver failure, may be accompanied by generalized cramps with the characteristics of “benign” cramps. Generalized benign cramps may also occur with ingestion of drugs that produce electrolyte disturbances such as diuretics and laxatives. Generalized painful muscle cramps are a feature of the Satoyoshi syndrome accompanied by alopecia, malabsorption and diarrhea (Satoh et al., 1983). Familial exercise-induced limb cramps affecting distal upper and lower limb muscles have also been described in a number of families (Jusic et al., 1972; Lazaro et al., 1981; Chiba et al., 1999). The clinical picture is similar in each but there has been no evidence of a neuropathy or peripheral nerve hyperexcitability. The cause is not known but a neural origin is suspected. 19.2.2.4. Isolated limb muscle cramps Linear scleroderma (en coup de sabre) of a limb may be accompanied by segmental atrophy of the skin, subcutaneous tissue and subjacent muscle. Muscles of the affected region may develop cramps. Continuous motor
unit activity and high frequency discharges are recorded from muscles underlying the affected area. These findings are consistent with localized neuromyotonia due to involvement of the terminal motor axons. Spontaneous or exercise-induced muscle cramps are common in multifocal motor neuropathy and other immune-mediated neuropathies. Painful cramps may develop in paretic muscles. The upper limbs and hands are particularly involved. The cramps are caused by rapidly discharging motor units. Myokymia and grouped or high-frequency motor unit discharges are not seen. Fasciculations may be evident on electromyography. 19.2.2.5. Isolated cramps in cranial muscles Cramps of masticatory and facial muscles occur in hemimasticatory spasm (Thompson and Carroll, 1983) and facial hemiatrophy (the Parry–Romberg syndrome), a localized form of scleroderma (en coup de sabre; Cruccu et al., 1994). In each case muscle activity appears to arise from trigeminal and facial nerve hyperexcitability with ectopic activation of motor axons producing brief repetitive trains of high-frequency motor unit discharges. 19.2.2.6. Cramps and the muscle pain–fasciculation syndrome This syndrome is a poorly defined combination of myalgia, cramps and fasciculations exacerbated by exercise. Exercise intolerance may be a prominent feature. Initial diagnostic considerations usually include denervation due to anterior horn cell disease and motor neuropathies. Long-term follow-up and further diagnostic evaluation may confirm these early suspicions, but a small number of patients with persisting symptoms do not have evidence of progressive lower motor neuron disease. In these cases, continuing symptoms of muscle cramp and pain are accompanied by persistent clinical and electromyographic signs of fasciculation, most prominent in the legs. Follow-up of these cases reveals a neuropathy (with additional distal sensory symptoms) (Hudson et al., 1978) or peripheral nerve hyperexcitability (Tahmoush et al., 1991) but in others there may be no evidence of a neuropathy or neuromyotonia (Kiernan et al., 2001).
19.3. Cramps and muscle diseases 19.3.1. Myotonic syndromes Myotonia refers to the phenomenon of muscle stiffness caused by persistent muscle contraction due to muscle fiber membrane hyperexcitability. Myotonia is the main feature of a number of primary muscle diseases that are discussed elsewhere in this volume. Symptoms of stiffness and limitation of movement are more common than
MUSCLE CRAMP SYNDROMES cramp in myotonia congenita (the chloride-channel myotonias) and the myotonia may ease with exercise. Paramyotonia congenita, a sodium-channel myotonia, is associated with cold-induced myotonia, electrically silent cramps, postmyotonic paresis and paradoxical myotonia that worsens with exercise. Electromyography during myotonia reveals characteristic waxing and waning (“myotonic”) discharges. This activity is provoked by voluntary movement, percussion, needle insertion and electrical stimulation of muscle. Myotonia does not occur at rest. Myotonic discharges persist for a minute or so after muscle contraction before subsiding. Myotonia occurs during sleep, after peripheral nerve or neuromuscular block, but is abolished by local infiltration of anesthesia into muscle.
393
muscle contractures. The muscle fails to relax after contraction because of a lack of sarcoplasmic energy for the reuptake of free calcium. Symptoms usually settle with rest but cramps may persist for hours. Rhabdomyolysis with myoglobinuria may occur. Attempts to straighten the muscle forcibly during cramp evoke severe pain (in contrast to physiological cramps). Cramps develop after variable levels of exercise and patients modify their activities accordingly. Some avoid precipitating cramps by lowering the level of activity when symptoms first appear, enabling continued exercise (the “second wind” phenomenon). Similar symptoms occur in phosphofructokinase deficiency. These conditions are discussed in greater detail in chapter 7. 19.3.4.2. Fatty acid oxidation disorders
19.3.2. Rippling muscle disease This familial condition presents with exercise-induced muscle stiffness and myalgia. A distinctive feature is the finding of visible localized muscle mounding lasting for several seconds after percussion of muscle, and a rippling or rolling motion of muscle induced by voluntary muscle contraction or stretching of muscle (Torbergson, 1975; Ricker et al., 1989; Burns et al., 1994). The muscle mounding and rippling wave is electrically silent (Torbergson, 1975; Ricker et al., 1989; Burns et al., 1994). Exercise-induced cramps in arms and legs have been described in some cases (Vorgerd et al., 1999). Creatine kinase levels may be elevated. The increased mechanical irritability of muscle in rippling muscle disease is associated with deficiency of caveolin 3 in the muscle membrane due to mutations in the gene coding caveolin 3 (see chapter 11). 19.3.3. Myalgia, cramps and dystrophinopathy A mild, variable and benign phenotype of myalgia and cramps has been described in association with certain deletions of the dystrophin gene, without significant muscle weakness (Gospe et al., 1989). Male and female family members complain of cramps, myalgia and exercise intolerance beginning in childhood. The condition is not progressive. Creatine kinase may be elevated and muscle may be dystrophic on biopsy (Sanchez-Arjona et al., 2005). 19.3.4. Metabolic myopathies
Disorders of fatty acid metabolism produce exerciseinduced myalgia, recurrent rhabdomyolysis with myoglobinuria and progressive weakness due to a lipid storage myopathy. The metabolic consequences of impaired fatty acid oxidation also result in a variable range of systemic effects including exercise and fasting-related encephalopathy. Cramps can occur during exercise and fasting but are less common than episodic rhabdomyolysis. 19.3.4.3. Ca2þ ATPase deficiency (Brody’s disease) This condition is characterized by a lifelong history of exercise-induced muscle stiffness, cramps and delayed muscle relaxation. All muscle groups are affected, including the facial muscles and especially the eyelids (Brody, 1969). Typically symptoms develop soon after the onset of brisk though not necessarily vigorous exercise. The delay in muscle relaxation produces stiffness and cramp. Continued exercise exacerbates the cramp and muscle relaxation is further impeded. Movement becomes more difficult, labored and slow. Eventually cramp may force the cessation of activity. Cramp and stiffness settle and disappear after a few minutes rest. The cramps are painless, in contrast to McArdle’s disease (Karpati et al., 1986), but as in McArdle’s disease the cramps are electrically silent contractures. The physiological mechanisms underlying exertional cramps in Brody’s disease are similar to those in the glycogenoses. Deficiency in sarcoplasmic reticulum transport Ca2þ ATPase impairs the Ca2þ pump and reuptake of Ca2þ into sarcoplasmic reticulum (Karpati et al., 1986). Elevation of intracellular calcium may increase the risk of rhabdomyolysis.
19.3.4.1. Glycogen storage disease Myophosphorylase deficiency (McArdle’s disease) and phosphofructokinase deficiency produce exerciseinduced myalgia, muscle stiffness and painful cramps. The cramps of McArdle’s disease are electrically silent
19.3.5. Endocrine myopathies Hypothyroidism commonly produces muscular symptoms including aches, stiffness and cramps. These
394
P. D. THOMPSON
complaints are most noticeable during and after voluntary contraction. Percussion of muscle produces a distinctive localized swelling or “mounding” of the muscle (myoedema). This response is electrically silent. Both the contraction and relaxation phases of muscle contraction are prolonged. In contrast, in myotonia, twitch contraction time is normal and the relaxation phase is prolonged by myotonic discharges. Electrolyte disturbances in Addison’s disease may also lead to cramps and muscle contractures are a rare feature. Hypoparathyroidism and hypocalcemia can lead to tetanic cramps. Hyperparathyroidism with hypercalcemia may be accompanied by myalgia. 19.3.6. Drug-induced muscle cramps The increase in use of lipid-lowering statin drugs (HMG coenzyme reductase A inhibitors) has been accompanied by a number of muscular complaints including myalgia and cramps. Symptoms can appear shortly after starting the medications or some time later. Symptoms may take several months to resolve after cessation of the offending drugs. The mechanism underlying the symptoms is not known. A number of other drugs cause myalgia which may be associated with cramps. These include cholinesterase inhibitors, salbutamol, beta blockers, calcium antagonists, lithium, danazol, cyclosporin, cimetidine, amphotericin B and E-aminocaproic acid (Mastaglia and Laing, 1996). 19.3.7. Considerations in the differential diagnosis of muscle cramps 19.3.7.1. Myopathies with contractures A number of myopathies are associated with fibrotic shortening of muscle and permanent contractures. These conditions may not necessarily be associated with cramp but are included here because the differential diagnosis often encompasses neuromuscular disease that produce continuous muscular contraction, abnormal shortening of muscle and muscle stiffness. Careful clinical examination and electromyography will usually resolve the question. Polymyositis (particularly affecting elbows), the rigid-spine syndrome (affecting limb muscles, cervical and thoracic paraspinal muscles), Bethlem muscular dystrophy (affecting elbows, fingers and ankles) and Emery– Dreifuss muscular dystrophy (paraspinal, elbow and finger contractures) may all present this conundrum. Inflammatory paraspinal myopathies can produce a striking weakness of extensors of the spine resulting in a syndrome of camptocormia (bent spine). The shortened muscles produce fixed limb postures that persist during sleep and anesthesia. Fibrotic muscles are electrically silent on electromyography.
19.3.7.2. Myalgia Complaints of chronic muscle pain and stiffness, with minimal or no abnormal neurological signs, and with or without muscle cramps, present a common diagnostic problem. Electromyography may be of value in excluding continuous muscle activity or an underlying myopathy. Where muscle weakness is present, further investigations may reveal an underlying myopathy such as polymyositis or myopathy with tubular aggregates which may present with myalgia and cramps. Muscle biopsy also may be necessary to exclude metabolic myopathies such as myoadenylate deficiency and mitochondrial disease that may be associated with myalgia. When myalgia is accompanied by constitutional symptoms, systemic diseases such as infections and polymyalgia rheumatica should also be considered. There remains a large group of patients with myalgia in whom extensive investigation fails to reveal an underlying cause. In such cases diffuse generalized muscle pain is usually the dominant feature. The pain is frequently focused on the lumbar and cervical regions and is more or less continuous at rest and during activity. Muscles may be tender to palpation. Various diagnoses are entertained in this clinical setting. “Fibromyalgia” is currently popular.
19.4. Central nervous system conditions 19.4.1. Stiff-person syndrome (SPS) This condition presents with muscle stiffness and axial rigidity due to continuous motor unit discharge in paraspinal (particularly thoracolumbar), abdominal wall and proximal leg muscles. Early complaints of stiffness, particularly during movement and often limiting the range of movement, may suggest a musculoskeletal disorder. As the condition evolves, the muscle rigidity and stiffness increases, producing an exaggerated lumbar lordosis and board-like rigidity of the abdominal wall. Prolonged spasms are superimposed on the truncal and leg rigidity increasing the muscle stiffness. These multisegmental spasms involve the lower trunk and legs and are a characteristic finding. The spasms are stimulus-sensitive, occurring in response to touch, noise and unexpected stimuli. Enhanced cutaneomuscular or exteroceptive reflexes contribute to generation of the spasms and demonstration this type of reflex activity is considered diagnostic of SPS (Meinck and Thompson, 2002). The continuous motor unit activity persists in all postures and disappears during sleep. There is evidence to suggest that the SPS has an autoimmune etiology. Antibodies to glutamic acid decarboxylase (GAD) are found in at least 60% of cases. Organspecific antibodies are detected against pancreatic islet
MUSCLE CRAMP SYNDROMES cells (60%), gastric parietal cells (50%) and thyroid microsomes (40%) and autoimmune endocrinopathies are present in around 20% of cases (Meinck and Thompson, 2002). Oligoclonal bands are found in the spinal fluid in 50% of cases (Meinck and Thompson, 2002). A paraneoplastic SPS in women with breast cancer is associated with anti-amphiphysin antibodies (Folli et al., 1993) and anti-GAD antibodies (Rosin et al., 1998). The role of these antibodies has been the subject of debate, particularly in light of the pathological findings in some cases of SPS of changes consistent with a chronic immune-mediated encephalomyelitis (Meinck and Thompson, 2002). In a recent study, the passive transfer of anti-amphiphysin antibodies to rats resulted in the development of an “SPS-like” illness with immunoglobulin fixation in the central nervous system (Sommer et al., 2005). These findings and the pathology support an immunomodulatory approach to the treatment of SPS. High-dose intravenous immunoglobulin (Dalakas et al., 2001), pulse methyl prednisolone and maintenance corticosteroids (Meinck and Thompson, 2002) and plasma exchange (Brashear and Phillips, 1991) have been reported to be of benefit.
