Hereditary Peripheral Neuropathies

G. Kuhlenbåumer z F. Stægbauer z E. B. Ringelstein z P. Young (Eds.)

Hereditary Peripheral Neuropathies

G. Kuhlenbåumer F. Stægbauer E. B. Ringelstein P. Young (Eds.)

Hereditary Peripheral Neuropathies With 32 Figures and 20 Tables

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Priv.-Doz. Dr. Gregor Kuhlenbåumer Leibniz Institute for Atherosclerosis Research Department of Neurology University of Mçnster Albert-Schweitzer-Str. 33 48129 Mçnster Germany Prof. Dr. E. Bernd Ringelstein Leibniz Institute for Atherosclerosis Research Department of Neurology University of Mçnster Albert-Schweitzer-Str. 33 48129 Mçnster Germany

Prof. Dr. Florian Stægbauer Department of Neurology Klinikum Osnabrçck Am Finkenhçgel 49076 Osnabrçck Germany Dr. Peter Young Department of Neurology University of Mçnster Albert-Schweitzer-Str. 33 48129 Mçnster Germany

ISBN 3-7985-1453-4 Steinkopff Verlag Darmstadt Bibliographic information published by Die Deutsche Bibliothek Die Deutsche Bibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data is available in the Internet at . This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer-Verlag. Violations are liable for prosecution under the German Copyright Law. Steinkopff Verlag Darmstadt a member of Springer Science+Business Media www.steinkopff.springer.de ° Steinkopff Verlag Darmstadt 2005 Printed in Germany The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about the application of operative techniques and medications contained in this book. In every individual case the user must check such information by consulting the relevant literature. Production: Klemens Schwind Cover Design: Erich Kirchner, Heidelberg Typesetter: K+V Fotosatz GmbH, Beerfelden SPIN 10925485

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Preface

Hereditary peripheral neuropathies are the most common inherited diseases of the nervous system. The high prevalence of 1 patient per 2500 inhabitants underscores the importance of these diseases in everyday clinical practice. Until the 1990s, the diagnosis of hereditary peripheral neuropathies was based on clinical findings alone. Very little was known about the various entities, their diagnostic differentiation, their natural course or biological background. This is why a firm diagnosis could often not be made. The advent of positional cloning opened up a completely new avenue for the identification of nosological entities, particularly by defining their underlying genetic defect. The first causative genetic alteration, i.e. the Charcot-MarieTooth 1A duplication on chromosome 17p11, was identified in 1991. Since this time, increasingly rapid progress was made, particularly after the publication of the human genome sequence. Most major forms of hereditary neuropathies can now be diagnosed with certainty on the molecular level. Knowledge of the defective genes led to equally rapid progress in unraveling the biological basis of these diseases, but also provided new and exciting insights into the complex biology of peripheral nerves in general. Although causative therapies are not available yet, the progress in the genetics and biology of these diseases makes effective therapies conceivable, for the first time ever. Since the groundbreaking book on peripheral neuropathies edited by P. J. Dyck in 1993, no comprehensive, clinically applicable, yet compact book has been published in this field making it extremely difficult for the interested clinician, as well as the clinical and basic scientist, to keep abreast with the rapid scientific development in this field. I hope that this book will fill the void and provide a practical source of information for anyone interested in hereditary peripheral neuropathies, particularly those just embarking on the journey to master this innovative field.

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This book summarizes the clinical, genetic and biologic state of knowledge including the latest scientific advances. It is written for the clinician and the geneticist with a special interest in peripheral neuropathies, as well as the clinical and basic scientist in this field appreciating a comprehensive but compact and concise overview of the field. The first section of the book is devoted to the clinical and biological basis of hereditary neuropathies containing chapters about the clinical and electrodiagnostic evaluation, the differential diagnosis and peripheral nerve pathology, as well as the structure and function of the normal peripheral nerve. The second part of the book features an overview of the diverse forms of hereditary neuropathies and contains separate chapters describing the most important different entities in detail. The third part provides detailed information about genetic testing, including diagnostic algorithms, medical and surgical treatment, genetic counseling and animal models. Practical information about clinical and molecular diagnostic centers, self-help groups and frequently updated sources of information on the Internet are given in the appendix. The readers, I am confident, will find this comprehensive overview highly instructive and stimulating. It will, hopefully, serve as a welcome milestone for all who need guidance in this new and fascinating but sometimes confusing area of hereditary neuropathies. Mçnster, July 2005

E. Bernd Ringelstein, M.D., F.A.H.A

Table of Contents

z General part 1

Architecture of the peripheral nerve . . . . . . . . . . .

P. Young, M. Boentert

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1 Cellular components of the PNS . . . . . . . 1.2 Architecture of the myelin compartment 1.2.1 The internode . . . . . . . . . . . . . . . . . . . . . 1.2.2 The node of Ranvier . . . . . . . . . . . . . . . . 1.2.3 The paranodal region . . . . . . . . . . . . . . . 1.2.4 The juxtaparanodal region . . . . . . . . . . . 1.3 Unmyelinated nerve fibers . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Clinical evaluation and differential diagnosis . . . .

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 General approach to the patient with peripheral neuropathy . . . . . . . . . . . . 2.2 Specific features in the history of patients with hereditary neuropathies . . . . . . . . . . . 2.2.1 Chief complaint and functional deficits noted by the patient . . . . . . . . . . . . . . . . . . . . . . . 2.2.2 Onset and time course of disease . . . . . . . . 2.2.3 Concomitant diseases . . . . . . . . . . . . . . . . . 2.2.4 Family history . . . . . . . . . . . . . . . . . . . . . . . 2.3 Specific features in the clinical examination of patients with suspected hereditary neuropathy . . . . . . . . . . . . . . . . . . . . . . . . .

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z Approach to the patient with suspected hereditary neuropathy 2

R. Kiefer, E. B. Ringelstein

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2.3.1 Neurological examination . . . . . . . . . . . . . . 2.3.2 General examination . . . . . . . . . . . . . . . . . . 2.4 Differential diagnosis in patients with suspected hereditary neuropathy . . . . 2.4.1 Distal symmetric leg weakness with peroneal preponderance . . . . . . . . . . . . . . . . . . . . . . . 2.4.2 Pes cavus and hammertoes . . . . . . . . . . . . . 2.4.3 The HNPP phenotype . . . . . . . . . . . . . . . . . 2.4.4 The HNA phenotype . . . . . . . . . . . . . . . . . . 2.4.5 Pain and the sensory abnormalities of HSAN . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.6 Nerve hypertrophy . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Electrodiagnostic evaluation of hereditary polyneuropathies . . . . . . . . . . . . . . .

M. Mçller

3.1 3.2

General considerations . . . . . . . . . . . . . . . . Electrodiagnostic evaluation of hereditary polyneuropathies . . . . . . . . . . . . . . . . . . . . 3.3 Electrodiagnostic features and differential diagnosis of different forms of hereditary polyneuropathies . . . . . . . . . . . . . . . . . . . . 3.3.1 Charcot-Marie-Tooth disease type 1 and 4 (CMT1/CMT4) . . . . . . . . . . . . . . . . . . . . . . . 3.3.2 Charcot-Marie-Tooth disease type 2 (CMT2) 3.3.3 Dominant intermediate CMT (DI-CMT) . . . 3.3.4 Charcot-Marie-Tooth disease X chromosomal (CMTX) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.5 Djerine-Sottas syndrome (DSS) . . . . . . . . . 3.3.6 Congenital hypomyelination (CH) . . . . . . . . 3.3.7 Hereditary motor neuropathies (dHMN) . . . 3.3.8 Hereditary sensory and autonomic neuropathies (HSAN)/hereditary sensory neuropathies (HSN) . . . . . . . . . . . . . . . . . . . . . . . 3.3.9 Hereditary neuropathy with liability to pressure palsy (HNPP) . . . . . . . . . . . . . . 3.3.10 Hereditary neuralgic amyotrophy (HNA) . . . 3.3.11 Giant axonal neuropathy (GAN) . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Principles of pathology and nerve biopsy . . . . . . .

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 Charcot-Marie-Tooth disease type 1 (CMT1) . . . . . . . . . . . . . . . . . . . . . . . . 4.1.1 Charcot-Marie-Tooth disease type 1A (CMT1A) . . . . . . . . . . . . . . . . . . . . . . . 4.1.2 Charcot-Marie-Tooth disease type 1B (CMT1B) . . . . . . . . . . . . . . . . . . . . . . . 4.1.3 Charcot-Marie-Tooth disease type 1C (CMT1C) . . . . . . . . . . . . . . . . . . . . . . . 4.1.4 Charcot-Marie-Tooth disease type 1D (CMT1D) . . . . . . . . . . . . . . . . . . . . . . . 4.1.5 Djerine-Sottas syndrome (DSS) . . . . . 4.1.6 Congenital hypomyelination (CH) . . . . 4.1.7 Hereditary neuropathy with liability to pressure palsy (HNPP) . . . . . . . . . . 4.2 Charcot-Marie-Tooth disease type 4 (CMT4) . . . . . . . . . . . . . . . . . . . . . . . . 4.2.1 Charcot-Marie-Tooth disease type 4A (CMT4A) . . . . . . . . . . . . . . . . . . . . . . . 4.2.2 Charcot-Marie-Tooth disease type 4B1 and 4B2 (CMT4B1, CMT4B2) . . . . . . . 4.2.3 Charcot-Marie-Tooth disease type 4C (CMT4C) . . . . . . . . . . . . . . . . . . . . . . . 4.2.4 Charcot-Marie-Tooth disease type 4D (CMT4D) . . . . . . . . . . . . . . . . . . . . . . . 4.2.5 Charcot-Marie-Tooth disease type 4E (CMT4E) . . . . . . . . . . . . . . . . . . . . . . . 4.2.6 Charcot-Marie-Tooth disease type 4F (CMT4F) . . . . . . . . . . . . . . . . . . . . . . . 4.3 X-linked Charcot-Marie-Tooth disease (CMTX) . . . . . . . . . . . . . . . . . . . . . . . . 4.4 Charcot-Marie-Tooth disease type 2 (CMT2) . . . . . . . . . . . . . . . . . . . . . . . . 4.5 Hereditary sensory and autonomic neuropathies (HSAN) . . . . . . . . . . . . . 4.5.1 Hereditary sensory and autonomic neuropathy type 1 (HSAN1) . . . . . . . . 4.5.2 Hereditary sensory and autonomic neuropathy type 2 (HSAN2) . . . . . . . . 4.5.3 Hereditary sensory and autonomic neuropathy type 3 (HSAN3) . . . . . . . .

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A. Schenone

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4.5.4 Hereditary sensory and autonomic neuropathy type 4 and 5 (HSAN4 and HSAN5) . . . . . . . . . . . . . . . 4.6 Hereditary motor neuropathies (HMN) . 4.7 Giant axonal neuropathy (GAN) . . . . . . . 4.8 Hereditary neuralgic amyotrophy (HNA) References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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z Specific neuropathies, treatment and counseling 5

Overview of the classification and genetics of hereditary peripheral neuropathies and rare unclassified forms . . . . . . . . . . . . . . . . . . . . . . . . .

G. Kuhlenbåumer

5.1 5.2 5.3 5.3.1 5.3.2 5.4 5.4.1 5.4.2

History . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical and electrophysiological phenotype of hereditary motor and sensory neuropathies (HMSNs) . . . . . . . . . . . . . . . . Classification of hereditary neuropathies . . The HMSN classification by Dyck, Chance, Lambert and Carney . . . . . . . . . . . . . . . . . . Classification of primary hereditary neuropathies according to clinical subgroups and genetic entities . . . . . . . . . . . . . . . . . . . Rare forms of hereditary peripheral neuropathies which do not fit into the current classification schemes . . . . . . . . . . . . . . . . . Giant axonal neuropathy ± gigaxonin (GAN) (OMIM 256850) . . . . . . . . . . . . . . . . . . . . . . Agenesis of the corpus callosum with peripheral neuropathy (ACCPN) or Anderman syndrome or hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) ± solute carrier family 12 member 6 gene (SLC12A6 coding for the protein: KCC3) (OMIM 218000) . . . . . . . . . . . . . . . . . . . . . .

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5.4.3 Congenital hypomyelinating neuropathy, central dysmyelination and intestinal (pseudo) obstruction (Waardenburg-Hirschsprung disease) ± SRY like box 10 transcription factor (SOX10) (OMIM 602229) . . 5.4.4 Hereditary peripheral neuropathy and deafness ± gap junction protein 3 (GJB3 or connexin31) . . . . . . . . . . . . . . . . . 5.4.5 Minifascicular peripheral neuropathy, partial gonadal dysgenesis ± desert hedgehog (DHH) (OMIM 607080) . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Charcot-Marie-Tooth disease type 1 (CMT1) and hereditary neuropathy with liability to pressure palsy (HNPP) . . . . . . . . . . . . . . . . . . . .

E. Nelis, P. de Jonghe, V. Timmerman

6.1 6.1.1 6.1.2 6.1.3 6.1.4 6.2

Autosomal dominant CMT1 and HNPP . Clinical features . . . . . . . . . . . . . . . . . . . . Electrodiagnostic and laboratory features Pathological features . . . . . . . . . . . . . . . . Genetics and pathomechanism . . . . . . . . Autosomal recessive demyelinating CMT or CMT4 . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.1 Clinical features . . . . . . . . . . . . . . . . . . . . 6.2.2 Electrodiagnostic features . . . . . . . . . . . . 6.2.3 Pathological features . . . . . . . . . . . . . . . . 6.2.4 Genetics and pathomechanism . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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CMT2, dominant intermediate CMT and CMTX . . . .

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1 Charcot-Marie-Tooth neuropathy type 2 7.1.1 Autosomal dominant CMT2 . . . . . . . . . 7.1.2 Autosomal recessive CMT2 . . . . . . . . . . 7.2 DI-CMT: dominant intermediate Charcot-Marie-Tooth neuropathy . . . . . 7.2.1 DI-CMTA ± chromosome 10q24.1-q25.1 (OMIM 606483 or CMTDIA) . . . . . . . . . 7.2.2 DI-CMTB ± chromosome 19p12-p13.2 (OMIM 606482 or CMTDIB) . . . . . . . . .

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7.2.3 DI-CMTC ± chromosome 1p34-p35 (OMIM 608323, CMTDIC) . . . . . . . . . . . . . . 7.2.4 DI-CMTD ± myelin protein zero (MPZ) (OMIM 607791, CMTDID) . . . . . . . . . . . . . . 7.2.5 DI-slowed nerve conduction velocities without Charcot-Marie-Tooth neuropathy ± rho guanine nucleotide exchange factor 10 gene (ARHGEF10) (OMIM 608236, slowed nerve conduction velocities, autosomal dominant) . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.6 HMSN-P ± chromosome 3p14.1-q13 (OMIM 604484, HMSNO or Okinawa type) . 7.3 CMTX: Charcot-Marie-Tooth neuropathy, X-linked types . . . . . . . . . . . . . . . . . . . . . . . 7.3.1 CMTX1 ± gap junction protein beta 1 gene (GJB1, formerly connexin 32 (Cx32) (OMIM 302800) . . . . . . . . . . . . . . . . . . . . . . 7.3.2 CMTX2 ± chromosome Xp22.2 (OMIM 302801) . . . . . . . . . . . . . . . . . . . . . . 7.3.3 CMTX3 ± chromosome Xq26 (OMIM 302802) . . . . . . . . . . . . . . . . . . . . . . 7.3.4 CMTX4 ± chromosome Xq24-26.1 (OMIM 310490, Cowchock syndrome or neuropathy, axonal motor-sensory with deafness and mental retardation, NAMSD) . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . .

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Distal hereditary motor neuropathies (dHMN) . . .

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.1 dHMN I ± small heat shock protein 27 (HSP27 or HSBP1) (OMIM 608634) . . . . . . 8.2 dHMN II ± small heat shock protein 22 (HSP22 or HSBP8) (OMIM 158590) . . . . . . 8.3 dHMN III ± chromosomal location unknown . . . . . . . . . . . . . . . . . . . . . . . . . . 8.4 dHMN IV ± chromosome 11q13 (OMIM 607088) . . . . . . . . . . . . . . . . . . . . . 8.5 dHMN V a and b ± Va: glycyl tRNA synthetase gene (GARS) (OMIM 600749) ± Vb: Berardinelli Seip congenital muscular dystrophy gene (BSCL2) (OMIM 270685) . 8.6 dHMN VI ± immunoglobulin l-binding protein 2 (IGHMBP2) (OMIM 604320) . . .

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F. Stægbauer, G. Kuhlenbåumer

Table of Contents

8.7

dHMN VIIa ± chromosome 2q14 (OMIM 158580) . . . . . . . . . . . . . . . . . . 8.8 dHMN VIIb ± dynactin (DCTN) (OMIM 607641) . . . . . . . . . . . . . . . . . . 8.9 dHMN pyramidal/amyotrophic lateral sclerosis 4 (ALS4), senataxin (SETX) (OMIM 602433) . . . . . . . . . . . . . . . . . . 8.10 dHMN Jerash type ± chromosome 9p21.1-p12 (OMIM 605726) . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Hereditary sensory and autonomic neuropathies (HSAN) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

157

P. De Jonghe, G. Kuhlenbåumer

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.1 Assessment of HSANs with autonomic and neurophysiological examinations . . . . . 9.1.1 Quantitative testing of thermal perception . 9.1.2 Histamine axonal flare test . . . . . . . . . . . . . 9.2 Forms of HSAN . . . . . . . . . . . . . . . . . . . . . 9.2.1 HSAN1/HSN I ± serine palmitoyltransferase 1, long chain subunit 1 gene (SPTLC1) (OMIM 162400) . . . . . . . . . . . . . . . . . . . . . . 9.2.2 HSAN2 ± hereditary sensory neuropathy II gene (HSN2) (OMIM 201300) . . . . . . . . . . . 9.2.3 HSAN3 ± (Syn: familial dysautonomia, RileyDay syndrome) ± inhibitor of kappa light polypeptide gene (IKBKAP, protein IKAP) . . 9.2.4 HSAN4 ± neurotrophin receptor tyrosine kinase 1 gene (NTRK1) (OMIM 256800) . . . 9.2.5 HSAN5 ± in some cases: nerve growth factor beta (NGFB), neurotrophin receptor tyrosine kinase 1 gene (NTRK1) (OMIM 256800) . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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10 Hereditary neuralgic amyotrophy (HNA) . . . . . . . .

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G. Kuhlenbåumer

10.1 10.1.1 10.1.2 10.1.3

Clinical features . . . . . . . . . . . . . . . . . . . . . Classical remitting-relapsing HNA . . . . . . . . Chronic undulating HNA . . . . . . . . . . . . . . . Sporadic brachial plexus neuropathy (sBPN) (also called idiopathic brachial plexus neuritis, Parsonage-Turner syndrome) . . . .

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10.2

Electrodiagnostic, laboratory and additional investigatons . . . . . . . . . . . . . . . . . . . . . . . . 10.3 Pathologic features . . . . . . . . . . . . . . . . . . . 10.4 Genetics and pathomechanism . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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11 Molecular genetic diagnosis of hereditary neuropathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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G. Kuhlenbåumer

11.1 Molecular genetic testing strategies . . . . . . 11.2 Molecular genetic tests . . . . . . . . . . . . . . . . 11.2.1 Methods for the detection of the chromosome CMT1A duplication/HNPP deletion . . 11.2.2 Mutation detection methods for other genetic defects causing hereditary neuropathies . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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12 Genetic counseling . . . . . . . . . . . . . . . . . . . . . . . .

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.1 Definition of genetic counseling and consequences . . . . . . . . . . . . . . . . . . 12.2 Course and general principles of genetic counseling . . . . . . . . . . . . . . . . . . . . . . . . 12.3 Diagnostic/molecular testing . . . . . . . . . 12.3.1 Predictive testing of late-onset disorders . 12.3.2 Prenatal testing . . . . . . . . . . . . . . . . . . . . 12.3.3 Preimplantation diagnostics . . . . . . . . . . 12.4 Special issues of genetic counseling . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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13 Medical treatment of hereditary neuropathies . . .

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M. Hoeltzenbein

P. Young

Introduction . . . . . . . . . . . . . . . . . . . . . 13.1 Causative therapy . . . . . . . . . . . . 13.1.1 Genetic treatment . . . . . . . . . . . . 13.1.2 Prevention of axonal degeneration 13.2 Symptomatic therapy . . . . . . . . . 13.2.1 Neuropathic pain . . . . . . . . . . . . . 13.2.2 Autonomic dysfunction . . . . . . . .

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13.2.3 Surgery of foot deformities . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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14 Orthopedic aspects in diagnosis, clinical management and therapy of CMT patients . . . . . .

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R. Forst, A. Ingenhorst

Introduction . . . . . . . . . . . . . . . . . . . 14.1 Upper extremities . . . . . . . . . . 14.2 Spine . . . . . . . . . . . . . . . . . . . . 14.3 Hip joint . . . . . . . . . . . . . . . . . 14.4 Knee joint . . . . . . . . . . . . . . . . 14.5 Ankle joint and foot . . . . . . . . 14.5.1 Clinical basics . . . . . . . . . . . . . 14.5.2 Pathogenesis of the deformities 14.5.3 Special diagnostic tests . . . . . . 14.5.4 Therapy . . . . . . . . . . . . . . . . . . 14.6 Fractures . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . .

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15 Animal models of hereditary neuropathies . . . . . .

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.1 Models for demyelinating CMT1A: peripheral myelin protein 22 (pmp22) . . . . 15.1.1 pmp22 transgenic rats . . . . . . . . . . . . . . . . . 15.1.2 pmp22 transgenic mice . . . . . . . . . . . . . . . . 15.1.3 Inducible pmp22 transgenic mice . . . . . . . . 15.1.4 pmp22 knockout mice . . . . . . . . . . . . . . . . . 15.1.5 Mice carrying point mutations in pmp22: trembler, trembler J, Tr-m1H, Tr-m2H . . . . . 15.2 Models for demyelinating CMT1B: myelin protein zero (mpz) knockout mice . . . . . . . 15.3 Models for demyelinating and axonal CMTX: gap-junction-protein beta 1 (gjb1) knockout mice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.4 Model for demyelinating CMT4F: periaxin (prx) knockout mice . . . . . . . . . . . . . . . . . . 15.5 Model for axonal CMT2A2: kinesin motor protein 1 beta (kif1b) knockout mice . . . . . 15.6 Model for axonal CMT2E: neurofilament light chain (nefl) knockout mice . . . . . . . . .

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15.7

Model for recessive CMT4C1: lamin A/C (lmna) knockout mice . . . . . . . . . . . . . . . . . 15.8 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

233 234 234

Appendix: genetic testing laboratories and support groups . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Authors' addresses

Dr. Mathias Boentert Department of Neurology University of Mçnster Albert-Schweitzer-Str. 33 48129 Mçnster Germany Prof. Phillip F. Chance, MD Division of Genetics and Developmental Medicine Department of Pediatrics Box 356320 University of Washington Seattle, WA 98195 USA Prof. Peter De Jonghe, MD, PhD Peripheral Neuropathy Group Department of Molecular Genetics (VIB8) Flanders Interuniversity Institute for Biotechnology University of Antwerp Universiteitsplein 1 2610 Antwerpen Belgium Prof. Dr. Raimund Forst Waldkrankenhaus St. Marien Rathsberger Str. 57 91054 Erlangen Germany Prof. Mark C. Hannibal, MD, PhD Division of Genetics and Developmental Medicine Department of Pediatrics Box 356320 University of Washington Seattle, WA 98195 USA

Dr. Maria Hoeltzenbein Max Planck Institut fçr Molekulare Genetik Department Prof. Ropers Ihnestr. 73 14195 Berlin Germany Dr. Gert Hçnermund Diakonie-Krankenhaus Wehrda Hebronberg 5 35041 Marburg Germany Dr. Anne Ingenhorst Waldkrankenhaus St. Marien Rathsberger Str. 57 91054 Erlangen Germany Prof. Dr. Reinhard Kiefer Department of Neurology University of Mçnster Albert-Schweitzer-Str. 33 48129 Mçnster Germany Priv.-Doz. Dr. Gregor Kuhlenbåumer Leibniz Institute for Atherosclerosis Research Department of Neurology University of Mçnster Albert-Schweitzer-Str. 33 48129 Mçnster Germany Dr. Markus Mçller Department of Neurology University of Mçnster Albert-Schweitzer-Str. 33 48129 Mçnster Germany

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Eva Nelis, PhD Peripheral Neuropathy Group Department of Molecular Genetics (VIB8) Flanders Interuniversity Institute for Biotechnology University of Antwerp Universiteitsplein 1 2610 Antwerpen Belgium Prof. Dr. E. Bernd Ringelstein Leibniz Institute for Atherosclerosis Research Department of Neurology University of Mçnster Albert-Schweitzer-Str. 33 48129 Mçnster Germany Priv.-Doz. Dr. Peter Young Department of Neurology University of Mçnster Albert-Schweitzer-Str. 33 48129 Mçnster Germany Prof. Dr. Angelo Schenone, MD Universita di Genova Dipartimento Scienze Neurologiche Via de Toni 5 16132 Genova Italy

Prof. Dr. Florian Stægbauer Department of Neurology Klinikum Osnabrçck Am Finkenhçgel 49076 Osnabrçck Prof. Dr. Ueli Suter ETH Hænggerberg Institut fçr Zellbiologie 8093 Zçrich Switzerland Prof. Vincent Timmerman, PhD Peripheral Neuropathy Group Department of Molecular Genetics (VIB8) Flanders Interuniversity Institute for Biotechnology University of Antwerp Universiteitsplein 1 2610 Antwerpen Belgium

General part

1 Architecture of the peripheral nerve P. Young, M. Boentert

Introduction The peripheral nerve is composed of myelinated and unmyelinated nerve fibers. Different fibers originate from different neurons like motor neurons in the ventral horn of the spinal cord, sensory neurons from dorsal root ganglia and autonomic neurons. Most forms of hereditary neuropathies (HN) affect the myelinated motor and/or sensory neurons. Autonomic dysfunction is seen in some special subforms of hereditary neuropathies like hereditary sensory and autonomic neuropathy (HSAN or HAN). Many genes encoding proteins which are located in the myelinated nerve fiber were identified as disease causing genes when mutated (reviewed [40]). The function of some of these proteins has been elucidated over the last few years but the function of many of these genes is not understood yet. In the following, the focus is laid on the proteins for which the biological function has been shown in appropriate experiments. The function of the peripheral nervous system (PNS) is to connect the central nervous system with the surrounding environment of the organism. For this purpose the normal function of the PNS is fundamentally dependent on the correct morphological and molecular organization of the peripheral nerve fiber.

1.1 Cellular components of the PNS The two major cellular components of peripheral nerves are (1) axons originating either from motor neurons located within the brainstem motor nuclei, from the ventral horn of the spinal cord or from sensory dorsal root ganglia and (2) glial cells, in the PNS represented by Schwann cells. In the PNS, two different kinds of Schwann cells can be found, unmyelinating and myelinating cells. Unmyelinating Schwann cells are responsible for the correct ensheathing of multiple axons which are smaller than 1 lm in diameter while myelinating Schwann cells ensheath single axons with a diameter of more than 1 lm with myelin. Myelinating Schwann cells align to a discrete part

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Fig. 1.1. Cross section of a single myelinated nerve fiber. A single Schwann cell is ensheathing a single axon in a 1 : 1 relation. The nucleus of the Schwann cell (SCN) is in close contact to the axon while the whole axon (A) is surrounded by compacted myelin (M). Arrow heads indicate the adaxonal compartment of the Schwann cell cytoplasm while the abaxonal compartment is indicated by SCC

of an axon in a 1 : 1 relation [12, 27]. The process of myelination is characterized by the formation of a defined number of wraps of compacted cell membrane of a single Schwann cell along the discrete segment of the axon [31]. The nucleus of the myelinating Schwann cell is located finally outside the myelin sheath and a small collar of cytoplasm persists at this outer side of the myelin compartment which is defined as the abaxonal compartment while the adaxonal compartment of the myelin sheath is defined as the small residual rim of cytoplasm of the Schwann cell at the innermost myelin wrap adjacent to the axon (Fig. 1.1). The abaxonal and the adaxonal compartment are linked via cytoplasmic channels called Schmidt-Lanterman incisures which enable traffic of substances between the inner and outer compartments of the Schwann cell. The abaxonal compartment is characterized by the presence of extracellular matrix receptors (ECM) [22]. The adaxonal compartment is characterized by the presence of molecules which mediate cell adhesion like the myelin associated glycoprotein (MAG) [35]. Besides Schwann cells and axons, fibroblasts are found in the PNS. Some immune cells are also found in the normal healthy nerve. The impact of immune cells and fibroblasts on inflammation, trauma, hereditary peripheral nerve diseases and axonal degeneration is not fully elucidated.

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1.2 Architecture of the myelin compartment Myelin is a highly specified material which is required for insulation of the axon against its surroundings and myelin enables saltatory nerve conduction along the axon. Besides insulating stretches along the axon, saltatory nerve conduction depends on gaps within the compacted myelin in which ion exchange is possible to maintain the electrical conduction. These gaps are called nodes of Ranvier. The node of Ranvier is characterized by a complex architecture comprising several proteins. Disruption of the compacted myelin sheath is further regularly seen in regions called SchmidtLanterman incisures consisting of uncompacted myelin. The myelin segments which extend between two nodes of Ranvier are called internodal regions of the peripheral myelinated nerve fiber (Fig. 1.2).

Fig. 1.2. Morphology and molecular architecture of the nodal, paranodal and juxtaparanodal region in myelinated nerve fibers. Longitudinal section of a myelinated nerve fiber showing a node of Ranvier. A and B The nodal region (N) of the axon (A) is flanked by the paranodal region (P). The flanking region is defined as the juxtaparanodal region (J). B Caspr is localized in the paranodal region of the axon while the potassium channel Kv1.2 is located in the juxtaparanodal region of the axon. Caspr and Kv1.2 are both expressed in the outer mesaxon (indicated by arrows)

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1.2.1 The internode The length of an internode depends on the axon diameter and is about 100 times the axon diameter. Internodes of 1 mm length are found in large fibers [13]. The internodes, making up most of the length of the myelinated nerve fibers, contain mainly compacted myelin lamellae. The compacted myelin sheath is formed by fusion of adjacent Schwann cell membranes resulting in a highly specific pattern of dark and light lines. Each period is separated into the dark major dense line and a bright line which is separated by a dark line called the intermediate line. The width of each period is strictly determined and is between 12 nm (in fixed tissue) up to a maximum of 19 nm (in unfixed tissue). The number of periods is strictly related to the axon diameter. Little is known about the mechanisms which lead to the specific axon diameter-dependent thickness of the myelin sheath. Axonal expression of neuregulins and glial expression of ERB-B receptor 2 were shown to have an important impact on the thickness of the myelin sheath [20]. The compacted myelin compartment consists mainly of cholesterol and sphingolipids. Further some specialized lipids like galactocerebrosides and sulfatides are found. Proteins are a small fraction of the compacted myelin. The myelin protein zero (P0, encoded by the MPZ gene), the peripheral myelin protein 22 (PMP22), and myelin basic protein (MBP) represent the major proteins found in the compacted myelin compartment of the PNS. P0 is the most abundant protein in the compacted myelin of the PNS. Its main function is to mediate and enable myelin compaction. It has been shown that P0 consists of a single immunoglobulin-like motif in its extracellular domain and has a highly positively charged intracellular domain [17]. This combination is postulated to be a prerequisite for myelin compaction. With the aid of the extracellular domains homophilically interacting tetramers can be formed within the same membrane (cis position) and with the apposing membrane (trans position) [18, 28]. Functional studies in P0 deficient cells and mice underlined the function of P0 in compaction [7, 10]. Thus, it is postulated that major dense line compaction is mediated by P0. PMP22 is a small tetraspan intrinsic membrane protein which has a major impact on myelination and myelin maintenance as well as Schwann cell proliferation. PMP22 function is regulated by many factors. The function of PMP22 is highly dosage dependent but the basis of this dosage dependency is far from being fully understood (reviewed in [33]). MBP is a minor protein component of the compacted myelin sheath [32]. Although it is found to be expressed within the major dense line its function is still unclear. In contrast to P0 and PMP22, MBP is also expressed in the myelin compartment of the central nervous system (CNS) [36]. Interactions between MBP and PMP22 or P0, respectively, have not been shown so far. The loss of MBP immunoreactivity is a reliable marker for demyelination in the PNS as well as in the CNS.

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The periaxonal space between the myelin sheath and the axon is sealed by the inner mesaxon. The inner mesaxon runs along the whole internode. The outer sealing of the myelin sheath, called the outer mesaxon, is achieved by the adhesion of two membrane loops of the Schwann cell forming two lips filled with cytoplasm and sealed to each other by adherens junctions. Within the outer mesaxon, E-cadherin and beta-catenin are specifically localized (Fig. 1.3). E-cadherin deficiency causes a widening of the outer mesaxon in mice but has no impact on the compacted myelin formation in these mice. At the axon in the regions apposing the inner mesaxon, which is the adaxonal membrane part of the ensheathing Schwann cell, contactin±associated protein 1 (caspr1), contactin and Kv1.1 and Kv1.2 are localized [1, 26] (Fig. 1.2). The compacted myelin compartment of the internode is regularly interrupted by uncompacted myelin bridges called Schmidt-Lanterman inci-

Fig. 1.3. Immunohistochemical staining with an antibody against E-cadherin on a myelinated nerve fiber. E-cadherin is expressed in the myelated nerve fiber in the uncompacted myelin compartment at the paranodal region of the node of Ranvier (arrow), the Schmidt-Lanterman incisures (asterisks) and the outer mesaxon (arrow heads)

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sures. These incisures show an accumulation of potassium channels, E-cadherin, beta-catenin, caspr and several tight junction markers. The function of the incisures is yet not fully understood but the expression of gap junction forming gap junction protein beta 1 (GJB1) in these structures suggests that they have an impact on the diffusion of several molecules since it was shown that radial dye radial transfer is mediated via diffusion across incisures [2].

1.2.2 The node of Ranvier The main proteins which are found accumulated axonally at the node of Ranvier are voltage-gated sodium channels belonging to a multigene family. However, the sodium channel Nav1.6 [6] is the main representative. Further sodium channels at the node of Ranvier are Nav1.2, Nav1.8 and Nav1.9 [4, 11, 15]. Sodium channels are anchored by two different splice variants of ankyrinG [16]. Furthermore spectrin is accumulated at the node. In contrast to the nodes of Ranvier found in the CNS, the nodal region in the PNS is covered by interdigitating microvilli originating from the lateral end of myelinating Schwann cells. The microvilli are in close contact with the axonal cytoskeleton [14]. The diameter of the axon itself is reduced at the nodal region. Microvilli contain F-actin and proteins like ezrin, radixin and moesin which all belong to the family of F-actin binding ERM proteins (ERM stands for ezrin, radixin and moesin). ERM proteins can bind to merlin, the gene product of the neurofibromatosis 2 gene.

1.2.3 The paranodal region The paranodal region is formed by uncompacted myelin loops formed out of the lateral edge of the myelin sheath. In thin fibers, each loop reaches the axon and forms close contacts to the axon. In large fibers not all loops reach the axon. Contacts between the paranodal loops and the axon are formed by septate-like junctions. Septate-like junctions contain contactin while the apposing axonal segment contains contactin associated protein (caspr) [8, 19, 25]. NF155, an isoform of neurofascin, is also expressed in the paranodal loops. Contactin and caspr heterodimers colocalize with NF155 within the paranodal region [34]. The paranodal region is also characterized by an accumulation of molecules which are involved in mediating adherens structures between the paranodal loops. Contactin and caspr are essential for the normal and stable architecture of the paranodal region as it was shown in mice deficient for these proteins [3, 5]. In these animals the spacing between the loops and the axon is enlarged and microvillar processes invade the periaxonal space and disturb the formation of the paranodal loops. Furthermore, these animals show a disturbed accumula-

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tion of potassium channels in the juxtaparanodal region which is the region adjacent to the paranodal region, providing evidence that the correct formation of septate like junctions is the basis for correct potassium channel assembly during myelination [3, 5]. A further group of molecules expressed in the paranodal region are members of the cadherin/catenin complex. They are expressed between paranodal loops of the same Schwann cell and are known to be involved in the establishment of adherens junctions [9, 29]. E-cadherin and beta-catenin are colocalized in the paranodal loops [9]. E-cadherin deficiency does not result in disturbance of the formation of paranodal loops [39]. Thus, the function of the cadherin/catenin complex is not understood so far. Other proteins expressed in the paranodal region are claudin and PAR3 which are associated with the formation of tight junctions [21].

1.2.4 The juxtaparanodal region The juxtaparanodal region of the myelinated nerve fiber is specified by the accumulation of delayed rectifying potassium channels as Kv1.1 and Kv1.2 [23, 24, 37, 38]. These channels form tetramers and are located in the axon. The distribution of these channels is tightly dependent on the correct localization of paranodally expressed caspr1. Caspr2, a homologue to caspr1, is localized in the juxtaparanodal compartment. Caspr2 and Kv1.1 and Kv1.2 may be linked to each other by a PDZ domain. Functionally potassium channels at the juxtaparanodal region are necessary for normal impulse generation in the axon since the deficiency for Kv1.1 in mice showed abnormal impulse generation near the neuromuscular junctions [30, 41].

1.3 Unmyelinated nerve fibers Unmyelinated nerve fibers have a diameter between 0.2 and 3 lm. In contrast to the myelinated fiber bundles unmyelinated fiber bundles are accompanied by a single Schwann cell. Unmyelinated fibers lack the above described organization of proteins found in myelinated fibers. Unmyelinated fibers are packed into bundles by unmyelinating Schwann cells. Accumulation of ion channels is not observed and proteins which take part in fiber bundling are not well described so far.

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References 1. Arroyo EJ, Xu YT, Zhou L, Messing A, Peles E, Chiu SY, Scherer SS (1999) Myelinating Schwann cells determine the internodal localization of Kv1.1, Kv1.2, Kvbeta2, and Caspr. J Neurocytol 28:333±347 2. Balice-Gordon RJ, Bone LJ, Scherer SS (1998) Functional gap junctions in the schwann cell myelin sheath. J Cell Biol 142:1095±1104 3. Bhat MA, Rios JC, Lu Y, Garcia-Fresco GP, Ching W, St Martin M, Li J, Einheber S, Chesler M, Rosenbluth J, Salzer JL, Bellen HJ (2001) Axon-glia interactions and the domain organization of myelinated axons requires neurexin IV/Caspr/Paranodin. Neuron 30:369±383 4. Boiko T, Rasband MN, Levinson SR, Caldwell JH, Mandel G, Trimmer JS, Matthews G (2001) Compact myelin dictates the differential targeting of two sodium channel isoforms in the same axon. Neuron 30:91±104 5. Boyle ME, Berglund EO, Murai KK, Weber L, Peles E, Ranscht B (2001) Contactin orchestrates assembly of the septate-like junctions at the paranode in myelinated peripheral nerve. Neuron 30:385±397 6. Caldwell JH, Schaller KL, Lasher RS, Peles E, Levinson SR (2000) Sodium channel Na(v)1.6 is localized at nodes of ranvier, dendrites, and synapses. Proc Natl Acad Sci USA 97:5616±5620 7. D'Urso D, Brophy PJ, Staugaitis SM, Gillespie CS, Frey AB, Stempak JG, Colman DR (1990) Protein zero of peripheral nerve myelin: biosynthesis, membrane insertion, and evidence for homotypic interaction. Neuron 4:449±460 8. Einheber S, Zanazzi G, Ching W, Scherer S, Milner TA, Peles E, Salzer JL (1997) The axonal membrane protein Caspr, a homologue of neurexin IV, is a component of the septate-like paranodal junctions that assemble during myelination. J Cell Biol 139:1495±1506 9. Fannon AM, Sherman DL, Ilyina-Gragerova G, Brophy PJ, Friedrich VL, Jr, Colman DR (1995) Novel E-cadherin-mediated adhesion in peripheral nerve: Schwann cell architecture is stabilized by autotypic adherens junctions. J Cell Biol 129:189±202 10. Filbin MT, Walsh FS, Trapp BD, Pizzey JA, Tennekoon GI (1990) Role of myelin P0 protein as a homophilic adhesion molecule. Nature 344:871±872 11. Fjell J, Hjelmstrom P, Hormuzdiar W, Milenkovic M, Aglieco F, Tyrrell L, Dib-Hajj S, Waxman SG, Black JA (2000) Localization of the tetrodotoxin-resistant sodium channel NaN in nociceptors. Neuroreport 11:199±202 12. Friede RL, Samorajski T (1968) Myelin formation in the sciatic nerve of the rat. A quantitative electron microscopic, histochemical and radioautographic study. J Neuropathol Exp Neurol 27:546±570 13. Hess A, Young JZ (1952) The nodes of Ranvier. Proc R Soc Lond B Biol Sci 140:301±320 14. Ichimura T, Ellisman MH (1991) Three-dimensional fine structure of cytoskeletalmembrane interactions at nodes of Ranvier. J Neurocytol 20:667±681 15. Kaplan MR, Cho MH, Ullian EM, Isom LL, Levinson SR, Barres BA (2001) Differential control of clustering of the sodium channels Na(v)1.2 and Na(v)1.6 at developing CNS nodes of Ranvier. Neuron 30:105±119 16. Kordeli E, Lambert S, Bennett V (1995) AnkyrinG. A new ankyrin gene with neural-specific isoforms localized at the axonal initial segment and node of Ranvier. J Biol Chem 270:2352±2359 17. Lemke G, Axel R (1985) Isolation and sequence of a cDNA encoding the major structural protein of peripheral myelin. Cell 40:501±508

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18. Martini R, Mohajeri MH, Kasper S, Giese KP, Schachner M (1995) Mice doubly deficient in the genes for P0 and myelin basic protein show that both proteins contribute to the formation of the major dense line in peripheral nerve myelin. J Neurosci 15:4488±4495 19. Menegoz M, Gaspar P, Le Bert M, Galvez T, Burgaya F, Palfrey C, Ezan P, Arnos F, Girault JA (1997) Paranodin, a glycoprotein of neuronal paranodal membranes. Neuron 19:319±331 20. Michailov GV, Sereda MW, Brinkmann BG, Fischer TM, Haug B, Birchmeier C, Role L, Lai C, Schwab MH, Nave KA (2004) Axonal neuregulin-1 regulates myelin sheath thickness. Science 304:700±703 21. Poliak S, Matlis S, Ullmer C, Scherer SS, Peles E (2002) Distinct claudins and associated PDZ proteins form different autotypic tight junctions in myelinating Schwann cells. J Cell Biol 159:361±372 22. Previtali SC, Feltri ML, Archelos JJ, Quattrini A, Wrabetz L, Hartung H (2001) Role of integrins in the peripheral nervous system. Prog Neurobiol 64:35±49 23. Rasband MN, Trimmer JS, Peles E, Levinson SR, Shrager P (1999) K+ channel distribution and clustering in developing and hypomyelinated axons of the optic nerve. J Neurocytol 28:319±331 24. Rasband MN, Trimmer JS, Schwarz TL, Levinson SR, Ellisman MH, Schachner M, Shrager P (1998) Potassium channel distribution, clustering, and function in remyelinating rat axons. J Neurosci 18:36±47 25. Rios JC, Melendez-Vasquez CV, Einheber S, Lustig M, Grumet M, Hemperly J, Peles E, Salzer JL (2000) Contactin-associated protein (Caspr) and contactin form a complex that is targeted to the paranodal junctions during myelination. J Neurosci 20:8354±8364 26. Rios JC, Melendez-Vasquez CV, Einheber S, Lustig M, Grumet M, Hemperly J, Peles E, Salzer JL (2000) Contactin-associated protein (Caspr) and contactin form a complex that is targeted to the paranodal junctions during myelination. J Neurosci 20:8354±8364 27. Samorajski T, Friede RL (1968) A quantitative electron microscopic study of myelination in the pyramidal tract of rat. J Comp Neurol 134:323±338 28. Shapiro L, Doyle JP, Hensley P, Colman DR, Hendrickson WA (1996) Crystal structure of the extracellular domain from P0, the major structural protein of peripheral nerve myelin. Neuron 17:435±449 29. Shapiro L, Fannon AM, Kwong PD, Thompson A, Lehmann MS, Grubel G, Legrand JF, Als-Nielsen J, Colman DR, Hendrickson WA (1995) Structural basis of cell-cell adhesion by cadherins. Nature 374:327±337 30. Smart SL, Lopantsev V, Zhang CL, Robbins CA, Wang H, Chiu SY, Schwartzkroin PA, Messing A, Tempel BL (1998) Deletion of the K(V)1.1 potassium channel causes epilepsy in mice. Neuron 20:809±819 31. Smith KJ, Blakemore WF, Murray JA, Patterson RC (1982) Internodal myelin volume and axon surface area. A relationship determining myelin thickness? J Neurol Sci 55:231±246 32. Streicher R, Stoffel W (1989) The organization of the human myelin basic protein gene. Comparison with the mouse gene. Biol Chem Hoppe Seyler 370:503±510 33. Suter U, Scherer SS (2003) Disease mechanisms in inherited neuropathies. Nat Rev Neurosci 4:714±726 34. Tait S, Gunn-Moore F, Collinson JM, Huang J, Lubetzki C, Pedraza L, Sherman DL, Colman DR, Brophy PJ (2000) An oligodendrocyte cell adhesion molecule at the site of assembly of the paranodal axo-glial junction. J Cell Biol 150:657±666 35. Trapp BD (1990) Myelin-associated glycoprotein. Location and potential functions. Ann NY Acad Sci 605:29±43

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36. Trapp BD, Hauer P, Lemke G (1988) Axonal regulation of myelin protein mRNA levels in actively myelinating Schwann cells. J Neurosci 8:3515±3521 37. Vabnick I, Shrager P (1998) Ion channel redistribution and function during development of the myelinated axon. J Neurobiol 37:80±96 38. Wang H, Kunkel DD, Martin TM, Schwartzkroin PA, Tempel BL (1993) Heteromultimeric K+ channels in terminal and juxtaparanodal regions of neurons. Nature 365:75±79 39. Young P, Boussadia O, Berger P, Leone DP, Charnay P, Kemler R, Suter U (2002) E-cadherin is required for the correct formation of autotypic adherens junctions of the outer mesaxon but not for the integrity of myelinated fibers of peripheral nerves. Mol Cell Neurosci 21:341±351 40. Young P, Suter U (2003) The causes of Charcot-Marie-Tooth disease. Cell Mol Life Sci 60:2547±2560 41. Zhou L, Zhang CL, Messing A, Chiu SY (1998) Temperature-sensitive neuromuscular transmission in Kv1.1 null mice: role of potassium channels under the myelin sheath in young nerves. J Neurosci 18:7200±7215

Approach to the patient with suspected hereditary neuropathy

2 Clinical evaluation

and differential diagnosis R. Kiefer, E. B. Ringelstein

Introduction Many clinicians experience the evaluation of patients with peripheral neuropathy as challenging and sometimes non-rewarding. While the clinical diagnosis of a length-dependent sensorimotor peripheral neuropathy is easily made by experienced neurologists, the cause of the disorder may remain unresolved in many cases despite extensive workup. Furthermore, some peripheral neuropathies may present with clinical features which are not easily recognized to be derived from disorders of the peripheral nerve at all. Thus, multifocal and pure motor neuropathic syndromes may be confused with myopathies or motor neuron disease, and neuropathies involving the cranial nerves may mimic brainstem diseases. Others may have additional involvement of central nervous system structures or may be accompanied by specific features in the general examination of the body such as facial stigmata or alterations of the skin and internal organs. Therefore, even the localization of the patient's problem to the peripheral nervous system may not be obvious in some cases. The structure of peripheral nerves is relatively simple. The cellular components directly related to the innate function of peripheral nerves, which is transmission of signals from the central nervous system to the periphery of the body and back, are only axons and Schwann cells orientated longitudinally along the nerve. As a consequence, damage to peripheral nerves can result in only a limited number of clinical and pathological phenotypes despite a great variability of causes. It is this seemingly homogenous presentation of peripheral neuropathy which makes the differential diagnosis appear difficult to many. However, not all peripheral neuropathies look the same. A careful clinical look and an organized approach offer many possibilities to structure the differential diagnosis and narrow down possible causes of the patient's disease. Hereditary neuropathies, in particular, often have clinical features that are fairly specific and are easily recognized. This chapter offers a general approach to the patient with peripheral neuropathy, elaborates on specific aspects of the history and clinical examination of patients with various forms of hereditary neuropathies, and suggests a logical approach to establish a differential diagnosis in these patients [3, 5, 7].

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2.1 General approach to the patient with peripheral neuropathy Patients with peripheral neuropathy are first evaluated on clinical grounds. History and physical examination are the cornerstones on which a first clinical differential diagnosis is based. Diagnosticians of peripheral nerve disorders assess the patient's symptoms and signs along a pathway providing answers to the following questions (see also Table 2.1): 1. At what age were the first symptoms noted? 2. What is the time course of the disease? 3. Which fiber types are involved? 4. Which is the distribution of the deficits? 5. Is there any indication of inheritance? 6. Is there evidence of other concomitant diseases or specific non-neurological features? Each type of neuropathy is associated with specific features described by these six major categories, and each combination of answers to these six questions forms a clinical syndrome with a specific differential diagnosis. Three examples are given: A person of any age with acute and rapidly progressive proximal symmetric weakness, with little sensory involvement, without other affected family members, and with a preceding diarrhea may suffer from GuillainBarr syndrome. Another person with subacute onset of weakness and sensory deficits first in the distribution of the tibial nerve on one side and the ulnar nerve on the other followed by progressive involvement of additional individual nerves has multiple mononeuropathy and may suffer from vasculitis, to name just one possible cause of this syndrome. In contrast, if the onset of the multiple mononeuropathy started years ago, the course was relapsing-remitting, the deficits were triggered by repetitive movements in affected limbs, an underlying polyneuropathy existed, and other family members were also suffering from a similar disease, the patient may rather have hereditary neuropathy with pressure palsies (HNPP). There are many other neuropathic clinical syndromes. A complete listing of the differential diagnoses of the various neuropathy syndromes is beyond the scope of this chapter focusing on hereditary neuropathies. Obviously, the clinical syndrome of lifelong disease (item 2), first noted in youth or early adulthood (item 1), weakness and sensory loss (item 3) in a distal and symmetric distribution with peroneal preponderance (item 5), evidence of autosomal dominant inheritance (item 4) and the presence of hammertoes and pes cavus suggests a hereditary neuropathy, most likely CMT1 or 2. Once a clinical differential diagnosis is made, neurophysiological tests are applied next. Their aims are threefold: to confirm the presence of a polyneuropathy, to assess fiber type involvement and distribution patterns, and to determine the relative degree of demyelination and axonal damage.

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z

Table 2.1. Important clinical features for the initial categorization of a patient's neuropathy Item 1: Age at onset

Item 2: Course

z z z z z z z

z z z z z

birth infancy childhood adolescence young adulthood midlife advanced age

acute subacute chronic-progressive lifelong relapsing-remitting

Item 3: Fiber types involved

Item 4: Inheritance

z pure motor z pure sensory ± pain and temperature ± light touch, vibration and position senses z pure autonomic z combinations of the above

z z z z

Item 5: Distribution of deficits

Item 6: Concomitant conditions

z z z z z z z z z

z z z z z z z z z z z

length-dependent (distal-symmetric) proximal symmetric marked asymmetry one nerve or multiple individual nerves radicular nerve plexus cranial nerves additional CNS symptoms and signs combinations of the above

autosomal dominant autosomal recessive X-linked none

diabetes mellitus renal or liver disease rheumatic disease and vasculitis malignancy gastrointestinal disorders malnutrition ocular disorders hearing loss alcohol and drug abuse neurotoxic drugs others

The role of clinical neurophysiology is discussed in detail in the next chapter. Once the neurophysiological examination is completed, a clearer picture of the differential diagnosis should have emerged, and discrimination between an axonal and a demyelinating neuropathy might have been achieved. In the third step, the cause of the neuropathy is sought. Based on the differential diagnosis drawn from the recognition of the specific clinical neuropathy syndrome and neurophysiological tests, laboratory studies, in-

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vestigations of other organ systems to determine concomitant disease, genetic studies, and nerve or skin biopsy are performed as needed. In certain hereditary neuropathies, the clinical picture together with the results from neurophysiological tests is already sufficiently clear to suggest a specific diagnosis [4, 6]. In such cases, one single genetic test may be all that is needed to confirm the diagnosis. A rational approach to genetic testing is described in the chapter ªMolecular genetic diagnosis of hereditary neuropathiesº of this book. In the fourth and final step of this general approach, the consequences of the now established diagnosis are structured and discussed with the patient. Whenever possible, specific treatments and symptomatic measures are initiated. Examples are immunotherapy for inflammatory neuropathies and treatment of neuropathic pain. When no specific therapy is available, the patient still needs to be informed about the nature of his or her illness and the perspectives. Physiotherapy and specific rehabilitative measures may be needed. In patients with hereditary neuropathy, genetic advice needs to be provided (see chapter: ªGenetic Counselingº).

2.2 Specific features in the history of patients with hereditary neuropathies 2.2.1 Chief complaint and functional deficits noted by the patient Patients may seek medical advice for a number of different reasons which vary depending on the type of hereditary neuropathy. The most common causes of seeking medical advice are summarized in Table 2.2. It should always be remembered that only CMT1A and B, CMTX, CMT2 and HNPP are diseases which are regularly encountered in neurological practice, while all other forms are extremely rare and may occur only in certain populations. The most common chief complaint in patients with hereditary neuropathy is disturbance of gait. Gait may be impaired due to weakness, proprioceptive loss, foot deformity or contracture of the Achilles tendon. Patients may fall over their feet due to weakness of peroneal muscles, while the ability to stand on the toes is usually preserved for some time. Walking on uneven ground may become difficult with distal weakness, and frequent ankle sprains may be another consequence of distal weakness. Proximal weakness is indicated by complaints of difficulties climbing stairs or raising from a chair. Proximal weakness, however, is an unusual feature of hereditary neuropathy and occurs only late in the disease in few cases, with the exception of the most severe forms such as Djerine-Sottas syndrome (DSS), some forms of CMT4 and the very rare hereditary motor and sensory neuropathy proximal type (HMSN-P) and is otherwise rather suggestive of acquired inflammatory polyradiculoneuropathy.

2 Clinical evaluation and differential diagnosis

z

Table 2.2. Common presenting complaints in patients with hereditary neuropathies CMT and distal HMN phenotype z Disturbance of gait z Weakness z Sensory loss (not distal HMN) z Foot deformities HNPP and HNA phenotype z Recurrent focal weakness z Foot deformities z Shoulder pain (HNA) HSAN phenotype (rare) z Pain z Excessive or lost sweating All hereditary neuropathies z Affected family members

Weakness of the hands with difficulties in writing, turning a key or grasping fine objects is rarely the presenting complaint in hereditary neuropathy but may occur later in the course of the disease. Exceptions are patients with CMT2D and the hereditary motor neuropathies type 5 (HMN V) as well as HMN VIIB whose illness begins in the hands with initially normal function of the legs. Progressive muscle wasting of the lower legs or hands may be another chief complaint while weakness may not have been noted. While the above complaints are typical for CMT and distal HMN patients, patients with HNPP usually report disturbances of gait due to uni- or bilateral peroneal palsy. Other peripheral nerves of the lower limb are less frequently affected, and quadriceps weakness is not a usual feature of this disease. Patients with HNPP may also complain of acute weakness and sensory loss in one or both arms which only on physical examination turn out to follow the distribution of individual nerves, mostly the ulnar nerve. Weakness is frequently triggered by repetitive movements, forced positions of the affected limbs for a prolonged period of time, or minor pressure on the nerve along its course. Further questioning may reveal similar insults at earlier times and evidence of an additional generalized neuropathy, the symptoms of which may only be reported when specifically asked for. Also, the history may reveal the preexisting diagnoses of multiple entrapment syndromes or surgery for carpal tunnel syndrome. In hereditary neuralgic amyotrophy (HNA), weakness is rarely the presenting complaint, but rather severe shoulder pain, followed by weakness and atrophy within days to weeks. Usually the pain subsides while weakness and atrophy set in. Sensory deficits in CMT patients add to postural imbalance and gait disturbance which are accentuated in the dark. Sensory loss may, however, go

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unnoticed for many patients with CMT, particularly in CMT2. Some patients may even insist on feeling normal sensation despite having total loss of vibration sense at the toes and severe sensory abnormalities on neurophysiological testing. The history alone may therefore not provide the necessary clues to differentiate between CMT and distal SMA. The very slow occurrence of deficits is the likely cause of unnoticed sensory loss in CMT and is a suggestive feature differentiating it from acquired neuropathies of shorter duration. In HNPP, sensory loss is focally distributed along the sensory fields of individual peripheral nerves. In addition, there may be distal sensory loss similar to that in CMT patients due to the underlying generalized neuropathy in HNPP. Pain is a prominent complaint in hereditary sensory and autonomic neuropathy type 1 (HSAN1). Also, it is highly characteristic of HNA where acute onset of uni- or bilateral shoulder pain is the chief complaint followed by weakness. Specific questioning may reveal similar episodes in the past. Loss of pain and distal loss of sweating are characteristics of HSAN except HSAN3 where excessive sweating is a feature. Some HSAN patients may also present because of poor wound healing and painless ulcers, or mutilations. Foot deformities including hammertoes and pes cavus are another frequent cause to seek medical advice, and such patients may first be seen by orthopedic surgeons rather than neurologists. When evaluating patients with longstanding polyneuropathy, a history of orthopedic surgery on the feet and ankles in earlier days may suggest a hereditary neuropathy. Foot deformities are seen in CMT1 and 2, CMTX, distal HMN patients and less frequently in HNPP. Finally, patients with affected family members may seek medical advice despite the absence of any physical complaints to find out whether they are also affected, and to obtain genetic counseling. In some individuals, the illness may then be detected by physical examination and neurophysiological testing.

2.2.2 Onset and time course of disease Although a lifelong disease, patients with CMT and distal HMN usually do not seek medical advice before the end of the first decade or in the second decade. Earlier onset points towards severe disease such as DSS, in which weakness is often present from birth, or one of the forms of CMT4. On the other hand, onset may be so insidious and progression so slow that it may remain unnoticed for many years. Some symptoms may only retrospectively be recognized when specifically asked for. In neuropathy patients with suspected hereditary neuropathy, it is therefore very important to specifically ask for early symptoms during childhood and adolescence and inquire about indirect hints for abnormal function. Low physical activity as

2 Clinical evaluation and differential diagnosis

z

a child or a dislike for wild play may provide clues, as do poor grades in sports at school. Affected persons will frequently report that they always had been slower than their peers. A child regularly assigned as goalkeeper when playing soccer may indicate poor running abilities. It may also be remembered that the feet looked funny from the early days and that shoes that fit were always difficult to buy, indicating that foot deformities had preexisted for years. In contrast, patients with HNPP and HNA may have been healthy until the first bout of disease, but again, this needs to be specifically asked for and may have gone unnoticed at first.

2.2.3 Concomitant diseases Medical conditions causing acquired peripheral neuropathy should be sought for as part of establishing a differential diagnosis. Their existence does, however, not preclude hereditary neuropathy. The time course of the disease and characteristic elements of the physical examination may help distinguish between the two.

2.2.4 Family history A considerable number of patients have no family history of neuropathy, amounting to 20% in CMT1. A negative family history, therefore, does not preclude the diagnosis of hereditary neuropathy. Also, affected family members may not have even noted their disease. It is therefore necessary to specifically ask for weakness, gait disturbance, foot deformities and other features of the disease in family members. It is also mandatory to explore a complete family tree including brothers and sisters, the parents and their brothers and sisters, the cousins, and the grandparents. A large family who all lived until old age will be informative. On the other hand, the absence of affected family members does not exclude even an autosomal dominant genetic trait. Potentially informative family members may have died early or were lost for other reasons. This may be particularly true in populations where families were destroyed or dispersed during war times. Finally, adoption or false paternity may obscure a genetic trait. Another not uncommon possibility is that the disease is caused by a de novo mutation and therefore the patient is the first affected member of the family.

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2.3 Specific features in the clinical examination of patients with suspected hereditary neuropathy 2.3.1 Neurological examination The most prominent abnormalities refer to the motor and sensory systems affecting the extremities. Cranial nerve abnormalities, vocal cord and respiratory problems and additional CNS features are rare but nevertheless represent important and informative findings in classifying hereditary neuropathy. Among the cranial nerve abnormalities, optic atrophy may rarely occur in CMT patients. Sensorineural hearing loss can be associated with CMTX, some forms of CMT4 and in very rare cases in patients with CMT1A. Vocal cord paralysis is a peculiar attribute of CMT2C as well as some forms of CMT4 and distal HMN. These conditions are also associated with early respiratory failure. Weakness and muscle atrophy in CMT occurs typically in a length-dependent pattern and shows a preponderance of peroneal muscles. The small muscles of the foot and the peroneal muscles of the lower leg are affected first, followed by the thigh muscles. As an exception to that rule, CMT2D, HMN V and HMN VIIB patients show initial weakness in the hands. Weakness in the distribution pattern of one or more peripheral nerves suggesting multiple entrapment syndromes is the typical finding in HNPP. In addition, distal weakness is often found in older patients due to the underlying generalized neuropathy in HNPP. A careful and detailed examination is required to recognize asymmetry in such patients and to detect the preponderance of weakness in selected peripheral nerves. Proximal weakness occurs only in the most severe forms of disease such as in DSS, in some families with CMT4, in the extremely rare HMSN-P and in very advanced cases of distal hereditary neuropathies late in life. Weakness of respiratory muscles is also infrequent, but occurs in certain rare forms as mentioned above, or in advanced cases of the more common hereditary neuropathies. In HNA, the pattern of weakness is rather different. The asymmetric brachial plexopathy associated with HNA is best appreciated after a detailed examination of all proximal and distal muscles of the arm and shoulder region. Head flexors and extensors are not affected. There is, however, often marked winging of the scapula due to involvement of one or both long thoracic nerves. Sensory abnormalities are absent in distal HMN and follow the distribution of weakness in CMT and HNPP. In CMT, there is a length dependent loss of all modalities. Perception of vibration sense is reduced first, followed by loss of perception of light touch. In many cases, affected patients deny any sensory abnormalities which may only be detected by careful testing of vibration sense.

2 Clinical evaluation and differential diagnosis

z

Pain and temperature sensation are preferentially lost in HSAN1 and CMT2B, and are selectively absent in HSAN4. In contrast, all sensory modalities are affected in HSAN2. Spontaneous pain is very rare in CMT1, most forms of CMT2 and CMTX but is prominent in CMT2B and HSAN1. Thickening of peripheral nerves due to a hypertrophic neuropathy should always be sought for in suspected hereditary neuropathy. It is best palpated and seen at the greater auricular nerve in the neck and at the ulnar and peroneal nerves. It is sometimes a prominent feature in DSS and about one half of patients with CMT1, but not in CMT2 and CMTX. A postural tremor is observed in about one third of patients with CMT1. Autonomic disturbances may affect sweating, blood pressure control, urinary and fecal continence and sexual functions. They are features of some forms of HSAN and are rare in CMT. Muscle tendon reflexes are commonly lost. Ankle reflexes are lost first in most types of hereditary neuropathy. In CMT1, generalized reflex loss is found early, while in CMT2, the more proximal reflexes are preserved longer. In HNPP, distal or generalized reflex loss indicates advanced generalized neuropathy, while early cases may show reflex loss only in affected nerves. Exaggerated muscle tendon reflexes with positive pyramidal signs indicate additional pyramidal tract involvement and can be found in giant axonal neuropathy (GAN) and some forms of distal HMN.

2.3.2 General examination z Skin changes Painless ulcerations of the skin, unnoticed burns and painless injuries can be found in patients with HSAN as well as patients with CMT2B where the perception of pain may be severely impaired or absent. To detect such changes, it is important to carefully examine the feet and particularly the soles. Cases of HSAN may show severe disturbances of sweating, ranging from distal anhidrosis in HSAN2 to complete inability to sweat in HSAN4. Alternating hyperhidrosis and anhidrosis occurs in HSAN3. Absent fungiform papillae of the tongue are a feature of HSAN3. Curly hair reminiscent of little corkscrews in a child with neuropathy is highly suggestive of GAN.

z Skeletal abnormalities Foot deformities are almost universally present in CMT. Pes cavus and hammertoes are both observed but do not necessarily need to occur together. Absence of foot deformities makes CMT unlikely but does not entirely exclude the diagnosis. The reason for these deformities are tone im-

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balances of the small foot muscles as well as the long flexor and extensor muscles of the lower leg. While the toe extensors innervated by the peroneal nerve are disproportionately weak, the muscles at the sole of the foot and particularly the long toe flexors innervated by the tibial nerve are better preserved, leading to a high-arched foot and hammertoes. The hands may be deformed in a similar way, with a claw like appearance. Deformities of the spine with severe kyphoscoliosis point towards tone imbalance of the paraspinal muscles and are associated with very severe forms of CMT including DSS and some forms of CMT4. A high-arched palate points towards weak palatal muscles during early development and is rarely seen in hereditary neuropathy. It may, though, occur in GAN. Neurogenic arthropathy, stress fractures, osteolysis and osteomyelitis due to uncontrolled skin infection are consequences of impaired pain sensation in HSAN. In HSAN2 in particular, this may lead to severe distal deformities.

z Ocular features and hearing loss Ocular manifestations are not a frequent feature of the hereditary neuropathies covered in this book. However, optic atrophy may occur in CMT. Sensorineural hearing loss may be found rarely in CMTX, some rare forms of CMT4 and in rare cases of CMT1A.

2.4 Differential diagnosis in patients with suspected hereditary neuropathy 2.4.1 Distal symmetric leg weakness with peroneal preponderance This is the most common and characteristic clinical presentation of CMT. Together with peroneal atrophy, hammertoes and pes cavus and in the presence of sensory abnormalities, this presentation is highly suggestive for CMT and argues against most other forms of acquired or inherited sensorimotor polyneuropathies. Among the hereditary forms, the neuropathy of Refsum's disease may present in a similar way, although there is also a relapsing-remitting presentation. A diagnosis of Refsum's disease can be suggested clinically by the presence of ichthyosis of the skin, retinitis pigmentosa and other ocular signs, shortened phalanges of the fingers and toes, and cardiac arrhythmias [8]. A distinctive feature of CMT compared with acquired neuropathies is the observation that sensory deficits are frequently not noted by the patients. In many cases, they are only detected by careful sensory testing on physical examination. This is likely due to the extremely slow progression and

2 Clinical evaluation and differential diagnosis

z

long-standing disease. In contrast, acquired neuropathies with sensory involvement cause notable sensory deficits which frequently form the presenting complaint. Also, pain is hardly ever a feature of CMT, and the presence of a painful neuropathy raises doubts about this diagnosis. Weakness in acquired length-dependent neuropathies may also affect foot elevators more than foot flexors. However, the difference between the anterior and posterior compartment muscles of the lower leg is frequently not as marked as in inherited neuropathy. Apart from the presence of a high-arched foot and hammertoes (see below), contractures of the Achilles tendon are highly unusual in acquired neuropathies but are a distinctive feature of inherited neuropathies. Also, the time course of the disease, age at onset and the presence of concomitant medical conditions may help to distinguish acquired from inherited neuropathies. If sensory symptoms and signs are completely absent, a diagnosis of distal HMN is suggested. In such purely motor cases, certain myopathies affecting peroneal muscles need to be excluded. These include facioscapulohumeral muscular dystrophy, myotonic dystrophy, central core disease, other congenital myopathies, and Nonaka myopathy. In most cases, these disorders are easily distinguished because of other characteristic features in the history and physical examination. A helpful sign is the absence of atrophy of the extensor digitorum brevis muscle and the small muscles at the sole of the foot in many peroneal myopathies, while atrophy is always present in distal HMN.