19.4.2. Tetanus Tetanus produces spasms superimposed on generalized rigidity of axial and cranial muscles. Early clinical features may include focal muscle stiffness affecting the jaw (lockjaw), face (risus sardonicus) or a limb.
19.4.3. Basal ganglia syndromes Dystonic cramps and spasm are not uncommon in untreated Parkinson’s disease and are increasingly recognized during “off-period” motor fluctuations in established treated Parkinson’s disease. In primary dystonia, muscle tone increases during movement and subsides with rest. The increase in muscle tone is accompanied by abnormal dystonic postures with superimposed muscle spasms. These spasms and the abnormal postures are often misinterpreted as cramps. Indeed, the commonest form of focal limb dystonia is referred to as “writer’s cramp”.
19.4.4. Corticospinal syndromes Occasionally the velocity dependent increase in tone in an upper motor neuron syndrome may give rise to a “catch” or a sensation of stiffness or spasm during movement.
395
19.4.4.1. Tonic spasms, seizures and paroxysmal dyskinesias Tonic spasms in multiple sclerosis induced by movement or hyperventilation may produce complaints of cramps. Tonic spasms are recurrent stereotyped attacks of painless abnormal posturing of one side of the body. The episodes are brief, lasting a few seconds, and often recur frequently. Tonic seizures also produce similar brief spasms and posturing of a limb. Paroxysmal dyskinesias may present as brief episodes of muscle spasm. The face, arm and leg are affected, usually in a stereotyped pattern. The characteristics of the involuntary movement are those of dystonia more than chorea. These movements often develop at the onset of sudden movement. Pain is not a feature. 19.4.4.2. Restless legs Occasionally the restless legs syndrome is confused with nocturnal physiological cramps. A careful history will reveal the presence of unpleasant sensations felt deep within the legs, particularly between the knee and ankle, beginning a short time after lying in bed, rather than painful cramps. These sensations are accompanied by an irresistible urge to move the legs. Often this sensation is so intense the patient gets out of bed and walks around. The latter behavior may be mistaken for the need to stand and straighten a leg to “break” a cramp.
19.5. Concluding remarks Since many diseases of diverse etiologies can produce muscle cramps it is necessary to guide and focus investigation of cramp syndromes by a careful history and examination. Signs of a myopathy, neuropathy or other neurological cause provide clear direction for investigation and diagnosis. It is important to recognize the clinical characteristics of benign cramps as these are the most important clue in identifying “benign” cramps that may be associated with many systemic diseases.
References Bertolasi L, De Grandis D, Bongiovanni LG, et al. (1993). The influence of muscular lengthening on cramps. Ann Neurol 33: 176–180. Brashear HR, Phillips LH (1991). Autoantibodies to GABAergic neurons and response to plasmaparesis in stiff man syndrome. Neurology 41: 1588–1592. Brody I (1969). Muscle contracture induced by exercise. A syndrome attributable to decreased relaxing factor. New Engl J Med 281: 187–192. Brunt ERP, van Weerden TW (1990). Familial paroxysmal kinesigenic ataxia and continuous myokymia. Brain 113: 1361–1382.
396
P. D. THOMPSON
Burns RJ, Bretag AH, Blumbergs PC, et al. (1994). Benign familial disease with muscle mounding and rippling. J Neurol Neurosurg Psychiatry 57: 344–347. Chiba S, Saitoh M, Hatanaka Y, et al. (1999). Autosomal dominant muscle cramp syndrome in a Japanese family. J Neurol Neurosurg Psychiatry 67: 116–119. Cruccu G, Inghilleri M, Berardelli A, et al. (1994). Pathophysiology of hemimasticatory spasm. J Neurol, Neurosurg Psychiatry 57: 43–50. Dalakas MC, Fujii M, Li M, et al. (2001). High dose immune globulin for the stiff person syndrome. New Engl J Med 345: 1870–1876. Denny-Brown D, Foley DM (1948). Myokymia and the benign fasciculation of muscular cramps. Trans Assoc Am Physicians 61: 88–96. Folli F, Solimena M, Cofiell M, et al. (1993). Autoantibodies to a 128kD synaptic protein in three women with the stiff man syndrome and breast cancer. New Engl J Med 328: 546–551. Gospe SMJr, Lazaro RP, Lava NS, et al. (1989). Familial Xlinked myalgia and cramps: a nonprogressive myopathy associated with a deletion in the dystrophin gene. Neurology 39: 1277–1290. Hahn AF, Parkes AW, Bolton CF, et al. (1991). Neuromyotonia in hereditary motor neuropathy. J Neurol Neurosurg Psychiatry 54: 230–235. Hart IK, Maddison P, Newsom-Davis J, et al. (2002). Phenotypic variants of autoimmune peripheral nerve hyperexcitability. Brain 125: 1887–1895. Hudson AJ, Brown WF, Gilbert JJ (1978). The muscular pain–fasciculation syndrome. Neurology 28: 1105–1109. Isaacs H (1964). A syndrome of continuous muscle-fibre activity. J Neurol Neurosurg Psychiatry 24: 319–325. Jusic A, Dogan S, Stojanovic V (1972). Hereditary persistent cramps. J Neurol Neurosurg Psychiatry 35: 379–384. Karpati G, Charuk J, Carpenter S, et al. (1986). Myopathy caused by a deficiency of Caþþ adenine triphosphatase in sacroplasmic reticulum (Brody’s disease). Ann Neurol 20: 38–49. Kiernan MC, Hart IK, Bostock H (2001). Excitability properties of motor axons in patients with spontaneous motor unit activity. J Neurol Neurosurg Psychiatry 70: 56–64. Lazaro RP, Rollinson RD, Fenichel GM (1981). Familial cramps and muscle pain. Arch Neurol 38: 22–24. Maddison P, Newsom-Davis J, Mills KR (1999). Strength duration properties of peripheral nerve in acquired neuromyotonia. Muscle Nerve 22: 823–830. Mastaglia FL, Laing NG (1996). Investigation of muscle disease. J Neurol Neurosurg Psychiatry 60: 256–274.
Meinck HM, Thompson PD (2002). Stiff man syndrome and related conditions. Mov Disord 17: 853–866. Mertens HG, Zschocke S (1965). Neuromyotonia. Klin Wochenschr 43: 917–925. Newsom-Davis J, Mills KR (1993). Immunological associations of acquired neuromyotonia (Isaac’s syndrome). Brain 116: 453–469. Nicole S, Davoine CS, Topaloglu H, et al. (2000). Perlecan, the major proteoglycan of basement membranes, is altered in patients with Schwartz–Jampel syndrome (chondrodystrophic myotonia). Nat Genet 26: 480–483. Norris FHJr, Gasteiger EL, Charfield PO (1957). An electromyographic study of induced and spontaneous muscle cramps. Electroencephalogr Clin Neurophysiol 9: 139–147. Ricker K, Moxley FT, Rohkamm R (1989). Rippling muscle disease. Arch Neurol 46: 405–408. Rosin L, DeCamilli P, Butler M, et al. (1998). Stiff man syndrome in a woman with breast cancer. Neurology 50: 94–98. Sanchez-Arjona MB, Rodriguez-Uranga JJ, Giles-Lima M, et al. (2005). Spanish family with myalgia and cramps syndrome. J Neurol Neurosurg Psychiatry 76: 286–289. Satoh A, Tsujihata M, Yoshimura T, et al. (1983). Myasthenia gravis associated with Satoyoshi syndrome: muscle cramps, alopecia and diarrhoea. Neurology 33: 1209–1211. Schwartz O, Jampel RS (1962). Congenital blepharophimosis associated with a unique generalised myopathy. Arch Ophthalmol 68: 52–57. Sommer C, Weishaupt A, Brinkhoff J, et al. (2005). Paraneoplastic stiff-person syndrome: passive transfer to rats by means of IgG antibodies to amphiphysin. Lancet 365: 309–320. Tahmoush AJ, Alonso RJ, Tahmoush GP, et al. (1991). Cramp-fasciculation syndrome: a treatable hyperexcitable peripheral nerve disorder. Neurology 41: 1021–1024. Thompson PD (2001). The shift man syndrome and related disorders. Parkinsonism and Related Disorders 8: 147–153. Thompson PD, Carroll WM (1983). Hemimasticatory spasm: a peripheral paroxysmal cranial neuropathy? J Neurol Neurosurg Psychiatry 46: 274–276. Torbergson T (1975). A family with hereditary myotonia, muscular hypertrophy and increased muscular irritability distinct from myotonia congenita Thomsen. Acta Neurol Scand 51: 225–232. Vorgerd M, Bolz H, Patzold T, et al. (1999). Phenotypic variability in rippling muscle disease. Neurology 52: 1453–1459. Wallis WE, Van Poznak A, Plum F (1968). Generalised muscular stiffness, fasciculations and myokymia of peripheral nerve origin. Arch Neurol 21: 270–289.
Handbook of Clinical Neurology, Vol. 86 (3rd series) Myopathies F. L. Mastaglia, D. Hilton-Jones, Editors # 2007 Elsevier B. V. All rights reserved
Chapter 20
Miscellaneous myopathies DAVID HILTON-JONES* Muscular Dystrophy Campaign, Muscle and Nerve Centre, Radcliffe Infirmary, Oxford, UK
20.1. Introduction
20.2.1. Celiac disease
Quite simply, this chapter discusses those conditions which do not fit readily into any of the other major chapters. It covers acquired and inherited disorders, some common, some vanishingly rare. Chronic fatigue syndrome is included, although there is little convincing evidence of primary muscle dysfunction.
This is an inflammatory disorder of the small intestine, characterized by loss of villous height and crypt hypertrophy, which leads to malabsorption. In early childhood it typically presents with failure to thrive, weight loss and abdominal distension. In older children it may present with growth retardation, or anemia (iron-deficient) due to malabsorption. In adults the commonest presentations are iron-deficiency anemia (which frequently occurs in the absence of intestinal symptoms), and bowel symptoms (abdominal discomfort, bloating, excess wind, altered bowel habit) that are often misdiagnosed as being due to irritable bowel syndrome (Jewell, 2003). The cause is sensitivity to gliadin in wheat (and similar compounds in rye and barley) and it is associated with circulating antibodies to gliadin and endomysium. It is strongly associated with the haplotype HLA B8DR3-DQ2, with over 90% of patients having DQ2 (compared with about 30% in the general population). The most commonly reported neurological associations with celiac disease include cerebellar ataxia and neuropathy, with only a few reports of myopathy (Hadjivassiliou et al., 1997; 2002). Such neurological involvement could arise either as a consequence of malabsorption or as part of the immune diathesis. In many of the (relatively few) reported cases it is impossible to be certain which is the more relevant mechanism.
20.2. Malabsorption and deficiency myopathies Several issues contribute to make this a confusing area. Most malabsorption syndromes are not selective and can lead to deficiency of more than one nutrient, not all of which may be assayed. Central nervous system and peripheral nerve involvement are more common than skeletal muscle involvement, and it may be difficult to dissect the specific causes of weakness and myopathological abnormalities. If improvement occurs following therapy, it may be impossible to distinguish between improvement due to treatment of the underlying disorder (e.g. celiac disease by exclusion diet) and that due to specific nutrient therapy (e.g. vitamin E supplementation). Furthermore, skeletal muscle involvement may be a direct result of the primary disease process rather than secondary to its consequences — thus in celiac disease myositis may be a consequence of the underlying immune diathesis rather than being secondary to the effects of malabsorption. The most clearly defined nutritional myopathy is that associated with osteomalacia — disorders of vitamin D and calcium metabolism are discussed elsewhere (Chapter 17). This section will deal with malabsorption syndromes, of which celiac disease is the most prevalent, and vitamin E and selenium deficiency.
20.2.1.1. Myopathy and celiac disease A handful of reports have described an association between celiac disease and myopathy. The most clearly defined is myopathy due to osteomalacia secondary to malabsorption. This is usually associated with bone pain and there is an excellent response to treatment with vitamin D, calcium and a gluten-free diet (Byrne et al., 2002;
*Correspondence to: David Hilton-Jones MD, FRCP, FRCPE, Clinical Director, Muscular Dystrophy Campaign, Muscle and Nerve Centre, Radcliffe Infirmary, Woodstock Road, Oxford, OX2 6HE, UK. E-mail:
[email protected], Tel: þ44-1865-224891, Fax: þ44-1865-790493.
398
D. HILTON-JONES
Jain et al., 2002; Wong et al., 2002; Kozanoglu et al., 2005). Bowel symptoms may be minimal or absent. A few cases have been described with an inflammatory myopathy and some reports have distinguished between inclusion-body myositis (Hadjivassiliou et al., 1997; Williams et al., 2003; Kleopa et al., 2005), dermatomyositis (Marie et al., 2001) and polymyositis (Henriksson et al., 1982; Evron et al., 1996). However, none has studied the myositis in sufficient immunopathological detail to be certain of the precise classification. In most of these cases, although the patient has had some bowel symptoms, there has been little evidence of significant malabsorption. Exceptions include a patient shown to have vitamin E deficiency, although the authors concluded that it was probably not contributory (Kleopa et al., 2005). There have been only a few reports describing the response of such inflammatory myopathies to treatment. A patient with an inclusion-body-like myopathy, who also had evidence of involvement of the cerebellum and optic and peripheral nerves, with documented vitamin E deficiency, responded over a few months to a gluten-free diet and vitamin E supplementation (Kleopa et al., 2005). In another patient polymyositis, associated with arthritis and proteinuria, responded to a gluten-free diet (Evron et al., 1996). Myopathy of an undetermined type in a child resolved on a gluten-free diet (Hardoff et al., 1980). On the basis of these few cases reports it is suggested that myositis may be associated with celiac disease and that it is more likely to reflect the immune diathesis than being secondary to malabsorption. It is associated with the presence of antigliadin antibodies, which appear to be more sensitive to gluten-sensitive neurological dysfunction than endomysial antibodies, although doubts remain about their specificity (Hadjivassiliou et al., 2002). Many questions remain unanswered. If there is indeed an associated myositis, what are the immunopathological characteristics? What is the target antigen? Is treatment with a gluten-free diet sufficient? Given that antigliadin antibodies are non-specific, and may be seen in the general population, is it helpful also to look at the HLA pattern in affected individuals? Further studies to confirm that gluten sensitivity, rather than the consequences of malabsorption, is indeed a cause of neurological illness (Hadjivassiliou et al., 2002) are required. 20.2.2. Other malabsorption syndromes Whatever the cause of malabsorption, the major cause of myopathy is osteomalacia (see chapter 17). Hypokalemia can also present with weakness, either persistent
or fluctuating, and rarely may precipitate rhabdomyolysis. In this form of secondary hypokalemic myopathy respiratory muscle involvement may occur, unlike in primary hypokalemic periodic paralysis when it is very rare. 20.2.3. Vitamin E and selenium deficiency Researchers are continuously on the lookout for animal models of human disease. Vitamin E deficiency therefore presents something of a paradox in that there is a huge veterinary literature covering vitamin E-deficiency myopathy (often combined with selenium deficiency), but virtually no convincing reports of an equivalent human syndrome. Vitamin E-deficiency myopathy is seen in many animal species, both domestic and wild, and in the former has serious economic implications. The typical appearance is of a necrotizing myopathy. Vitamin E deficiency involves the central nervous system (CNS; e.g. ataxia, retinitis pigmentosa) (Aslam et al., 2004) and peripheral nerves (Puri et al., 2005), and it is possible that some of these more central features may mask the symptoms and signs of skeletal muscle involvement. Thus, in one report of four patients with vitamin E deficiency secondary to a chronic cholestatic syndrome, although myopathological abnormalities were observed, it was felt unlikely that they contributed significantly to the clinical presentation, which was dominated by CNS features (Neville et al., 1983). An inclusion-body myositis-like syndrome with vitamin E deficiency was noted above, but again it was felt unlikely that the vitamin E deficiency was of relevance (Kleopa et al., 2005). The case most frequently cited as representing a vitamin E-deficient myopathy involved a 7- year-old boy with severe malabsorption from birth (Tomasi, 1979). He presented with a neuromuscular syndrome with progressive external ophthalmoplegia, proximal weakness, peripheral neuropathy, and Babinski signs. Muscle biopsy showed type 2 fiber atrophy. His vitamin E level was very low. There was improvement, but not resolution of symptoms or signs, following vitamin E therapy. It is impossible to be certain to what extent myopathy, as opposed to neuropathy, contributed to the clinical picture. The muscle biopsy findings were non-specific, and not typical of changes seen in vitamin E-deficient animals with myopathy. Since 1979 there have been no more-convincing publications describing human vitamin E-deficiency. Selenium is an essential trace element. As noted above, combined deficiency of selenium and vitamin E is an established cause of muscle disease in animals. In humans, selenium deficiency has been associated with a proximal, often painful, myopathy with elevation
MISCELLANEOUS MYOPATHIES of the serum creatine kinase. However, only a very small proportion of patients with selenium deficiency develop myopathy, not all of those with selenium deficiency and myopathy respond to selenium replacement, and there is clear evidence in many patients that additional factors are relevant to the myopathy. There appear to be three main conditions associated with selenium deficiency (Chariot and Bignani, 2003).
399
In brief summary, selenium deficiency should be considered in all of the above clinical settings. Low levels will be identified frequently, and should probably be treated empirically with supplementation, but only a very small proportion of patients will have related myopathic symptoms, and not all of those will respond to supplementation.
20.3. Chronic fatigue syndrome 20.2.3.1. Insufficient intake in areas with low soil selenium content Such areas include parts of China, Africa, New Zealand and Europe. The relationship with skeletal myopathic symptoms is unclear, in that selenium supplementation is not always effective, and in one study no more effective than placebo (Robinson et al., 1981). Keshan syndrome, named after the Chinese province, is an endemic cardiomyopathy associated with selenium deficiency in which skeletal muscle involvement, usually subclinical, has also been reported. There is evidence that selenium deficiency is but a cofactor to the condition and viral infection, particularly Coxsackie, is also involved (Li et al., 2000). 20.2.3.2. Parenteral or enteral nutrition, or malabsorption There have been occasional reports of myopathy in patients with selenium deficiency secondary to enteral and parenteral nutrition, and those with malabsorption. Selenium deficiency is common in patients receiving parenteral nutrition, despite selenium supplementation, but even when severe may not be associated with cardiac or skeletal myopathy (Rannem et al., 1995), all suggesting that factors other than just selenium deficiency must be involved. Chariot and Bignani (2003) identified 14 articles describing 20 patients with selenium-deficient myopathy, typically causing proximal weakness with pain and tenderness and elevation of serum creatine kinase. Myopathological changes were non-specific. Symptoms responded to selenium supplementation with a median delay of 4 weeks. 20.2.3.3. Chronic conditions associated with oxidative stress such as chronic alcoholism and HIV infection Selenium deficiency is common in both of these disorders, but its precise relationship to symptomatology is unclear. In one study of alcoholic patients there was a significant association between low selenium levels and skeletal myopathy (Ward and Peters, 1992). In HIV, low selenium levels are an independent predictor of mortality (Baum et al., 2000), and myopathy, whether HIV or zidovudine-related, is commoner in those with marked selenium deficiency (Chariot et al., 1997).
Chronic fatigue syndrome (CFS) remains a controversial area, fuelled in large part by patient support groups and other interested parties (e.g. Gulf War syndrome campaigners). Recent letters to the lay press from such organizations bemoan the lack of research, and in particular financial support for such research from government agencies. At the time of writing an electronic literature search revealed 3025 papers on CFS, belying a lack of effort on behalf of the research community. Campaign groups repeatedly state that many doctors “deny” the existence of the condition and believe that it is “all in the mind”, but few if any publications proposing such views are ever cited. The sterile argument of whether it is a “psychological” or “physical” illness is again one voiced by lay organizations rather than the medical fraternity. For an excellent and succinct review see Sharpe (2003). Although numerous research publications, often of extremely poor quality, have reported “abnormalities” in many physical areas (e.g. central and peripheral nervous system, skeletal muscle, circulation, haematological, immune, metabolic), none have shown a consistent change that provides a rational explanation for the condition. Recent literature has reported altered gene expression in peripheral blood mononuclear cells in patients with CFS compared with healthy controls (Grans et al., 2005; Kaushik et al., 2005). One study looked at exercise responsive genes in peripheral blood before and after exercise challenge, but the study was restricted to females (Whistler et al., 2005). It remains to be seen whether any consistent results are obtained. Whilst many studies have shown features indicative of stress and emotional disorder (e.g. criteria for depression and anxiety disorders), leading to the proposal that CFS is a somatization disorder, they are clearly an inadequate explanation of the illness in many patients. With respect to skeletal muscle, myalgia is a frequent but not invariable complaint. Patients frequently equate their fatigue with a sense of weakness, but (by definition) objective weakness is never present. Some early studies purported to show evidence of metabolic dysfunction in skeletal muscle, but failed to take into account the normal biochemical response of muscle to inactivity. Similarly, reports of pathological changes
400
D. HILTON-JONES
relating to fiber type and mitochondrial distribution have not been substantiated. Recent studies have failed to show any evidence of physiological or metabolic dysfunction in the skeletal muscle of patients with CFS, other than changes that can be attributed to inactivity (McCully et al., 2004). The main conclusion is that in CFS there is altered central activation, and a dysfunction of effort sense mechanisms (Sacco et al., 1999; Schillings et al., 2004; Wallman et al., 2004). In summary, there is no evidence that there is any primary pathological process within skeletal muscle in patients with CFS. However, it must be remembered that many neuromuscular disorders, perhaps most notably myasthenia gravis, enter into the differential diagnosis of CFS and myologists will frequently be asked to assess such patients to exclude specific entities. It must also be remembered that electromyography and muscle biopsy frequently produce false-positive results, and that there is no clearly defined upper limit of the “normal” serum creatine kinase level. Indiscriminate use of such tests can compound what is often a difficult management problem. The only specific therapeutic options that have been shown to be of benefit, in some but not all CFS patients, are cognitive behavioral therapy, antidepressants, and the use of a graded exercise program. Muscle specialists may be able to offer advice with respect to the last.