2.4.2 Pes cavus and hammertoes Foot deformities typical for CMT are not unique for this group of disorders, nor are they always present. Pes cavus und hammertoes do not necessarily need to occur together. Since the deformities are caused by longstanding dysbalance of muscle tone between peroneal and tibial muscles of the lower leg, other conditions causing such an imbalance may also result in pes cavus and/or hammertoes. These include other inherited neuropathies like Refsum's disease and certain myopathies as mentioned above, but also central nervous system disorders. Since central paraparesis of the lower legs leaves muscle force acting against gravity better preserved, foot flexors are stronger than foot elevators in a centrally paretic leg. Hence, genetic disorders causing slow degeneration of pyramidal tracts such as hereditary spastic paraplegia and Friedreich ataxia may also cause higharched feet and hammertoes. Although these deformities are characteristic of genetic disorders, they can also rarely occur in acquired disease. Very occasionally, patients with acquired distal polyneuropathy and peroneal involvement will report that their toes become slowly bent with time and the interphalangeal joints come up. Pes cavus is not a usual feature of acquired spasticity due to spinal cord or cerebral lesions.

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Pes cavus and hammertoes can also occur in the absence of any detectable neurological deficit. In rare cases, familial foot deformities have been described.

2.4.3 The HNPP phenotype The hallmark of HNPP is the occurrence of recurrent sensorimotor deficits in individual nerves, typically provoked by minor nerve trauma or compression. The most important differential diagnosis is that of common pressure palsies, e.g., of the ulnar nerve at the elbow, of the median nerve in the carpal tunnel and of the peroneal nerve at the fibular head. Hints towards HNPP are the mild degree of trauma causing the pressure palsy, the frequently recurring pressure palsies, and a positive family history. Furthermore, the presence of an underlying generalized demyelinating polyneuropathy points towards HNPP. It should, however, be noted that generalized neuropathies of other causes such as amyloid neuropathy and diabetic neuropathy may vice versa predispose to pressure palsies, particularly in the carpal tunnel. Other sensorimotor multiple mononeuropathies may need to be considered. These include vasculitis of the peripheral nerve, sarcoidosis, leprosy, lymphomatous polyneuropathy, and multifocal acquired demyelinating sensory and motor neuropathy, a multifocal variant of chronic inflammatory demyelinating polyneuropathy. All the above disorders are usually progressive rather than recurrent, and do not present as pressure palsies. Also, concurrent medical disease will be indicative in some cases. Multifocal motor neuropathy is easily differentiated by the lack of sensory symptoms and is a progressive disease.

2.4.4 The HNA phenotype Recurrent shoulder pain followed by brachial plexopathy is the main clinical feature of HNA. A first and single episode is clinically indistinguishable from sporadic neuralgic amyotrophy or Parsonage-Turner syndrome. However, neuralgic amyotrophy rarely occurs before the third decade and is seen until old age, while HNA may occur in children and in most cases the onset is before 30 years. HNA is sometimes associated with facial dysmorphic features like hypotelorism, epicanthus and cleft palate while these are not associated with Parsonage-Turner syndrome. Other conditions to be considered are infiltrative disorders of the brachial plexus, which are highly unlikely in bilateral disease. Myopathies affecting the periscapular muscles may cause secondary shoulder pain but are rarely difficult to differentiate. Compression injury of the long thoracic nerve causes scapular winging, but no other evidence of plexopathy is found. Tangier disease has also been reported to present in this way.

2 Clinical evaluation and differential diagnosis

z

2.4.5 Pain and the sensory abnormalities of HSAN Most acquired painful neuropathies, including diabetic neuropathy, HIV-associated neuropathy, vasculitic neuropathy and acquired amyloid neuropathy, are usually disorders of adults. In contrast, the HSAN family of painful neuropathies manifests in nearly all cases very early in life, with the exception of HSAN1 presenting not before the second or third decade. However, even in HSAN1, the clinical features are sufficiently distinct to avoid confusion. Transthyretin amyloid neuropathy is a rare painful neuropathy with additional autonomic involvement [1]. However, age at onset is older, and motor nerves are also affected. There are also distinctive non-neurological manifestations, including severe heart disease and various ocular manifestations. Fabry's disease presents in adolescence with burning limb pain in the absence of other symptoms and signs of neuropathy. The presence of cutaneous angiokeratomas, cardiac arrhythmias, characteristic ocular manifestations and renal failure help to identify this disease [2]. The neuropathy of Tangier disease may present with pain in a peculiar distribution over the chest and neck with sparing of the legs and sometimes manifests in childhood. There is multiorgan involvement with hepatomegaly and a characteristic yellowish-orange discoloration of enlarged and lobulated tonsils [6].

2.4.6 Nerve hypertrophy Nerve hypertrophy belongs to the most distinctive features of CMT1 and DSS. Very few other neuropathies cause nerve hypertrophy. Lepromatous neuropathy is the most prevalent neuropathy causing enlarged peripheral nerves in some parts of the world. Refsum's disease also causes nerve thickening.

References 1. Adams D (2001) Hereditary and acquired amyloid neuropathies. J Neurol 248:647± 657 2. Brady RO, Schiffmann R (2000) Clinical features of and recent advances in therapy for Fabry disease. JAMA 284:2771±2775 3. Dyck PJ, Grant IA, Fealey RD (1996) Ten steps in characterizing and diagnosing patients with peripheral neuropathy. Neurology 47:10±17 4. Kuhlenbåumer G, Young P, Hunermund G, Ringelstein B, Stogbauer F (2002) Clinical features and molecular genetics of hereditary peripheral neuropathies. J Neurol 249:1629±1650 5. McLeod JG (1995) Investigation of peripheral neuropathy. J Neurol Neurosurg Psychiatry 58:274±283

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6. Pareyson D (2003) Diagnosis of hereditary neuropathies in adult patients. J Neurol 250:148±160 7. Rosenberg NR, Portegies P, de Visser M, Vermeulen M (2001) Diagnostic investigation of patients with chronic polyneuropathy: evaluation of a clinical guideline. J Neurol Neurosurg Psychiatry 71:205±209 8. Wanders RJ, Jansen GA, Skjeldal OH (2001) Refsum disease, peroxisomes and phytanic acid oxidation: a review. J Neuropathol Exp Neurol 60:1021±1031

3 Electrodiagnostic evaluation

of hereditary polyneuropathies M. Mçller

This chapter will first give some general considerations of electrodiagnostics in hereditary polyneuropathies. The electrophysiological features of different types of hereditary polyneuropathies will then be discussed.

3.1 General considerations An electrophysiological examination is an important step in assessing a patient with suspected hereditary neuropathy and is necessary to plan rational genetic testing. Nerve conduction studies are the cornerstones of the electrophysiological investigation if a hereditary neuropathy is suspected. The main goal is to distinguish between a demyelinating and an axonal type of pathology or to provide evidence for an intermediate process [6, 13]. Together with the clinical examination and the patient's history, the electrophysiology should also help to exclude acquired neuropathies. A complete neuromuscular examination is necessary to plan the electrophysiological tests and to choose the right nerves and muscles to examine.

3.2 Electrodiagnostic evaluation of hereditary polyneuropathies Physical examination and a comprehensive history of a patient with a suspected hereditary neuropathy are fundamental in order to plan the following electrophysiological evaluation. Detailed information can be found in the previous chapter of this book. The complete electrodiagnostic evaluation should provide necessary information to determine whether the disorder primarily affects the axon, the myelin sheath or both. In addition, the involvement of sensory nerve fibers, motor fibers or both types of fibers should be clarified. This is essential to choose reasonable genetic tests for the patient (Table 3.1). Nerve conduction studies are the most important part of the electrodiagnostic workup. At least three sensory nerves (e.g., sural, median and

both sensory and motor

primarily axonal damage

demyelinating and axonal damagemotor > sensory in variable degree

z CMT2

z DI-CMT

both sensory and motor

severe demyelinating and secondary axonal damage

severe myelinating deficit and secondary axonal damage

axonal damage

both axonal and demyelinating damage

z DSS

z CH

z HSAN

z HNPP

both sensory and motor

sensory

both sensory and motor

demyelinating and axonal damage in variable degree

z CMTX

both sensory and motor

both sensory and motor

primarily demyelinating with secondary axonal damage

z CMT1

Fibers involved

conduction blocks and underlying diffuse demyelination of mainly sensory fibers

sensory and/or autonomic impairment with preserved motor system

severe reduction of NCV, CMAPs and SNAPs; diffuse distribution

severe reduction of NCV, CMAPs and SNAPs; diffuse distribution

both NCV slowing and reduction of CMAPs and SNAPs, heterogeneous in one nerve and between nerves of an individual; involvement of CNS pathways

NCVs between CMT1 and CMT2, reduction of CMAPs

reduction of CMAPs and SNAPs with only minor NCV reduction, diffusely distributed. Pathologic discharges in EMG

slowing of NCVs, diffusely distributed

Electrophysiological hallmarks

differential diagnosis to CIDP and diabetic neuropathy is important

subtypes differ in their electrophysiological profile

clinical improvement over time without changed NCVs possible

clinical deterioration over time

conduction blocks possible

Comment

z

Pathology

Table 3.1. Electrodiagnostic features of hereditary polyneuropathies

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3 Electrodiagnostic evaluation of hereditary polyneuropathies

z

Fig. 3.1. Nerve conduction studies of a patient suffering from CMT1 and his healthy brother. MNCV from lower and upper extremities from patient suffering from CMT1. MNCVs are abundantly slowed and dispersed. The tibial nerve conduction is utterly dispersed which results in a low CMAP. The ulnar nerve conduction is less altered. The NCV is reduced while the CMAP is preserved. The F-waves of the tibial nerve are absent (A). In contrast, the MNCVs and the Fwaves (tibial nerve) of the healthy brother are normal (B)

ulnar nerve) and three motor nerves (e.g., peroneal, tibial and median nerve) should be examined. The results from the physical examination must be taken into account when choosing the nerves to be examined. As a rule for nerve conduction studies in general, impeccable technique and monitoring of skin temperature are mandatory to obtain meaningful data. To complete nerve conduction studies, the F-waves should be measured. Because of the long pathway measured by the F-waves, mild but diffuse peripheral nerve lesions can be detected very early and precisely. In contrast F-waves are often not well suited to measure lesions which affect only a short segment of the peripheral nerve. To confirm the results obtained in the nerve conduction studies, a needle electromyography is useful in patients with suspected hereditary peripheral neuropathy (Fig. 3.1). The primary aim of this examination is the detection of pathologic spontaneous and voluntary electrical activity. The electromyography substantiates the impression of axonal loss or demyelination derived from nerve conduction studies. Pathologic spontaneous discharges in the form of positive sharp waves and fibrillation potentials confirm suspected axonal damage but would be less common in a primarily demyelinating neuropathy. In addition, somatosensory and motor evoked potentials might be useful to confirm the nerve conduction findings.

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3.3 Electrodiagnostic features and differential diagnosis of different forms of hereditary polyneuropathies 3.3.1 Charcot-Marie-Tooth disease type 1 and 4 (CMT1/CMT4) Autosomal dominant CMT1 and autosomal recessive CMT4 are very similar in their electrophysiological profile. The hallmark is the marked reduction of motor nerve conduction velocities (MNCVs) to less than 38 m/s in upper limb nerves, usually defined by MNCV reduction in the ulnar nerve. The borderline NCV value of 38 m/s was defined by A.E. Harding and P.K. Thomas who could discriminate CMT1 and CMT2 by an MNCV of 38 m/s [13], but it is notable that some genetically confirmed CMT1 patients have NCVs over 40 m/s [16, 17]. Therefore, the MNCVs in CMT1 may vary widely between 9 m/s and 41 m/s. Typically, MNCVs are around 25 m/s. MNCV reduction is significantly more severe in the rare autosomal recessive forms of CMT1 which are named CMT4 [13]. The distribution of the NCV reduction is typically diffuse and uniform. Sensory nerve action potentials (SNAPs) particularly of the lower limbs may be absent. In this case, near nerve needle recordings may help to obtain a result and to discriminate between sensory axonal and sensory demyelinating events. If measurable, the SNAPs show marked temporal dispersion. The compound motor action potentials (CMAPs) of the lower limbs are sometimes not recordable when registered from the M. extensor digitorum brevis or M. abductor hallucis longus but may still be recordable from the more proximal anterior tibial muscle showing a markedly prolonged response. Stimulation at different sites usually shows a well preserved waveform without marked reduction in amplitude. Distal motor latencies are prolonged in both upper and lower extremities. In addition to the pathologic NCVs and CMAPs, Fwaves are often absent or delayed. There is no overlap in NCVs between affected individuals and their healthy relatives indicating complete genetic penetrance from early childhood [26]. In affected individuals, the NCVs are normal or only slightly reduced at birth but reach rapidly their minimum during the first five years of life [12, 35]. The typical clinical symptoms may not occur until the second decade of life. In a six month old child without clinical abnormalities and with a normal electrophysiology, CMT1 is practically excluded. Later on the NCVs remain stable or decreases only slightly over the decades [18]. Cranial nerves are sometimes involved in patients with longstanding CMT1. The facial nerve's motor latency will then be prolonged up to three times of the control value [19]. Corresponding pathologic blink reflexes typically demonstrate that efferent, facial nerve fibers are more impaired than the afferent trigeminal fibers. CMT patients might have reduced pulmonary function secondary to diaphragmatic dysfunction. In these cases, a phrenic nerve conduction study and electromyography of the diaphragm may help to clarify the diagnosis [8].

3 Electrodiagnostic evaluation of hereditary polyneuropathies

z

In contrast to CMT2, electromyographic abnormalities are not necessarily prominent. Corresponding to the increasing axonal damage and CMAP reduction in the course of disease there are signs of a neurogenic lesion with increased insertional activity, spontaneous activity, large and polyphasic motor unit potentials with limited recruitment. Regarding the recruitment of motor units, a study in patients with genetically confirmed 17p11.2 duplication demonstrated a reduced recruitment in all patients examined [33]. There are some reports on central pathway involvement in CMT1, detected by acoustically or visually evoked potentials [7, 20, 28]. The genetic status in these studies has not been clarified for all patients. It is, therefore, possible that patients with other types of CMT in which CNS involvement is more common (e.g., CMTX) were included in some of these studies. Corresponding to the demyelinating process somatosensory evoked potentials (SSEPs) are typically symmetrically prolonged and correlated with motor nerve impairment. Central conduction times are normal [28].

3.3.2 Charcot-Marie-Tooth disease type 2 (CMT2) CMT2 is not clearly distinguishable from CMT1 by clinical criteria. An electrophysiological workup is necessary to clarify the diagnosis. In contrast to CMT1 where NCVs are commonly uniformly reduced, the NCVs in CMT2 are typically above 38 m/s in upper limb nerves [4, 13]. SNAP and CMAPs are significantly reduced [4, 13]. If SNAPs are not detectable by routine methods, near-nerve needle recordings may be useful to detect small SNAPs which should demonstrate well preserved SNCVs in CMT2. Sensory deficits are usually less severe than the motor deficit. The distal motor latency is expected to be normal or mildly increased. Axillary and facial nerve conduction studies which are often impaired in CMT1 are not affected in CMT2 [11]. This is helpful to distinguish between the two neuropathic entities. Corresponding to the axonal damage, electromyographic studies show large motor unit potentials, fasciculation potentials, fibrillation potentials, and positive sharp waves. Complex repetitive discharges can be observed in some patients with CMT2. Involvement of the phrenic nerve in a CMT2 patient with hoarseness was described. The different mutations leading to a CMT2 phenotype may also have different electrophysiological profiles. CMT2A patients which have most often a mutation in the mitochondrial GTPase mitofusin 2 typically have reduced CMAPs and nearly normal NCVs (MNCV at median nerve 40±62 m/s) [37], whereas patients with CMT2E, caused by mutations in the neurofilament light chain gene, have reduced CMAPs and NCVs which vary widely. Autosomal recessive CMT2 is extremely rare and is characterized by a severe axonal damage and correspondingly reduced CMAPs which are often impossible to elicit distally.

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3.3.3 Dominant intermediate CMT (DI-CMT) Members of families with DI-CMT have MNCVs which are in between the NCVs measured in patients with CMT1 and CMT2. MNCVs are reported to be between 25 and 45 m/s. CMAP amplitudes are often severely reduced.

3.3.4 Charcot-Marie-Tooth disease X chromosomal (CMTX) CMTX caused by mutations in the GJB1 gene is the second most common form of CMT. Other forms of CMTX are exceedingly rare and often only a single family is known. Therefore, they are not discussed in this chapter. The electrophysiological characteristics of CMTX differ from the electrophysiological features found in other types of hereditary neuropathies. CMTX shows electrophysiological features of both demyelination and axonal loss. MNCV of the upper limb may vary between 18 and 60 m/s; the velocity is intermediate between CMT1 and CMT2 in males, and in the lower range of CMT2 (42±60 m/s) in females [25, 26]. SNCVs and SNAPs are also reduced. NCVs of different nerves in an affected person may vary significantly. In addition, demyelination of a single nerve trunk may be heterogeneous, leading to temporal dispersion and may even mimic a conduction block. CMAPs are typically reduced in the peripheral nerves. Regarding the CMAPs and the DMLs, which are prolonged, the median nerve is often more affected than the ulnar nerve. In contrast to most other types of HMSN, acoustically evoked potentials (AEP) may be delayed [24] and visual evoked potentials (VEP) [23] may also be impaired in CMTX. Some patients may have abnormalities in AEP, VEP and central motor evoked potentials (MEP) which might even be not recordable [2].

3.3.5 Djerine-Sottas syndrome (DSS) The term Djerine-Sottas syndrome (DSS) is used for very severe demyelinating CMT, originally with autosomal recessive inheritance. Today it is known that DSS is genetically heterogeneous. But DSS is still a useful term to describe a severe demyelinating hereditary neuropathy with early age of onset. The available data concerning the electrophysiology is collected primarily from case reports, because DSS is a very rare disease. In addition, it is difficult to examine these patients. Nerves of patients with DSS have a high stimulation threshold. Therefore, it is necessary to use long stimulus duration (around 500 ls) in combination with a high, often maximal, current to get a supramaximal stimulus. For the patient, this is an extraordinary torture because the pain sensation is usually relatively preserved in DSS. MNCVs are extremely reduced: MNCVs of the upper limb nerves are typically less than 10 m/s, sometimes around 1±2 m/s [3]. Distal motor la-

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tencies are severely increased. Comparing proximal to distal CMAPs, a temporal dispersion is observable. Due to axonal loss, CMAPs are often severely reduced. SNAPs are typically absent.

3.3.6 Congenital hypomyelination (CH) Congenital hypomyelination is a congenital disorder of myelination. In contrast to the severe demyelination in DSS, there is a primary myelination deficit in CH. CH is not distinguishable from DSS by electrophysiological properties. CMAPs are often not detectable at all or are severely reduced. NCVs are also severely reduced, while SNAPs are absent in both upper and lower limps. In contrast to DSS, clinical symptoms may improve over time without an increase of NCVs [27].

3.3.7 Hereditary motor neuropathies (dHMN) Distal hereditary motor neuropathies (dHMN) are characterized by distal paresis and atrophy without sensory loss or autonomic symptoms. The second motor neuron is the affected structure in dHMNs. In contrast to HMSN, mNCVs are usually normal. In some cases they are slightly reduced (35±60 m/s) related to the loss of large fibers and the CMAPs are reduced. The SNAPs are normal. Electromyography reveals typical signs of denervation which are most prominent in distal muscles. MUAPs may show high, so called ªneurogenicº potentials with an amplitude of over 10 mV. Pathologic spontaneous activity, consisting of fibrillations, complex repetitive discharges and positive sharp waves, is often observed [10, 13, 14].

3.3.8 Hereditary sensory and autonomic neuropathies (HSAN)/ hereditary sensory neuropathies (HSN) Autonomic and sensory disturbances with largely preserved motor function are the hallmark of the HSANs. HSANs are divided into five subgroups and these subgroups show some electrophysiological differences which may aid in the diagnosis. In general, HSANs are small fiber neuropathies which often display no pathologic findings in routine electrophysiological examinations. Quantitative sensory testing might be useful for clinical and research studies but not in a routine diagnostic setting [30]. The sympathetic skin response (SSR) is useful to examine postganglionic sympathetic axons. The SSR reflects sympathetic cholinergic sudomotor function which induces changes in skin resistance to electrical conduction. To record SSRs, electrodes should be placed on the palm or sole with the reference over the dorsum of the respective extremity. Many modalities of stimulation exist. We recommend an electrical impulse at the dorsum of the upper arm, with an intensity between

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30 and 50 milliampere (mA). For clinical purposes it is most important to determine whether the SSR is present or absent. It is important to know that the SSR follows a complex pathway which involves central structures and may, therefore, be disturbed by many factors apart from peripheral neuropathies. On the one hand, the reflex might be absent in healthy individuals, and, on the other hand, a normal SSR does not exclude autonomic disturbances. In conclusion, the diagnostic value of SSRs is limited [36]. HSAN type 1 is the most prevalent type with a typical degeneration of the dorsal root ganglions, early loss of SNAPs, and preserved sympathetic skin responses (SSR). Clinical findings in HSAN type 1 are lancinating spontaneous pain but loss of pain and temperature sensation elicited by external stimuli, areflexia and development of ulcers on the lower limbs but not on the upper limbs. There are only a few reports describing the electrophysiological features of the disease. SNAPs are absent in both upper and lower limbs. Motor nerve conduction velocities and CMAPs are normal or show minor involvement of the motor fibers. In contrast, perception of pain and temperature is severely impaired because of the dysfunction of Ad and C fibers. Detection of a small amount of spontaneous activity in electromyography may occur and represent the involvement of the motor system mentioned earlier [29]. HSAN type 2 affects both the lower and upper limbs. Nerve conduction studies always show a complete absence of SNAPs and borderline slow MNCVs. Some reports describe reduced CMAP amplitude in the peroneal nerve. In comparison to HSAN type 1, electrophysiological alterations are somewhat more severe than in HSAN type 2 but too similar to distinguish the two entities by electrophysiology [9, 32, 34]. Electromyography may reveal minimal fibrillation potentials and polyphasic motor action unit potentials. HSAN type 3, also called Riley-Day syndrome or familial dysautonomia (FD), is the most common form of HSAN and affects in the overwhelming majority of cases Ashkenazi Jews. It has recently been estimated that as many as 1 in 27 Ashkenazi Jews is a carrier of FD. The FD gene has been identified as IKBKAP, and two disease-causing mutations have been identified [21]. Peripheral autonomic and sensory neurons are involved. Signs of autonomic dysregulation and feeding problems may be already prominent in the neonatal period. Sensory symptoms appear later and in contrast to the other types of HSAN, autonomic dysfunction is prominent while only minor sensory disturbances occur. The available electrodiagnostic data are limited and do not reveal the presence of dramatic alterations in FD. Typically, MNCVs and the CMAP are moderately decreased [22]. In contrast to HSAN type 4, the sweat production and, therefore, the SSR is well preserved in HSAN type 3 [15]. HSAN type 4 and type 5 are clinically similar. They are very rare disorders with recurrent unexplainable fever, anhidrosis, self-mutilating behavior and mental retardation [31]. A defect in the NTRK1 gene leads to a nearly complete loss of unmyelinated fibers in HSAN type 4 and a loss of small myelinated fibers with a good preservation of unmyelinated fibers in HSAN type 5.

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3.3.9 Hereditary neuropathy with liability to pressure palsy (HNPP) HNPP manifests commonly between the second and fourth decade of life. Painless focal peripheral nerve lesions after a minimal nerve lesion occur, most often at sites where the nerve is exposed to pressure or at physiological entrapment sites. Compression palsy commonly affects the ulnar, radial and peroneal nerve, but isolated brachial plexopathy may also occur. Motor symptoms are prominent, although sensory symptoms may also appear. The electrophysiological profile in HNPP is especially important because it is quite different from the other HMSNs. In addition, HNPP can easily be misdiagnosed as an entrapment syndrome. Chronic inflammatory demyelinating neuropathy (CIDP) and diabetic neuropathy may have a similar electrophysiological pattern. Corresponding to the prominent clinical signs, electrophysiological abnormalities can be found. Conduction blocks, slowing of MNCVs, temporal dispersion and prolonged distal latencies are typical electrophysiological findings in HNPP. Focal conduction abnormalities are commonly found at physiological compression sites in paretic limbs but also in clinically unaffected nerves. Examination of normal nerves reveals nerve conduction abnormalities in most of the patients and some unaffected relatives. In contrast to entrapment syndromes in patients without a HNPP, signs of a generalized nerve conduction abnormality regularly occur in HNPP patients and are compatible with the diagnosis. Sensory NCVs are significantly more affected than MNCVs, which may help to discriminate HNPP from diabetic neuropathy or CIDP in which motor and sensory NCVs are equally affected [1].

3.3.10 Hereditary neuralgic amyotrophy (HNA) The clinical hallmark of HNA are relapsing-remitting, painful brachial plexus neuropathies which can be triggered by infections, delivery, trauma or even unusually strenuous exercise. Symptoms often occur with a delay of some days after exposure to the trigger factor. During the attack, electrophysiological signs of brachial plexus involvement are found in most cases. Clinical or electrophysiological signs of a generalized neuropathy are absent. A careful electrophysiological examination of the brachial plexus based on the clinical findings is mandatory. Nerve conduction studies should be performed including stimulation from proximal sites, e.g., stimulating arm nerves at the supraclavicular fossa, to detect brachial plexus lesions. An important parameter to evaluate in plexopathies is the CMAP amplitude. A drop in amplitude across a presumptive lesion site or in comparison to the other side suggests axonal loss or a conduction block. Upper limb SSEPs are useful to support the findings of the nerve conduction studies. Axonal damage in HNA can be confirmed by detection of spontaneous activity in the electromyographic examination. The pattern of muscle involvement does not match the distribution of a single peripheral nerve or spinal segment.

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The pattern of spontaneous activity in the examined upper limb muscles allows to narrow down the site of the lesion. But one has to take into account that spontaneous activity occurs with a delay of 1±6 weeks after the axonal damage.

3.3.11 Giant axonal neuropathy (GAN) Giant axonal neuropathy (GAN) is a rare disease affecting both PNS and CNS. It is traditionally listed and reviewed together with the hereditary neuropathies. The prognosis is poor. Most patients die before the age of 30 years. The lower extremity SNAPs are typically absent and the upper extremity SNAPs are reduced in amplitude. The NCVs and distal latencies are normal or only mildly affected. The data concerning needle electromyography is poor, but spontaneous activity, high amplitude, polyphasic MUAPs and reduced MUAP recruitment have been described [5].

References 1. Andersson PB, Yuen E, Parko K, So YT (2000) Electrodiagnostic features of hereditary neuropathy with liability to pressure palsies. Neurology 54:40±44 2. Bahr M, Andres F, Timmerman V, Nelis ME, Van Broeckhoven C, Dichgans J (1999) Central visual, acoustic, and motor pathway involvement in a Charcot-Marie-Tooth family with an Asn205Ser mutation in the connexin 32 gene. J Neurol Neurosurg Psychiatry 66:202±206 3. Benstead TJ, Kuntz NL, Miller RG, Daube JR (1990) The electrophysiologic profile of Dejerine-Sottas disease (HMSN III). Muscle Nerve 13:586±592 4. Berciano J, Combarros O, Figols J, Calleja J, Cabello A, Silos I, Coria F (1986) Hereditary motor and sensory neuropathy type II. Clinicopathological study of a family. Brain 109:897±914 5. Bruno C, Bertini E, Federico A, Tonoli E, Lispi ML, Cassandrini D, Pedemonte M, Santorelli FM, Filocamo M, Dotti MT, Schenone A, Malandrini A, Minetti C (2004) Clinical and molecular findings in patients with giant axonal neuropathy (GAN). Neurology 62:13±16 6. Brust JC, Lovelace RE, Devi S (1978) Clinical and electrodiagnostic features of Charcot-Marie-Tooth syndrome. Acta Neurol Scand 68 (Suppl):1±142 7. Carroll WM, Jones SJ, Halliday AM (1983) Visual evoked potential abnormalities in Charcot-Marie-Tooth disease and comparison with Friedreich's ataxia. J Neurol Sci 61:123±133 8. Carter GT, Kilmer DD, Bonekat HW, Lieberman JS, Fowler WM, Jr (1992) Evaluation of phrenic nerve and pulmonary function in hereditary motor and sensory neuropathy, type I. Muscle Nerve 15:459±462 9. Cavanagh NP, Eames RA, Galvin RJ, Brett EM, Kelly RE (1979) Hereditary sensory neuropathy with spastic paraplegia. Brain 102:79±94 10. De Jonghe P, Auer-Grumbach M, Irobi J, Wagner K, Plecko B, Kennerson M, Zhu D, De Vriendt E, Van Gerwen V, Nicholson G, Hartung HP, Timmerman V (2002) Autosomal dominant juvenile amyotrophic lateral sclerosis and distal hereditary

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motor neuronopathy with pyramidal tract signs: synonyms for the same disorder? Brain 125:1320±1325 Emeryk-Szajewska B, Badurska B, Kostera-Pruszczyk A (1998) [Hereditary sensorimotor neuropathy in electrophysiological studies]. Neurol Neurochir Pol 32:295±308 Gutmann L, Fakadej A, Riggs JE (1983) Evolution of nerve conduction abnormalities in children with dominant hypertrophic neuropathy of the Charcot-MarieTooth type. Muscle Nerve 6:515±519 Harding AE, Thomas PK (1980) The clinical features of hereditary motor and sensory neuropathy types I and II. Brain 103:259±280 Harding AE, Thomas PK (1984) Peroneal muscular atrophy with pyramidal features. J Neurol Neurosurg Psychiatry 47:168±172 Hilz MJ, Stemper B, Axelrod FB (1999) Sympathetic skin response differentiates hereditary sensory autonomic neuropathies III and IV. Neurology 52:1652±1657 Kaku DA, Parry GJ, Malamut R, Lupski JR, Garcia CA (1993) Nerve conduction studies in Charcot-Marie-Tooth polyneuropathy associated with a segmental duplication of chromosome 17. Neurology 43:1806±1808 Kaku DA, Parry GJ, Malamut R, Lupski JR, Garcia CA (1993) Uniform slowing of conduction velocities in Charcot-Marie-Tooth polyneuropathy type 1. Neurology 43:2664±2667 Killian JM, Tiwari PS, Jacobson S, Jackson RD, Lupski JR (1996) Longitudinal studies of the duplication form of Charcot-Marie-Tooth polyneuropathy. Muscle Nerve 19:74±78 Kimura J (1971) An evaluation of the facial and trigeminal nerves in polyneuropathy: electrodiagnostic study in Charcot-Marie-Tooth disease, Guillain-Barre syndrome, and diabetic neuropathy. Neurology 21:745±752 Kowalski JW, Rasheva M, Zakrzewska B (1991) Visual and brainstem auditory evoked potentials in hereditary motor-sensory neuropathy. Electromyogr Clin Neurophysiol 31:167±172 Leyne M, Mull J, Gill SP, Cuajungco MP, Oddoux C, Blumenfeld A, Maayan C, Gusella JF, Axelrod FB, Slaugenhaupt SA (2003) Identification of the first non-Jewish mutation in familial dysautonomia. Am J Med Genet A 118:305±308 Low PA, Burke WJ, McLeod JG (1978) Congenital sensory neuropathy with selective loss of small myelinated fibers. Ann Neurol 3:179±182 Marques W, Jr, Hanna MG, Marques SR, Sweeney MG, Thomas PK, Wood NW (1999) Phenotypic variation of a new P0 mutation in genetically identical twins. J Neurol 246:596±599 Nicholson G, Corbett A (1996) Slowing of central conduction in X-linked Charcot-Marie-Tooth neuropathy shown by brain stem auditory evoked responses. J Neurol Neurosurg Psychiatry 61:43±46 Nicholson G, Nash J (1993) Intermediate nerve conduction velocities define Xlinked Charcot-Marie-Tooth neuropathy families. Neurology 43:2558±2564 Nicholson GA, Yeung L, Corbett A (1998) Efficient neurophysiologic selection of X-linked Charcot-Marie-Tooth families: ten novel mutations. Neurology 51:1412± 1416 Phillips JP, Warner LE, Lupski JR, Garg BP (1999) Congenital hypomyelinating neuropathy: two patients with long-term follow-up. Pediatr Neurol 20:226±232 Scaioli V, Pareyson D, Avanzini G, Sghirlanzoni A (1992) F response and somatosensory and brainstem auditory evoked potential studies in HMSN type I and II. J Neurol Neurosurg Psychiatry 55:1027±1031 Shivji ZM, Ashby P (1999) Sympathetic skin responses in hereditary sensory and autonomic neuropathy and familial amyloid neuropathy are different. Muscle Nerve 22:1283±1286

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30. Shy ME, Frohman EM, So YT, Arezzo JC, Cornblath DR, Giuliani MJ, Kincaid JC, Ochoa JL, Parry GJ, Weimer LH (2003) Quantitative sensory testing: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 60:898±904 31. Swanson AG (1963) Congenital insensitivity to pain with anhydrosis. A unique syndrome in two male siblings. Arch Neurol 8:299±306 32. Tenembaum SN, Reisin RC, Taratuto AL, Fejerman N (1996) Spastic paraparesis and sensory neuropathy. Muscle Nerve 19:649±653 33. Thomas PK, Marques W, Jr, Davis MB, Sweeney MG, King RH, Bradley JL, Muddle JR, Tyson J, Malcolm S, Harding AE (1997) The phenotypic manifestations of chromosome 17p11.2 duplication. Brain 120 (Pt 3):465±478 34. Thomas PK, Misra VP, King RH, Muddle JR, Wroe S, Bhatia KP, Anderson M, Cabello A, Vilchez J, Wadia NH (1994) Autosomal recessive hereditary sensory neuropathy with spastic paraplegia. Brain 117 (Pt 4):651±659 35. Vanasse M, Dubowitz V (1981) Dominantly inherited peroneal muscular atrophy (hereditary motor and sensory neuropathy type I) in infancy and childhood. Muscle Nerve 4:26±30 36. Vetrugno R, Liguori R, Cortelli P, Montagna P (2003) Sympathetic skin response: basic mechanisms and clinical applications. Clin Auton Res 13:256±270 37. Zuchner S, Mersiyanova IV, Muglia M, Bissar-Tadmouri N, Rochelle J, Dadali EL, Zappia M, Nelis E, Patitucci A, Senderek J, Parman Y, Evgrafov O, Jonghe PD, Takahashi Y, Tsuji S, Pericak-Vance MA, Quattrone A, Battaloglu E, Polyakov AV, Timmerman V, Schroder JM, Vance JM (2004) Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat Genet 36:449±451

4 Principles of pathology

and nerve biopsy A. Schenone

Introduction Pathologic examination of peripheral nerves was the only valuable diagnostic tool for hereditary neuropathies, until molecular genetic diagnosis became available. In fact, after the original description of a duplication of chromosome 17p11.2, containing the gene coding for peripheral myelin protein 22 (PMP22), in Charcot-Marie-Tooth (CMT) neuropathy type 1A [59, 76], several other genes involved in the pathogenesis of the different types of CMT and of other inherited neuropathies have been discovered. The diagnosis of hereditary neuropathies now mostly depends upon the search for mutations in all the known genes. The diagnostic biopsy of a peripheral nerve is, therefore, limited to selected cases of unknown origin, in spite of a wide search for mutations in the most commonly involved genes. Typically, pathologic examination of peripheral nerves is reserved for sporadic cases where an inherited neuropathy is strongly suspected, but acquired neuropathies like chronic inflammatory demyelinating polyneuropathy (CIDP) need to be excluded. In general terms, a peripheral nerve has to be sampled in carefully selected patients only, because of the potential neurologic deficits following a nerve biopsy. Moreover, the diagnostic value of a nerve biopsy is influenced by: z the small amount of tissue removed; z the fact that very few nerves in the body are suitable for sampling; z the availability of a specialized laboratory to process and analyze the tissue; z the need of relating histologic measures with physiologic, biochemical and pharmacological results [26]. The nerve to biopsy has to be accurately chosen. It should be a cutaneous nerve affected by the neuropathic process, easily accessible to neurophysiologic studies prior to biopsy, constant and superficial in location. The sural nerve meets all these criteria [26]. Alternatively, the radial cutaneous nerve in the arms and the superficial peroneal nerve in the legs may be selected [78]. The sural nerve is a sensory nerve and contains, in the endoneurial space, the axonal processes of neurons located in the dorsal root ganglia,

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Fig. 4.1. Normal sural nerve. Semithin section showing a normal number of myelinated and unmyelinated fibers. The distribution of myelinated fibers is typically bimodal. Toluidine blue; bar: 15 lm

surrounded by myelinating and non-myelinating Schwann cells, and by fibroblasts (Fig. 4.1). Present in the epineurium, perineurium and endoneurium are also several blood vessels, whose examination may be useful in case of a suspected vasculitis. Since hereditary neuropathies are normally diffuse processes, two or three nerve fascicles (fascicular biopsy) may be sufficient to provide enough tissue to perform a pathological examination. However, a careful comparison between fascicular and whole sural nerve biopsies showed no differences in residual deficits between the two surgical procedures [73]. Moreover, when hereditary disorders like familial amyloid polyneuropathy (FAP) are suspected, a whole sural nerve biopsy is necessary to detect the amyloidotic deposits. Postoperative symptoms after sural nerve biopsy are usually mild and include sensory deficit, dysesthesia and pain in the cutaneous distribution of the nerve. Among patients with neuropathy, 93% reported sensory symptoms however, only 33% had mild persistent pain and 19% persistent dysesthesia [34]. Over time, dysesthesia tends to improve and pain to completely subside [34]. The sural nerve is removed under sterile conditions in the operating room by a specialized surgical team. After local anesthesia, the nerve is exposed at the distal calf level, where it lies adjacent to the saphenous vein, which is the optimal anatomical landmark for locating the sural nerve. After removal, the nerve is processed for the morphological studies. Normally, the specimen is divided into three segments, each one 2±2.5 cm long, which are suspended in glutaraldehyde 2.5%, paraformaldehyde 4% and frozen in liquid nitrogen, respectively. After fixation, specimens are embedded in paraffin or in epoxy resin for examination at the light and electron microscopic levels. One segment of the nerve, fixed in glutaraldehyde and osmium tetroxide, is used for teased fiber preparations

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(Fig. 4.2). The examination of teased fibers allows the study of a single myelinated fiber over a distance of 3±15 internodes and is useful to identify the incidence of fibers undergoing Wallerian degeneration and segmental demyelination or remyelination. Sometimes specific changes, such as the sausage-like thickenings of the myelin sheath, which are typical of the he-

Fig. 4.2. Normal sural nerve. Teased fiber preparation. Several normally myelinated internodes and nodes of Ranvier (arrows) may be seen along a single fiber (A through D). O.T. 2%

Fig. 4.3. Normal human sural nerve. A normal myelinated fiber and several unmyelinated fibers (arrows) are present. Electron microscopy. Lead citrate and uranyl acetate; bar: 0.5 lm

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reditary neuropathy with liability to pressure palsy (HNPP), are easier to detect in teased fibers than in paraffin- or in epoxy-embedded sections. Electron microscopic examination (Fig. 4.3) is useful when the study of unmyelinated fibers or a search for specific inclusions in Schwann cells, as observed in hereditary storage disorders, are necessary. Immunohistochemical techniques may be performed, mainly in acquired neuropathies, to detect and characterize inflammatory infiltrates. On paraffin embedded sections, specific stains, like Congo red or immunolabeling with antitransthyretin or anti-light chain antibodies are useful to detect endoneurial amyloid deposits and to distinguish between FAP and neuropathy due to a monoclonal gammopathy. Morphometry of sural nerve biopsies can be used to determine the number, density, diameter distribution and shape of myelinated and unmyelinated fibers. In the past, morphometric studies were helpful in correlating morphological and electrophysiological findings in hereditary motor and sensory neuropathies (HMSN) [42] and to separate CMT1 (also called HMSN 1) from Djerine-Sottas syndrome (DSS, also called HMSN 3) [70]. The ratio of axon diameter to fiber diameter (g-ratio) is a useful measurement to grade hypomyelination and to detect signs of axonal atrophy in sural nerve biopsies. In case of hypomyelination the g-ratio is higher (> 0.75), whereas axonal atrophy is suspected when g-ratios are < 0.4.

4.1 Charcot-Marie-Tooth disease type 1 (CMT1) The neuropathological phenotype of patients affected by CMT1 is characterized by diffuse demyelinating changes. This finding is in agreement with the neurophysiological studies showing reduced motor and sensory nerve conduction velocities (< 38 m/s).

4.1.1 Charcot-Marie-Tooth disease type 1A (CMT1A) Sural nerve biopsies of CMT1A patients, due to the 17p11.2 duplication, show rather stereotyped abnormalities. There is a reduction in myelinated fiber density, ranging from moderate to severe [44]. Unmyelinated fibers may be normal or slightly affected [44]. Compared to normal nerves, there is an increase in transverse fascicular area, which may also be demonstrated by non-invasive ultrasonographic techniques (Fig. 4.4) [64]. Onion bulbs, made up of thinly or near normally myelinated axons surrounded by concentric layers of Schwann cell cytoplasm, are frequently present in sural nerves of CMT1A patients (Fig. 4.5). Up to 85% of myelinated fibers may consist of onion bulbs [44]. Some onion bulbs may contain several myelinated or unmyelinated axons that are believed to be nerve sprouts. The occasional presence of large axons devoid of a myelin sheath, some-

4 Principles of pathology and nerve biopsy

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Fig. 4.4. Ultrasonography of median nerve in a CMT1A patient. With high frequency transducers, peripheral nerves show a typical fascicular structure in transverse sections. In CMT1A (A) the nerve and the fascicles (arrows) appear enlarged compared to a normal control (B)

Fig. 4.5. Sural nerve biopsy from a CMT1A patient. At lower magnification (A) the density of the myelinated fibers appears to be decreased from normal. At higher magnification (B) onion bulbs (arrows), made up of concentric proliferation of Schwann cell cytoplasm around normally or thinly myelinated fibers, can be seen. Semithin section, toluidine blue; bars: 10 lm

times surrounded by onion bulb formation, confirms the demyelinating nature of the pathological process. This is even more evident in the teased fiber preparation, where most of the remaining fibers show segmental demyelination and/or remyelination (Fig. 4.6). Morphometric studies show that larger fibers are more affected than smaller ones. The mean internodal length is lower than in normal nerves, meaning that remyelination occurs in nerve fibers of patients affected by

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Fig. 4.6. Sural nerve biopsy from a CMT1A patient. Teased fiber preparation. Several internodes lacking of myelin (demyelinated internodes) can be seen along a single fiber (A through F). O.T. 2%

CMT1A. The observation of myelinated fibers with a reduced axon diameter as compared to myelin thickness suggests the presence of an associated axonal impairment [28]. The relevance of axonal atrophy in CMT1A nerves has been confirmed in xenografts of sural nerves from CMT1A patients into nude mice sciatic nerves [77]. CMT1A phenotypes caused by mutations in the PMP22 gene are rare. In these cases the neuropathological picture may be more severe than in typical duplication cases, but specific changes in sural nerve biopsies have not been detected. Sometimes, inflammatory changes may be observed in sural nerve biopsies of CMT1A patients [38, 99]. This observation suggests the possibility of a genetic susceptibility to immune mediated demyelination in certain CMT families and explains previous reports on steroid-responsive inherited neuropathies [28].

4.1.2 Charcot-Marie-Tooth disease type 1B (CMT1B) CMT1B, caused by point mutations in the MPZ gene, has a more severe clinical and neuropathological phenotype than CMT1A. In typical cases, the sural nerve biopsy shows a variable loss of myelinated fibers, onion bulbs made up of concentric layers of Schwann cell cytoplasm surrounding thinly myelinated fibers and segmental demyelination in teased fibers [44]. Focal thickenings of the myelin sheath have been observed in CMT1B patients (Fig. 4.7) [31, 36]. Although not specific, focally folded myelin seems to be particularly frequent in a subgroup of patients harboring mutations in the extracellular domain of MPZ [31]. Focally folded myelin is also a hallmark of some very rare forms of CMT4. In other families, ultrastruc-

4 Principles of pathology and nerve biopsy

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Fig. 4.7. Sural nerve biopsy from a CMT1B patient. The density of myelinated fibers is from moderately to severely decreased from normal. Some fibers show focal thickenings of the myelin sheath (arrow). Toluidine blue; bar: 10 lm

Fig. 4.8. Sural nerve biopsy from a CMT1B patient. Electron microscopy shows, in some thinly myelinated fibers, uncompaction of myelin lamellae (arrows). Bar: 0.1 lm

tural examination shows uncompacted myelin in several fibers (Fig. 4.8), thus, suggesting two divergent neuropathological phenotypes in CMT1B, the first dominated by myelin thickenings and the second by loosening of myelin lamellae [36]. Morphometric studies show, like in CMT1A, a preferential loss of larger fibers. Total transverse fascicular area is not as enlarged as in typical CMT1A. Most of the remaining fibers, outside of the myelin thickenings, have high gratios, thus, confirming the severity of the demyelinating process [36].

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4.1.3 Charcot-Marie-Tooth disease type 1C (CMT1C) CMT1C, due to mutations in the LITAF/SIMPLE gene, shares clinical and electrophysiological features with typical CMT1 [91]. The neuropathological phenotype is also suggestive of a hypertrophic demyelinating neuropathy. In particular, myelin loss and onion bulbs similar to those observed in CMT1A have been reported in a family with CMT1C [92].

4.1.4 Charcot-Marie-Tooth disease type 1D (CMT1D) Mutations in the EGR2 zinc-finger transcription factor have been demonstrated in a few cases of CMT1, DSS and congenital hypomyelination (CH) phenotypes [100]. Patients with CMT1D show a typical CMT1 phenotype [81, 96] and display neuropathological changes ranging from severe to relatively mild fibers loss and demyelination. Onion bulbs, although present, are not as prominent as in CMT1A (Fig. 4.9). Fibers showing a reduced axon diameter compared to myelin thickness have also been observed, in a CMT1D family, and may suggest an associated axonal atrophy [96].

4.1.5 Djerine-Sottas syndrome (DSS) DSS may be considered, from the neuropathological point of view, as a severe variant of demyelinating CMT. Originally, the distinction between DSS (HMSN III) and CMT1 (HMSN I) was based on the presence of a significantly lower density of myelinated fibers > 8 lm in diameter, a greater frequency of

Fig. 4.9. Sural nerve biopsy from a CMT1D patient. The density of myelinated fibers is moderately decreased from normal. Several onion bulbs (arrows) may be seen, sometimes surrounding thinly myelinated fibers. Semithin section, toluidine blue; bar: 10 lm

4 Principles of pathology and nerve biopsy

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Fig. 4.10. Sural nerve biopsy from a DSS patient. The density of myelinated fibers is severely decreased from normal. Onion bulbs formed by Schwann cell processes wrapping around thinly myelinated axons may be seen (arrow). Semithin section, toluidine blue; bar: 5 lm

onion bulbs and higher g-ratios in DSS [70]. Molecular genetic studies made this distinction less important. In fact, mutations in the PMP22, MPZ, EGR2 and PRX genes may cause either a CMT1 or a DSS phenotype [11, 12, 45, 71, 96]. Sural nerve biopsies have been performed in most of these cases, but genotype-phenotype correlations based on neuropathological features are not possible, because specific changes for each genotype have not been observed. Patients with DSS show a diffuse loss of myelinated fibers (Fig. 4.10). Unmyelinated fiber density is also, but less severely, decreased. Onion bulbs are made up of multiple layers of Schwann cell cytoplasm with or without a central axon (denervated onion bulbs). Several larger axons devoid of myelin may also be observed. Hypertrophy of peripheral nerves is a common feature and enlargement of nerve roots has been found in a family with a MPZ point mutation [89]. Focally folded myelin, especially at paranodes, has been observed in a patient with mutations in the PRX gene [94].

4.1.6 Congenital hypomyelination (CH) CH is characterized by a defect in myelination, probably due to a primary failure in myelin formation. It may be clinically undistinguishable from severe, early onset CMT1 and DSS. Sural nerve biopsy (Fig. 4.11), although not diagnostic, shows a severe loss of myelinated fibers with all the residual axons lacking a myelin sheath or surrounded by very thin myelin and onion bulbs made up of multiple laminae of double layered Schwann cell basement membranes (basal lamina onion bulbs). However, most authors considered CH as a more severe variant of DSS. Molecular genetic studies confirmed that mutations in the same genes known to cause DSS or severe

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Fig. 4.11. Sural nerve biopsy from a patient with a CH phenotype and a mutation in the P0 gene. The density of myelinated fibers is severely decreased. Several axons are either demyelinated (thick arrows) or surrounded by an extremely thin myelin sheath (thin arrows). Toluidine blue; bar: 10 lm

CMT1, like PMP22, MPZ and EGR2, can be found in CH families [32, 62, 100]. Neuropathological genotype-phenotype correlations are virtually impossible in all these cases.

4.1.7 Hereditary neuropathy with liability to pressure palsy (HNPP) HNPP is clinically characterized by recurrent episodes of peripheral nerve palsies, due to mechanical compression of the nerve trunks. Various pathologic changes have been described in association with HNPP. However, the most common abnormality, in sural nerve biopsies, is constituted by focal thickenings of the myelin sheath, named tomacula by the sausage-like appearance they give to the myelinated fiber in longitudinal sections or in teased fiber preparations (Fig. 4.12). Typical tomacula have been described as focal enlargements of the myelin sheath, in the internodal or paranodal segment of the fiber, which are between 40 and 250 lm long (Fig. 4.13) [101]. In transverse sections, tomacula are characterized by an extremely thickened myelin sheath wrapping around an axon of reduced diameter. It is not known whether this is due to a constriction of the axon by the thickened myelin or to an ongoing axonal atrophy. However, the observations that neurofilament density is increased in the narrowed area of the

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Fig. 4.12. Sural nerve biopsy from a HNPP patient. The density of myelinated fibers is within normal limits. Several focal thickenings of the myelin sheath (tomacula) (arrows) may be seen. Toluidine blue; bar: 10 lm

Fig. 4.13. Sural nerve biopsy from an HNPP patient. Teased fiber preparation. Several thickenings of the myelin sheath (tomacula) may be seen along the fibers. Sometimes tomacula are up to 250 lm long (arrows). O.T. 2%

axon [101], lower g-ratios correlate to the levels of PMP22 mRNA in HNPP patients [82] and that xenografts of HNPP nerves in mice sciatic nerves result in axonal atrophy [77] suggest that axonal impairment does occur in HNPP. Rarely, tomacula may be absent in transverse semithin sections of HNPP sural nerves. Therefore, the analysis of longitudinal sections and teased fiber preparations is needed to identify these peculiar myelin abnormalities. Sometimes, focal thickenings of the myelin sheath have been observed in other hereditary neuropathies, particularly those due to P0 mutations [31]. However, in the author's experience, typical tomacula, as defined above, may be observed only in HNPP sural nerves. The density of myelinated fibers may be normal or slightly reduced from normal. Onion bulbs are usually absent or observed occasionally. Rarely, HNPP sural nerves show a severe reduction of myelinated fibers and a large number of onion bulbs. These patients, although carrying the 17p11.2 deletion, develop a clinical and neurophysiological phenotype undistinguishable from CMT1 [61]. The teased fiber preparation shows a variable degree of segmental demyelination and remyelination. This corresponds to the electrophysiologic observation of slowing of conduction velocity in clinically unaffected

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nerves [101]. At the electron microscopic level, tomacula look like redundant loops of myelin with irregularly folded lamellae, which are also enormously increased in number. Madrid and Bradley identified several mechanisms by which focal thickenings are formed, several years before the discovery of the genetic abnormality underlying HNPP [60]. These include branching and duplication of the mesaxon (the Schwann cell membrane adjacent to the axon), transnodal myelination, the participation of two or more Schwann cells in the formation of the myelin sheath, and the degeneration of myelin in the adaxonal or intramyelin regions between an intact outer layer of the myelin sheath and the axon. The knowledge that a reduced dosage of the PMP22 gene is present in HNPP patients [83, 97] is not sufficient to understand the mechanisms of tomacula formation and the relationship between these structural changes and mechanic compression. However, it is possible that low levels of PMP22 affect the structural integrity of the myelin sheath and make it more susceptible to damage from external trauma [88].

4.2 Charcot-Marie-Tooth disease type 4 (CMT4) The autosomal recessive forms of CMT1 are traditionally called CMT4. The different forms of CMT4 are extremely rare. They are neuropathies characterized by a neuropathological phenotype, which in some cases, like CMT4B1, is characterized by extremely peculiar changes.

4.2.1 Charcot-Marie-Tooth disease type 4A (CMT4A) CMT4A is caused by mutations in the ganglioside-induced differentiationassociated protein-1 gene (GDAP1). Neuropathological findings in CMT4A range from an axonal to a demyelinating phenotype [7, 20]. Irrespective of the prevalence of axonal or demyelinating changes, a severe loss of myelinated fibers, especially affecting the larger fibers has been found in all sural nerve biopsies of CMT4A patients. Onion bulbs have been described, but in most cases they are scattered and atypical, since they enclose regenerating axons and show only few concentric layers of Schwann cell cytoplasm [10, 87]. Demyelinated axons and abundant onion bulbs have been observed in only a few affected individuals [7]. In most families, neither demyelinated axons nor abnormalities in myelin compaction could be found [10, 67, 87]. However, some cases do show signs of de-remyelination along with axonal changes [67]. Morphometric studies confirm the morphological observations and show that larger fibers (> 8 lm) are always lacking, whereas there are more smaller fibers (< 3 lm) [67, 87]. These observations may suggest that axonal regeneration is a prominent feature of CMT4A.

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Fig. 4.14. Sural nerve biopsy from a CMT4A patient. The density of myelinated fibers is decreased from normal. Several thinly myelinated fibers may be seen, occasionally surrounded by concentric layers of the Schwann cell cytoplasm forming a small onion bulb (arrow). Semithin section, toluidine blue; bar: 10 lm

The g-ratio ranges from normal (0.7) to low values (< 0.4), suggesting that an axonal atrophy is present in some fibers [10, 87]. In agreement with these observations, we found in sural nerves of patients carrying a M116R mutation at exon 4 of the GDAP1 gene [E. Di Maria, personal communication] a loss of myelinated axons, especially affecting larger fibers. Several of the remaining fibers showed a reduction in myelin thickness. Sometimes, thinly myelinated axons surrounded by Schwann cell processes concentrically organized to form small onion bulbs are also observed (Fig. 4.14). Occasionally, clusters of small regenerating fibers may be found. An association of axonal and demyelinating features has also been recently reported in other CMT4A families [85]. Therefore, although the number of mutations in the GDAP1 gene described so far is too low for reliable genotype-phenotype correlations, it is possible that CMT4A, similarly to CMTX, combines axonal and demyelinating changes. This may be due to a combined, negative effect of GDAP1 mutations on neurons and Schwann cells [93]. However, further studies on the function of this protein are needed to explain these mixed changes.

4.2.2 Charcot-Marie-Tooth disease type 4B1 and 4B2 (CMT4B1, CMT4B2) Mutations in different members of the myotubularin-related gene family cause CMT4B [5, 13]. In particular, CMT4B1 is due to mutations in the myotubularin related protein-2 (MTMR2) [13] and CMT4B2 to mutations in the MTMR13 gene [5]. However, sural nerve biopsy findings do not dif-

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Fig. 4.15. Sural nerve biopsy from a CMT4B patient. The density of myelinated fibers is severely decreased from normal. The majority of fibers show the typical abnormalities of the myelin sheath, which is redundant and irregularly folded (arrows). Semithin section, toluidine blue; bar: 10 lm

Fig. 4.16. Sural nerve biopsy from a CMT4B patient. Electron microscopy shows complex outfoldings of the myelin sheath surrounding the axon (asterisk). Bar: 1 lm

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fer between the two types of CMT4B and are characterized by typical abnormalities of the myelin sheath, which is redundant and irregularly folded (Figs. 4.15, 4.16). These changes are called myelin outfoldings. Myelin outfoldings were first related to autosomal recessive hereditary motor and sensory neuropathies and described in detail by Onishi et al. in 1989 [69]. In CMT4B up to 90% of the fibers presents myelin outfoldings, discriminating this disorder from all the other autosomal dominant or recessive forms of CMT [75, 80]. A profound loss of myelinated fibers is also observed. Occasionally, small onion bulbs may be seen [80].

4.2.3 Charcot-Marie-Tooth disease type 4C (CMT4C) The neuropathological features of CMT4C, which has been recently related to mutations in a gene encoding a SH3/TPR domain protein [86], have been known since 1999, when the phenotypic characterization of an autosomal recessive demyelinating CMT linked to chromosome 5q23-q33 was described [35]. The sural nerve biopsy shows a predominantly demyelinating neuropathy with a severe loss of large myelinated fibers (> 8 lm), abnormally thin myelin sheaths in the remaining fibers and extensive onion bulbs formation [53]. Onion bulbs made up of concentric, basal membrane layers surrounding a demyelinated axon are frequently seen (basal lamina onion bulbs).

4.2.4 Charcot-Marie-Tooth disease type 4D (CMT4D) Sural nerve biopsy findings, in CMT4D, also known as hereditary motor and sensory neuropathy of the Lom type (HMSN-L), are suggestive of a severe demyelinating neuropathic process [52]. In fact, a profound loss of myelinated fibers and prominent hypertrophic changes, characterized by frequent onion bulbs consisting of multiple layers of Schwann cell cytoplasm and basal lamina around thinly myelinated or unmyelinated axons, have been described [17, 52, 54]. Interestingly, onion bulbs are more evident in younger patients and seem to subside with aging [52]. Why there is a regression of the onion bulbs in CMT4D is unknown; however, it may be related to the axonal loss which is striking in this hereditary neuropathy [54]. With electron microscopy, various abnormalities both in the axons and in the Schwann cells of CMT4D patients have been shown, like axonal inclusions consisting of tubular or small curvilinear profiles, pleomorphic material in the adaxonal Schwann cell cytoplasm and uncompaction of the myelin lamellae adjacent to the axon [54]. However, none of these ultrastructural abnormalities seem to be specific of CMT4D.

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4.2.5 Charcot-Marie-Tooth disease type 4E (CMT4E) Point mutations in the EGR2 gene, besides causing autosomal dominant CMT1, DSS and CH phenotypes, may also be responsible for severe demyelinating autosomal recessive CMT, now classified as CMT4E [55]. However, the neuropathological phenotype does not allow clear differentiation of CMT4E from autosomal dominant CH. In fact, the sural nerve biopsy shows a diffuse loss of myelinated fibers with absence of myelin in virtually all the remaining fibers [100].

4.2.6 Charcot-Marie-Tooth disease type 4F (CMT4F) CMT4F is due to mutations in the PRX gene [94]. PRX encodes two PDZ domain proteins, L- and S-periaxin, which are required for the maintenance of peripheral nerve myelin. To date, most of the mutations responsible for an autosomal recessive demyelinating neuropathy affect L-periaxin and only one family shows a homozygous mutation in the region common to both forms and therefore affecting both L- and S-periaxin [94]. However, the neuropathological findings do not allow a distinction between mutations of the L- or S-periaxin. The sural nerve biopsies in patients carrying mutations in the PRX gene, even if the clinical phenotype may vary from a severe demyelinating sensory motor neuropathy to a milder, mainly sensory phenotype, show similar features. A severe loss of myelinated fibers accompanied by prominent onion bulb formation is always present [12, 23, 40, 94]. Onion bulbs are made up of Schwann cell cytoplasm and basal lamina. Hypermyelination and tomacula are also frequently observed in CMT4F [40, 94]. The paranodal region shows incomplete myelination and separation of multiple terminal myelin loops from the axon, suggesting that PRX may play an important role in mediating Schwann cellaxon adhesion at the node of Ranvier [94]. Finally, it is important to underscore that the PRX null mice develop a neuropathic process which is strikingly similar to the human pathology, supporting the view that this animal model may lead to a better understanding of the human disease [37].

4.3 X-linked Charcot-Marie-Tooth disease (CMTX) CMTX is in nearly all cases due to mutations in the GJB1 gene, coding for Cx32, a protein belonging to the family of gap junction proteins and highly expressed in the Schwann cells at the nodes of Ranvier and Schmidt-Lanterman incisures. Cx32 mediates the transport of low molecular weight substances from the adaxonal to the outer myelin lamellae [6]. This type of CMT is also known as CMTX1 [55]. In fact, neurophysiological studies reveal a slowing of conduction velocities intermediate between a demyelinating and an axonal CMT. However, given the peculiar localization and function of

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Fig. 4.17. Sural nerve biopsy from a CMTX1 patient. The density of myelinated fibers is moderately decreased from normal. Several clusters of thinly myelinated fibers (arrows) may be seen. Fibers with thin myelin sheath occasionally surrounded by concentric layers of Schwann cell cytoplasm to form small onion bulbs (arrow heads) are occasionally present. Semithin section, toluidine blue; bar: 10 lm

Cx32, the relationship between Schwann cells and axon should be particularly affected in CMTX1 patients and the compact myelin relatively preserved [88]. Sural nerve biopsies show that axonal features are predominant in CMTX1 patients [44]; however, concomitant demyelination has been described [41, 79, 84]. Myelinated fiber density is reduced, unmyelinated fibers are relatively well preserved and the density of small myelinated fibers is less affected than that of larger ones, due to the frequency of axonal sprouting (Fig. 4.17) [84]. Onion bulbs, sometimes surrounding normally myelinated fibers, may be seen. Teased fiber preparations show an increased rate of remyelinating fibers, mainly secondary to axonal damage. Rarely, fibers undergoing segmental demyelination have been described [44, 79]. Due to the pattern of inheritance, males are normally more affected than females and this is also evident in sural nerve biopsies [41]. According to the distribution of Cx32, electron microscopy analysis reveals unusual findings at the nodal and paranodal regions. Widening of the Schmidt-Lanterman incisures and of the nodes of Ranvier have been described along with a separation of the myelin sheath from the axon leaving a clear periaxonal space that appeared either empty or contained vesicular material and whose significance is still unknown [41]. An extremely rare form of CMTX is linked to chromosome Xq24-q26.1 (CMTX2) [74]. In the original report this type of CMTX was described as an axonal HMSN II with additional clinical features (deafness and mental retardation) [18]. The sural nerve biopsy shows typical axonal changes, like a slight reduction of myelinated fibers density with axonal loss and sprouting, but no onion bulb formation or segmental demyelination.

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4.4 Charcot-Marie-Tooth disease type 2 (CMT2) CMT2 is the axonal form of CMT. Classically, conduction velocity studies allow a distinction between CMT2 and CMT1 [42]. However, in the past, neuropathological studies have also been performed to distinguish axonal from demyelinating CMT [28]. Typical CMT2 is autosomal dominant and in most cases the genetic defect is unknown. Point mutations in a few genes have been now identified to cause CMT2, e.g. GTPase mitofusin 2 and the kinesin motor protein-1-b (KIFBb) (CMT2A), the neurofilament light chain (NEFL) (CMT2E), the RAS-related GTP binding protein 7 (RAB7) (CMT2B), the glycyl-tRNA synthetase (GARS) (CMT2D), the MPZ, the heat shock protein 27 (HSP27) genes [3, 4, 30, 63, 66, 98, 102, 103]. Since the neuropathological phenotype of CMT2 patients is similar, irrespective of the different genotype, the sural nerve biopsy changes will be described as a whole. The number of myelinated fibers is slightly decreased, the larger fibers being more affected than the smaller ones (Fig. 4.18). The reduced density of myelinated fibers is more severe in distal than in proximal nerves. No abnormalities in the distribution of unmyelinated fibers have been described [28]. Occasionally, clusters of small regenerating fibers or small onion bulbs may be seen. Sometimes, irregular foldings of the myelin sheath have been described, particularly in biopsies of patients with MPZ and NEFL mutations [22, 50]. Teased fiber preparations frequently show fibers with short internodes, but in the absence of clear segmental demyelination. An autopsy report demonstrated a distal to proximal gradient of atrophy and fiber loss in the peripheral nerves, depletion of anterior horn and dorsal root ganglion cells maximal in the lumbosacral region and secondary axonal loss in

Fig. 4.18. Sural nerve biopsy from a CMT2 patient. The density of myelinated fibers is slightly decreased from normal, particularly for large fibers. Several fibers show small axonal caliber compared to myelin thickness (arrows). Occasionally small onion bulbs (arrow heads) and clusters of regenerating fibers may be seen. Semithin section, toluidine blue; bar: 10 lm

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the gracile fasciculi [9]. All these findings have been interpreted as the result of neuronal atrophy and degeneration of peripheral motor and sensory neurons [28]. The genetic studies demonstrating mutations in genes related to the axonal cytoskeleton (NEFL) and transport (KIF1Bb) in some CMT2 families fully confirmed these observations made only on a neuropathological basis. Although specific genotype-phenotype correlations are not possible based on sural nerve biopsy findings alone, a few peculiar changes have been found in different types of CMT2. For example, in patients carrying mutations in the NEFL gene, sural nerve biopsies reveal a relatively high frequency of thin onion bulbs, which could be suggestive of a demyelinating process secondary to the axonal impairment [50]. The recent observation of giant axons in the sural nerve biopsy of a family with a Pro22Ser mutation of NEFL, strengthen the concept of CMT2E as a primary axonopathy with secondary demyelination [33]. As giant axons have been previously observed, although rarely, in other hereditary motor and sensory neuropathies [9, 104], it is still unclear whether they are a specific neuropathological marker of CMT2E or not [33]. Autosomal recessive forms of CMT2 (AR-CMT2) have been also described. As expected, the neuropathological phenotype seems to be more severe in AR-CMT2 than in the autosomal dominant types. In AR-CMT2 due to mutations in the LaMiN A/C (LMNA) gene, a profound loss of myelinated and unmyelinated fibers was observed in the absence of onion bulbs or regenerating clusters [16]. However, in AR-CMT genotype-phenotype correlations based on sural nerve biopsy findings are also very difficult. In fact, similar to AR-CMT2 due to mutations in the LMNA gene, patients carrying GDAP-1 mutations may show a severe axonal phenotype with myelin loss and no signs of demyelination and remyelination [20].