20.4. Amyloid myopathy Amyloidosis is characterized by the deposition of abnormal protein fibrils. Although a wide variety of proteins (about 20) are involved, and the different forms of amyloidosis are defined by the major protein constituent of the fibrils, amyloid fibrils are of similar structure and physiological and chemical behavior. The common structure involves b-pleated sheets. They are insoluble and resistant to proteolysis. Amyloid stains pink with haematoxylin and eosin (and is easily missed unless specifically considered), but with Congo red produces characteristic apple-green birefringence when viewed under polarized light (Fig. 20.1). Many clinical disorders are known to be associated with amyloidosis and clinically silent amyloid deposits are a normal part of the aging process in several tissues. Neurologists are familiar with a number of conditions in which there is localized deposition of amyloid, including Alzheimer’s disease, cerebral amyloid angiopathy and inclusion body myositis (IBM). With respect to IBM (see chapter 13) there is increasing evidence that the primary pathological process involves degenerative changes, which includes amyloid deposition, and that the inflammatory changes
Fig. 20.1. Amyloid myopathy. Muscle biopsy viewed under polarized light shows characteristic apple-green birefringence.
are secondary rather than primary (Askanas and Engel, 2003). There are three main forms of systemic amyloidosis: Reactive systemic (AA) amyloidosis is seen in association with chronic inflammatory disorders (e.g., rheumatoid arthritis) and chronic infections (e.g., bronchiectasis). It is not associated with myopathy. AL amyloidosis is characterized by fibrils derived from monoclonal immunoglobulin light chains (k and l) and is seen in association with dyscrasia of B-lymphocytes (“benign” monoclonal gammopathy, multiple myeloma, malignant lymphoma and macroglobulinemia). The commonest association is with otherwise isolated monoclonal gammopathy. Occasionally, deposition of AL amyloid may be the first and only clinical evidence of the dyscrasia. Diagnosis can be difficult. Urine and serum electrophoresis may fail to identify a paraprotein in up to 10% of patients with AL amyloid, the diagnosis only
MISCELLANEOUS MYOPATHIES being reached after more detailed assessment. There is potential for confusion with inherited forms of amyloidosis and it is essential to “type” the specific amyloid fibril protein (Pepys and Hawkins, 2003). This is the form of amyloidosis most frequently associated with myopathy. Hereditary systemic amyloidosis is rare but has been associated with myopathy. Mutations, mostly autosomal dominant, in various proteins can give rise to amyloid fibril deposition. Transthyretin mutations are associated with the autosomal dominant conditions familial amyloid polyneuropathy, oculoleptomeningeal amyloidosis, and cardiac amyloidosis. Gelsolin mutations cause an autosomal-dominant syndrome characterized by cranial neuropathy, peripheral neuropathy and lattice corneal dystrophy.
20.4.1. AL amyloidosis A recent review identified 79 English-language reports of amyloid myopathy, the vast majority of which had AL amyloidosis (Chapin et al., 2005). This and many previous reports have emphasized that the diagnosis can be difficult and is often overlooked, with a plea being to consider the diagnosis and to include Congo red in the routine battery of muscle biopsy stains (Spuler et al., 1998). The classical presentation is with proximal weakness and with the muscles being enlarged, firm (“woody”) and sometimes nodular (Fig. 20.2). Passive movements may be restricted. Less commonly there is muscle atrophy, or a distal predilection. Macroglossia was seen in 27 of 79 patients and is highly suggestive of the diagnosis (Chapin et al., 2005). Dysphagia, relating in large part to the macroglossia, is relatively common. Jaw opening may be restricted. A few patients have presented with respiratory failure (Ashe et al., 1992). Cardiac involvement may be manifest as cardiac failure and is due to a restrictive cardiomyopathy. Echocardiography characteristically shows a speckled pattern. Additional features include renal, bowel, skin and peripheral nerve (including autonomic) involvement. The prognosis, relating mainly to cardiac and renal involvement, is poor and was less than 2 years from presentation to death in one review (Chapin et al., 2005). Treatment is similar to that for multiple myeloma and is based on melphalan and steroids, although recently there have been more promising results with vincristine and doxorubicin, and autologous peripheral blood stem-cell transplantation (Gono et al., 2004; Perz et al., 2004).
401
20.4.2. Hereditary amyloidosis Three forms of hereditary amyloidosis can have predominant neurological involvement. Autosomal-dominant familial amyloid polyneuropathy is usually associated with transthyretin mutations, less commonly apolipoprotein A–I mutations. Gelsolin mutations cause an autosomal-dominant disorder with lattice corneal dystrophy, cranial neuropathy and peripheral neuropathy. In all three there are varying degrees of visceral involvement and amyloid is deposited widely, in blood vessel walls and in connective tissue. As expected, the peripheral neuropathy is usually associated with distal muscle weakness and atrophy. Although there have been reports of “myopathy” in association with these familial forms of amyloidosis, most reports suggest that even when weakness is predominantly or solely proximal, the mechanism is still neurogenic (Yamada et al., 1988; Prayson, 1998; Spuler et al., 1998; Yamashita et al., 2005). Amyloid deposition is mainly within the walls of blood vessels and, to a lesser extent, in the perimysium and endomysium. A unique case described the association of sporadic inclusion body myositis (s-IBM) with homozygosity for the transthyretin Val122Ile allele (Askanas et al., 2000). The particular interest of this case lies in the possible association between a mutation associated with systemic amyloidosis, and a condition (s-IBM) characterized pathologically by intracellular amyloid deposition (Askanas and Engel, 2003). No further such cases have been reported and it remains possible that this was nothing more than a chance association, although it is postulated that the transthyretin mutation may act as a predisposing factor to s-IBM (Askanas et al., 2003).
20.5. Compartment syndromes In parts of the body muscle is contained within semi-rigid fibro-osseous compartments. In practice, the most important are the anterior tibial compartment and the volar compartment of the forearm. Less commonly involved are the thigh and upper arm. A compartment syndrome, which can be acute or chronic, develops when the pressure within the compartment is raised, causing microvascular compromise. Common causes are those that lead to muscle ischemia with trauma, in various guises, being the most important (Kostler et al., 2004). Ischemic muscle swells. Causes of ischemia and swelling include arterial insufficiency (e.g., compression due to a displaced bone fracture, limb hematoma, tourniquet pressure, penetrating injury and iatrogenic causes such as clamping during surgery), direct trauma
402
D. HILTON-JONES
Fig. 20.2. Amyloid myopathy. (A, B) Muscle hypertrophy; (C) restriction of neck flexion due to loss of compliance of the neck extensor muscles; (D) muscle hypertrophy. The enlarged quadriceps muscle has caused stretching of the skin and prominent visibility of superficial veins.
to muscle (crush injury) including sustained pressure such as body pressure on a limb in an unconscious patient, and drugs which can cause rhabdomyolysis (e.g., heroin, alcohol). Within a rigid compartment, swelling leads to a rapid rise in pressure which further impedes capillary flow and thus exacerbates the ischemia, leading to a vicious cycle of worsening. Compression of nerves within the compartment leads to weakness and sensory disturbance, which can become permanent if the nerve infarcts (e.g., peroneal nerve in the leg, and anterior interosseous, median and ulnar nerves in the forearm).
The contracture due to fibrosis of the damaged muscle, and sensorimotor disturbance due to nerve injury, is referred to as Volkmann’s ischemic contracture and is seen most frequently affecting the long finger flexors following a supracondylar fracture of the humerus. The main clinical features are pain (often out of proportion to the injury), which is exacerbated by stretching the muscle, weakness, and sensory symptoms, but usually without typical distal signs of limb ischemia such as reduced pulses or impaired cutaneous circulation. In the unconscious patient, the very young and the elderly these observations may easily be missed.
MISCELLANEOUS MYOPATHIES An important concept is the perfusion pressure (with a close analogy with intracranial pressure observations). The Dp is derived from the diastolic blood pressure minus the compartment pressure. When less than 30, serious sequelae are likely. If the diagnosis is evident clinically it may not be necessary or helpful to measure the compartment pressure. If there is diagnostic doubt, and when it is felt appropriate to monitor the situation rather than proceeding directly to surgical intervention, then monitoring the compartment pressure is valuable. However, there is considerable variation in surgical practice and in the availability of pressure-measuring equipment (Williams et al., 1998). Management consists of removing external causes of compression, maintaining blood (perfusion) pressure, additional oxygen and fasciotomy of the relevant compartment. The term chronic compartment syndrome is used for a condition in which physical exercise, either relating to normal daily activities or, more typically, to sporting activity, leads to the development of pain, with or without paresthesiae, relating to a muscle compartment. It may occur spontaneously, in response to unaccustomed exercise, or develop as a consequence of previous bone fracture. Most commonly it involves the leg (“shin splints”) but may also involve the forearm. The term is probably overused and confirmation of the diagnosis rests on pressure measurements and, arguably, relief of symptoms by fasciotomy (Turnipseed, 2002; Fraipont and Adamson, 2003; Shah et al., 2004).
20.6. Polymyalgia rheumatica Despite its name and the patient’s (and sometimes the physician’s) perception that the problem is in the muscles, polymyalgia rheumatica (PMR) is not primarily a myopathy. In its classic form it really should not be confused with a myopathy, even myositis, but the differential diagnosis includes several other rheumatological disorders. The etiology is unclear, as is its relationship with giant cell arteritis (Salvarani et al., 2002; Cantini et al., 2004). The typical musculoskeletal features of the condition can be attributed to synovitis affecting predominantly the proximal joints (Salvarani et al., 2004). The presence or absence of significant pathological changes in skeletal muscle is controversial. A recent study, in just two patients, reported the presence of IgG, IgA and fibrinogen deposits in the perifascicular area of the perimysium (Shintani et al., 2002) which the authors considered significant, whereas many other studies have reported either normal muscle or changes that at best can be considered non-specific (e.g., group atrophy,
403
angulated fibers, moth-eaten appearance, fiber splitting, type 1 or type 2 fiber atrophy). The major clinical features of PMR are incorporated into established diagnostic criteria (Table 20.1). The criteria of Bird (Bird et al., 1979) have been shown to have a diagnostic sensitivity of 99.5%, and those of Hunder (Chuang et al., 1982) a sensitivity of 93.3% (Bird et al., 2005). Onset under the age of 50 years is rare, and extremely rare under the age of 45 years. There is a female preponderance. The presentation is often acute and the major symptoms fully established within a few weeks. Pain and stiffness is often initially more marked around the shoulder than the pelvic girdle, but both are involved. Early morning stiffness, which can be profound, is marked. There is systemic upset with malaise, fatigue, anorexia, weight loss, night sweats, fever and depression. Peripheral joint involvement and carpal tunnel syndrome are under-recognized features. Most patients show an acute-phase response with substantial elevation of the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), but up to 10% of patients may have normal results (Salvarani et al., 2005). A mild hypochromic normocytic anemia is common, as is slight elevation of the serum alkaline phosphatase and g-glutamyl transferase. Serum creatine kinase is not elevated. Electromyography and muscle biopsy, as noted, are either normal or show non-specific abnormalities. As with other rheumatological disorders, PMR is in many patients a self-limiting disease and treatment Table 20.1 Diagnostic criteria for polymyalgia rheumatica (PMR) Bird (Bird et al., 1979) Bilateral shoulder pain/stiffness Duration onset <2 weeks Initial ESR >40mm/h Stiffness >1 hour Age >65 years Depression and/or weight loss Bilateral upper arm tenderness Probable PMR ¼ 3 or more of above Hunder (Chuang et al., 1982) Age >50 years Bilateral aching/tenderness for 1 month or more of: Neck or torso Shoulders or upper arms Hips or thighs ESR >40mm/h Exclusion of other diagnoses Definite PMR ¼ all of the above ESR ¼ erythrocyte sedimentation rate
404
D. HILTON-JONES
can be withdrawn after 2 or 3 years, although in others longer-term treatment is required. In a few patients nonsteroidal anti-inflammatory drugs may control symptoms adequately but, in large part because of the anxiety associated with the link with giant cell arteritis and also the often dramatic therapeutic efficacy of steroids, in most patients prednisolone is the choice of treatment from diagnosis. Numerous steroid regimens have been used but most clinicians use daily prednisolone. Given the age and sex distribution of the PMR population, it is not surprising that steroid-induced osteoporosis and other steroid-related side effects are common. Osteoporosis prophylaxis seems reasonable, but between and even within different countries there remains debate as to the appropriate approach — local guidelines should be consulted. Attempts to use “steroid-sparing” drugs such as azathioprine and methotrexate have met with mixed success (De Silva and Hazleman, 1986; Caporali et al., 2004). The response to prednisolone is usually rapid and often dramatic. The dose is then tapered to find the minimum dose required to control symptoms, based more on clinical response than laboratory measures such as the ESR. Many patients can withdraw treatment after 2 or 3 years — there is a danger of continuing treatment unnecessarily. As has been pointed out, anxieties about the association with giant cell arteritis and sudden blindness, and forgetting the commonness of non-specific middle-aged muscle ache, has led to overdiagnosis and overtreatment (Mowat, 2003).
20.7. Myositis ossificans An alternative term is heterotopic calcification, and can be defined as the development of lamellar bone at an inappropriate site, in this case skeletal muscle. Two major variants exist which although very different in their etiology share similar pathological features. Despite their names, there is no evidence of true myositis. 20.7.1. Localized myositis ossificans This is an acquired disorder associated with muscle trauma. Typically a single site is involved and the problem is not recurrent. The trauma may be external, and penetrating or non-penetrating, be surgical, or relate simply to “muscle strain”. With respect to the latter, there is a large literature relating to localized myositis ossificans in athletes, most commonly of the quadriceps muscle. Recurrence is rare, but has been reported following surgery and in an athlete (Miller et al., 2006). Minor degrees of ectopic bone formation following injury are probably relatively common if sought (Ryan
et al., 1991) and, for example, chest X-rays may show asymptomatic bone formation in shoulder girdle muscles relating to previous trauma. The characteristic clinical features include an initial localized area of swelling and tenderness, which over several weeks is replaced by a hard, sometimes painful, mass. Radiographic evidence of bone formation is demonstrable within 1–2 months. Small lesions may resolve spontaneously, or become smaller and painless so that no further action is required. Much less commonly a large area of ossification may inhibit movement, as well as sometimes being painful, in which case surgical excision may be appropriate. 20.7.2. Myositis ossificans progressiva It is unclear whether this is a single disease or a group of closely related disorders. The name fibrodysplasia ossificans progressiva (FOP) is preferred by some. There remains controversy as to the significance of recent reports relating to putative causative mutations in the noggin gene. Muscle involvement develops in the first decade of life, often in the first couple of years. The neck and shoulder muscles tend to be involved first, the pelvic and lower limb muscle later. Trauma may precipitate an episode. An area of muscle becomes hot, swollen and painful and then, as in the localized form, there is replacement by a hard area of bone deposition. Progressive muscle involvement leads to increasing disability and immobility due to restriction of muscle and joint movement and most patients are wheelchair-bound by early adult life. Ulceration and secondary infection of ossified muscle may occur. The condition is associated with a range of congenital abnormalities including absence or smallness of the digits (including digits with a single phalanx), clinodactyly, malformed cervical vertebrae and femoral necks, deafness, baldness, abnormalities of the teeth and ear lobules, hypogonadism and mild mental retardation. Although many cases are sporadic, there is evidence of autosomal-dominant inheritance in some families, with variable expressivity. Linkage studies have suggested genetic heterogeneity, with linkage to 4q27– q31 and 17q21–q22 (Feldman et al., 2000; Lucotte et al., 2000). In four Spanish patients from three families, three heterozygous mutations were reported in the noggin gene (Semonin et al., 2001), but another group suggested that the results were due to PCR errors (Xu et al., 2002). Subsequently a further mutation in the noggin gene has been reported in a French family (Fontaine et al., 2005). The noggin protein is an antagonist of a bone-inducing morphogen, bone morphogenetic protein4 (BMP 4), which has been shown to be
MISCELLANEOUS MYOPATHIES overexpressed by lymphocytes in patients with fibrodysplasia ossificans progressiva (Shafritz et al., 1996). No effective treatment has yet been demonstrated. Surgical excision of lesions is not usually appropriate because of the widespread and recurrent nature of the problem. Many drugs have been tried, all either unsuccessfully or with evidence of only very limited benefit (e.g., steroids, T3, EDTA, etidronate). A single report suggested that bone marrow transplantation appeared to prevent progression (Spruce et al., 1983), but its efficacy has not been substantiated.
20.8. Tumors of muscle Both primary and secondary tumors of muscle are rare, which is perhaps surprising given the relative bulk of muscle within the body, its vascularity, and its several components (e.g., muscle, connective tissue, vascular elements, nerves). Furthermore, such tumors rarely seem to come the way of myologists. Tumors are most likely to present as a single focal lesion, only very rarely with more diffuse involvement that might cause diagnostic confusion with systemic myopathies. Rhabdomyomas in the heart are hamartomatous lesions, typically associated with tuberous sclerosis. Extracardiac rhabdomyomas can be divided into three categories, adult, fetal and genital (sarcoma botryoides). The adult and fetal forms have a prediction for the head and neck region and may present with aerodigestive obstruction. They are usually single, rarely multifocal (Delides et al., 2005). The classification of soft tissue sarcomas is complex and has been the subject of recent review (Fletcher et al., 2001; Massi et al., 2004). Lesions arise in the extremities or trunk wall. Prognosis is very variable and relates to the precise tumor type. Local invasion of skeletal muscle by tumor is not uncommon, for example the pectoral muscle by breast carcinoma. Although distant metastasis to skeletal muscle has been reported for virtually every known primary tumor, it is very rare. Although an early paper identified skeletal muscle metastasis in 16% of 38 cases (Pearson, 1959), the general consensus is that the incidence is less than 1% of all malignant metastases (Menard and Parache, 1991). Disorders that may initially mimic muscle tumor include abscesses, muscle herniation through fascia, and tendon rupture.
20.9. Cancer-associated myopathies Direct involvement of skeletal muscle by primary or secondary tumor is described above. In many patients with malignant disease there may be several systemic
405
factors contributing to wasting, weakness and fatigue, including cachexia, malnutrition, infection, bone and joint disease and inactivity. In many patients with cancer-associated weakness it may be unclear whether the primary cause is muscle or motor nerve dysfunction — extensive investigation, particularly invasive tests such as muscle biopsy, may be inappropriate in a terminally ill patient. This section is concerned with those myopathies that are a distant, non-metastatic, consequence of tumor. In some the cause of myopathy is specific metabolic dysfunction (e.g., electrolyte disturbance, hormone deficiency or excess); in others there is strong evidence or proof of an immune-mediated disorder (e.g., dermatomyositis, myasthenia gravis). 20.9.1. Metabolic and endocrine myopathies Both hypokalemia and hyperkalemia may cause muscle weakness, which is typically persistent but may be episodic (secondary periodic paralysis). Addison’s disease caused by adrenal gland destruction by secondary tumor can cause hyperkalemia. Tumors causing hypokalemia include aldosterone-producing adrenal adenomas (Conn’s syndrome) renin-secreting tumors, and pituitary adenomas and tumors causing ectopic adrenocorticotrophic hormone (ACTH) production (Cushing’s syndrome). Endocrine myopathies are discussed in detail in chapter 17. Functioning or non-functioning adenomas may lead to hormone excess or deficiency. Myopathy may be associated with an excess of ACTH (pituitary adenoma, ectopic production), growth hormone (pituitary adenoma), glucocorticoids (pituitary or adrenal adenoma, ectopic ACTH production), catecholamines (phaeochromocytoma), thyroxine (functional thyroid adenoma) or parathormone (parathyroid adenoma, ectopic production). Myopathy may be associated with a deficiency of anterior pituitary hormones (pituitary adenoma, craniopharyngioma, secondary pituitary tumor), or of adrenocortical hormones (Addison’s disease due to destruction of adrenal by secondary tumor). Often, the metabolic and endocrine disturbance is multifactorial and there may be uncertainty as to the principal cause of weakness (e.g., hypoadrenalism is also associated with hyperkalemia and hyponatremia). 20.9.2. Immune-mediated myopathies 20.9.2.1. Myasthenia gravis Possibly the best-defined disorder, and certainly the commonest paraneoplastic myopathy, is the association between thymoma and myasthenia gravis. Thymoma is identified in about 10% of patients with myasthenia gravis, and conversely about one-third of patients with
406
D. HILTON-JONES
thymoma develop myasthenia. Thymic hyperplasia is seen in about 75% of patients with myasthenia. Although debate continues about the precise role of thymectomy in treating myasthenia, it is perhaps somewhat curious, given that it is a paraneoplastic disorder, that removal of a thymoma is much less likely to help the myasthenia than removal of a hyperplastic gland. 20.9.2.2. Lambert–Eaton myasthenic syndrome Although a disorder of peripheral nerve function, albeit at the neuromuscular junction, Lambert–Eaton myasthenic syndrome (LEMS) is frequently initially misdiagnosed as a myopathy. It is a paraneoplastic disorder in about 60% of cases, associated in particular with small-cell lung cancer (SCLC). In a prospective series, the incidence of LEMS in patients with SCLC was about 3% (Elrington et al., 1991). Anti-voltage-gated calcium channel antibodies underlie the disease and are detectable in the majority of patients (methodological issues probably account for the apparently negative cases), whether cancer-associated or not. 20.9.2.3. Myositis Myositis may be a paraneoplastic disorder, the link being firmly established with dermatomyositis, with a less certain association with polymyositis. There have been several reports of an acute necrotizing myopathy in association with malignancy (Smith, 1969; Urich and Wilkinson, 1970; Swash, 1974), these cases being distinguished from myositis by the absence of mononuclear cell infiltrates in the muscle. However, such patients may be steroid-responsive and probably represent a form of immune-mediated idiopathic inflammatory myopathy despite the absence of inflammatory infiltrates (Bronner et al., 2003). Dermatomyositis (DM) and polymyositis (PM) are reviewed in detail elsewhere (see chapter XX). In brief, both are thought to be autoimmune disorders. Current evidence, although still much debated, suggests that in DM the efferent limb of the immune response is mediated predominantly by humoral factors, against capillaries in muscle and skin, whereas in PM the efferent limb is cell-mediated cytotoxicity, directed against muscle fibers. The afferent limb of the immune response in both disorders is less well defined, but is clearly of relevance when considering the possibility of these conditions being, at times, paraneoplastic in origin. Thus, one potential mechanism is tumor antigens causing the development of antibodies that cross-react with components in muscle, such as capillaries in DM. A major difficulty in evaluating the literature relating to the association between cancer and DM/PM is the
failure in earlier, and even some more recent papers, to distinguish between DM and PM on the basis of currently accepted diagnostic criteria. There have been innumerable case reports and a few relatively large series. In a Swedish population-based study (Sigurgeirsson et al., 1992) 39 of 396 patients with PM were diagnosed as having cancer at the time of diagnosis of PM or later, giving a relative risk of developing cancer, compared with the general population, of 1.8 in men and 1.7 in women. For DM, cancer was diagnosed in 59 of 392 patients, giving a relative risk of 2.4 in men and 3.4 in women. An analysis of the then published data, in 1994, also suggested that the association between myositis and cancer was greater for DM than PM (Zantos et al., 1994). The overall odds ratio for the association of cancer with DM was 4.4, and for PM 2.1. The temporal relationship between the diagnosis of cancer and myositis suggested a specific association between cancer and DM. For PM there was only an increased incidence of diagnosis of malignancy after diagnosis of the PM which could have reflected cancer detection bias — that is, cancer is sought because of the clinical presentation, but there is no true cause–effect relationship. In a Scottish retrospective population-based cohort study (Stockton et al., 2001) of 705 patients with DM or PM, the risk of cancer was assessed by calculating the standardized incidence ratio (SIR). The SIR was 2.1 for PM and 7.7 for DM. The excess risk of cancer was highest around the time of diagnosis and remained high in DM for at least 2 years after diagnosis. The risk was elevated for both sexes, but only significantly so for women. A pooled analysis of published national data from Sweden, Denmark and Finland identified cancer in 198 of 618 patients with DM, and in 137 of 914 patients with PM (Hill et al., 2001). It concluded that there was a strong association between DM and cancer, and a modestly increased risk of cancer in association with PM. The standardized incidence ratios (SIR) suggested that some cancers were more strongly associated with DM than others; ovarian (SIR 10.5), lung (5.9), pancreatic (3.8), non-Hodgkin lymphoma (3.6), stomach (3.5), colorectal (2.5). An earlier study had also suggested a particular association with ovarian malignancy (Cherin et al., 1993). An Australian study of biopsy-proven inflammatory myopathy produced somewhat similar results (Buchbinder et al., 2001). The standardized incidence ratio for the incidence of malignancy was 6.2 for DM, 2.0 for PM, and 2.4 for inclusion body myositis (IBM). There is little other support for an association between malignancy and IBM and, as noted above, it
MISCELLANEOUS MYOPATHIES is possible that the modest increase in PM and IBM reflects cancer detection bias. Some paraneoplastic disorders are strongly associated with a specific malignancy, such as Lambert–Eaton syndrome and small-cell lung cancer. As noted above, myositis has been associated with a very wide range of cancers, although in women gynecological malignancies may be particularly common. Another specific relationship appears to be between DM and nasopharyngeal carcinoma in Taiwan, suggesting the possibility of genetic factors influencing susceptibility (Chen et al., 2001). There is some evidence that there may be clinical and laboratory differences between those patients with cancer-associated myositis and those with primary myositis. In a study which found an association between DM, but not PM, and cancer the cancer-associated DM patients were older and had more severe muscle and skin involvement, more frequent dysphagia and diaphragmatic involvement, but less frequent extramuscular features such as arthritis, Raynaud’s phenomenon and interstitial lung disease than patients with primary myositis (Ponyi et al., 2005). Although there have been a few case reports, the general consensus is that childhood DM is only very rarely associated with malignancy. 20.9.2.4. Impact on clinical practice On available evidence, the possibility of an underlying malignancy should be suspected strongly in all patients presenting with adult-onset DM, that suspicion increasing with the patient’s age. There should be a lesser degree of suspicion for patients with PM, although some patients may be considered to be in a higher-risk group, for example smokers and patients with a history of certain malignancies known to have a familial basis (e.g., breast, ovarian, bowel). Even if initial screening is negative, there should be appropriate surveillance for at least 2 years following diagnosis of myositis. The history may provide clues; e.g., family history, smoking, change in bowel habit. It may be appropriate to supplement general physical examination with vaginal and rectal examination, but more important is appropriate further investigation which may include occult bloods and urine testing, routine blood tests, cancer-associated antigen testing and imaging. The choice of imaging will depend on clinical suspicions, availability and the advice of local imaging specialists. In general, it is appropriate to look at the chest, abdomen and, especially in women, the pelvis. The optimal approach to screening remains to be defined, but in the future may include whole-body magnetic resonance imaging (MRI), low-dose computed tomography (CT), and positron-emission tomography (PET) studies.