4.5 Hereditary sensory and autonomic neuropathies (HSAN) HSAN are clinically characterized by predominant peripheral sensory and autonomic disturbances. The neuropathological findings, represented by a prevailing degeneration and loss of fibers in the sensory nerves and in the posterior columns, posterior roots and spinal ganglia, mirror the clinical picture [27]. As for CMT disease and related neuropathies, different varieties of HSAN have been identified based on mode of inheritance, natural history, neurophysiological and neuropathological abnormalities [27]. Only recently have mutations in known genes been related to different variants of HSAN [55].

4.5.1 Hereditary sensory and autonomic neuropathy type 1 (HSAN1) In patients affected by HSAN1, mutations in the serine palmitoyltransferase-1 (SPTLC1) gene have been recently found [8, 21]. Classically, the neuropathological studies have focused on the morphological abnormalities

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and the class of fibers affected in the sural nerve. However, a degeneration of nerve fibers and a loss of neuronal cells were also observed in posterior columns and dorsal root ganglia [8, 27]. Unfortunately, due to the relatively low number of HSAN1 patients with SPTLC1 mutations and the overall rarity of the disease, studies addressing phenotype-genotype correlations in this hereditary neuropathy are not available. In typical HSAN1 patients, the sural nerve biopsy shows a loss of myelinated and unmyelinated fibers. Dyck and coauthors found a lower fiber density at the ankle than at the midcalf level and a predominant axonal degeneration in the teased fiber preparation [25]. Unmyelinated fibers, however, were not markedly decreased at the ankle level. These results may suggest that small fibers are slightly more affected that larger ones, and axonal atrophy and degeneration occur in HSAN1 [27]. Whether this is due to a neuronopathy affecting sensory neurons or to a distal axonopathy in sensory fibers is still unclear. The function of SPTLC1 as an enzyme of sphingolipid synthesis and the elevated concentrations of glucosyl-ceramide, a molecule inducing cells apoptosis [46], within the lymphoblasts of HSAN1 patients may suggest pathogenetic mechanisms involving neuronal death in sensory ganglia [51, 55].

4.5.2 Hereditary sensory and autonomic neuropathy type 2 (HSAN2) HSAN2 is characterized by autosomal recessive inheritance and is caused by mutations in a novel gene of unknown function [56]. The sural nerve biopsy shows an almost complete absence of myelinated fibers with a relative preservation of unmyelinated fibers [27] (Fig. 4.19). Nerve fascicles

Fig. 4.19. Sural nerve biopsy from an HSAN type 2 patient. There is a severe loss of myelinated fibers with relative preservation of unmyelinated fibers. Semithin section, toluidine blue; bar: 1 lm

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also show a decrease in transverse fascicular area. Ohta and coauthors found a gradient of fiber loss from midcalf to the ankle level and, in the deep peroneal nerve, a low percentage of fibers undergoing axonal degeneration along with segmental demyelination and remyelination, suggesting a degenerative process beginning in utero or in infancy [24, 27, 68].

4.5.3 Hereditary sensory and autonomic neuropathy type 3 (HSAN3) HSAN3, also known as familial dysautonomia or Riley-Day syndrome, is an autosomal recessive disease, affecting Ashkenazi Jews, recently related to mutations in the inhibitor of kappa light polypeptide (IKBKAP) gene [2, 27, 90]. Interestingly, genetic tests allowed the identification of an IKBKAP mutation in a patient with typical HSAN3, but no Ashkenazi Jewish ancestry [57]. In typical HSAN3 patients, examination of the sural nerve shows an approximately normal density of myelinated fibers and a striking loss of unmyelinated fibers, no active axonal degeneration and a decreased number of Schwann cell cytoplasmic clusters compared to other neuropathies [1]. A marked reduction of autonomic and spinal ganglia volume, and a decreased density of sympathetic and sensory neurons were also observed in HSAN3 [27]. These findings may suggest an arrest of embryogenesis in the neural crest [27]. However, although the function of the protein coded by the IKBKAP gene in the transcription control is known, the pathomechanisms of HSAN3 remain to be elucidated [90].

4.5.4 Hereditary sensory and autonomic neuropathy type 4 and type 5 (HSAN4 and HSAN5) These two rare and clinically similar disorders of the sensory system have been recently related to mutations in genes related to neurotrophic factors, namely the neurotrophin receptor tyrosin kinase-1 (NTRK1) gene [48, 49], which encodes for the nerve growth factor (NGF) high affinity receptor TRK1 and the NGF beta (NGFB) gene [29], which encodes for NGFB itself. The neuropathological picture, however, is somehow different in these two diseases. In fact, the sural nerve biopsy, in the previously described cases of HSAN4, showed a nearly normal density of myelinated fibers and a virtual absence of unmyelinated fibers [39, 72]. Instead, in HSAN5, a selective decrease of the small myelinated and of the unmyelinated fibers was found in the sural nerve biopsy [58]. However, too few patients have been described with these disorders and NTRK1 or NGFB mutations to correctly describe genotype-phenotype correlations from the neuropathological point of view. Finding mutations in genes involved in the NGF pathway may explain why these patients have a loss of small myelinated and unmyelinated fibers, which are sustained by NGF in their embryonic development.

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4.6 Hereditary motor neuropathies (HMN) Distal HMN are genetically heterogeneous disorders, which normally present as a classical peroneal muscular atrophy without sensory symptoms [43]. Therefore, the neurophysiology and neuropathology of sensory nerves is, by definition, normal. In fact, although rarely performed, the peripheral nerve biopsy does not show abnormalities in HMN patients [19, 65, 95]. The muscle biopsy, which has been more frequently carried out in HMN patients in the past, shows mainly denervation atrophy. Autopsy studies showed atrophy of spinal roots, loss of anterior horn cells and chromatolisis of the motor neurons [15].

4.7 Giant axonal neuropathy (GAN) GAN is a rare autosomal recessive disorder commonly characterized by a progressive motor and sensory neuropathy with early onset of an associated involvement of the central nervous system [28]. Mutations in the gigaxonin gene, located on chromosome 16q24.1 have been recently found in GAN patients [14]. The neuropathological hallmark of the disease is the presence, in the sural nerve biopsy, of giant axonal swellings due to a massive accumulation of neurofilaments in axons (Fig. 4.20). Similar changes have been also described in the central nervous system [28]. As suggested by the neuropathological features, a generalized impairment of intermediate filaments organization and transport may be responsible for the clinical phenotype.

Fig. 4.20. Sural nerve biopsy from a giant axonal neuropathy patient, carrying a gigaxonin mutation. Several axons are severely enlarged (giant axons) and show an abnormally thin myelin sheath (asterisks). Semithin section, toluidine blue; bar: 10 lm

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This hypothesis is also supported by the observation that giant axons may be found in toxic neuropathies induced by iminodipropionitrile and 2,5-hexanedione, which are known to affect the slow axonal transport of neurofilaments [47]. Moreover, as reported in the CMT2 section, giant axons have been also found in patients with CMT2E neuropathy, carrying a mutation in the NEFL gene [33]. However, as the number of giant axons is higher in the sural nerve of GAN patients than in any other known hereditary neuropathy, these neuropathological features may be still considered diagnostic for GAN. Nevertheless, since a genetic test is now available for the disease, performing a diagnostic sural nerve biopsy should be considered with caution.

4.8 Hereditary neuralgic amyotrophy (HNA) HNA is a rare, autosomal-dominant, recurrent focal neuropathy whose genetic basis has yet to be identified [55, 101]. Descriptions of the pathologic changes in this condition is very limited. A motor fascicle from an affected nerve was examined in the past, but specific neuropathological changes were not found [101]. A sural nerve biopsy is useless because in most cases there is no evidence of a generalized neuropathy. In the past, sausageshaped thickenings of the myelin sheath (tomacula) were occasionally reported in the sural nerve of patients suffering of a transient brachial plexopathy, but because the genetic test was not yet available, these were probably cases of HNPP than HNA, which are now known to be genetically different diseases [55].

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Specific neuropathies, treatment and counseling

5 Overview of the classification

and genetics of hereditary peripheral neuropathies and rare unclassified forms G. Kuhlenbåumer

This chapter introduces the second part of the book dealing with the biology, genetics, clinical features and therapy of specific hereditary neuropathies. The classification and overview presented in the chapter serve as a framework for the following chapters, dealing with specific genetic entities.

5.1 History The history of hereditary peripheral neuropathies can be divided into four periods: the first ranging from the first concise description in 1886 to 1956 [44]. This period was devoted to the clinical and pathological description of the disease. The second period ranging from 1956 to 1982 applied electrophysiologic techniques and refined pathological methods, especially electron microscopy, for the study of hereditary neuropathies. The third period, lasting from 1982 to today is concerned with the genetic mapping and elucidation of causative genetic defects. The genetic defects underlying most major forms of hereditary neuropathies are now known and we are already in the middle of the fourth period focussing on the understanding of the biology and pathobiology of the peripheral nerve based on the knowledge of the causative genetic defects which will be followed by the development of effective therapeutic approaches. In 1886, J. M. Charcot, P. Marie and, independently, H. H. Tooth concisely described for the first time a hereditary peripheral neuropathy [12, 46]. The main symptoms were distal weakness and atrophy affecting mainly the legs and especially the small foot muscles and peroneal muscles. In addition, fasciculations, frequent cramps and preservation of the proximal muscles were noted. Only a few years later the description of clinically distinct forms (e.g., Djerine-Sottas syndrome (DSS), also called HMSN III) showed that hereditary neuropathies are a heterogeneous group of diseases [16]. In the following decades numerous descriptions of clinically and genetically distinct forms of hereditary neuropathies were published and led to the first attempt of a classification by Dawidenkow in 1927 [14, 15]. The introduction of the measurement of motor nerve conduction velocities (MNCV)

74

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G. Kuhlenbåumer

into the clinical evaluation of patients with neuromuscular disease allowed the distinction between patients with severely reduced and nearly normal NCVs [30]. These were later termed hereditary motor and sensory neuropathy type I (HMSN I or CMT1) and hereditary motor and sensory neuropathy type II (HMSN II or CMT2) [20]. Improved pathologic methods showed that severely reduced MNCVs correlate with de- and remyelination in sural nerve biopsies [18]. The detailed neurophysiological and microscopic examination of large families allowed further subclassification [19]. In 1980, Bird and coworkers were the first to find a genetic linkage with the Duffy blood group antigens on chromosome 1 in a family with Charcot-Marie-Tooth disease [5]. This finding was the advent of the molecular genetic era. The first causative genetic defect ± the CMT1A causing duplication on chromosome 17p11 ± was identified in 1991 [32, 42]. This genetic defect turned out to be the most common cause of hereditary neuropathies accounting for between 50 and 70% of all hereditary peripheral neuropathies [36]. The underlying genetic defects for most common forms of hereditary peripheral neuropathies have now been identified. At present, animal and cellular models ± most of them based on the genes identified by genetic research ± are fundamentally changing our understanding of the biology of the peripheral nerve and the pathomechanisms underlying hereditary peripheral neuropathies. In the future, these models will lead to the development of novel therapeutic tools. The first successful trials of ascorbic acid and a progesterone antagonist in animal models of CMT1A give hope that this goal will be attainable in the not too far future [39, 43].

5.2 Clinical and electrophysiological phenotype of hereditary motor and sensory neuropathies (HMSNs) A detailed account of the clinical and electrophysiological features of hereditary neuropathies is given in the corresponding chapters. This section provides only the most essential information needed to understand the genetics and classification of HMSNs. HMSNs are clinically characterized by slowly progressive distal muscle weakness and atrophy that primarily affect the small foot muscles, peroneal muscles and later those of the hands and forearms. In all cases, distal, usually symmetrical sensory deficits are present. Most patients have foot deformities, mostly pes cavus and clawtoes/hammertoes. The tendon reflexes are diminished or absent, especially the ankle jerk. The course of these diseases is often benign, and most patients do not ± or only very late in life ± become wheelchair dependent. Slowed motor nerve conduction velocities (MNCVs) in patients with HMSN were described for the first time in the 1950s [30]. Later it was shown that the MNCVs of HMSN patients follow a nearly bimodal distri-

5 Overview of the classification and genetics of hereditary peripheral neuropathies

z

bution. One group has severely reduced MNCVs (below 38 m/s, in most cases below 30 m/s) and prolonged terminal latencies corresponding to a distal and predominantly demyelinating neuropathy (HMSN I or CMT1). The other group has normal or only slightly reduced MNCVs (above 38 m/s) corresponding to a predominantly axonal neuropathy (HMSN II or CMT2) [22]. The cut-off value between CMT1 and CMT2 was originally defined as a MNCV of the median nerve of 38 m/s [22]. The amplitude of the compound motor nerve action potential (CMAP) is severely reduced in CMT2 patients but nearly all adult CMT1 patients also have reduced CMAPs due to secondary axonal damage [28]. The amplitude of the sensory nerve action potentials (SNAP) is severely reduced or the potentials are not recordable at all. Patients with an X-linked mode of inheritance (CMTX) caused by mutations in the gap junction protein beta 1 gene (GJB1) can exhibit a CMT1, a CMT2 or an intermediate phenotype with MNCVs that do not allow for unequivocal allocation to the categories CMT1 or CMT2. Electromyographic examination of distal muscles (e.g., the anterior tibial muscle) often shows signs of chronic denervation and sometimes, pathologic spontaneous discharges in all forms of HMSN.

5.3 Classification of hereditary neuropathies (Table 5.1) 5.3.1 The HMSN classification by Dyck, Chance, Lambert and Carney The HMSN classification is mainly a clinical one. Although not always in good agreement with the more recently defined molecular genetic entities anymore, it remains a landmark in the scientific exploration of hereditary neuropathies and a valuable tool in clinical practice; thus, an outline will be presented here. Hereditary motor and sensory neuropathies had been subdivided by Harding and Thomas into a group with motor nerve conduction velocities (MNCV) below 38 m/s (HMSN I or CMT1) and a group with MNCVs above 38 m/s (HMSN II or CMT2) [22]. This electrophysiology-based classification is still valid. In the literature HMSN I and HMSN II are commonly referred to as Charcot-Marie-Tooth disease type 1 and 2 (CMT1 and CMT2). HMSN III is equivalent to Djerine-Sottas syndrome (DSS) [16, 21]. DSS is clinically defined as a severe, demyelinating neuropathy manifesting in infancy. Nerve conduction velocities are strongly reduced and the protein content of the cerebrospinal fluid is elevated in some cases. The inheritance of DSS was formerly assumed to be exclusively autosomal recessive. Today, we know that DSS is not a genetic entity and that many of the presumably recessive cases turned out to be caused by dominant de novo mutations in a number of different genes. Nevertheless, the term DSS remains useful for the clinical description of a severe demyelinating peripheral neuropathy

75

z CMT4B2

z CMT4B1

z CMT4A

CMT4

z CMT1F

z CMT1C z CMT1D

z CMT1B

z HNPP

recessive hypertrophic-demyelinating CMT (mNCV <38 m/s) severe neuropathy, onset in first decade, Tunisian families (allelic to CMT4C4) focally folded myelin, early childhood onset (~34 months), Italian families focally folded myelin, onset in first or 2nd decade, Tunisian families, MIM: 607739: with early onset glaucoma rare rare

AR

rare

rare

rare

rare rare

common

AR

AR

AR

AD

AD AD

AD

common

AD AD

common

AD

dominant hypertrophic-demyelinating CMT (mNCV < 38 m/s) typical HMSN, childhood ± typically onset in 2nd decade, optional tremor, + deafness also called CMT1E recurrent painless pressure palsies and entrapment syndroms, histology: tomacula, onset very variable often more severe than CMT1A, congenital to 2nd decade onset typical CMT1, childhood ± onset in second decade often more severe than CMT1A, congenital or first decade onset CMT1 often severe, early onset, NEFL mutations cause also CMT2E

CMT1

z CMT1A

common

AD and AR

hereditary motor and sensory neuropathies

HMSN

Frequency

Inheritance

Typical features

MPZ (P0)

PMP22

PMP22

Gene

11p15

11q23

8q13-q21

8p21

601382

214400

607734

601098 607678

118200

162500

A: 118220; E: 118300

OMIM Acc. Nr.

MTMR13/SBF2 604563; +Glaucoma 607739

MTMR2

GDAP1

NEFL

16p13.1-p12.3 LITAF/SIMPLE 10q21.1-q22.1 EGR2

1q22-q23

17p11.2

17p11.2

Locus

z

Form

Table 5.1. Classification of hereditary neuropathies

76 G. Kuhlenbåumer

z DI-CMT

z DI-CMTD

z DI-CMTC

z DI-CMTB

DI-CMT (dom. intermediate) z DI-CMTA

dominant intermediate forms, intermediate mNCV typical CMT, axonal and myelin pathology, intermediate mNCV, onset in first decade typical CMT, axonal and myelin pathology, intermediate mNCV, onset in first decade typical CMT, median mNCVs between 30 m/s and normal, onset 10±60 years typical CMT, ulnar mNCVs between 33±48 m/s, some sensory and proximal muscle involvement no clinical symptoms, mNCV *27±45 m/s, normal CMAPs, slightly reduced SNAPs

clinically CMT1 like, onset mostly in 1st decade, scoliosis, peculiar myelin pathology z CMT4D (HMSN-L) progressive deafness, onset in first decade, Bulgarian Gypsies (from the town of Lom) severe neuropathy, hypomyelination, congenital z CMT4E (CH) onset z CMT4F (MIM: DSS) severe neuropathy, early childhood onset (12±24 months), prominent sensory deficit, (focally folded myelin) z CCFDN congenital cataracts facial dysmorphism and neuropathy, Wallachian Gypsies z HMSN-R severe form, onset in first or second decade, Bulgarian Gypsies (type Russe)

z CMT4C

rare rare

AR AR

AD

AD

AD

AD

rare (?)

rare

rare

rare

rare

rare

AR

AD

rare

AR

rare

rare

AR

AD

rare

AR transcript KIAA1985 NDRG1

unknown, EGR2

CTDP1

8p23

1q22-q23

1p34-p35

19p12-p13.2

ARHGEF10

MPZ (P0)

unknown

unknown

10q24.1-q25.1 unknown

10q23

18q23-qter

19q13.1-q13.3 PRX

10q21.1-q22.1 EGR2

8q24

5q32

608236

607791

608323

606482

606483

605285

604186

DSS: 145900; PRX: 605725

605253

601455

601596

5 Overview of the classification and genetics of hereditary peripheral neuropathies z

77

AD

proximal form of CMT, mNCV *38 m/s, onset in 3rd decade ± rapid progress

mNCV >38 m/s, autosomal dominant AD typical CMT, onset 1±52 years, median motor NCVs AD 40-62 m/s, no proximal involvement, not wheelchair bound AD similar to classical CMT, adult onset (mean *20 years) mainly sensory neuropathy, acral ulcerations, onset AD in 2nd or 3rd decade (could be classified as HSAN) early onset predominantly motor, axonal neuropathy AD with vocal cord and respiratory muscle involvement AD predominant upper limbs and motor neuropathy, onset in 2nd or 3rd decade, slow progression (allelic to dHMN5) typical CMT, intermediate mNCVs, onset in the 2nd AD or 3rd decade, NEFL mutations cause also CMT1E AD allelic to HMN(1), similar to classical CMT but trophic changes, onset in 2nd or 3rd decade, Russian family typical CMT, onset mostly in second decade, CMAP AD and SNAPS reduced

z HMSN-P (MIM: Okinawa ty.)

CMT2 z CMT2A1

z CMT2G

z CMT2F

z CMT2E

z CMT2D

z CMT2C

z CMT2B

z CMT2A2

Inheritance

Typical features

12q12-q13.3

7q11-21

rare rare

8p21

7p14

rare rare

12q23-q24

3q13-q22

1p35-p36

1p35-36

3p14.1-q13

Locus

rare

rare

rare

common common (?)

rare

Frequency

607684

601472

606071

600882

118210

118210

604484

OMIM Acc. Nr.

unknown

608591

HSBP1 (HSP27) 606595

NEFL

GARS

unknown

RAB7

KIF1B (beta)

MFN2

unknown

Gene

z

Form

Table 5.1 (continued)

78 G. Kuhlenbåumer

z CMTX2 z CMTX3 z CMTX4 (NADMR or Cowchock Sy.)

z CMTX or CMTX1

CMTX

z CMT4C3 (MIM: CMT2B2) z CMT4C4 (MIM: CMT2K)

X-linked form of CMT, often intermediate mNCV classical X-linked CMT, females often less severely affected than males mental retardation, infantile onset pyramidal signs, onset in 2nd decade severe distal weakness, deafness, mental retardation, congenital or early childhood onset

severe neuropathy with proximal muscle involvement, onset in the 2nd decade, Moroccan and Algerian families signs of upper motor neuron involvement, onset in first decade, could be allelic to CMT4C4 or CMT4A, Tunisian typical HMSN, onset in 4th decade, only one Costa Rican family known severe neuropathy, childhood onset, vocal cord paralysis, allelic to CMT4A

z CMT4C1 (MIM: CMT2B1)

z CMT4C2 (MIM: CMT2H)

autosomal recessive forms of CMT2

XR XR XR

XR/XD

rare rare rare

common

common

rare

AR XR and XD

rare

AR

rare

rare

AR AR

rare

rare

rare

AR

hearing loss, pupillary dysfunction in some CMT2J AD pat. (could be classified as DI-CMT), onset in 4th or 5th decade onset 15-33 years, clinically typical HMSN, normal AD NCVs, candidate region overlaps with dHMN2 region

CMT4C or AR-CMT2

z CMT2L

z CMT2I and J

Xp22.2 Xq26-q28 Xq24-q26

Xq13.1

8q21

19q13.3

8q21.3

1q21.2-q21.3

12q24

1q22-q23 I: 607677; J: 607736

unknown unknown unknown

GJB1 (Cx32)

GDAP1

unknown

unknown

LMNA

302801 302802 310490

302800

607706

605589

607731

605588

HSBP8 (HSP22) 608014

MPZ (P0)

5 Overview of the classification and genetics of hereditary peripheral neuropathies z

79

hereditary motor neuropathies (no sensory deficit, mostly normal NCV) allelic to CMT2F, juvenile onset, distal muscle a trophy (not fully described yet) distal paresis and atrophy, onset in 3rd or 4th decade lower limb predominance, distal to proximal, onset 0±20 years, unable to walk between 12 and > 30 years predominant upper limb involvement, onset in 2nd decade (allelic to CMT2D) also called Silver Sy., onset: 8±40 years, spastic paraplegia, predominant upper limb diaphragmatic spinal muscular atrophy (SMARD1), early death, onset in the first month of life vocal cord paralysis, onset in 2nd decade onset early adulthood, vocal cord paralysis, breathing difficulties, facial weakness distal weakness and atrophy, pyramidal tract signs, age of onset varies widely between families pyramidal involvement, onset in first decade

distal HMN

z distal HMN Vb/SPG17 z distal HMN VI (SMARD1) z distal HMN VIIA z distal HMN VIIB (MIM: PLMND) z distal HMNpyramidal/ALS4 z distal HMNJerash-type

z distal HMN Va

z distal HMN IV

z distal HMN II

z distal HMN I

Typical features

rare rare rare rare rare rare

AD AR AD AD AD AR

rare

rare

AR AD

rare

rare

rare

Frequency

AD

AD

AD and AR

Inheritance OMIM Acc. Nr.

SETX unknown

9p21.1-p12

unknown DCTN1

BSCL2 (Prot: Seipin) IGHMBP2

GARS

±

605726

602433

158580 607641

604320

270685

600794

607088

HSBP8 (HSP22) 158590

HSBP1 (HSP27) 608634

Gene

9q34

2q14 2p13

11q13-q23

11q12-14

7p

11q13

12q24

7q11-21

Locus

z

Form

Table 5.1 (continued)

80 G. Kuhlenbåumer

hereditary sensory and/or autonomous neuropathies lancinating pain, loss of pain and temperature sensation, acral ulcerations, onset ~20 years glove and stocking dist., early onset, absence of cutaneous sensory receptors/fibers, no autonomous symptoms Riley-Day syndrome, familial dysautonomia, neonatal onset, ªcommonº in Ashkenazi jews (1/3700 live births) congenital insensitivity to pain and anhidrosis (CIPA), fever, mental retardation, early childhood onset HSN1 phenotype without ulcerations, with adult onset chronic cough and esophageal reflux childhood onset, severe reduction of deep pain sensation, Charcot joints, normal sweating

Hereditary recurrent focal neuropathies recurrent painful brachial plexus palsies, z HNA no generalized neuropathy, onset in first to 3rd decade

z HSN1 with cough and reflux z HSN

z HSAN4

z HSAN3

z HSAN2

z HSAN1

HSAN/HSN

rare

rare

AR

AD

rare

AD

rare

rare

AR AR

rare

rare

rare

AR

AD

AR

17q25

1p11.2-p13.2

3p22-p24

1q21-q22

9q31-q33

12p13.33

9q22

unknown

NGFB

±

NTRK1 (TrkA)

IKBKAP

HSN2

SPTLC1

162100

±

608088

256800

223900

201300

162400

5 Overview of the classification and genetics of hereditary peripheral neuropathies z

81

Unclassified peripheral neuropathies z GAN PNS and CNS involvement, giant axons filled with (Giant Axonal neurofilaments, onset in first decade Neuropathy) agenesis of corpus callosum with peripheral z ACCPN neuropathy, mental retardation, dysmorphic (Anderman features syndrome) z CH and Hirschvariable: congenital hypomyelination, CNS sprung disease dysmyelination, intestinal (pseudo)obstruction, deafness z Peripheral pred. sensory, demyelinating neurop., trophic neuropathy and changes, mNCVs 30±55 m/s, mild hearing loss, deafness only 1 family with partial gonadal dysgenesis, demyelination z Minifascicular and ªminifasciclesº neuropathy

Typical features

rare rare rare rare rare

AR AD AD AD

Frequency

AR

Inheritance

12q13.12

1p34.3

22q13.1

15q13-q14

16q24.1

Locus

DHH

GJB3 (Cx31)

SOX10

SLC12A6 (KCC3 Pro)

GAN

Gene

607080

603324

602229, 609136

218000

256850

OMIM Acc. Nr.

z

Form

Table 5.1 (continued)

82 G. Kuhlenbåumer

5 Overview of the classification and genetics of hereditary peripheral neuropathies

z

with onset in infancy but should be amended by the causative mutation if available. HMSN IV is equivalent to Refsum's disease, a complex neurological disorder characterized by polyneuropathy, cerebellar ataxia, cardiac abnormalities and retinitis pigmentosa. Refsum's disease is a phytanic acid storage disease. Because of these features, Refsum's disease is usually considered as a complex neurological storage disease and not classified with the hereditary peripheral neuropathies any more. The categories HMSN V, VI and VII stand for polyneuropathies with additional clinical features but do not represent single known genetic entities. HMSN V describes the relatively rare combination of an inherited peripheral motor and sensory neuropathy combined with spastic paraparesis. The inheritance is described as autosomal dominant. Only a few pedigrees have been reported and no chromosomal loci or genetic defects are known. A report describes exclusion mapping of known HMSN and hereditary spastic paraplegia (HSP) loci in families with HMSN V [34]. Troyer's syndrome ± a form of complicated HSP with an additional peripheral neuropathy ± could be regarded as a complicated autosomal recessive form of HMSN V. It is caused by mutations in the spartin gene (SPG20) [40]. Some forms of HMSN show signs of involvement of the first motor neuron without pronounced spastic paraplegia [13, 26, 50]. The category HMSN VI is used for HMSN associated with optic atrophy. The first family was reported by Vizioli in 1879, but very few families with this entity have been reported since [48]. The chromosomal loci and underlying genetic defects are not known. Four relatively recent descriptions report that inheritance may be autosomal dominant or recessive and that the neuropathy is of the HMSN II type [10, 11, 27] and one of the families is large enough to hopefully allow the elucidation of the underlying genetic defect [49]. HMSN VII stands for HMSN with retinitis pigmentosa. Pure HMSN VII is most likely exceedingly rare and to our knowledge no pedigrees have been reported recently.

5.3.2 Classification of primary hereditary neuropathies according to clinical subgroups and genetic entities In recent years numerous hereditary neuropathies were mapped chromosomally and the underlying genetic defect was identified. It became clear that the earlier classifications are often discordant with the newly defined molecular genetic entities. This led to continuously changing, sometimes confusing classifications. Some authors continued to use clinically oriented classifications while others preferred classification systems solely based on genes and mutations [2, 35]. In this book, a hierarchical classification system is used, which tries to take into account clinical as well as genetic information. The hereditary neuropathies are first grouped into categories based on clinical similarities. For this purpose, the principal categories of

83

84

z

G. Kuhlenbåumer

the classification system developed by Dyck and colleagues are used. The primary hereditary neuropathies are subdivided clinically into the hereditary motor and sensory neuropathies (HMSN), the hereditary sensory and autonomic neuropathies (HSAN) and the hereditary motor neuropathies (HMN) [1]. Another clinically distinct group are the hereditary recurrent focal neuropathies (HNPP ± hereditary neuropathy with liability to pressure palsy and the HNA ± hereditary neuralgic amyotrophy) [51]. In our classification, the HNPP will be grouped with the HMSNs because refined clinical methods revealed that the HNPP is a generalized neuropathy with focal exacerbations caused by pressure on nerve trunks and because the HNPP is caused by genetic defects affecting the same gene as the HMSN IA/CMT1A. This leaves only HNA as a recurrent focal neuropathy in the true sense. Further subdivisions are named ªCMTº and numbered or indicated by letters if no other names were given by the first describers. The HMSN is further subdivided into CMT1 and CMT2 according to electrophysiological criteria (see section ªClinical and electrophysiological phenotype of hereditary motor and sensory neuropathies (HMSNs)º). Subdivisions are made according to the mode of inheritance (autosomal dominant ± AD, autosomal recessive ± AR, X-linked ± XR) and finally according to the causative defective genes, respectively chromosomal loci if the genes are not known. A few genetic entities that do not fit any of these categories are placed in separate categories. Numerous unmapped clinical subtypes of hereditary neuropathies have been described over the years, but without linkage data it is difficult to determine whether these subtypes represent truly novel genetic entities. The clinically defined categories Djerine-Sottas syndrome (DSS or HMSN III) and congenital hypomyelination (CH) are genetically very heterogeneous and are therefore not listed as separate genetic entities in Table 5.1 but are regarded as severe forms of clinically differing neuropathies resulting from mutations in the same genes. Even though it is for clinical purposes necessary to distinguish between demyelinating and axonal polyneuropathies, it is quite clear that most hereditary neuropathies affect both components of the peripheral nerve. Different mutations in the same gene may cause either a predominantly demyelinating phenotype or a predominantly axonal phenotype (see e.g., CMT1B due to mutations in MPZ or CMTX due to mutations in GJB1). This may be due to the specific effect of the mutation if the protein is expressed both in the Schwann cell and in the axon or it may be caused by a disturbed interaction between the Schwann cell and the axon (e.g., MPZ mutation causing a predominantly axonal phenotype despite the fact that MPZ is not expressed in the axon: see chapter 3.3.3 and 4.4). In the last decade, it is an emerging theme that genetic defects in the Schwann cell almost invariably affect the axon as well and vice versa (e.g., see chapter 4.1.1). Table 5.1 gives a rough overview of the classification used in this book including the most prominent clinical features, genetic features, and the Online Mendelian Inheritance in Man accession numbers (OMIM; http://

5 Overview of the classification and genetics of hereditary peripheral neuropathies

z

www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM). OMIM is a frequently updated Internet resource of monogenic traits. A second very valuable Internet resource is the ªInherited Peripheral Neuropathies Mutation Databaseº (IPNMDB; http://www.molgen.ua.ac.be/CMTMutations/) which provides a comprehensive and frequently updated list of all currently known mutations causing hereditary peripheral neuropathies.

5.4 Rare forms of hereditary peripheral neuropathies which do not fit into the current classification schemes Numerous rare inherited multisystem diseases cause a peripheral neuropathy among a plethora of other organ manifestations. Some of them are sometimes assigned to the group of hereditary peripheral neuropathies and will be shortly discussed here but it has to be borne in mind that this selection is somewhat arbitrary and not comprehensive.

5.4.1 Giant axonal neuropathy ± gigaxonin (GAN) (OMIM 256850) z Clinical features: Giant axonal neuropathy (GAN) is an autosomal recessive neurological disease affecting both the PNS and the CNS and probably the most common disease of the ones described in this chapter [4]. GAN has been described in many countries and usually manifests in childhood with retardation of psychomotor development. The children develop a severe, progressive axonal peripheral neuropathy involving the cranial nerves, ataxia, dysarthria, nystagmus and dementia. The EEG is often abnormal and MRI of the brain shows a disturbance of the myelin formation in the CNS. Very characteristic and diagnostically important is dull curly hair not resembling the hair of the healthy parents. The prognosis is poor. Most patients are wheelchair-bound in the first or second decade and die before the age of 30 years. The combination of CNS and PNS symptoms with the characteristic appearance of the hair in a young child with healthy parents is highly diagnostic. The differential diagnosis includes several toxic substances including n-hexane and polyacrylamide which may cause similar neuropathologic changes in the PNS. Menkes disease (OMIM 3909400) is an X-linked disorder with hair changes resembling GAN and severe CNS pathology. Most children with Menkes disease die before the age of two years. Infantile neuroaxonal dystrophy (Seitelberger disease, OMIM 256600) and metachromatic leukodystrophy (OMIM 250100) are two other diseases affecting the CNS and the PNS which have been mentioned as possible differential diagnosis. Both diseases do not cause the characteristic hair changes.