407
References Ashe J, Borel CO, Hart G, et al. (1992). Amyloid myopathy presenting with respiratory failure. J Neurol Neurosurg Psychiatry 55 (2): 162–165. Askanas V, Engel WK (2003). Proposed pathogenetic cascade of inclusion-body myositis: importance of amyloidbeta, misfolded proteins, predisposing genes, and aging. Curr Opin Rheumatol 15 (6): 737–744. Askanas V, Engel WK, Alvarez RB, et al. (2000). Inclusion body myositis, muscle blood vessel and cardiac amyloidosis, and transthyretin Val122Ile allele. Ann Neurol 47 (4): 544–549. Askanas V, Engel WK, McFerrin J, et al. (2003). Transthyretin Val122Ile, accumulated Abeta, and inclusion-body myositis aspects in cultured muscle. Neurology 61 (2): 257–260. Aslam A, Misbah SA, Talbot K, et al. (2004). Vitamin E deficiency induced neurological disease in common variable immunodeficiency: two cases and a review of the literature of vitamin E deficiency. Clin Immunol 112 (1): 24–29. Baum MK, Miguez-Burbano MJ, Campa A, et al. (2000). Selenium and interleukins in persons infected with human immunodeficiency virus type 1. J Infect Dis 182 (Suppl. 1): S69–S73. Bird HA, Esselinckx W, Dixon AS, et al. (1979). An evaluation of criteria for polymyalgia rheumatica. Ann Rheum Dis 38 (5): 434–439. Bird HA, Leeb BF, Montecucco CM, et al. (2005). A comparison of the sensitivity of diagnostic criteria for polymyalgia rheumatica. Ann Rheum Dis 64 (4): 626–629. Bronner IM, Hoogendijk JE, Wintzen AR, et al. (2003). Necrotising myopathy, an unusual presentation of a steroid-responsive myopathy. J Neurol 250 (4): 480–485. Buchbinder R, Forbes A, Hall S, et al. (2001). Incidence of malignant disease in biopsy-proven inflammatory myopathy. A population-based cohort study. Ann Intern Med 134 (12): 1087–1095. Byrne MF, Razak AR, Leader MB, et al. (2002). Disabling osteomalacic myopathy as the only presenting feature of coeliac disease. Eur J Gastroenterol Hepatol 14 (11): 1271–1274. Cantini F, Niccoli L, Storri L, et al. (2004). Are polymyalgia rheumatica and giant cell arteritis the same disease? Semin Arthritis Rheum 33 (5): 294–301. Caporali R, Cimmino MA, Ferraccioli G, et al. (2004). Prednisone plus methotrexate for polymyalgia rheumatica: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 141 (7): 493–500. Chapin JE, Kornfeld M, Harris A (2005). Amyloid myopathy: characteristic features of a still underdiagnosed disease. Muscle Nerve 31 (2): 266–272. Chariot P, Bignani O (2003). Skeletal muscle disorders associated with selenium deficiency in humans. Muscle Nerve 27 (6): 662–668. Chariot P, Dubreuil-Lemaire ML, Zhou JY, et al. (1997). Muscle involvement in human immunodeficiency virusinfected patients is associated with marked selenium deficiency. Muscle Nerve 20 (3): 386–389.
408
D. HILTON-JONES
Chen YJ, Wu CY, Shen JL (2001). Predicting factors of malignancy in dermatomyositis and polymyositis: a casecontrol study. Br J Dermatol 144 (4): 825–831. Cherin P, Piette JL, Herson S, et al. (1993). Dermatomyositis and ovarian cancer: a report of 7 cases and literature review. J Rheumatol 20 (11): 1897–1899. Chuang TY, Hunder GG, Ilstrup DM, et al. (1982). Polymyalgia rheumatica: a 10-year epidemiologic and clinical study. Ann Intern Med 97 (5): 672–680. De Silva M, Hazleman BL (1986). Azathioprine in giant cell arteritis/polymyalgia rheumatica: a double-blind study. Ann Rheum Dis 45 (2): 136–138. Delides A, Petrides N, Banis K (2005). Multifocal adult rhabdomyoma of the head and neck: a case report and literature review. Eur Arch Otorhinolaryngol 262 (6): 504–506. Elrington GM, Murray NM, Spiro SG, et al. (1991). Neurological paraneoplastic syndromes in patients with small cell lung cancer. A prospective survey of 150 patients. J Neurol Neurosurg Psychiatry 54 (9): 764–767. Evron E, Abarbanel JM, Branski D, et al. (1996). Polymyositis, arthritis, and proteinuria in a patient with adult celiac disease. J Rheumatol 23 (4): 782–783. Feldman G, Li M, Martin S, et al. (2000). Fibrodysplasia ossificans progressiva, a heritable disorder of severe heterotopic ossification, maps to human chromosome 4q27– 31. Am J Hum Genet 66 (1): 128–135. Fletcher CD, Gustafson P, Rydholm A, et al. (2001). Clinicopathologic re-evaluation of 100 malignant fibrous histiocytomas: prognostic relevance of subclassification. J Clin Oncol 19 (12): 3045–3050. Fontaine K, Semonin O, Legarde JP, et al. (2005). A new mutation of the noggin gene in a French fibrodysplasia ossificans progressiva (FOP) family. Genet Couns 16 (2): 149–154. Fraipont MJ, Adamson GJ (2003). Chronic exertional compartment syndrome. J Am Acad Orthop Surg 11 (4): 268–276. Gono T, Matsuda M, Shimojima Y, et al. (2004). VAD with or without subsequent high-dose melphalan followed by autologous stem cell support in AL amyloidosis: Japanese experience and criteria for patient selection. Amyloid 11 (4): 245–256. Grans H, Nilsson P, Evengard B (2005). Gene expression profiling in the chronic fatigue syndrome. J Intern Med 258 (4): 388–390. Hadjivassiliou M, Chattopadhyay AK, Davies-Jones GA, et al. (1997). Neuromuscular disorder as a presenting feature of coeliac disease. J Neurol Neurosurg Psychiatry 63 (6): 770–775. Hadjivassiliou M, Grunewald RA, Davies-Jones GA (2002). Gluten sensitivity as a neurological illness. J Neurol Neurosurg Psychiatry 72 (5): 560–563. Hardoff D, Sharf B, Berger A (1980). Myopathy as a presentation of coeliac disease. Dev Med Child Neurol 22 (6): 781–783. Henriksson KG, Hallert C, Norrby K, et al. (1982). Polymyositis and adult coeliac disease. Acta Neurol Scand 65 (4): 301–319.
Hill CL, Zhang Y, Sigurgeirsson B, et al. (2001). Frequency of specific cancer types in dermatomyositis and polymyositis: a population-based study. Lancet 357 (9250): 96–100. Jain V, Angitii RR, Singh S, et al. (2002). Proximal muscle weakness — an unusual presentation of celiac disease. J Trop Pediatr 48 (6): 380–381. Jewell D (2003). Coeliac disease. In: D Warrell, T Cox, J Firth (Eds.), Vol. 2, Oxford University Press, Oxford, pp. 585–589. Kaushik N, Fear D, Richards SC, et al. (2005). Gene expression in peripheral blood mononuclear cells from patients with chronic fatigue syndrome. J Clin Pathol 58 (8): 826–832. Kleopa KA, Kyriacou K, Zamba-Papanicolaou E, et al. (2005). Reversible inflammatory and vacuolar myopathy with vitamin E deficiency in celiac disease. Muscle Nerve 31 (2): 260–265. Kostler W, Strohm PC, Sudkamp NP (2004). Acute compartment syndrome of the limb. Injury 35 (12): 1221–1227. Kozanoglu E, Basaran S, Goncu MK (2005). Proximal myopathy as an unusual presenting feature of celiac disease. Clin Rheumatol 24 (1): 76–78. Li Y, Peng T, Yang Y, et al. (2000). High prevalence of enteroviral genomic sequences in myocardium from cases of endemic cardiomyopathy (Keshan disease) in China. Heart 83 (6): 696–701. Lucotte G, Bathelier C, Mercier G, et al. (2000). Localization of the gene for fibrodysplasia ossificans progressiva (FOP) to chromosome 17q21–22. Genet Couns 11 (4): 329–334. Marie I, Lecomte F, Hachulla E, et al. (2001). An uncommon association: celiac disease and dermatomyositis in adults. Clin Exp Rheumatol 19 (2): 201–203. Massi D, Beltrami G, Capanna R, et al. (2004). Histopathological re-classification of extremity pleomorphic soft tissue sarcoma has clinical relevance. Eur J Surg Oncol 30 (10): 1131–1136. McCully KK, Smith S, Rajaei S, et al. (2004). Muscle metabolism with blood flow restriction in chronic fatigue syndrome. J Appl Physiol 96 (3): 871–878. Menard O, Parache RM (1991). [Muscle metastases of cancers]. Ann Med Interne (Paris) 142 (6): 423–428. Miller AE, Davis BA, Beckley OA (2006). Bilateral and recurrent myositis ossificans in an athlete: a case report and review of treatment options. Arch Phys Med Rehabil 87 (2): 286–290. Mowat AG (2003). Polymyalgia and giant-cell arteritis. In: D Warrell, T Cox, J Firth (Eds.), Vol. 3, Oxford University Press, Oxford, pp. 103–106. Neville HE, Ringel SP, Guggenheim MA, et al. (1983). Ultrastructural and histochemical abnormalities of skeletal muscle in patients with chronic vitamin E deficiency. Neurology 33 (4): 483–488. Pearson CM (1959). Incidence and type of pathologic alterations observed in muscle in a routine autopsy survey. Neurology 9: 757–766. Pepys MB, Hawkins PN (2003). Amyloidosis. In: D Warrell, T Cox, J Firth (Eds.), Vol. 2, Oxford University Press, Oxford, pp. 162–173.
MISCELLANEOUS MYOPATHIES Perz JB, Schonland SO, Hundemer M, et al. (2004). Highdose melphalan with autologous stem cell transplantation after VAD induction chemotherapy for treatment of amyloid light chain amyloidosis: a single centre prospective phase II study. Br J Haematol 127 (5): 543–551. Ponyi A, Constantin T, Garami M, et al. (2005). Cancerassociated myositis: clinical features and prognostic signs. Ann N Y Acad Sci 1051: 64–71. Prayson RA (1998). Amyloid myopathy: clinicopathologic study of 16 cases. Hum Pathol 29 (5): 463–468. Puri V, Chaudhry N, Tatke M, et al. (2005). Isolated vitamin E deficiency with demyelinating neuropathy. Muscle Nerve 32 (2): 230–235. Rannem T, Ladefoged K, Hylander E, et al. (1995). The effect of selenium supplementation on skeletal and cardiac muscle in selenium-depleted patients. J Parenter Enteral Nutr 19 (5): 351–355. Robinson MF, Campbell DR, Stewart RD, et al. (1981). Effect of daily supplements of selenium on patients with muscular complaints in Otago and Canterbury. N Z Med J 93 (683): 289–292. Ryan JB, Wheeler JH, Hopkinson WJ, et al. (1991). Quadriceps contusions. West Point update. Am J Sports Med 19 (3): 299–304. Sacco P, Hope PA, Thickbroom GW, et al. (1999). Corticomotor excitability and perception of effort during sustained exercise in the chronic fatigue syndrome. Clin Neurophysiol 110 (11): 1883–1891. Salvarani C, Cantini F, Boiardi L, et al. (2002). Polymyalgia rheumatica and giant-cell arteritis. N Engl J Med 347 (4): 261–271. Salvarani C, Cantini F, Boiardi L, et al. (2004). Polymyalgia rheumatica. Best Pract Res Clin Rheumatol 18 (5): 705–722. Salvarani C, Cantini F, Niccoli L, et al. (2005). Acute-phase reactants and the risk of relapse/recurrence in polymyalgia rheumatica: a prospective followup study. Arthritis Rheum 53 (1): 33–38. Schillings ML, Kalkman JS, van der Werf SP, et al. (2004). Diminished central activation during maximal voluntary contraction in chronic fatigue syndrome. Clin Neurophysiol 115 (11): 2518–2524. Semonin O, Fontaine K, Daviaud C, et al. (2001). Identification of three novel mutations of the noggin gene in patients with fibrodysplasia ossificans progressiva. Am J Med Genet 102 (4): 314–317. Shafritz AB, Shore EM, Gannon FH, et al. (1996). Overexpression of an osteogenic morphogen in fibrodysplasia ossificans progressiva. N Engl J Med 335 (8): 555–561. Shah SN, Miller BS, Kuhn JE (2004). Chronic exertional compartment syndrome. Am J Orthop 33 (7): 335–341. Sharpe M (2003). Chronic fatigue syndrome. In: DA Warrell, TM Cox, JD Firth, et al. (Eds.), Vol. 1, Oxford University Press, Oxford, pp. 860–863. Shintani S, Shiigai T, Matsui Y (2002). Polymyalgia rheumatica (PMR): clinical, laboratory, and immunofluorescence studies in 13 patients. Clin Neurol Neurosurg 104 (1): 20–29. Sigurgeirsson B, Lindelof B, Edhag O, et al. (1992). Risk of cancer in patients with dermatomyositis or polymyositis.
409
A population-based study. N Engl J Med 326 (6): 363–367. Smith B (1969). Skeletal muscle necrosis associated with carcinoma. Journal of Pathology 97: 207. Spruce WE, Forman SJ, Blume KG, et al. (1983). Successful second bone marrow transplantation in a patient with myositis ossificans progressiva and aplastic anemia. Am J Pediatr Hematol Oncol 5 (4): 337–340. Spuler S, Emslie-Smith A, Engel AG (1998). Amyloid myopathy: an underdiagnosed entity. Ann Neurol 43 (6): 719–728. Stockton D, Doherty VR, Brewster DH (2001). Risk of cancer in patients with dermatomyositis or polymyositis, and follow-up implications: a Scottish population-based cohort study. Br J Cancer 85 (1): 41–45. Swash M (1974). Acute fatal carcinomatous neuromyopathy. Arch Neurol 30: 324. Tomasi LG (1979). Reversibility of human myopathy caused by vitamin E deficiency. Neurology 29 (8): 1182–1186. Turnipseed WD (2002). Diagnosis and management of chronic compartment syndrome. Surgery 132 (4): 613–617discussion 617–619.. Urich H, Wilkinson M (1970). Necrosis of muscle with carcinoma: myositis or myopathy? J Neurol Neurosurg Psychiatry 33: 398. Wallman KE, Morton AR, Goodman C, et al. (2004). Physiological responses during a submaximal cycle test in chronic fatigue syndrome. Med Sci Sports Exerc 36 (10): 1682–1688. Ward RJ, Peters TJ (1992). The antioxidant status of patients with either alcohol-induced liver damage or myopathy. Alcohol Alcohol 27 (4): 359–365. Whistler T, Jones JF, Unger ER, et al. (2005). Exercise responsive genes measured in peripheral blood of women with chronic fatigue syndrome and matched control subjects. BMC Physiol 5 (1): 5. Williams PR, Russell ID, Mintowt-Czyz WJ (1998). Compartment pressure monitoring —current UK orthopaedic practice. Injury 29 (3): 229–232. Williams SF, Mincey BA, Calamia KT (2003). Inclusion body myositis associated with celiac sprue and idiopathic thrombocytopenic purpura. South Med J 96 (7): 721–723. Wong M, Scally J, Watson K, et al. (2002). Proximal myopathy and bone pain as the presenting features of coeliac disease. Ann Rheum Dis 61 (1): 87–88. Xu MQ, Shore EM, Kaplan FS (2002). Reported noggin mutations are PCR errors. Am J Med Genet 109 (2): 161author reply 163–164.. Yamada M, Tsukagoshi H, Hatakeyama S (1988). Skeletal muscle amyloid deposition in AL- (primary or myelomaassociated), AA- (secondary), and prealbumin-type amyloidosis. J Neurol Sci 85 (2): 223–232. Yamashita T, Ando Y, Katsuragi S, et al. (2005). Muscular amyloid angiopathy with amyloidgenic transthyretin Ser50Ile and Tyr114Cys. Muscle Nerve 31 (1): 41–45. Zantos D, Zhang Y, Felson D (1994). The overall and temporal association of cancer with polymyositis and dermatomyositis. J Rheumatol 21 (10): 1855–1859.
Index Page numbers in italic, e.g. 128, refer to figures. Page numbers in bold, e.g. 378, denote tables. acid maltase deficiency (AMD), 175, 176, 194 actin myopathy, 8, 10 acute quadriplegic myopathy, 330–1 acute rhabdomyolysis, 325–6 acyl-CoA dehydrogenase deficiencies, 188–9 acylcarnitine analysis, 197 acylglycines, 195–6 adult-onset autophagic vacuolar myopathy 211–2 African trypanosomiasis, 313–4 aging and gene expression, 368–9 muscle changes associated with, 357–70 muscle disease associated with, 370–7 AL amyloid, 401 alcoholic myopathy, 332–3 alcoholism, 399 aldolase deficiency, 174 Alpers syndrome, 138–9 a-glucosidase deficiency, 194 American trypanosomiasis, 313 amiodarone, 332 AMP-activated protein kinase (AMPK) deficiency, 169 amyloid myopathy, 400–1, 402 Anderson-Tawil syndrome (ATS), 80, 81, 82, 85–6, 96–7 treatment of, 92 animals, myotonias in, 65, 70–1 anti-T lymphocyte globulin, 263 antioxidants, 263 apoptosis, 363 arthrogryposis multiplex congenita, 20 autoimmune inflammatory myopathies, 273–95 epidemiology of, 273 immunogenetics of, 273–4 autosomal dominant EDMD, 41 autosomal dominant LGMD, 36 autophagic myopathies generally, 331–2
autophagic vacuolar myopathy adult-onset form of, 211–2 congenital, 212–3 infantile, 210–1 autophagic vacuoles with sarcolemmal features (AVSF), 206–7 autosomal dominant inclusion body myopathy (IBM3), 21 autosomal PEO, 141–2
bacterial myositis, 308–11 basal ganglia syndromes, 395 b-adrenoreceptor blockers, 328–9 b-enolase deficiency, 174, 194 b-interferon, 263 b-oxidation defects, 187–90 (Thomsen and) Becker myofonius, 61–3 Bethlem myopathy, 36–9 blood, biochemical measurement in, 197 brain white matter disease, 250–1 branching enzyme deficiency, 177–8, 194 Brody’s disease, 393 buccal hyperpigmentation, 349 calcitonin, 351 calcium-channel periodic paralysis, 93–4 camptocormia, 370–1 cancer-associated myopathies, 405–7 carbohydrate metabolism, disorders of, 167–79 cardiac glycosides, 325 carnitine palmitoyltransferase deficiency, 185–7 carnitine transport defects, 184–5 caveolinopathy, 235 celiac disease, 397–8 central core disease (CCD), 12–4, 24, 116–7 central nervous system conditions, 394–5 centronuclear myopathy, 19–20 cestode infection, 314–6
Chagas’ disease, 313 chloride channel myotonias, 61–6 chloroquine, 331 cholesterol-lowering agents, 323–4 chronic fatigue syndrome (CFS), 399–400 clostridial myositis, 309 clostridial toxins, 334–5 colchicine, 332 compartment syndromes, 401–3 congenital contracture disorders, 20–1 congenital fiber type disproportion, 16–7 congenital muscular dystrophy, 43–53 type 1A (MDC1A), 46–9 type 1C (MDC1C), 52–3 variants of, 53–4 with severe mental retardation (MDC1D), 53 congenital myopathies, 1–27 classification of, 1–2 future treatments for, 26 inheritance of, 2–3 magnetic resonance imaging of, 23, 24, 25, 26 management of patients, 24–6 and muscle spindle excess, 54 with identified gene, 4 without identified genes, 22–3 congenital myotonic dystrophy, 54 contraction-induced injury to and repair of muscle, 360–2 contractures, myopathies with, 394 corticospinal syndromes, 395 corticosteroid myopathy, 329–30 corticosteroids, 262–3, 347–9 costimulatory molecules, 289 Coxsackie virus myositis, 305–6 cramps and muscle diseases, 392–4 differential diagnosis of, 394 drug-induced, 322, 394 generalized, 392 isolated, 392 of peripheral nerve origin, 389–90 creatine kinase, 244 Cushing’s syndrome, 347–9
412 cysticercosis, 314–5 cytokines, 368 cytopathy, mitochondrial, 197 cytotoxic drugs, 263 cytotoxic T-cells, 288
Danon disease, 207–9 dantrolene, 112 debrancher deficiency, 175–7, 194 deficiency myopathies, 397–9 dermatomyositis, 274–6 immunopathology of, 284–6 treatment of, 292–3 desminopathy, 233 diabetic neuromyopathy, 350 dietary treatments for lipid metabolism disorders, 190 for periodic paralysis, 91 distal arthrogryposis, 20 distal dysferlinopathy, 227–9 distal myopathy, 215–37 and cardiomyopathy, 233 early-onset form of, 229–32 late-onset form of, 225–7 and Paget’s disease, 235 and rimmed vacuoles, 229 with known gene defects, 216 without known gene defects, 218 distal phenotype in non-distal myopathies, 219, 234–5 DNA diagnosis in malignant hyperthermia, 114–5 drug-induced muscle cramps, 394 drug-induced myopathy, 322 dyskalemic myopathy, 327 dysphagia, 261 dystrophinopathy, 35, 393
early contractures, myopathies with, 35–54 early-onset distal myopathy (EODM), 229–32 echinococcosis, 315–6 ecstasy (MDMA), 119 electromyographic (EMG) examination, 61–3, 68, 70, 258, 280 electrophysiology, 244 Emery-Dreifuss muscular dystrophy (EDMD), 39–43 emetine, 325 endocrine disturbances, 147–8 endocrine myopathies, 343–52, 393–4, 405 endomysial T-cells, 288 enteral nutrition, 399 envenomation, myopathies due to, 534