85

86

z

G. Kuhlenbåumer

z Electrophysiology: GAN patients show signs of a severe, predominantly axonal peripheral neuropathy with severely reduced CMAPs and absent SNAPs. NCVs are normal to moderately reduced. The EEG often shows increased slow wave activity and auditory evoked potentials (AEP), visual evoked potentials (VEP) and somatosensory evoked potentials (SSEP) are often abnormal. z Pathology, genetics and pathomechanism: Nerve biopsies show giant axons ± distorted nerve fibers with large axonal swellings ± with an increase of neurofilaments [37]. Giant axons are also found in the CNS of GAN patients. Giant axons are not exclusively found in giant axonal neuropathy but have also been demonstrated in an Italian family with a so far unclassified CMT2 syndrome [33]. Giant axonal neuropathy is caused by mutations in the gigaxonin gene (GAN) on chromosome 16q24 [3, 6, 8, 29]. GAN belongs to the family of so called BTB/kelch proteins. GAN does most likely play a role in the crosstalk between intermediary filaments (IF) and microtubules (MT) in the axon [7].

5.4.2 Agenesis of the corpus callosum with peripheral neuropathy (ACCPN) or Anderman syndrome or hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) ± solute carrier family 12 member 6 gene (SLC12A6 coding for the protein: KCC3) (OMIM 218000) z Clinical features: ACCPN is an autosomal recessive condition with early childhood onset which is quite common in parts of the province Quebec (Canada) but has rarely been reported worldwide. The main clinical symptoms are a predominantly axonal sensorimotor but also demyelinating neuropathy (average onset of walking 3.8 years, average loss of ambulation at 14 years), mild to moderate mental retardation and psychotic episodes with delusions and hallucinations [17]. The neuropathy also affects the cranial nerves (ptosis, palsy of upward gaze). Achilles tendon retractions and scoliosis are common. Tendon reflexes are usually absent. Partial or complete agenesis of the corpus callosum is found in approximately 70% of patients on CT examination. The average age of death is around 30±35 years. z Electrophysiology: Median MNCVs are very variable reaching from 11±39 m/s in adults [17]. SNAPs are usually absent and chronic neurogenic changes predominate on needle EMG. z Pathology, genetics and pathomechanism: Sural nerve biopsies show mainly a lack of large myelinated fibers and signs of axonal loss. Cranial nerves as well as dorsal and ventral roots display swollen axons [17]. ACCPN was mapped to chromosome 15q13-q14 [9]. Mutations in the SLC12A6 gene encoding the KCC3 K+-Cl± cotransporter were found in Canadian patients

5 Overview of the classification and genetics of hereditary peripheral neuropathies

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and a founder effect has been demonstrated for various mutations [23]. SLC12A6 is expressed in all brain regions but expression is low in dorsal root ganglia and ischiatic nerve. Heterologous expression of a mutated channel shows that the channel is expressed but does not function [23]. KCC3 is most likely involved in ion homeostasis (Cl± equilibrium). SLC12A6 deficient mice show a peripheral neuropathy and deficits in behavioral tests but the corpus callosum appears histologically normal [23]. A theory explaining the pathomechanism of ACCPN will have to bring together the co-existence of developmental (ACC) and degenerative (peripheral neuropathy) defects caused by mutations in one gene.

5.4.3 Congenital hypomyelinating neuropathy, central dysmyelination and intestinal (pseudo) obstruction (Waardenburg-Hirschsprung disease) ± SRY like box 10 transcription factor (SOX10) (OMIM 602229) z Clinical features: Mutations in the SOX10 gene cause a variety of phenotypes, most of them featuring intestinal (pseudo)obstruction. A number of dominant mutations have been described which cause a neurologic phenotype including the following features: (1) intestinal (pseudo)obstruction; (2) CNS myelin-related pathology; (3) a congenital hypomyelinating (CH) peripheral neuropathy and (4) deafness [24, 25, 41]. The onset is congenital and the clinical features varied widely. z Electrophysiology: NCVs varied widely. At least in one case the symptoms and electrophysiologic parameters improved with increasing age [41]. Brain stem-evoked potentials were also abnormal. z Pathology, genetics and pathomechanism: Pathologic examination of peripheral nerves showed nearly complete absence of myelin and myelinated fibers in an autopsy case [24]. The disease is caused by mutations in the transcription factor SOX10 which plays an important role in initiating CNS as well as PNS myelination by turning on other transcription factors (e.g., OCT6 and EGR2), which in turn activate myelin genes like PLP (CNS), PMP22 and MPZ (PNS).

5.4.4 Hereditary peripheral neuropathy and deafness ± gap junction protein 3 (GJB3 or connexin 31) z Clinical features: This neuropathy is characterized by a variable degree of hearing loss and peripheral, predominantly sensory and demyelinating neuropathy [31]. In some cases ulceromutilating changes with chronic skin ulcers and osteomyelitis leading to amputation were found. So far only one family has been described.

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z Electrophysiology: NCVs are only mildly reduced. CMAPs as well as SNAPs were reduced. z Pathology, genetics and pathomechanism: Sural nerve biopsy in one patient demonstrated a demyelinating phenotype [31]. This neuropathy is autosomal dominant and caused by the deletion of one amino acid (D66del) of the GJB3 gene [31]. GJB3 encodes the pore forming connexin 31 protein. Mutations in a number of other connexins have been identified as the cause of sensorineural deafness and mutations in GJB1 cause X-linked CMT. Mutations in GJB3 cause in most cases isolated dominant or recessive deafness.

5.4.5 Minifascicular peripheral neuropathy, partial gonadal dysgenesis ± desert hedgehog ± (DHH) (OMIM 607080) z Clinical features: To our knowledge, only one patient with this phenotype has been reported. The patient showed premature female genitalia and a sparsely characterized peripheral neuropathy [47]. z Pathology, genetics and pathomechanism: The sural nerve biopsy demonstrated extensive formation of so called ªminifasciclesº. Minifascicles contain several axon-Schwann cell units that are separated by one-to-several layers of flattened cell processes with the morphology of perineurial cells, which are normally found surrounding large nerve fascicles. The possibility of a mutation in the desert hedgehog (DHH) gene was suggested by a similar phenotype of the DHH-deficient mouse [38]. A point mutation in the translation initiation codon of the DHH gene was found in the patient. A very similar phenotype without a mutation in the coding region of the DHH gene was described recently [45].

References 1. Dyck PJ, Thomas PK (1993) Inherited Peripheral Neuropathy. In: Dyck PJ, Thomas PK (eds) Peripheral neuropathy. Saunders, Philadelphia, pp 1015±1218 2. Auer-Grumbach M, Wagner K, Fazekas F, Loscher WN, Strasser-Fuchs S, Hartung HP (1999) Hereditary motor-sensory neuropathies (Charcot-Marie-Tooth syndrome) and related neuropathies. Current classification and genotype-phenotype correlation. Nervenarzt 70:1052±1061 3. Ben Hamida C, Cavalier L, Belal S, Sanhaji H, Nadal N, Barhoumi C, M'Rissa N, Marzouki N, Mandel JL, Ben Hamida M, Koenig M, Hentati F (1997) Homozygosity mapping of giant axonal neuropathy gene to chromosome 16q24.1. Neurogenetics 1:129±133 4. Berg BO, Rosenberg SH, Asbury AK (1972) Giant axonal neuropathy. Pediatrics 49:894±899

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5. Bird T, Ott J, Giblett E (1982) Evidence for linkage of Charcot-Marie-Tooth neuropathy to the Duffy locus on chromosome 1. Am J Hum Genet 34:388±394 6. Bomont P, Cavalier L, Blondeau F, Ben Hamida C, Belal S, Tazir M, Demir E, Topaloglu H, Korinthenberg R, Tuysuz B, Landrieu P, Hentati F, Koenig M (2000) The gene encoding gigaxonin, a new member of the cytoskeletal BTB/kelch repeat family, is mutated in giant axonal neuropathy. Nat Genet 26:370±374 7. Bomont P, Koenig M (2003) Intermediate filament aggregation in fibroblasts of giant axonal neuropathy patients is aggravated in non dividing cells and by microtubule destabilization. Hum Mol Genet 12:813±822 8. Bruno C, Bertini E, Federico A, Tonoli E, Lispi ML, Cassandrini D, Pedemonte M, Santorelli FM, Filocamo M, Dotti MT, Schenone A, Malandrini A, Minetti C (2004) Clinical and molecular findings in patients with giant axonal neuropathy (GAN). Neurology 62:13±16 9. Casaubon LK, Melanson M, Lopes-Cendes I, Marineau C, Andermann E, Andermann F, Weissenbach J, Prevost C, Bouchard JP, Mathieu J, Rouleau GA (1996) The gene responsible for a severe form of peripheral neuropathy and agenesis of the corpus callosum maps to chromosome 15q. Am J Hum Genet 58:28±34 10. Chalmers RM, Bird AC, Harding AE (1996) Autosomal dominant optic atrophy with asymptomatic peripheral neuropathy. J Neurol Neurosurg Psychiatry 60:195± 196 11. Chalmers RM, Riordan-Eva P, Wood NW (1997) Autosomal recessive inheritance of hereditary motor and sensory neuropathy with optic atrophy. J Neurol Neurosurg Psychiatry 62:385±387 12. Charcot J-M, Marie P (1886) Sur une forme particulire d'atrophie musculaire progressive, souvent familiale, debutant par les pieds et les jambes et atteignant plus tard les mains. Rev Md 6:97±138 13. Christodoulou K, Zamba E, Tsingis M, Mubaidin A, Horani K, Abu-Sheik S, ElKhateeb M, Kyriacou K, Kyriakides T, Al-Qudah AK, Middleton L (2000) A novel form of distal hereditary motor neuronopathy maps to chromosome 9p21.1±p12. Ann Neurol 48:877±884 14. Dawidenkow S (1927) Ûber die neurotische Muskelatrophie Charcot-Marie. Z Ges Neurol Psychiat 107:259±265 15. Dawidenkow S (1927) Ûber die neurotische Muskelatrophie Charcot-Marie. Z Ges Neurol Psychiat 108:344±445 16. Dejerine J, Sottas J (1893) Sur la nvrite interstitielle, hypertrophique et progressive de l'enfance. C R Soc Biol (Paris) 45:63±96 17. Dupre N, Howard HC, Mathieu J, Karpati G, Vanasse M, Bouchard JP, Carpenter S, Rouleau GA (2003) Hereditary motor and sensory neuropathy with agenesis of the corpus callosum. Ann Neurol 54:9±18 18. Dyck PJ (1966) Histologic measurements and fine structure of biopsied sural nerve: normal, and in peroneal muscular atrophy, hypertrophic neuropathy, and congenital sensory neuropathy. Mayo Clin Proc 41:742±774 19. Dyck PJ, Chance P, Lebo R, Carney JA (1993) Hereditary motor and sensory neuropathy. In: Dyck PJ, Thomas PK (eds) Peripheral Neuropathy. Saunders, Philadelphia, pp 1094±1136 20. Dyck PJ, Lambert EH (1968) Lower motor and primary sensory neuron diseases with peroneal muscular atrophy I. Neurologic, genetic and electrophysiologic findings in hereditary polyneuropathies. Arch Neurol 18:603±618 21. Gabreels-Festen A (2002) Dejerine-Sottas syndrome grown to maturity: overview of genetic and morphological heterogeneity and follow-up of 25 patients. J Anat 200:341±356 22. Harding AE, Thomas PK (1980) The clinical features of hereditary motor and sensory neuropathy types I and II. Brain 103:259±280

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23. Howard HC, Mount DB, Rochefort D, Byun N, Dupre N, Lu J, Fan X, Song L, Riviere JB, Prevost C, Horst J, Simonati A, Lemcke B, Welch R, England R, Zhan FQ, Mercado A, Siesser WB, George AL Jr, McDonald MP, Bouchard JP, Mathieu J, Delpire E, Rouleau GA (2002) The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum. Nat Genet 32:384±392 24. Inoue K, Shilo K, Boerkoel CF, Crowe C, Sawady J, Lupski JR, Agamanolis DP (2002) Congenital hypomyelinating neuropathy, central dysmyelination, and Waardenburg-Hirschsprung disease: phenotypes linked by SOX10 mutation. Ann Neurol 52:836±842 25. Inoue K, Tanabe Y, Lupski JR (1999) Myelin deficiencies in both the central and the peripheral nervous systems associated with a SOX10 mutation. Ann Neurol 46:313±318 26. Ionasescu VV, Trofatter J, Haines JL, Summers AM, Ionasescu R, Searby C (1991) Heterogeneity in X-linked recessive Charcot-Marie-Tooth neuropathy. Am J Hum Genet 48:1075±1083 27. Ippel EF, Wittebol-Post D, Jennekens FG, Bijlsma JB (1995) Genetic heterogeneity of hereditary motor and sensory neuropathy type VI. J Child Neurol 10:459±463 28. Krajewski KM, Lewis RA, Fuerst DR, Turansky C, Hinderer SR, Garbern J, Kamholz J, Shy ME (2000) Neurological dysfunction and axonal degeneration in Charcot-Marie-Tooth disease type 1A. Brain 123:1516±1527 29. Kuhlenbåumer G, Young P, Oberwittler C, Hunermund G, Schirmacher A, Domschke K, Ringelstein B, Stogbauer F (2002) Giant axonal neuropathy (GAN): case report and two novel mutations in the gigaxonin gene. Neurology 58:1273± 1276 30. Lambert EH, Bastron JA, Mulder DW (1958) Conduction velocity of motor fibers of peripheral nerves in peroneal muscular atrophy (Charcot-Marie-Tooth disease). Read at the annual meeting of the American Academy of Neurology, Philadelphia, April 1958 31. Lopez-Bigas N, Olive M, Rabionet R, Ben-David O, Martinez-Matos JA, Bravo O, Banchs I, Volpini V, Gasparini P, Avraham KB, Ferrer I, Arbones ML, Estivill X (2001) Connexin 31 (GJB3) is expressed in the peripheral and auditory nerves and causes neuropathy and hearing impairment. Hum Mol Genet 10:947±952 32. Lupski J, de Oca-Luna R, Slaugenhaupt S, Pentao L, Guzzetta V, Trask B, SaucedoCardenas O, Barker D, Killian J, Garcia C (1991) DNA duplication associated with Charcot-Marie-Tooth disease type 1A. Cell 66:219±232 33. Lus G, Nelis E, Jordanova A, Lofgren A, Cavallaro T, Ammendola A, Melone MA, Rizzuto N, Timmerman V, Cotrufo R, De Jonghe P (2003) Charcot-Marie-Tooth disease with giant axons: A clinicopathological and genetic entity. Neurology 61:988±990 34. Mostacciuolo ML, Rampoldi L, Righetti E, Vazza G, Schiavon F, Angelini C (2000) Hereditary spastic paraplegia associated with peripheral neuropathy: a distinct clinical and genetic entity. Neuromuscul Disord 10:497±502 35. Nelis E, Timmerman V, De Jonghe P, Van Broeckhoven C, Rautenstrauss B (1999) Molecular genetics and biology of inherited peripheral neuropathies: a fast-moving field. Neurogenetics 2:137±148 36. Nelis E, Van Broeckhoven C, De JP, Lofgren A, Vandenberghe A, Latour P, Le GE, Brice A, Mostacciuolo ML, Schiavon F, Palau F, Bort S, Upadhyaya M, Rocchi M, Archidiacono N, Mandich P, Bellone E, Silander K, Savontaus ML, Navon R, Goldberg SH, Estivill X, Volpini V, Friedl W, Gal A (1996) Estimation of the mutation frequencies in Charcot-Marie-Tooth disease type 1 and hereditary neuropathy with liability to pressure palsies: a European collaborative study. Eur J Hum Genet 4:25±33

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37. Ouvrier RA (1989) Giant axonal neuropathy. A review. Brain Dev 11:207±214 38. Parmantier E, Lynn B, Lawson D, Turmaine M, Namini SS, Chakrabarti L, McMahon AP, Jessen KR, Mirsky R (1999) Schwann cell-derived Desert hedgehog controls the development of peripheral nerve sheaths. Neuron 23:713±724 39. Passage E, Norreel JC, Noack-Fraissignes P, Sanguedolce V, Pizant J, Thirion X, Robaglia-Schlupp A, Pellissier JF, Fontes M (2004) Ascorbic acid treatment corrects the phenotype of a mouse model of Charcot-Marie-Tooth disease. Nat Med 10:396±401 40. Patel H, Cross H, Proukakis C, Hershberger R, Bork P, Ciccarelli FD, Patton MA, McKusick VA, Crosby AH (2002) SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia. Nat Genet 31:347±348 41. Pingault V, Guiochon-Mantel A, Bondurand N, Faure C, Lacroix C, Lyonnet S, Goossens M, Landrieu P (2000) Peripheral neuropathy with hypomyelination, chronic intestinal pseudo-obstruction and deafness: a developmental ªneural crest syndromeº related to a SOX10 mutation. Ann Neurol 48:671±676 42. Raeymaekers P, Timmerman V, Nelis E, De Jonghe P, Hoogendijk JE, Baas F, Barker DF, Martin JJ, De Visser M, Bolhuis PA (1991) Duplication in chromosome 17p11.2 in Charcot-Marie-Tooth neuropathy type 1a (CMT 1a). The HMSN Collaborative Research Group. Neuromuscul Disord 1:93±97 43. Sereda MW, Meyer zu Horste G, Suter U, Uzma N, Nave KA (2003) Therapeutic administration of progesterone antagonist in a model of Charcot-Marie-Tooth disease (CMT-1A). Nat Med 9:1533±1537 44. Sturtz FG, Chazot G, Vandenberghe AJ (1992) Charcot-Marie-Tooth disease from first description to genetic localization of mutations. J Hist Neurosci 1:47±58 45. Sugie K, Futamura N, Suzumura A, Tate G, Umehara F (2002) Hereditary motor and sensory neuropathy with minifascicle formation in a patient with 46XY pure gonadal dysgenesis: a new clinical entity. Ann Neurol 51:385±388 46. Tooth HH (1886) The peornual type of progressive muscular atrophy. HK Lewis & Co, London 47. Umehara F, Tate G, Itoh K, Yamaguchi N, Douchi T, Mitsuya T, Osame M (2000) A novel mutation of desert hedgehog in a patient with 46,XY partial gonadal dysgenesis accompanied by minifascicular neuropathy. Am J Hum Genet 67:1302± 1305 48. Vizioli (1889) Dell'atrofia progresiva nervosa. Boll R Acad Medico-chir, Napoli 49. Voo I, Allf BE, Udar N, Silva-Garcia R, Vance J, Small KW (2003) Hereditary motor and sensory neuropathy type VI with optic atrophy. Am J Ophthalmol 136:670±677 50. Vucic S, Kennerson M, Zhu D, Miedema E, Kok C, Nicholson GA (2003) CMT with pyramidal features. Neurology 60:696±699 51. Windebank A (1993) Inherited recurrent focal neuropathies. In: Dyck P, Thomas P, Griffin J (eds) Peripheral Neuropathy. WB Saunders, Philadelphia, pp 1137± 1148

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6 Charcot-Marie-Tooth disease type 1

(CMT1) and hereditary neuropathy with liability to pressure palsy (HNPP) E. Nelis, P. De Jonghe, V. Timmerman

6.1 Autosomal dominant CMT1 and HNPP 6.1.1 Clinical features Charcot-Marie-Tooth disease type 1 (CMT1), also called hereditary motor and sensory neuropathy type I (HMSN I), shows a classical CMT phenotype with progressive muscular atrophy of the distal muscles, foot deformities (pes cavus and claw toes) and absent deep tendon reflexes [29, 158]. In all cases, a varying degree of symmetrical sensory loss is present. Different types have been designated on the basis of genetic classification, i.e., by locus or by gene. Therefore, the different CMT1 types do not necessarily reflect different clinical phenotypes. In CMT1A, caused by a 1.4 Mb duplication on chromosome 17p11 or by point mutations in PMP22, the first overt symptoms usually appear in the second decade of life, but careful neurological examination reveals earlier neurologic deficits with a mean age of onset around four years [13]. The course is mild to moderately severe. In some cases, a visible and palpable hypertrophy of peripheral nerves, especially the great auricular nerve, can be found. CMT1A patients with point mutations are usually more severely affected than patients with a CMT1A duplication. Patients homozygous for the CMT1A duplication have a more severe phenotype and an earlier onset age (< 1 year) than the heterozygous CMT1A duplication patients [82]. In a few CMT1A patients, deafness and/or vocal cord dysfunction have been observed [20, 67, 129]. CMT1B, caused by point mutations in the MPZ gene, is usually more severe than CMT1A. The age of onset is very variable as well as the expressivity (severity of the disease) in different members of the same CMT1B family [136]. Some CMT1B patients have special features, such as significant sensory signs, early involvement of upper extremities [178], bulbar signs [28], auditory involvement [142], and pupillary abnormalities [36]. Patients with CMT1C, caused by point mutations in the LITAF gene, manifest characteristic CMT symptoms, including high-arched feet, distal muscle weakness and atrophy, depressed deep-tendon reflexes and sensory impairment [12]. Most patients with CMT1D, caused by point

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mutations in EGR2, are severely affected. In some CMT1D patients, cranial nerve involvement occurs but it is not clear whether the palsies were of peripheral or central origin [19, 108]. CMT1F, caused by point mutations in NEFL, is in most cases characterized by an age of onset below 15 years and in some cases neonatal or early childhood onset with delayed motor development [61]. Roussy-Levy syndrome (RLS) comprises clinical features of CMT1 combined with static tremor of the upper limbs and gait ataxia [127]. RLS usually begins in infancy or childhood and manifests as a delay in starting to walk with clumsiness and frequent falls. This condition resembles CMT1 in its dominant inheritance, foot deformity, weakness and atrophy of distal limb muscles, especially the peroneal muscles, absent tendon reflexes, and some distal sensory loss. There was a long-lasting debate whether or not RLS is a separate genetic entity (see section ªGenetics and pathomechanismº). Djerine-Sottas syndrome (DSS), also referred to as HMSN III, shares considerable overlap with CMT1, although the symptoms of DSS have an earlier onset (< 3 years) and are more severe. The original patients [37] showed clubfoot, kyphoscoliosis, generalized weakness and muscular atrophy with fasciculations beginning first in the leg muscles, decreased reactivity to electric stimulation, areflexia, marked distal sensory loss in all four extremities, in-coordination in the arms, Romberg sign, miosis, decreased pupillary reaction to light, and nystagmus. About one third of the patients diagnosed as DSS remain ambulant for walking distances of at least one kilometer into the fourth decade of life despite the early and severe initial presentation [44]. Some patients with multiple cranial nerve hypertrophy were described [139, 175]. The mode of inheritance can be autosomal dominant or recessive (see section ªGenetics and pathomechanismº). In many patients with a seemingly recessive mode of inheritance, dominant de novo mutations have been identified [44]. Congenital hypomyelination (CH) is characterized clinically by congenital onset of hypotonia, areflexia and distal muscle weakness. There has been some controversy and difficulty in differentiating congenital hypomyelination from DSS since there is considerable overlap in the clinical presentation. Since in most CH and DSS patients mutations in the same genes associated with CMT1 have been identified, DSS and CH can be considered as variants of the same group of demyelinating HMSN, but some reports suggest that CH improves during the first years of life, while DSS progresses [114]. Hereditary neuropathy with liability to pressure palsy (HNPP), also called tomaculous neuropathy, is autosomal dominantly inherited and often manifests between the 20th and 40th year of life. After minimal trauma or compression load, the patients suffer painless focal peripheral nerve lesions that are mostly located at sites where the nerve is exposed to pressure (e.g., ulnar sulcus, head of the fibula), or at physiologic entrapment sites like the carpal tunnel. The symptoms improve over days to months [169]. Painless brachial plexus lesions and involvement of the hypoglossal nerve

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have also been described as symptoms of HNPP [104, 170]. Some patients develop a slowly progressive neuropathy clinically indistinguishable from CMT1, while others show electrophysiological, but not clinical signs of a generalized neuropathy [84]. Atypical manifestations of the disorder include pes cavus, scoliosis, and deafness [45]. HNPP can mimic the symptoms of carpal tunnel syndrome, since the peripheral nerve entrapment can include median nerve compression at the carpal canal. A family with dominantly inherited carpal tunnel syndrome was associated with the deletion in chromosome 17p11 that causes HNPP [117].

6.1.2 Electrodiagnostic and laboratory features Slowed motor nerve conduction velocities (MNCVs) in CMT patients were first described in the 1950s [71, 72]. In CMT1, MNCVs are uniformly slowed to less than 38 m/s for the motor median nerve [54]. Because of secondary axonal damage in CMT1, compound muscle action potentials (CMAP) are often reduced. The degree of neurological dysfunction correlates much better with the degree of CMAP reduction (secondary axonal damage) than with the degree of MNCV slowing [68]. The amplitudes of the sensory nerve action potentials (SNAP) are severely reduced or the potentials are not recordable. In a study of 105 CMT1A duplication patients belonging to 45 unrelated families, the median MNCV ranged from 10 to 42 m/s. The majority of the values fell between 16 and 30 m/s [34]. In a series of 119 patients with the CMT1A duplication [17], the MNCV was found to be uniformly reduced in all nerves. The SNAPs were consistently abnormal. An early age of onset and more severely reduced MNCVs were predictive of a more severe disease course. Although the disease is clinically progressive, median MNCV and CMAP amplitudes did not change during the course of the disease. A longitudinal study of children with the CMT1A duplication showed that all subjects had abnormal motor and sensory NCV from the age of 2 [14]. The CMAP from extensor digitorum brevis was reduced or absent in 50% and 100% at the ages of 5 and 10 years, respectively. CMT1A patients with point mutation in PMP22 have slower NCVs than CMT1A duplication patients: some patients with PMP22 point mutations have been described as DSS or even CH patients. The MNCVs of CMT1B patients are often very slow (< 20 m/s) and the electrophysiological delineation from DSS is not clearly defined. Some CMT1B patients have near normal NCVs [88]. The two original CMT1C pedigrees have a mean median MNCV of 23 m/s and 26 m/s, respectively. There was prominent temporal dispersion and evidence for conduction block, especially in the tibial nerves [12, 144]. In CMT1 patients with NEFL mutations, NCVs are usually within the CMT1 range [35, 61], while some patients may have NCVs that approach the normal range [91]. DSS patients have by definition markedly reduced MNCVs (less than 10±12 m/s) and usually absent SNAPs [44]. Elevated protein content of the cerebrospinal fluid is not a mandatory feature of DSS as suggested in the

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past. On the contrary, it might be a feature of very early onset chronic inflammatory demyelinating neuropathy (CIDP) and should be followed up with a nerve biopsy in order to detect inflammatory infiltrates. CH patients have extremely reduced MNCVs (3±8 m/s) or no CMAPs are detectable at all. No conduction blocks are present. Electrophysiological examination in HNPP patients shows prolonged distal latencies, slowing of MNCVs and conduction blocks, especially at physiological pressure or entrapment sites, in nearly all patients as well as in asymptomatic carriers, disclosing a mild underlying generalized neuropathy [2, 9].

6.1.3 Pathological features Pathological examination of peripheral nerves in CMT1 shows a marked decrease in the density of myelinated fibers and de- and remyelination with formation of so called ªonion bulbsº [151]. Onion bulbs are altered myelin structures generated by repeated de- and remyelination. They usually consist of Schwann cell processes, and more rarely of basal membranes. In CMT1A duplication patients, the onion bulbs are small to moderate in size, appear with a moderate frequency and are more prominent in nerves with less severe axonal loss. In the early stage, the myelin sheaths are thicker than normal, later the axons become thinly myelinated. A large reduction in the number of myelinated axons is observed. In CMT1A patients with PMP22 point mutations, onion bulbs are large and present on most axons. The myelin sheaths are thinner than normal. In some patients, uncompacted myelin or tomaculae (lat. ªsausagesº), focal thickenings of the myelin sheath, are observed. In CMT1B patients, sural nerve biopsies often show demyelination, onion bulbs and uncompacted myelin but other myelin features, e.g., focally folded myelin, have also been observed [49]. In rare CMT1B cases, segmental demyelination/remyelination in combination with axonal degeneration/regeneration is observed [74]. A sural nerve biopsy of a CMT1C patient demonstrated onion bulb hypertrophy typical of demyelinating CMT [144]. In CMT1D, nerve biopsy showed a severe loss of myelinated fibers with numerous onion bulbs [108, 177]. A single nerve biopsy of a CMT1 patient with a NEFL mutation showed axonal pathology with axonal regeneration clusters and onion bulb formations [61]. In DSS (also called HMSN III), hypertrophic nerves and abundant onion bulbs are noted on nerve biopsies. The onion bulbs are sometimes composed of basal lamina material [26]. CH is characterized by hypomyelination of most or all fibers, without signs of demyelination, and is considered to result from a congenital impairment in myelin formation. In contrast, DSS is thought to be due to aberrant demyelination and subsequent remyelination of the peripheral nerve. A correlation of morbidity and mortality was found with the presence/absence of onion bulbs: patients with few onion bulbs died in early infancy, usually because of difficulty in swallow-

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ing and respiration after birth. Patients with atypical onion bulbs survived but developed severe motor and sensory impairment [53]. Biopsies of the sural nerve of HNPP patients show characteristic tomaculae, signs of de- and remyelination with onion bulbs and variable axonal loss [150]. Tomaculae are sausage-shaped enlargements consisting of focal thickenings of the myelin sheath composed of redundant loops of myelin with normal periodicity. These are not absolutely specific for HNPP but may also infrequently be present in other hereditary peripheral neuropathies and in CIDP [130].