INDEX enzyme deficiency, 194 enzyme studies, 197 eosinophilia-myalgia syndrome, 328 eosinophilic myositis, 282–3 epinephrine, 351 exophthalmic Grave’s disease, 346
familial hyperkalemic periodic paralysis, 78, 79–80 familial hypokalemic periodic paralysis, 77–9 facioscapulohumeral syndrome, 251 fatty acid oxidation, 184, 189, 194–7, 393 fibrates, 324 FKRP gene-related congenital muscular dystrophy, 52–3 focal myopathy, 333 free carnitine, analysis of, 195–7 Fukuyama congenital muscular dystrophy (FCMD), 49–51 fungal myositis, 311–2
gasoline sniffing, 335 gastrointestinal tract disorders, 148 gene encoding for glycosyl-transferases, 49–53 gene expression with aging, 368–9 genetic counselling, 149–50 genetic studies of metabolic myopathies, 198 of muscle disorders, 199–200 genetic suspectibility to inclusion-body myositis, 266–7 genetic testing, 84–9 glucocorticoid, 292 deficiency of, 349 glycogen, 167–8 glycogen storage disorders, 193–4, 393 glycogenoses, 169–79, 193–4 glycosides, cardiac, 325 glycosylation, abnormal, 53 glycosyltransferases, gene encoding for, 49–53 GNE biochemistry, 247–8 GNE disease, 229 GNE function in h-IBM, 248 Grave’s disease, 346 growth hormones, 349–50, 367 GSD II deficiency, 175 GSD IV deficiency, 177–8 GSD V deficiency, 170–1 GSD VII deficiency, 171–2 GSD VIII deficiency, 169 GSD IX deficiency, 172 GSD X deficiency, 174
GSD XI deficiency, 174 GSD XII deficiency, 174 GSD XIII deficiency, 174
Haff disease, 334 heart disease, 146–7 heat-shock proteins, 266 heatstroke, 119 hereditary amyloidosis, 401 hereditary inclusion body myopathy (h-IBM), 243–50 epidemiology of, 247 GNE function in, 248 molecular genetics of, 246–7 and sialylation, 248–9 HIV infection, 399 HIV-related myopathies, 306–7 hormonal influences on muscle disease, 367 HTLV-1 polymyositis, 307–8 hyaline body myopathy, see myosin storage myopathy hydatidosis, 315–6 hyperkalemic periodic paralysis (hyperPP), 70, 78, 79–80 hyperparathyroidism, 350–1 hyperthermia, malignant, 107–16 hyperthyroid myopathy, 343–4 hypokalemic periodic paralysis (hypoPP), 77–9 hypopituitarism, 349–50 hypothyroid myopathy, 344–5 IGF-1 signalling, 367–8
immune-mediated myopathies, 405–7 immunomodulating therapy, 263, 292–4 immunopathogenesis, 283–92 immunosuppressive therapy, 292–3 inclusion body myopathy, Paget’s disease and fronto-temporal dementia (IBM-PFD), 250 inclusion-body myositis, 255–67, 276–7 diagnostic criteria for, 259–61 immunopathogenesis of, 287 management of, 261–4 treatment of, 293–4 infantile autophagic vacuolar myopathy, 210–1 infective myopathies, 303–17 classification of, 304 inflammatory myopathies, 327–8 autoimmune, 273–95 conditions and factors associated with, 278 diagnostic criteria for, 279 rare forms of, 282
INDEX influenza virus myositis, 303–5 insulin, 350, 367–8 intranuclear rod myopathy, 10, 11 intravenous immunoglobin, 263 isolated mitochondrial myopathy in adolescents and adults, 143 in infants, 139
Kearns-Sayre syndrome, 141 kidney disease, 147 King-Denborough syndrome (KDS), 118
lactate dehydrogenase (LDH) deficiency, 174 Lafora disease, 178–9 Laing’s distal myopathy, 229–32 Lambert-Eaton myasthenic syndrome, 406 late-onset distal myopathy (LODM), 225–7 late-onset mitochondrial myopathy (LOMM), 371 LCHAD deficiency, 188 Leber hereditary optic neuropathy (LHON), 142–3 Leigh syndrome, 135–7 LHON disease, 142–3 limb girdle muscular dystrophies (LGMD), 35–6 lipid metabolism, disorders of, 183–90 lipodystrophy, 350 liver disease, 147 long-chain 3-hydroxyacyl CoA dehydrogenase (LCHAD) deficiency, 188 lysosomal myopathies, 205–13
McArdle’s disease, 170–1, 193–4 macrophagic myofasciitis, 283, 328 magnetic resonance imaging (MRI), 23, 24, 25, 26, 137, 138, 140, 142, 346 malabsorption syndromes, 397–9 malaria, 314 malignant hyperthermia (MH), 107–19 anesthesia for susceptible patients, 115–6 clinical presentation of, 110–1 DNA diagnosis in, 114–5 genetics of, 109–10 related conditions, 116–9 screening for, 112–5 treatment of, 112 malignant necrotizing streptococcal myositis, 309–10
Mallory-body myopathy, 15 Markesbery-Griggs disease, 225–7 MCAD deficiency, 188–9 MDMA (ecstasy), 119 medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, 188–9 MELAS syndrome, 139 membrane excitability, 61 membrane voltage, 65, 66 MERRF syndrome, 140–1 metabolic myopathies, 193–202, 393, 405 metabolite analysis, 195 microsporidiosis, 314 mitochondrial disease genetics of, 126–34 prenatal onset of, 135 mitochondrial DNA (mtDNA) deletions, 141–2 maintenance, 132–4 mutations, 126–30 mitochondrial encephalomyopathies, 125–50 clinical phenotypes, 134–43 epidemiology of, 245 genetic counselling, 149–50 organ manifestations of, 144–8 treatment of, 148–9 mitochondrial myopathy, 326–7 late-onset form of, 371 mitochondrial oxidative phosphorylation, 197–202 mitochondrial treatments for inclusionbody myositis, 263 mixed myopathies, 16 Miyoshi myopathy (MM), 227–9 motor unit remodeling, 362 multiminicore disease (MmD), 14–6 multisystemic triglyceride storage disorder, 190 muscle molecular genetic studies of, 199–200 vascular properties of, 369–70 muscle biopsy, 113–4, 244–5, 258–9, 258–9, 280–2 muscle cramp syndromes, 389–95 according to site of origin, 390 see also see also cramps muscle diseases, 357–77 associated with aging, 370–7 associated with malignant hyperthermia, 116 muscle enzymes, 279–80 muscle fibers, loss of, 360 by apoptosis, 363 muscle imaging, 258, 280
413 muscle pain fasciculation syndrome, 392 muscle spindle excess, 54 muscle tumours, 405 muscular dystrophy, 35–53 congenital, 43–53 oculopharyngeal, 371–3 tibial, 221–5 myalgia, 322, 393–4 myasthenia gravis, 405–6 myofasciitis, 282–3, 328 myofibrillar myopathies, 235 myoglobinuria, 326 myonuclear abnormalities, 266 myophosphorylase deficiency, 170–1, 193–4 myosin storage myopathy, 17–8 myosinopathy, 229–32 myositis ossificans, 404–5 myotilinopathy, 232–3 myotonic disorders, 61–72, 322, 392–3 glossary of, 61 myotonic dystrophy type 1, 63–4 type 2, 64–5
NARP syndrome, 141 nebulin (NEB), 9 nebulinopathy, 232 necrotizing myopathy, 323–5 necrotizing myositis, 283, 309–10 nemaline myopathy, 3–12, 24 treatment of, 12 nematode infection, 316–7 neuroleptic malignant syndrome (NMS), 118–9 nicotinic acid, 324 Nonaka myopathy, 229 nuclear DNA, 131 nuclear-encoded proteins, 131–4 nuclear gene mutations, 130–4
oculopharyngeal muscular dystrophy, 371–3 oculopharyngodistal myopathy, 235, 251 ophthalmoplegia, 250 organic acids, analysis of, 195–6 organophosphates, 335 osteomalacia, 351 “overlap” syndrome, 279 oxandrolone, 263 oxidative change, 365–7 oxidative stress, 266, 399 OXPHOS system, 126–34
414 Paget’s disease, 235, 250 paramyotonia congenita, 68–70 parasitic infections, 312–7 parathormone, 350–1 parenteral nutrition, 399 paroxysmal dyskinesias, 395 Pearson syndrome, 137–8 Penisson-Besnier distal myopathy, 232–3 perhexiline, 331 periodic paralysis, 77–98 and anesthesia, 92 thyrotoxic, 345–6 peripheral nerve hyperexcitability syndromes, 390–1 PFK deficiency, 171–2, 173, 194 PGAM deficiency, 174, 194 PGK deficiency, 172, 194 phaeochromocytoma, 351 phosphofructokinase, see PFK deficiency phosphoglycerate kinase deficiency, see PGK deficiency phosphoglycerate mutase deficiency, see PGAM deficiency phosphorylase kinase, 169, 194 polymyalgia rheumatica, 403–4 polymyositis, 276, 327–8 HTLV-1, 307–8 immunopathology of, 286–92 treatment of, 292–3 polypeptide genes, 129–30 Pompe’s disease, 194 potassium-aggravated myotonias, 66–8 potassium-channel gene KCNJ2, 85, 85–6 potassium-channel periodic paralysis, 96–7 PROMM, see myotonic dystrophy type 2 protein degradation, changes in, 364–5 protein metabolism, 363–4 protein synthesis, changes in, 364 protozoan infections, 312–4 proximal myopathy, 250 pseudohyperparathyroidism, 351 pulse steroid therapy, 292 pyomyositis, 308–9
quadriceps-sparing, 249 quadriplegic myopathy, 330–1 quail myopathy, 334
INDEX reducing body myopathy, 54 respiratory chain subunits, assembly of, 131–4 restless legs, 395 retroviruses and related myopathies, 290, 306–8 rhabdomyolysis, 325–6 rigid spine muscular dystrophy, 14–5 rimmed vacuolar myopathies, 205–6, 243–51 rippling muscle disease, 393 RR-MAD defects, 189–90 rRNA gene, 129
S-aminocaproic acid, 324–5 sarcopenia, 357–60 at cellular level, 360–3 sarcopenic atrophy, 360 sarcopenic muscle, 362–3 sarcosporidiosis, 314 sarcotubular myopathy, 21 SCAD deficiency, 189 scapuloperoneal syndrome, 251 Schwartz-Jampel syndrome, 391–2 SCN4A gene, 85, 87–8 secondary periodic paralysis, 82–4 selenium deficiency, 398–9 selenoprotein-N-related myopathies, 14–6 sex hormones, 367 short-chain acyl-CoA dehydrogenase (SCAD) deficiency, 189 sialylation, 248–9 skeletal muscle a-actin (ACTA1), 9–10 skeletal muscle disease, 145–6 skin disorders, 148, 285–6 snake venoms, 334 sodium-channel myotonias, 66–72 sodium-channel periodic paralysis, 94–6 solvents, 335 somatic mosaics, 3 spider venoms, 334 sporadic inclusion body myositis (s-IBM), 286–92, 373–7 pathogenesis of, 290–2 stains, 323–4 static halothane test, 113, 114 steroid myopathy, 347–9 stiff-person syndrome (SPS), 394–5 sudden infant death syndrome (SIDS), 119, 189
Tarui disease, 171–2 TCR gene, 288 Tel Hashomer camptodactyly syndrome (THCS), 54 telethoninopathy, 235 testosterone, 351–2 tetanus, 395 tetany, 392 Thomsen and Becker myotonias, 61–3 thyroid-associated ophthalmopathy, 346 thyrotoxic periodic paralysis, 81–2, 97–8, 345–6 treatment of, 92–3 thyroxine, 343–6 tibial muscular dystrophy (TMD), 221–5 titinopathy, 221–5 tonic spasms, 395 toxoplasmosis, 312–3 trifunctional enzyme deficiency, 187–8 tRNA gene, 129 tropomyosin, 8–9 troponin T (TNNT1), 10 trypanosomiasis, African and American, 313–4
Udd distal myopathy, 221–5 Ullrich congenital muscular dystrophy (UCMD), 44–6 uniform fiber typing, 21–2
vascular endothelium, 284–5 venoms, 334 vincristine, 332 viral infections associated with autoimmune inflammatory myopathies, 290 viral myositis, 303–8 Vitamin D deficiency, 398–9
Walker-Warburg syndrome, 51–3 wasp venoms, 334 Welander distal myopathy, 215–21
X-linked congenital autophagic vacuolar myopathy, 212–3 X-linked myopathy with excessive autophagy (XMEA), 209–10 X-linked myotubular myopathy, 18–9