6.1.4 Genetics and pathomechanism Molecular genetic studies have shown that autosomal dominant CMT1 is genetically heterogeneous and four loci have been mapped: CMT1A to chromosome 17p11.2 [164], CMT1B to 1q22-q23 [16], CMT1C to 16p13.1 [144] and CMT1D to 10q21.1-22.1 [166]. The CMT1 causing genes for all these loci have been identified over the last decade and are PMP22, MPZ, LITAF and EGR2, respectively. Furthermore, mutations in NEFL, originally associated with CMT2, are also found in autosomal dominant CMT1 patients [61]. In the following paragraphs, we will discuss how positional cloning strategies and candidate gene approaches have contributed to the identification of the loci and genes for autosomal dominant CMT1.

z The CMT1A duplication and HNPP deletion The CMT1A locus was assigned to chromosome 17p by Vance et al. [164] in an American CMT family. At that time detailed genetic maps were not available and the genetic markers ± restriction fragment length polymorphisms ± used in positional cloning strategies had a low informativity. However, thanks to the availability of multigenerational pedigrees, others confirmed linkage to the CMT1A locus in several large families, and refined it to a large region (30cM) on chromosome 17p11.2-p12 [90, 92, 111, 120, 155]. In 1991, two research groups independently identified a tandem duplication of a chromosomal segment in 17p11.2-p12 in CMT1A patients [82, 121]. This duplication occurred de novo via an unequal crossing-over event and was subsequently transmitted to the next generations. The de novo appearance of the CMT1A duplication is a frequent finding in isolated CMT1 patients [55]. These de novo duplications are usually of paternal origin and arise from unequal crossing-over events during male spermatogenesis [105]. In addition, a few duplications of maternal origin have been described [18, 85]. Large genetic epidemiological studies estimated that the frequency of the CMT1A duplication in dominant CMT1 cases is about 71% CMT1 [102, 171]. Physical mapping experiments were performed and the size of the CMT1A duplication region was estimated to be 1.5 Mb [113, 122]. The unequal crossing-over event in CMT1A occurs dur-

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Fig. 6.1. Model of unequal crossing over between misaligned CMT1A-REPs leading to the CMT1A duplication (1) and HNPP deletion (2). The blue boxes represent the proximal CMT1AREP, the bright blue boxes the distal CMT1A-REP flanking the 1.4 Mb region, whereas the dark blue boxes represent the PMP22 gene

ing meiosis via a chromosomal misalignment of large repeat elements, called the ªCMT1A-REPsº, flanking the CMT1A region (Fig. 6.1) [113]. With the exception of a few rare cases, the CMT1A duplication always has the same size, i.e., 1.5 Mb, suggesting that the repeat sequences in this region influence this constant DNA rearrangement. A patient, mosaic for the CMT1A duplication, was reported to have a reversion of the 1.5 Mb CMT1A duplication in several somatic tissues [79]. Interestingly, Chance et al. [27] reported patients affected with HNPP to have a reciprocal deletion of the 1.5 Mb CMT1A region on 17p11.2-p12. Subsequent studies confirmed that the large majority of HNPP patients carried the 1.5 Mb deletion [102]. At the molecular level this implies that three copies of the CMT1A-REP sequence are located on the CMT1A duplication chromosomes while only one copy is present on the HNPP deletion chromosomes. It is unknown why HNPP seems to be much rarer than CMT1A. It has been hypothesized that a significant proportion of HNPPs are never diagnosed because the course is mild and patients may present only once in their life with a pressure induced palsy. Further detailed analysis of the CMT1A duplication/HNPP deletion mutations demonstrated a ªhotspotº region of frequent unequal crossing over within the CMT1A-REP elements in a cohort of unrelated CMT1A and HNPP patients of North American [124], European [81, 156] and Japanese [174] origin. The sequence within the hotspot of recombination showed 98% identity between the proximal and distal CMT1A-REP elements [66, 123]. Sequence comparison of the low copy CMT1A-REPs revealed a mariner transposon-like element (MITE) near the hotspot of unequal recombination. However, it is unlikely that the MITE codes for an actively transcribed transposase since the open reading frame contains several frame-

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shift mutations [124]. Physical mapping strategies using large insert clone contigs (P1 and bacterial artificial chromosomes: PACs and BACs) were performed to delineate the complete nucleotide sequence of the CMT1A/ HNPP genomic segment to 1,421,129 bp of DNA. This latter study did not only allow the identification of several genes in the region, but also explains an evolutionary mechanism relevant for the formation of the CMT1A-REP by DNA rearrangement during primate speciation [59].

z CMT1A and related disorders ± peripheral myelin protein 22 gene (PMP22) (OMIM 118220, 118300) One year after the identification of the CMT1A duplication, PMP22 was assigned to the CMT1A region [89, 112, 154, 162]. Importantly, the smaller duplications and deletions reported in the literature, still contained the PMP22 gene [105, 161], supporting a gene dosage effect as the disease mechanism [83]. Furthermore, over- and underexpression of PMP22 has been confirmed at the transcript and protein level in CMT1A and HNPP patient nerve biopsies, respectively [163]. The dosage sensitivity of PMP22 transcripts and protein was nicely illustrated by the genotype-phenotype correlations in man and rodents over- and underexpressing PMP22 (reviewed in [15, 101]). Beside the CMT1A duplication and HNPP deletion, point mutations in the PMP22 gene can result in the following distinct phenotypes: classical CMT1 (CMT1A), HNPP and the more severe DSS and CH (IPNMDB; http://www.molgen.ua.ac.be/CMTMutations/) (Table 6.1). Mutations that truncate or severely alter the protein sequence and are rapidly degraded, mimicking underexpression resulting from the deletion, are predicted to lead to an HNPP phenotype. Indeed, most loss-of-function mutations result in HNPP, while gain-of-function mutations lead to CMT1 or DSS, either by an increased dosage of a normal PMP22 protein or by a toxic effect of the mutated PMP22 molecule. In vitro studies have demonstrated that missense mutations lead to impaired intracellular trafficking of PMP22 resulting in an accumulation of the mutant protein in the endoplasmic reticulum and Golgi apparatus. The mutant protein also traps normal PMP22 resulting in a decreased amount of PMP22 available for incorporation in the myelin membrane [95]. The PMP22 gene was first cloned as the human homologue of the mouse growth arrest-specific 3 gene (Gas3) [87]. The gene is located on mouse chromosome 11, a syntenic region to human chromosome 17p11.2. It encodes a membrane protein comprising 2±5% of total peripheral myelin protein content [107]. PMP22 expression in the peripheral nervous system (PNS) is most likely regulated by axonal contact [141]. The PMP22 gene has two tissue-specific promoters, one being nerve-specific [145]. The PMP22 protein has four transmembrane domains, two extracellular loops, and cytoplasmic amino and carboxy termini. After synthesis in the rough endoplasmic reticulum, the majority of PMP22 becomes rapidly degraded

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and only a small fraction is processed in the Golgi apparatus and transported to the cell membrane [106]. Although PMP22 has been known for almost two decades, its function is still unclear. Initial in vitro studies showed that PMP22 is a growth arrest and apoptosis-specific protein [42, 86]. Mouse pmp22 has been detected during development and in distinct adult neural and non-neural tissues. The zebrafish orthologue of PMP22 also shows expression in embryonic neural crest cells, suggesting a role in the early development of the PNS [172]. Moderate overexpression of PMP22 can induce susceptibility to apoptosis in some cell types. When this apoptotic response is counteracted, PMP22 can still modulate cell shaping and cell spreading. Therefore, PMP22 may have an important role in Schwann cell differentiation and myelination [25]. In the adult PNS, PMP22 most likely functions as an integral membrane protein since it is confined to the compact myelin of Schwann cells [69, 140]. Co-immunoprecipitation and confocal microscopy experiments demonstrated that PMP22 and myelin protein zero (MPZ/P0), the major component of the peripheral myelin membrane, form complexes suggesting a complementary role of both proteins in cell adhesion of compact myelin [33]. Mutated or overexpressed PMP22 causes a ªgain-of-functionº endoplasmatic reticulum retention phenotype. Recently, it was demonstrated that PMP22 associates in a specific, transient, and oligosaccharide processing-dependent manner with the lectin chaperone calnexin (CNX) [39]. In the Tr-j mouse, a prolonged association of mutant PMP22 with CNX was found. Since CNX and PMP22 co-localize in large intracellular myelin-like figures, sequestration of CNX in intracellular myelin-like figures may be relevant for the CMT pathology.

z CMT1B and related disorders ± myelin protein zero gene (MPZ) (OMIM 118200) The myelin protein zero gene (MPZ) is located on chromosome 1q22-q23. It encodes a 219 amino acid, 28±30 kDa glycoprotein that accounts for more than 50% of total PNS myelin protein. The protein called P0 has one transmembrane domain, an extracellular aminoterminus and an intracellular carboxy-terminus. Crystallographic 3-D structural analysis of the extracellular domain shows similarity to an immunoglobulin variable domain [137]. During Schwann cell development, P0 is simultaneously induced with genes encoding other myelin proteins, such as PMP22, myelin basic protein (MBP) and myelin-associated glycoprotein (MAG) [78]. P0 is upregulated at the onset of myelination. As a compact myelin protein, P0 most likely acts as a `double adhesive protein'. It holds myelin together at the intraperiod line through interactions of its extracellular, selfadhesive immunoglobulin domain [137] and at the major dense line via interactions of its cytoplasmic domain [40]. Apart from its structural role in myelination, P0 plays a regulatory role as well. P0-overexpressing mice show failure in axon sorting and a myelination arrest at early mesaxon formation. In early developing Schwann cells, high P0 overexpression inhibits polarization of Schwann cell membranes into

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appropriate functional domains, dynamic axonal interaction and Schwann cell membrane expansion required for appropriate axonal sorting and myelination [176]. Most MPZ mutations cause a classical CMT1 phenotype (CMT1B). However, some MPZ mutations lead to a more severe DSS or CH phenotype (reviewed in [99]). Specific MPZ mutations are also associated with CMT2, the axonal form of CMT (Table 6.1). The Thr124Met mutation is associated with a distinct CMT2 phenotype with pupillary abnormalities and deafness [28, 36, 93, 135]. Mutant P0 could affect myelin formation in three ways: (1) by not reaching the myelin membrane, (2) by reaching the myelin membrane but having lost its adhesive properties, or (3) by reaching the myelin membrane and having a dominant negative effect on the wildtype P0. In vitro studies have shown that mutated P0 can indeed reduce adhesion [41, 173]. The complex-formation between PMP22 and P0 might clarify the remarkable similarity between the CMT1A and CMT1B phenotypes [33]. Alterations in either protein may interfere with the normal association of P0 and PMP22 into one functional complex. The disturbed interaction would subsequently result in demyelination as a common pathological pathway in CMT1A and CMT1B.

z CMT1C ± lipopolysaccharide-induced tumor necrosis factor gene (LITAF) (OMIM 601098) Two autosomal dominant CMT1 families were reported to have a locus mapping to 16p13.1-p12.3 (CMT1C) [144]. Only recently, three missense mutations in LITAF were identified in the two previously known CMT1C families and confirmed in a third family of different origin [143]. The LITAF protein (also known as SIMPLE; small integral membrane protein of lysosome/late endosome) is widely expressed and encodes a 161-amino acid protein that might be involved in protein degradation pathways. The missense mutations (G112S, T115N, W116G) cluster in a domain of the LITAF protein relevant for peripheral nerve function [12]. The function of LITAF is currently unknown, but the subcellular localization and putative domains point to a ubiquitinmediated lysosomal degradation protein. LITAF is located in the lysosome/ late endosome [94], its murine orthologue interacts with NEDD4 an E3-ubiquitin ligase [60], and it contains a conserved motif known to interact with another protein involved in sorting of ubiquitinated proteins to the multi-vesicular body [157]. Further mutation analysis of LITAF in CMT1 patients is needed to estimate the frequency of LITAF mutations in the total CMT1 population, and to delineate the associated phenotype.

z CMT1D ± early growth response element 2 gene (EGR2) (OMIM 607678) The EGR2 gene is located on chromosome 10q21.1-q22.1 [62] and encodes a 51 kDa protein of 475 amino acids. EGR2 is the human homologue of the mouse Krox20 gene [30], with an overall amino acid identity of 89%

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(100% in the zinc finger domain) [167]. EGR2 is a member of the EGR family. The EGR proteins encode transcription factors containing Cys2His2 zinc finger domains, which bind a GC-rich consensus binding site [147]. Analysis of homozygous and heterozygous Krox20 knockout mice has shown that Krox20 is important in the development and segmentation of the hindbrain [131, 146]. Surviving homozygous Krox20 knockout mice have hypomyelination of the PNS with Schwann cells blocked at an early stage of differentiation, causing a trembling phenotype [159]. Krox20 expression is activated before onset of myelination in the PNS and is essential for the final differentiation of myelinating Schwann cells [181]. These data suggest that Krox20 and its human homologue EGR2 are transcription factors required for the transactivation of PNS myelination-specific genes. Indeed, using microarray expression profiling, 98 known genes were identified that were induced by Egr2 in Schwann cells [96]. The putative Egr2 target genes included myelin proteins and enzymes required for synthesis of normal myelin lipids. RT-PCR to monitor Schwann cell gene expression confirmed that Egr2 is sufficient for induction of target genes including MPZ, PMP22, MBP, MAG, GJB1 and PRX. Furthermore, a dominant-negative inhibition of wildtype Egr2-mediated induction of essential myelin genes using EGR2 DNA-binding domain mutants was demonstrated [96]. A recent study, however, provides evidence that myelin-related signaling in Schwann cells can be independent of Krox20 [109]. Several mutations in EGR2 have been described in patients with different phenotypes, i.e., classical CMT1, DSS and CH [153, 166]. Some of these mutations were present in the homozygous and others in the heterozygous state (Table 6.1). One mutation causes a CMT1 phenotype with cranial nerve deficits [108]. Clinical involvement of cranial nerves is unusual for CMT1 and may demonstrate a similar role for Krox20 and EGR2 in brainstem and cranial nerve development [108]. The effect of some mutations on the DNA binding capacities of EGR2 has been studied in order to correlate the residual DNA binding capacities to the clinical severity. The results confirm that the severity of CMT1D correlates with the residual amount of DNA binding of the mutated EGR2 [167]. The dominant nature of these mutations seems to be in contrast with the Krox20 heterozygous knockout mouse, which shows no phenotypical abnormalities [131]. This suggests that these mutations do not cause a loss of function, but rather have a dominant negative or a gain-of-function effect. Another mutation was shown to interfere with the binding of NGFI-A binding proteins, possible co-repressors of EGR2, probably leading to increased transcription of EGR2 [167].

z CMT1F ± neurofilament light polypeptide gene (NEFL) (OMIM 607734) Mutations in NEFL were recently reported as a cause for autosomal dominant axonal CMT linked to chromosome 8p21 (CMT2E) [91]. Further analysis of NEFL in CMT patients showed that patients with NEFL mutations have an early disease onset and are usually severely affected, with moder-

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Table 6.1. Genes associated with CMT1 and related peripheral neuropathies Gene

Locus

Inheritance

Phenotype

z PMP22 (duplication) z PMP22 (duplication) z PMP22 (deletion) z PMP22 z PMP22 z MPZ z MPZ z LITAF z EGR2 z EGR2 z NEFL z GDAP1 z MTMR2 z SBF2/MTMR13 z KIAA1985 z NDRG1 z PRX z CTDP1

CMT1A CMT1A HNPP CMT1A, HNPP CMT1A CMT1B CMT1B CMT1C CMT1D CMT4E CMT2E CMT4A CMT4B1 CMT4B2 CMT4C CMT4D CMT4F CCFDN

AD AR AD AD AR AD AR AD AD AR AD AR AR AR AR AR AR AR

CMT1, RLS DSS HNPP CMT1, HNPP, DSS, CH DSS CMT1, CMT2, DSS, CH, RLS DSS CMT1 CMT1, DSS CH CMT1, CMT2, DSS CMT1, CMT2, DSS CMT1, CH CMT1 CMT1 HMSN-L CMT1, DSS CCFDN

ately to severely slowed NCVs. Based on the clinical characteristics, some of them were diagnosed with DSS [35, 61]. NEFL encodes a 62 kDa structural protein, which is one of the most abundant cytoskeletal components of neuronal cells [43]. NEFL assembles with neurofilaments of higher molecular mass, medium (NEFM) and heavy (NEFH) chain polypeptides, into intermediate filaments and forms an extensive fibrous network in the cytoplasm of the neuron. Neurofilament accumulation tightly correlates with radial growth of axons during myelination. Neurofilaments determine the axonal diameter and, hence, the conduction velocity of peripheral nerves [4, 75]. Nefl knockout mice do not have a CMT-like phenotype [180], while transgenic mice have a severe peripheral neuropathy with massive motor neuron death [76].

z Roussy-Levy syndrome ± myelin protein zero gene (MPZ), peripheral myelin protein 22 gene (PMP22) (OMIM 180800) Plant-Bordeneuve et al. [115] identified a point mutation in MPZ in the original family studied by Roussy and Levy. This finding shows that the family belongs to the CMT1B subtype. Other RLS patients, however, showed the CMT1A duplication [5, 152] (Table 6.1). These findings provide evidence against the RLS as a distinct genetic entity, but suggest a close re-

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lation with CMT1. What causes the additional features of gait ataxia and essential tremor needs further clarification. Roussy-Levy syndrome (RLS) comprises clinical features of CMT1 combined with static tremor of the upper limbs and gait ataxia [127].

6.2 Autosomal recessive demyelinating CMT or CMT4 6.2.1 Clinical features The autosomal recessive forms of demyelinating CMT are traditionally designated CMT4. These forms are rare. Every subform has been described in a few families only, each with particular ethnic, pathologic, or clinical characteristics: Many of these families are living in North Africa, or they belong to genetically isolated populations in Europe like the Bulgarian Sinti or Roma Gypsies. Many of these neuropathies are clinically severe and could also be classified as DSS. CMT4A was identified in Tunisian families [10]. The disease usually manifests with delayed motor milestones in the second year of life. Patients develop a severe, predominant motor neuropathy and often become wheelchair-dependent in the first or second decade [10]. Foot deformities and scoliosis are often present. CMT4B1 is a relatively severe neuropathy with both distal and proximal paresis, foot deformities, scoliosis and onset in early childhood [119]. Patients become wheelchair-dependent in the third decade, and death occurs in the 4th to 5th decade [119]. Additional features, such as weakness of the jaw and of the facial and bulbar muscles and diaphragmatic weakness [56], have been noticed in some CMT4B1 patients. In CMT4B2, the onset of the neuropathy occurs in the first two decades and patients show a clinically typical but rather severe type of demyelinating CMT. One family features early-onset glaucoma as an additional clinical sign [6]. CMT4C patients show clinically a typical CMT1-like presentation in the first or second decade, which is complicated by a rather severe scoliosis in some patients [47, 77]. CMT4D, also known as HSMN-L, is a rare form of HMSN identified in Bulgarian Roma living close to the town of Lom [64, 65]. The disease manifests in childhood with weakness of the legs followed by palsies of the hands between 5 and 15 years of age. Many patients between the age of 26 and 50 years are unable to walk. Deafness is an invariant feature of the phenotype and usually develops in the third decade [65]. CMT4E patients present with a floppy infant syndrome at birth. Motor milestones are delayed, but the two patients described by Warner et al. eventually learned to walk with crutches [166]. Weakness and atrophy are distally accentuated but proximal weakness is also present. In CMT4F patients, the disease manifested with slightly delayed motor development (sitting at approximately 12 to 18 months, walking at approxi-

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mately 24 months). The gait was unsteady and wide-based. At the age of approximately 9 to 10 years the typical signs of CMT became apparent in the legs and at approximately 14 to 15 years also in the arms [38]. Typical foot deformities and scoliosis were present. Marked sensory impairment ± sometimes more prominent than the motor deficits ± is a characteristic feature of CMT4F [22, 148]. HMSN-R, identified in Roman gypsies, is a steadily progressive neuropathy leading to total paralysis of the muscles of the lower legs in the fourth to fifth decade. All patients showed foot deformity, and most showed hand deformity. In addition, patients develop prominent sensory deficits [126]. Congenital cataracts facial dysmorphism neuropathy (CCFDN) is clinically characterized by a number of pathological features in addition to a rather severe predominantly demyelinating peripheral neuropathy: congenital cataracts with microcornea, facial dysmorphic features, mild cognitive deficit, short stature and hypogonadism, pyramidal signs and a number of additional CNS abnormalities [160].

6.2.2 Electrodiagnostic features The motor and sensory NCVs in CMT4A are slowed to 25±35 m/s [10]. In CMT4B, MNCVs ranged from 15 to 17 m/s in the upper limbs of the youngest patients to undetectable in the adult patients. Sensory action potentials were almost always absent. In all patients, auditory evoked potentials showed abnormally delayed interpeak I±III latencies [11, 119]. In CMT4C patients the mean motor MNCV was 22.6 m/s [133]. MNCVs of CMT4D patients in the median, ulnar, tibial, and peroneal nerves are severely reduced in the youngest patients and unattainable after the age of 15 years. Decreased conduction velocity and CMAP amplitude are also found proximally, in the axillary and facial nerves. Brainstem auditory evoked potentials (AEP) are markedly abnormal, with prolonged interpeak latencies consistent with demyelination [64, 65]. In CMT4E MNCVs are extremely reduced to 3±8 m/s [166]. The results of NCV studies performed on five CMT4F patients revealed the total absence of any sensory or motor evoked response in the upper and lower limbs. EMG showed normal insertional activity, absence of spontaneous activity, and moderately reduced recruitment of motor-unit potentials in the distal muscles of four limbs [38]. Motor NCVs in HMSN-Russe was moderately reduced in the upper limbs but unobtainable in the legs. Sensory nerve action potentials were absent [149]. Motor and sensory conduction studies in CCFDN showed slowing to 20±34 m/s [160].

6.2.3 Pathological features In CMT4A, nerve biopsies show typical features of a severe demyelinating neuropathy with onion bulb formation and loss of large myelinated axons [10]. In other CMT4A patients, loss of myelinated fibers without demyeli-

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nation is found. Focally folded redundant myelin sheaths are the histological hallmark of the CMT4B forms [46]. CMT4C is associated with a peculiar myelin pathology consisting of large cytoplasmic Schwann cell extensions and atypical multilayered wrapping of basal membranes around several axons [48]. Neuropathologic investigations in CMT4D showed that myelinated fibers were severely reduced in number and those that remained were of very small size. In CMT4E patients, sural nerve biopsies show virtual absence of myelin [166]. CMT4F is associated with a mixed demyelinating and axonal picture with multiple small onion bulbs [38]. Occasionally tomacula formation with focal myelin thickening was observed. Furthermore, abnormalities of the paranodal myelin loops and focal absence of paranodal septate-like junctions between the terminal loops and axon were present [148]. In HMSN-Russe, there was loss of larger myelinated nerve fibers and profuse regenerative activity in the sural nerve [149]. Nerve biopsy examination of CCFDN cases indicated generalized hypomyelination superimposed upon which were demyelination and axonal degeneration in older subjects [126].

6.2.4 Genetics and pathomechanism Extremely rapid progress in the identification of the genetic defects causing the recessive types of CMT has been made in the last three years. This rapid progress is, on the one hand, due to technology improvement and the availability of the human genome sequence but, on the other hand, also caused by the fact that homozygosity mapping often permits the delineation of very small candidate regions. Currently only one genetically mapped subtype with unknown genetic cause remains.

z CMT4A ± ganglioside-induced differentiation associated protein 1 gene (GDAP1) (OMIM 214400) CMT4A was identified in Tunisian families and maps to chromosome 8q13-q21 [10]. CMT4A is caused by point mutations in the ganglioside-induced differentiation associated protein 1 gene (GDAP1) and a Hispanic founder mutation for some families has been identified [8, 21]. Interestingly a locus for axonal AR CMT with pyramidal features was mapped to chromosome 8q21.3 [7]. This locus was also mapped in an inbred Tunisian family and overlaps with the CMT4A locus. This raises the possibility that this axonal AR CMT form and demyelinating CMT4A could be allelic. The finding of mutations in GDAP1 in families displaying an axonal type of CMT (CMT4C4) associated with vocal cord paresis supports this hypothesis [31]. Furthermore, GDAP1 mutations are also identified in CMT patients with both demyelinating and axonal features [1, 98, 132]. GDAP1 had been cloned in a screen for genes that are involved in ganglioside-induced differentiation of a mouse neuroblastoma cell line [80]. GDAP1 is

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expressed in brain and peripheral nerve. The exact function of GDAP1 in the PNS needs to be determined. It might be involved in neural differentiation [80]; however, the glutathione S-transferase domain points to a function in detoxification and protection against free radicals [128].

z CMT4B1 ± myotubularin related protein 2 gene (MTMR2) (OMIM 601382) CMT4B1 is caused by point-mutations in the myotubularin related protein 2 gene (MTMR2) on chromosome 11q23 [23, 24, 56, 97]. Some mutations are found in patients with a very severe phenotype, diagnosed as CH. Mutations in the myotubularin gene (MTM1), which is the first cloned member of this gene family, cause X-linked recessive myotubulary myopathy [73]. The MTM1 and MTMR2 genes code for tyrosine phosphatases which influence transcription and cell proliferation [32]. MTMR2 physically interacts with the NEFL protein which is mutated in CMT2E, but the function of this interaction is yet unknown [118].

z CMT4B2 ± myotubularin related protein 13 gene (MTMR13 or SBF2) (OMIM 604563 and 607739) CMT4B2 was found in Tunisian families and maps to chromosome 11p15 [11]. Two groups identified causative mutations in a novel gene of the MTMR family named MTMR13 or set binding factor 2 (SBF2) [6, 134]. Mutations in MTMR13 in the original family described by Ben Othmane have not yet been reported [11]. MTMR13 is a catalytically inactive member of the MTM gene family that might be involved in the regulation of active family members. MTMR13/SBF2 is expressed in multiple tissues, including brain and sciatic nerve [6].

z CMT4C ± unknown transcript KIAA1985 (OMIM 601596) The CMT4C locus on chromosome 5q23-q33 was identified in two Algerian families [77]. Causative mutations have been identified in a novel transcript of yet unknown function called KIAA1985 [133]. Mutations in the originally linked families have not been reported. KIAA1985 is strongly expressed in neural tissues, including peripheral nerve tissue. The translated protein defines a new protein family of unknown function with putative orthologues in vertebrates. Comparative sequence alignments indicate that members of this protein family contain multiple sarc homology (SH3) and tetratricopeptide repeat (TPR) domains that are likely involved in the formation of protein complexes.

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z CMT4D synonymous to HMSN-Lom ± N-myc downstream regulated gene 1 (NDRG1) (OMIM 601455) In HMSN-L (CMT4D) families, linkage to chromosome 8q24 was found. Conserved disease haplotypes suggested genetic homogeneity and a single founder mutation [64]. Mutation analysis of the N-myc downstream regulated 1 gene (NDRG1) revealed a homozygous nonsense mutation in all patients [63]. The exact function of NDRG1 is unknown. Computer analysis has predicted that the NDRGs belong to the a/b hydrolase superfamily; however they do not appear to be active hydrolases [138]. NDRG1 is expressed in multiple tissues including Schwann cells and probably plays a role in growth control and cell differentiation. Only recently, a second NDRG1 mutation was identified [57]. CMT4E, often presenting as CH, is caused by recessive mutations in the EGR2 gene, which is discussed in detail in the section on ªCMT1Dº in this chapter.

z CMT4F ± periaxin gene (PRX) (OMIM 605725) A CMT4F locus on chromosome 9p13 was found in a Lebanese family with a severe CMT1 phenotype [38], and a mutation in PRX was identified in this family [51]. PRX mutations were also identified in patients with a DSS or CMT1 phenotype [22, 148]. The pathogenesis of PRX mutations is not fully understood. However, progress is being made by studying both the periaxin-null mouse and the protein-protein interactions of periaxin. Lperiaxin is a constituent of the dystroglycan-dystrophin-related protein-2 complex linking the Schwann cell cytoskeleton to the extracellular matrix. Although periaxin-null mice myelinate normally, they develop a demyelinating peripheral neuropathy later in life. This suggests that periaxin is required for the stable maintenance of a normal myelin sheath. Sciatic nerve crushes in periaxin-null mice and showed that although the number of myelinated axons had returned to normal, the axon diameters remained smaller than in the contralateral uncrushed nerve. Not only do periaxinnull mice have more hyper-myelinated axons than their wildtype counterparts but they also recapitulate this hypermyelination during regeneration. Therefore, periaxin-null mice can undergo peripheral nerve remyelination, but the regulation of peripheral myelin thickness is disrupted [50, 168].

z Congenital cataract facial dysmorphism neuropathy (CCFDN) ± C-terminal domain phosphatase of RNA polymerase II gene (CTDP1) (OMIM 604186) CCFDN was identified in 19 Wallachian Gypsy families and mapped to chromosome 18qter [3]. A conserved haplotype suggested a single founder mutation. CCFDN is caused by a single-nucleotide substitution in an antisense Alu element in intron 6 of CTDP1, an essential component of the eu-

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karyotic transcription machinery, resulting in a rare mechanism of aberrant splicing and an Alu insertion in the processed mRNA. CCFDN thus joins the group of `transcription syndromes' and is the first `purely' transcriptional defect identified that affects polymerase II-mediated gene expression. A clinically sometimes very similar disease is Marinesco-Sjogren syndrome, distinguished from CCFDN by its genetic locus on chromosome 5q31 [70].

z Recessive mutations in the peripheral myelin protein 22 gene (PMP22) and the myelin protein zero gene (MPZ) In a few cases, recessive mutations are found in genes for dominant forms of CMT1. In PMP22, a single homozygous missense mutation was found in 3 sibs with DSS. The parents, carrying the mutation in the heterozygous state, are clinically and electrophysiologically unaffected [110]. Two hemizygous PMP22 point mutations were described in CMT1 patients. Individuals heterozygous for the mutation are unaffected, while individuals with a PMP22 deletion on the other allele have a CMT1 phenotype [103, 125]. It is still controversial if these PMP22 mutations represent recessive CMT1 mutation or functionally irrelevant polymorphisms [100, 179]. Several MPZ mutations occur in the heterozygous as well as in the homozygous/compound heterozygous state. The heterozygous individuals are asymptomatic or have CMT1, while the homozygous/compound heterozygous individuals are severely affected, mostly they are diagnosed as DSS [58, 74, 116, 165].

z HMSN-Russe ± chromosome 10q22 CMT Russe (HMSN-R) is linked to chromosome 10q22 [52, 126]. Fine mapping reduced the critical candidate region to only 70 kb [52]. The fact that no sequence variant has been detected in the known genes in the critical region indicates that the HMSN-R mutation affects a novel gene that remains to be identified.

z Acknowledgements Our research is funded by grants of the Fund for Scientific Research ± Flanders (FWO-Vlaanderen), the Special Research Fund of the University of Antwerpen, the Medical Foundation Queen Elisabeth, the Association Belge contre les Maladies Neuro-Musculaires, the Interuniversity Attraction Poles program P5/19 of the Belgian Federal Science Policy Office (Belgium) and the Muscular Dystrophy Association (USA). EN is a postdoctoral fellow of the FWO-Vlaanderen.

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7 CMT2, dominant intermediate CMT

and CMTX

M. C. Hannibal, P. F. Chance

Introduction A widely accepted classification system distinguishes demyelinating forms of Charcot-Marie-Tooth neuropathy (also designated as CMT type 1 or CMT1) from those due to axonal degeneration (CMT type 2 or CMT2) [29]. Individuals with CMT1 have electrophysiological findings of reduced motor and sensory nerve conduction velocities (mNCVs < 38 m/s) and pathologic findings of hypertrophic demyelinating neuropathy. By contrast, in CMT2 there are normal or near-normal NCVs and relative preservation of the myelin sheath. CMT3 refers to Djerine-Sottas disease (DSS). CMT4 refers to autosomal recessive forms of CMT (with features of either CMT1 or CMT2), and CMTX to X-linked varieties. There are also some families with autosomal dominant CMT with intermediate mNCVs that span the dividing line of 38 m/s that distinguishes CMT1 from CMT2. This CMT type is designated dominant intermediate CMT (DI-CMT). For the most part, distinct genetic loci distinguish the various types of CMT, but there can be a variety of clinical presentations by mutations in the same gene, as will be evidenced by neuropathies caused by mutations in the myelin protein zero gene (MPZ), ganglioside induced differentiation associated protein 1 (GDAP1), neurofilament light chain gene (NEFL) as well as the X-linked gap junction protein 1 gene (GJB1). Different mutations in these genes have variably been described as causing CMT1, CMT2 or the intermediate type neuropathy. The various CMT disorders discussed in this chapter are listed in Table 7.1.

7.1 Charcot-Marie-Tooth neuropathy type 2 7.1.1 Autosomal dominant CMT2 CMT2 is less common than CMT1, accounting for *30% of all hereditary motor and sensory neuropathies. Many loci are identified for CMT2 in different families, with both autosomal dominant (designated CMT2) and

Similar to classical CMT2, mutation found in one of two linked Japanese families, multiple other ethnically diverse families linked, adult onset (mean *20 years)

Distal leg motor deficit often precedes the acral ulcero-mutilating sensory neuropathy, 2 mutations reported to date, onset in 2nd or 3rd decade (could be classified as HSAN)

Associated with vocal cord and diaphragm paralysis. One linked N. American family of English/Scottish descent

Predominantly upper limb involvement, onset in 2nd or 3rd decade, allelic to distal HMN5, four reported mutations identified span these phenotypes

Typical CMT, Russian and Slovenian families, intermediate mNCVs, onset in 2nd or 3rd decade (could be classified as DI-CMT)

Similar to classical CMT2 but additional trophic changes, onset in 2nd or 3rd decade, Russian family

z CMT2A

z CMT2B

z CMT2C

z CMT2D

z CMT2E

z CMT2F

Charcot-Marie-Tooth type 2, autosomal dominant (HMSNII)

Typical features

AD

rare

rare

rare

AD

AD

rare

rare

rare

Frequency

AD

AD

AD

Inh.

7q11-q21

8p21

7p14

12q23-q24

3q21

1p36-p35

Locus

unknown

NEFL

GARS

unknown

RAB7

KIF1B

Gene Ref.

CMT2F, 606595

CMT2E, 607684

CMT2D, 601472

CMT2C, 606071

CMT2B, 600882

CMT2A, 118210

OMIM Alias and OMIM#

z

Type

Table 7.1. Clinical and genetic features of CMT2, DI-CMT and CMTX disorders

122 M. C. Hannibal, P. F. Chance

Hearing loss and pupillary dysfunction in some patients with D75V, E97V or T124M mutations in MPZ, later onset in 4th to 6th decade, allelic to CMT1B and CMT2I

z CMT2J

Severe onset in 2nd decade with rapid evolution and involvement of proximal muscles in some individuals, Moroccan family linked, four Algerian families have identical homozygous R298C mutations

Tunisian family with pyramidal features, onset in 1st decade

Costa Rican family, onset 3rd to 5th decade

Severe childhood onset with vocal cord paresis, allelic to CMT4C5, demyelinating CMT4A, and possibly CMT4C2

Homozygous S194X mutations cause severe childhood onset but no pyramidal features, cranial nerve nor vocal cord paresis; allelic to CMT4C4, demyelinating CMT4A, and possibly CMT4C2; this same homozygous mutation has also been shown to cause CMT4C4 and CMT4A in other families

z CMT4C1

z CMT4C2

z CMT4C3

z CMT4C4

z CMT4C5

Charcot-Marie-Tooth type 2, autosomal recessive axonal type

Typical or mild CMT2 but often with later onset in 4th to 6th decade, allelic to CMT1B and CMT2J

z CMT2I

rare rare rare

AR AR

rare

rare

rare?

common?

AR

AR

AR

AD

AD

8q13.3

8q13.3

19q13.3

8q13.3

1q21.2

1q22

1q22

GDAP1

GDAP1

unknown

unknown GDAP1?

LMNA

MPZ

MPZ

CMT2K, 607831

CMT2G, 707706

CMT2B2, 605589

CMT2H, 607731

CMT2B1, 605588

CMT2J, 607736

CMT2I, 607677

7 CMT2, dominant intermediate CMT and CMTX z

123

Decreased NCVs, but mixed pathology, Turkish family had homozygous single base pair insertion in exon 3 and German patient had homozygous intron 4 donor splice site mutations, early childhood onset

One family, mixed pathology and intermediate NCV, onset in 2nd decade

Okinawa type, proximal CMT, onset in 3rd decade, associated with painful muscle cramps, elevated CK, hyperlipidemia and diabetes mellitus

Macedonian family with onset in 4th to 6th decade

z DI-CMTB

z HMSN-P

z DI-CMTC

z DI-NCV slowing 12 members of a family had motor median NCVs 34±42 m/s but no CMT symptoms

Mixed pathology and intermediate NCV, onset in 1st decade

z DI-CMTA

Dominant intermediate Charcot-Marie-Tooth (DI-CMT)

z RI-CMTA or CMT4???

Recessive intermediate Charcot-Marie-Tooth?

Typical features

AD

AD rare

rare

rare

rare

AD AD

rare

rare

Frequency

AD

AR

Inh.

unknown

GDAP1

Gene

8p23

1q22

3q13.1

ARHGEF10

MPZ

unknown

10q24.1-q25.1 unknown

19p13.2-p12

8q13.3

Locus Ref.

Slowed nerve conduction velocity, autosomal dominant, 608236

CMTDI3, 607791

HMSNO, 604484

CMTDI1, 606482

CMTDI2, 606483

None

OMIM Alias and OMIM#

z

Type

Table 7.1 (continued)

124 M. C. Hannibal, P. F. Chance

XR XR

Infantile onset with mental retardation

Onset in 2nd decade, pyramidal signs

z CMTX3

z CMTX4

XR

Early onset, severe distal weakness associated with deafness and mental retardation

z CMTX2

XD

Females often mildly affected, childhood onset, usually demyelinating but some axonal features, occasional transient CNS symptoms with cerebral white matter changes

z CMTX1

Charcot-Marie-Tooth X-linked (CMTX)

rare

rare

rare

common

Xq24-q26.1

Xp22.2

Xq24-q26.1

Xq13.1

unknown

unknown

unknown

GJB1

NAMSD, Cowchock syndrome, 310490

CMTX3, 302802

CMTX2, 302801

CMTX1, 302800

7 CMT2, dominant intermediate CMT and CMTX z

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autosomal recessive inheritance (designated AR-CMT2 or CMT4C). The Xchromosome linked hereditary motor and sensory neuropathies may also show NCVs in the normal range, further confusing the clinical and genetic evaluation. While the chromosome 17p11 gene duplication including PMP22 in CMT1A, MPZ mutations in CMT1B or GJB1 (formerly Cx32) mutations in CMTX are fairly common, it is not exactly known whether mutations in any other gene will be a common cause of autosomal dominant CMT2, but MFN2 mutations in CMT2A2 [96] and mutations in the GDAP1 gene may be emerging as a common cause of autosomal recessive CMT2 (CMT4C4) [15, 24]. In many cases, CMT2 has a later age of onset, produces less involvement of the intrinsic muscles of the hands, and lacks palpably enlarged nerves. Extensive demyelination with ªonion bulbº formation is not present in CMT2. Axonal pathological changes consist of a loss of large myelinated axons and signs of regeneration with abundant small thinly myelinated axons [88]. Motor NCVs (mNCVs) are normal (> 40 to 45 m/s) or occasionally only slightly reduced (30±40 m/s) in affected persons. EMG testing may show neuropathic changes such as positive sharp waves, polyphasic potentials, fibrillations and reduced amplitudes of evoked motor and sensory responses. A subset of patients who were initially thought to have CMT2, because of only mild slowing of NCVs, have been found to have CMT1 or CMTX with MPZ or GJB1 mutations, respectively. Clinical DNA testing is not widely available for most forms of CMT2, but a few reference laboratories will sequence the NEFL gene that causes CMT2E (see Appendix). Sequencing of the GDAP1 gene is also available for recessive forms of CMT that span the range of phenotypes ranging from severe demyelinating CMT4A to severe axonal CMT4C4 showing vocal cord paresis in some cases.

z CMT2A1 ± mitofusin 2 (MFN2) (OMIM 118210) z Clinical features: The mean age of onset is 20 years (*1±47 years). The disease always starts with progressive foot drop and in many cases pes cavus [10, 49, 70]. Tendon jerks in the legs are usually absent and all patients show some sensory impairment. z Electrophysiology: The mNCVs are nearly normal, *40 m/s in the lower and *50 m/s in the upper extremities [52]. z Pathology, genetics and pathomechanism: CMT2A1 families are linked to chromosome 1p35-p36 [10, 59, 70, 74]. Very recently mutations in the mitofusin gene 2 (MFN2) were identified in seven families, demonstrating that MFN2 mutations are possibly the commonest mutations in CMT2A [96]. MFN2 is a mitochondrial GTPase which is ubiquitously expressed [76]. MFN2 is located to the outer mitochondrial membrane and regulates the mitochondrial network architecture by fusion of mitochondria. Homo-

7 CMT2, dominant intermediate CMT and CMTX

z

zygous MFN2 knockout mice are not viable and die in midgestation due to placental defect while heterozygote mice are reported to phenotypically normal [21].

z CMT2A2 ± kinesin motor protein 1 B (KIF1B) (OMIM 118210) z Clinical features: Onset of the disease was in the first decade of life for most individuals in a Japanese CMT2A pedigree with typical clinical features of CMT2A and a disease onset between 3 and 15 years [74]. z Electrophysiology: The NCVs were normal in the arms and slightly decreased (about 38 m/s) in the legs. Compound muscle action potentials (CMAP) and sensor nerve action potentials (SNAP) were markedly reduced [74]. z Pathology, genetics and pathomechanism: CMT2A2 shows linkage to the same chromosome 1p36.2 locus as CMT2A1, but a causative mutation in the kinesin motor protein 1B gene (KIF1B) was found [74, 94]. KIF1B belongs to a family of proteins playing an important role in axonal transport. Heterozygous KIF1B deficient mice show a slowly progressive axonal peripheral neuropathy [94]. The mutation found in the family with CMT2A (Gln98Lys) is localized in an ATP-binding domain and leads to significant reduction of ATPase activity of the protein and to an altered subcellular localization of the mutated protein [94].

z CMT2B ± ras related RAB7 gene (RAB7) (OMIM 600882) z Clinical features: The onset of symptoms is in the second or third decade of life. The neuropathy ranges from mild to severe, with distal muscle weakness, wasting and prominent sensory loss leading to foot ulcers, infections and amputations of the toes [4, 49]. Some have argued that this disorder could be classified as a hereditary sensory and autonomic neuropathy (HSAN), but motor features are common. z Electrophysiology: NCVs in the upper limbs were normal (*50±60 m/s) and slightly reduced (32±43 m/s) in the legs. CMAPs und SNAPs were severely reduced [4]. z Pathology, genetics and pathomechanism: The gene for CMT2B maps to chromosome 3q13-q22 and causative mutation were found in the RAB7 gene, a member of the Rab family of ras-related GTPases involved in intracellular membrane trafficking [49, 90]. Three Austrian families share a haplotype associated with the L129F mutation, while an American and Scottish family share a haplotype with the V162M mutation, but an Austrian patient and a Belgian patient with this latter missense mutation do not share the haplotype [4, 25, 49, 90].

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z CMT2C ± chromosome 12q23-q24 (OMIM 606071) z Clinical features: Further genetic heterogeneity within CMT2 is evidenced by the identification of kindreds with the features of axonal neuropathy, weakness of the diaphragm, and vocal cord paralysis not mapping to one of the known CMT2 loci [30]. The onset is typically slow and insidious, with respiratory symptoms and alterations in voice. The muscles of the hand become weak and atrophy, but leg weakness is often asymptomatic. If the onset of symptoms is in childhood, the disease tends to be severe with a shortened lifespan from respiratory failure and complications. z Electrophysiology: The mNCV of the median nerve was normal or very slightly reduced in all patients (> 48 m/s). z Pathology, genetics and pathomechanism: Such pedigrees carry the designation of CMT2C that has been mapped to chromosome 12q23-q24 [48]. It is not known if a European family with similar features demonstrates linkage to the chromosome 12q locus [77].

z CMT2D ± glycyl-tRNA synthetase (GARS) (OMIM 601472) z Clinical features: CMT2D presents with prominent upper limb involvement. Onset in one North American family was in the second or third decade of life, with sensory deficits reaching the same prevalence as motor impairment. Progression seems to be mild [2, 40, 70]. z Electrophysiology: mNCVs are normal or slightly reduced. z Pathology, genetics and pathomechanism: CMT2D maps to chromosome 7p14 and results from mutations in the glycyl-tRNA synthetase gene (GARS) [2, 40, 70]. Four mutations in GARS have been reported in ethnically diverse kindreds [2]. Some families show evidence of distal hereditary motor neuropathy type 5 (see also chapter 8 and 8.5), or features of dHMN V in some family members while other family members present with sensory abnormalities as well proving these are allelic disorder [31, 75]. GARS is ubiquitously expressed and is responsible for the coupling between tRNA and the cognate amino acid. The mechanism by which this essential and widely expressed gene causes a peripheral neuropathy if mutated remains to be determined.

z CMT2E ± neurofilament light chain gene (NEFL) (OMIM 607684) z Clinical features: A typical CMT with an age of onset in the second or third decade of life characterizes the patients in the family described first [57]. Distal leg involvement with obligatory pes cavus precedes distal arm

7 CMT2, dominant intermediate CMT and CMTX

z

involvement, and all patients were ambulatory 20±30 years after disease onset. A second Slovenian family with a slowly progressive CMT, onset in the first decade of life and very heterogeneous NCVs has been identified [36]. z Electrophysiology: In some families CMT2 like, in others, very heterogeneous NCVs within the family, e.g., 21±54 m/s for the median nerve [36]. NEFL mutations might also lead to a typical CMT1 phenotype (see section: ªCMT1Fº). z Pathology, genetics and pathomechanism: In a large Russian pedigree having an autosomal dominant axonopathy, a CMT2 gene was mapped to chromosome 8p21 and a mutation was found in the neurofilament-light (NEFL) gene. A nonconservative missense mutation (A998C, Gln333Pro) in the neurofilament light chain gene (NEFL) cosegregates with CMT2E [57]. The NEFL gene encodes a protein that is one of three major neurofilament (NF) protein constituents. The NEFL Gln333Pro mutation site is located within the coil 2B domain of the NEFL protein, the last and largest of four coil domains that form the rod region. Supporting evidence of the single point mutation found within the Russian pedigree comes from murine studies. A Leu394Pro mutation in the same coil domain in the mouse ortholog resulted in a severe peripheral neuropathy [22, 51]. Interestingly, Nefl null mice do not have a CMT-like phenotype, suggesting a dominant gain-of-function mechanism for these NEFL mutations, but they do show delayed regeneration of myelinated axons after injury [95]. NEFL mutations have also been associated with CMT1 type F (CMT1F) with some patients in these pedigrees having near normal NCVs, suggesting that phenotypic overlap between CMT1 and CMT2 may occur with an identical mutation in a family [27, 45].

z CMT2F ± small heat-shock protein 27 gene (HSBP1 or HSP27) (OMIM 606595) z Clinical features: A Russian family has been reported with CMT2, onset between 15 and 20 years, initial lower limb involvement and trophic alterations of the feet leading to slowly progressive disability. Mild to moderate sensory deficits, including pain and temperature, occur in the feet and hands. Lifespan was not decreased. z Electrophysiology: mNCVs were between 42 and 59 m/s for the median nerves with a mean of 48 m/s. CMAPs were decreased to 10% in the legs. z Pathology, genetics and pathomechanism: Linkage analysis identified a locus on chromosome 7q11-q21 [44]. Very recently missense mutations in the HSP27 were found in some families with CMT2 as well as in families with a clinical picture of dHMN1 [32]. For details regarding the genetics and pathomechanism see paragraph ªdHMN1º in the chapter ªDistal hereditary motor neuropathiesº.

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M. C. Hannibal, P. F. Chance

z CMT2G ± chromosome 12q12-q13.3 (OMIM 608591) z Clinical features: Only one large Spanish family has been described [12]. The age of onset varies between 9±76 years (mean *20 years). Patients present with very slowly progressive, but typical, CMT disease. Ankle reflexes were present in some affected individuals. z Electrophysiology: mNCVs were slightly slowed in some patients, but entirely normal in others. EMG examination showed chronic neurogenic changes only. z Pathology, genetics and pathomechanism: Histological studies showed loss of large myelinated fibers, atrophic axons and loss of anterior horn and dorsal root ganglion neurons. Linkage analysis mapped the causative genetic defect to a 13.2 Mb region on chromosome 12q12-q13.3 [62].

z CMT2I and J ± myelin protein zero gene (MPZ) (OMIM 607677 and 607736) z Clinical features: CMT2I is characterized by a late onset (47±60 years) and prominent sensory involvement leading to gait disturbance [5, 55, 79]. CMT2J presents with a characteristic clinical phenotype including late onset, marked sensory abnormalities, pupillary abnormalities and deafness [20, 26, 58]. z Electrophysiology: mNCVs in both forms are normal or only slightly reduced. z Pathology, genetics and pathomechanism: The sural nerve biopsy of a CMT2J patient showed loss of myelinated axons, clusters of axonal regeneration, but also thin myelin and some onion bulbs [26]. Both forms are described together because they are both due to missense mutations in the MPZ gene. The MPZ Thr124Met mutation leads to the characteristic phenotype of CMT2J [26]. Detailed information on the biology of MPZ is found in the chapter describing CMT1.

z CMT2L ± small heat-shock protein 22 gene (HSBP8 or HSP22) (OMIM 608014) z Clinical features: The age of onset of CMT2L in a single Chinese family is between 15 and 33 years presenting with a typical CMT2 picture. Progression was slow and patients do not become wheelchair dependent [86]. z Electrophysiology: Median NCVs were completely normal ranging from 56 to 69 m/s but CMAPs and SNAPs were decreased [86]. z Pathology, genetics and pathomechanism: CMT2L is a typical axonal neuropathy with loss of large myelinated fibers and a large number of clusters with thinly myelinated fibers. CMT2L maps to chromosome 12q24 [86].

7 CMT2, dominant intermediate CMT and CMTX

z

The small heat-shock protein 22 (HSBP8) was found to have a Lys141Asn mutation in this family, identical to the mutation found in some distal hereditary motor neuropathy type II (dHMN II) pedigrees [43, 87].

7.1.2 Autosomal recessive CMT2 CMT2B1 (OMIM 605588), CMT2B2 (OMIM 605589), CMT2H (OMIM 607731) and CMT2K (OMIM 607706) are the OMIM designations corresponding to different forms of autosomal recessive CMT, which will be called CMT4C in this book. In yet another classification scheme, autosomal recessive CMT is designated AR-CMT2. All forms of autosomal recessive CMT2 are exceedingly rare.

z CMT4C1 ± lamin A/C nuclear envelope protein gene (LMNA) (OMIM 605588 or CMT2B1) z Clinical features: Affected members of a consanguineous Moroccan family had a severe onset in the second decade of life with rapid evolution extending to involvement of the proximal muscles in six of nine individuals [17]. Three of these severely affected individuals developed kyphoscoliosis [17]. Similar features were found in three Algerian families mapping to the same chromosomal locus [28]. z Electrophysiology: mNCVs of the median nerve were normal (> 50 m/s). z Pathology, genetics and pathomechanism: The Moroccan family defined a new locus for this autosomal recessive, axonal neuropathy on chromosome 1q21.2-1q21.3 [17]. In three consanguineous Algerian families, a founder mutation was identified in the LMNA gene encoding lamin A/C nuclear envelope protein [28]. Lamin A/C mutations can lead to a variety of disorders, including dominant or recessive Emery-Dreifuss muscular dystrophy (EDMD2), dominant limb-girdle muscular dystrophy type 1B (LGMDB1), dominant dilated cardiomyopathy with atrioventricular conduction defect (CMD1A), and dominant Dunnigan type familial partial lipodystrophy (FPL) [35]. Homozygous Lmna null mice exhibit axonal neuropathic features upon examination of their sciatic nerves [28]. Nerve biopsies showed the typical features of CMT2: loss of large myelinated axons and clusters of regeneration [17, 28].

z CMT4C2 ± chromosome 8q21 (OMIM 607731 or CMT2H) z Clinical features: An early onset, autosomal recessive, axonal form of Charcot-Marie-Tooth disease was described in a large Tunisian family [8]. Pyramidal involvement with brisk patellar and upper limb reflexes distinguishes this type from the other recessive forms of CMT2. Typically, ankle

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M. C. Hannibal, P. F. Chance

reflexes were absent and plantar reflexes unattainable because of extensor muscle paralysis of the big toe [8]. The natural history begins with difficulty with walking at 4±8 years of age, with progressive weakness and wasting in the lower limbs followed by involvement of the distal muscles in the upper limbs. Distal sensory disturbances were present in all patients. Only two of the thirteen adults examined were nonambulatory [8]. z Electrophysiology: Not reported. z Pathology, genetics and pathomechanism: Linkage analysis has placed this disorder at 8q21.11, between markers D8S1807 and D8S548, near the recessive CMT4A gene GDAP1; thus it might be allelic with this disorder [11, 24]. Detailed information on GDAP1 may be found in the sections for ªCMT4Aº and below for ªCMT4C4º.

z CMT4C3 ± chromosome 19q13.3 (OMIM 605589 or CMT2B2) z Clinical features: Only one large family from Costa Rica of predominantly Spanish ancestry has been described. The age of onset was rather late, in the third to fifth decade of life, and patients showed a typical CMT2 phenotype [13]. z Electrophysiology: Normal or slightly reduced NCVs and reduced CMAPs/ SNAPs. z Pathology, genetics and pathomechanism: CMT4C3 was mapped to chromosome 19q13.3 [50].

z CMT4C4 ± ganglioside- induced differentiation associated protein 1 gene (GDAP1) (OMIM 607706-with vocal cord involvement; 607831 or CMT2K and 608340-recessive intermediate CMT) z Clinical features: CMT4C4 may either present as a recessive axonal CMT with severe childhood onset and vocal cord paresis [24] or as an early onset severe CMT phenotype without vocal cord involvement [15]. The upper extremities progressed to developing claw-like hands by the end of the first decade of life. All had mild scoliosis [15]. Patients often become wheelchair bound. In the latter form, a number of individuals are below the age of 20 and might still develop vocal cord paresis. Most families are from Spanish ancestry. z Electrophysiology: NCVs may vary widely depending on the mutation, normal or nearly normal NCVs as well as quite severely reduced NCVs have been found. GDAP1 mutations do also cause a recessive CMT1-like presentation (CMT4A) [9]. z Pathology, pathomechanism and genetics: Both forms are due to mutations in the GDAP1 gene, encoding the ganglioside-induced differentiation-asso-

7 CMT2, dominant intermediate CMT and CMTX

z

ciated protein-1 [15, 24]. It is clear now that a spectrum of allelic neuropathies is associated with mutations in GDAP1. CMT4A, a recessive demyelinating CMT1, was the first phenotype found with GDAP1 mutations in four Tunisian families [9]. As described above GDAP1 mutations were also found to cause CMT4C4 either with or without vocal cord paralysis. One particular mutation (S194X) has been associated with a wide range of phenotypes ranging from a recessive demyelinating neuropathy where the mutation was present in the homozygous state (CMT4A) [9], over intermediate phenotypes also caused by homozygous mutation reported by Nelis et al. [61] to a recessive CMT2-like presentation, with the S194X mutation present as a compound heterozygote state [24] or homozygous state [15]. GDAP1 mutations will likely be one of the leading causes of autosomal recessive axonal or demyelinating CMT. The Online Mendelian Inheritance in Man (OMIM) database gives different names to each of the slightly different phenotypes of axonal or mixed axonal and demyelinating CMT due to mutations in GDAP1 (see title of this paragraph). The full range of phenotypic and pathologic features will only be known by more longitudinal studies following patients into adulthood but most recessive neuropathies caused by GDAP1 mutations share the early onset and relatively severe course often leading to wheelchair dependency. GDAP1 mutations will likely be the leading cause of autosomal recessive axonal or demyelinating CMT. GDAP1 is involved in cell differentiation with neurite sprouting and is expressed in the spinal cord as well as in the brain but the exact function remains to be elucidated.

7.2 DI-CMT: dominant intermediate Charcot-Marie-Tooth neuropathy A number of CMT families show intermediate mNCVs that make it impossible to assign either the label CMT1 or CMT2. For instance, the mNCVs in the patients of one family ranged from 24-54 m/s [47]. Intermediate mNCVs are a typical feature of CMT linked to the X-chromosome (see ªCMTXº) [64]. DI-CMT is distinguished from these forms by autosomal dominant inheritance with direct male-to-male transmission. Some dominantly inherited CMT types currently labeled as CMT2 could also be classified as DI-CMT with regard to the mNCVs. These include CMT2E due to mutations in the NEFL gene (mNCVs 25 to 52 m/s) [27, 57] and CMT2J due to certain MPZ mutations (e.g., Thr124Met, mNCVs 24±59 m/s) [26].

7.2.1 DI-CMTA ± chromosome 10q24.1-q25.1 (OMIM 606483 or CMTDIA) z Clinical features: DI-CMTA is an autosomal dominant CMT with intermediate features between a pure demyelinating and axonal phenotype. The age of onset is in the first and second decade of life. Progression is slow.

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M. C. Hannibal, P. F. Chance

There appears to be more rapid progression in the fifth decade with severe distal weakness in the lower leg and hands. However no patients have been wheelchair bound, but many over seventy years of age require crutches. z Electrophysiology: mNCV span the cutoff value of 38 m/s between CMT1 and CMT2. The mNCVs of the median nerve fall into the range of 25±45 m/s. z Pathology, genetics and pathomechanism: Axonal degeneration as well as onion bulb formation is found. Peripheral nerve biopsies showed prevalent demyelinating features including onion bulbs and myelin splits with uncompacted and irregularly enlarged lamellae. These were typically located at the Schmidt-Lantermann incisures and in the paranodal region. Axonal features were also described with regeneration clusters, large fiber loss, Bungner's bands and unmyelinated fiber involvement [53]. DI-CMTA was mapped to chromosome 10q24.1-q25.1 [89] in a previously reported Italian family [73, 92].

7.2.2 DI-CMTB ± chromosome 19p12-p13.2 (OMIM 606482 or CMTDIB) z Clinical features: DI-CMTB is another autosomal dominant CMT with intermediate features described in a large, four-generation Australian family [47]. Little clinical data are available to describe the natural history in this family. z Electrophysiology: Median mNCVs ranged from 24±54 m/s [47]. z Pathology, genetics and pathomechanism: Sural nerve biopsy showed axonal degeneration, loss of large-diameter fibers, rare segmental demyelination and remyelination with onion bulb formation. DI-CMTB shows linkage to 19p12-p13.2 between the markers D19S586 and D19S546 [47].

7.2.3 DI-CMTC ± chromosome 1p34-p35 (OMIM 608323, CMTDIC) z Clinical features: Only two unrelated families are known [46]. The age of onset is varies widely between 7 and 59 years. The clinical features are not distinguishable from other forms of typical CMT. z Electrophysiology: The mNCVs of the median nerve vary between 30 m/s and normal (> 50 m/s) [46]. z Pathology, genetics and pathomechanism: Sural nerve biopsy showed clusters of regeneration and age dependent reduction in myelin thickness and fiber density, but no onion bulbs. The disease was mapped to chromosome 1p34-p35 [46].

7 CMT2, dominant intermediate CMT and CMTX

z

7.2.4 DI-CMTD ± myelin protein zero (MPZ) (OMIM 607791, CMTDID) z Clinical features: DI-CMTD was reported in a Macedonian family, in which some family members also displayed more proximal involvement with weakness of the knee and hip flexors in addition to distal weakness [56]. z Electrophysiology: Median mNCVs of 24±41 m/s were found in this family. z Pathology, genetics and pathomechanism: Nerve biopsy showed predominantly axonal degeneration with some evidence of segmental demyelination and remyelination. DI-CMTD is caused by mutations in myelin proteinzero (MPZ) that produce and intermediate phenotype. Linkage was confirmed to the MPZ gene location, and a G to T nucleotide transversion resulted in a nonconservative change of the sixth amino acid in the processed protein (Asp6Tyr). Another MPZ mutation caused a phenotype with characteristics of DI-CMT: a Thr124Met missense mutation, due to a C to T nucleotide transition, was demonstrated in seven Belgian families and two isolated CMT patients [26] but these patients are usually classified as having CMT2J (see section ªCMT2I and Jº). Haplotype analysis showed shared alleles in all of these patients, suggesting a common founder. For a detailed description of MPZ, see the section for ªCMT1Bº.

7.2.5 DI-slowed nerve conduction velocities without Charcot-MarieTooth neuropathy ± rho guanine nucleotide exchange factor 10 gene (ARHGEF10) (OMIM 608236, slowed nerve conduction velocities, autosomal dominant) z Clinical features: The proband of a single family was identified during evaluation for vascular problems of the leg. z Electrophysiology: mNCVs of the median nerve were in the range 34± 42 m/s (normal ³ 49 m/s) and segregated in an autosomal dominant manner without any clinical signs of a peripheral neuropathy [91]. z Pathology, genetics and pathomechanism: A nerve biopsy, obtained at 54 years of age, showed numerous relatively thin myelin sheaths, slight onionbulb formation and few axonal-regeneration clusters. This subclinical, nonprogressive, intermediate slowing of NCVs cosegregated with marker alleles at chromosome 8p23 and a Thr109Ile mutation in the Rho guanine-nucleotide exchange factor 10 gene (ARHGEF10) [91]. Whether any more severe disorders are caused by changes in this gene remains to be seen. ARHGEF10 is highly expressed in peripheral nerves and might play a role during the myelination process, but the exact pathomechanism is unknown.

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7.2.6 HMSN-P ± chromosome 3p14.1-q13 (OMIM 604484, HMSN-O or Okinawa type) z Clinical features: Hereditary motor and sensory neuropathy, proximal type, HMSN-P is an autosomal dominant disorder with a founder on the Japanese island of Okinawa [83]. Eight families were described with proximal muscle weakness occurring after 30 years of age, absent deep tendon reflexes and sensory disturbances. Muscle cramps in the extremities or abdominal muscles were the most common initial symptom. Fasciculations were noted early in the course of this disorder, primarily in the truncal and extremity muscles. Mild peripheral dysesthesia was the most common sensory symptom. Weakness was progressive with relative sparing of neck flexor and extensor muscles. Most were nonambulatory 5 to 20 years after disease onset. Some patients required artificial ventilation. Some patients show tongue atrophy dysarthria, dysphagia and respiratory muscle involvement in late stages of the disease and these patients are difficult to clinically distinguish from those with amyotrophic lateral sclerosis. Associated findings included creatine kinase elevation (average 301Ô243 IU/L, normal 26±200 IU/L), type II hyperlipidemia, and diabetes mellitus. Seven of sixteen had non-insulin-dependent diabetes mellitus and four had impaired glucose tolerance. z Electrophysiology: Electrophysiologic studies are compatible with axonal degeneration. Sensory nerve action potentials were absent or reduced [83]. Posterior tibial nerve conduction velocities were slowed, but median mNCVs were normal except in one patient in whom no action potentials were detected. z Pathology, genetics and pathomechanism: Sural nerve biopsy showed a marked decrease of large myelinated fibers and a moderate decrease of small myelinated fibers [83]. There were no onion bulbs. One autopsy study showed loss of neurons in the dorsal root ganglia, severe loss of anterior horn cells and loss of myelinated fibers in the dorsal funiculus and peripheral nerves. Linkage analysis of these families has identified a locus at 3p14.1-q13 [84].

7.3 CMTX: Charcot-Marie-Tooth neuropathy, X-linked types Characteristic for X-linked inheritance is the absence of direct male-to-male transmission of the disease. All daughters of affected fathers carry the genetic defect and they transmit it to half of their children. CMTX is the second most common form of CMT (after CMT1A). Except for a few cases that do not play a role in normal clinical practice, CMTX is caused by mutations affecting the gap junction protein beta 1 gene (GJB1) formerly called connexin 32 (Cx32).

7 CMT2, dominant intermediate CMT and CMTX

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While there have been four types of CMT mapped to the X chromosome, CMTX1 clearly is the most common type, accounting for *10% of all patients with a demyelinating CMT (i.e., CMT1).

7.3.1 CMTX1 ± gap junction protein beta 1 gene (GJB1, formerly connexin 32 (Cx32)) (OMIM 302800) (Terminology: human gene = GJB1; human protein = connexin 32; the gene was formerly also called connexin 32 (Cx32); mouse gene = gjb1; mouse protein = gjb1) z Clinical features: CMTX1 is a common neuropathy with absence of male-tomale transmission, and an earlier age of onset and faster rate of progression in males. CMTX1 usually presents clinically with typical features of CMT. The severity of the clinical picture is very variable. Some patients show central nervous system (CNS) involvement, e.g., deafness, intellectual impairment and cerebellar symptoms [39, 54, 69, 85]. The inheritance is dominant, but females are less often only subclinically affected [16]. CMTX1 accounts for *10% of all patients thought to have a type of demyelinating CMT (i.e., CMT1). CMTX1 should be suspected when the commonly associated chromosome 17 duplication is not present and there is no history of father-toson transmission of the neuropathy. z Electrophysiology: On electrophysiological evaluation, CMTX1 shows either a CMT1, an intermediate or a CMT2 phenotype. The mNCVs of male patients are mostly in the range between 25±40 m/s, the mNCVs of female patients are between 25±50 m/s [66, 67]. The variation of mNCVs can be very large within families and even among different nerves of the same patient [37]. The cMAPs are nearly always severely reduced in CMTX1 [37, 82]. In contrast to most other types of HMSN, many CMTX1 patients show electrophysiological evidence of CNS involvement and some patients develop overt CNS-related symptoms. Several authors describe a delay of the central components of the acoustically evoked potentials (AEP) or even deafness [6, 65, 66, 80]. Changes of the visually evoked potentials (VEP), intellectual impairment, cerebellar symptoms and recurrent transient white matter lesions on MRI of the head have been reported [39, 54, 69, 85]. z Pathology, genetics and pathomechanism: The main pathological features in the peripheral nerve are alterations of the paranodal myelin and signs of axonal damage [38]. CMTX1 has been mapped to the proximal long arm of the X-chromosome in 1985 [33, 34]. Causal mutations in the GJB1 gene were identified in 1993 [14]. GJB1 encodes a major component of gap junctions and is expressed in peripheral nerves. Connexin 32 protein is structurally similar to PMP22, the protein involved in CMT1A. Both proteins contain four putative transmembrane domains in similar orientation. Over

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260 different mutations in the GJB1 gene have been described in patients with CMTX1, and the distribution pattern of these mutations suggests that all parts of the connexin 32 protein are functionally important ([60] and IPNMDB). DNA testing is clinically available for GJB1 mutations causing CMTX1. GJB1/Cx32 has a time pattern of expression in peripheral nerve similar to that of other structural myelin genes, that is, the expression of GJB1/Cx32 is immediately down regulated following crushed or transected nerve experiments. However, immunohistochemical studies show a different localization for the connexin 32 protein. Unlike PMP22 and MPZ, which are present in compact myelin, connexin 32 is located at uncompacted folds of Schwann cell cytoplasm around the nodes of Ranvier and at Schmidt-Lantermann incisures [19]. Connexin 32 protein forms hexamers with a central pore termed connexons. The connexons of opposing membranes form channels. The connexons allow fast transport of low molecular weight substances from the adaxonal to the outer myelin lamellae [7]. Connexin 32 forms four transmembrane domains, two extracellular loops and an intracellular portion. The second transmembrane domain plays an important role in voltage gating of connexons (voltage- dependent changes in their permeability) [81]. Mutations in GJB1 may have a number of different functional consequences: (1) disturbance of the transport of the GJB1 protein from the endoplasmic reticulum (ER) to the cytoplasm, (2) formation of non-functional channels, (3) formation of functional channels with abnormal properties regarding, e.g., voltage gating or pH sensitivity, (4) mutations with unknown functional consequences [18, 68, 72, 93]. In gjb1 deficient mice peripheral myelin develops normally during the first weeks. Four month old mice show a mild neuropathy that histologically resembles the changes seen in CMTX1 patients [3, 63]. Two transgenic mouse models with point mutations in the transgene show similar histologic characteristics [1, 78].

7.3.2 CMTX2 ± chromosome Xp22.2 (OMIM 302801) z Clinical features: Males were affected in infancy, with weakness and atrophy of the lower leg muscles [41, 42]. Pes cavus developed and reflexes were absent. Two of five affected males had mental retardation. Carrier females were unaffected. z Electrophysiology: The electrophysiologic studies showed both signs of demyelination and of an axonal phenotype with slowed motor NCVs and denervation, respectively [41, 42]. z Pathology, genetics and pathomechanism: CMTX2 has been mapped to Xp22.2 in only one family [41, 42].

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7.3.3 CMTX3 ± chromosome Xq26 (OMIM 302802) z Clinical features: Onset was early in the second decade of life, with distal weakness and atrophy. One family showed pyramidal signs with spastic paraparesis in the two affected males, but very long chain fatty acids were normal, ruling out adrenomyeloneuropathy [41, 42]. z Electrophysiology: Slowed motor NCVs and denervation were evident on electrophysiologic studies. z Pathology, genetics and pathomechanism: The disease was mapped to chromosome Xq26-q28, but the locus has never been proved, since suggestive, but not conclusive LOD scores were reached in two families [41, 42].

7.3.4 CMTX4 ± chromosome Xq24-26.1 (OMIM 310490, Cowchock syndrome or neuropathy, axonal motor-sensory with deafness and mental retardation, NAMSD) z Clinical features: CMTX4, also known as Cowchock syndrome, is an axonal motor and sensory neuropathy with features of sensorineural deafness and mental retardation [23, 71]. The onset of distal weakness in males occurred in the first few years of life, with severe signs of muscle atrophy, areflexia, pes cavus, hammertoe and sensory loss. Hearing loss occurred in five of seven affected males, with three of those also showing mental retardation. The heterozygous females were asymptomatic. z Electrophysiology: mNCVs were normal or slightly slowed. z Pathology, genetics and pathomechanism: Cowchock syndrome maps to the distal long arm of the X chromosome in bands Xq24-q26.1 [23, 71].

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91. Verhoeven K, De Jonghe P, Van De Putte T, Nelis E, Zwijsen A, Verpoorten N, et al. (2003) Slowed conduction and thin myelination of peripheral nerves associated with mutant rho guanine-nucleotide exchange factor 10. Am J Hum Genet 73 92. Villanova M, Timmerman V, De Jonghe P, Malandrini A, Rizzuto N, Van Broeckhoven C, et al. (1998) Charcot-Marie-Tooth disease: an intermediate form. Neuromuscul Disord 8:392±393 93. Werner R, Levine E, Rabadan-Diehl C, Dahl G (1991) Gating properties of connexin32 cell-cell channels and their mutants expressed in Xenopus oocytes. Proc R Soc Lond B Biol Sci 243:5±11 94. Zhao C, Takita J, Tanaka Y, Setou M, Nakagawa T, Takeda S, et al. (2001) CharcotMarie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1Bbeta. Cell 105:587±597 95. Zhu Q, Couillard-Despres S, Julien JP (1997) Delayed maturation of regenerating myelinated axons in mice lacking neurofilaments. Exp Neurol 148:299±316 96. Zuchner S, Mersiyanova IV, Muglia M, Bissar-Tadmouri N, Rochelle J, Dadali EL, et al. (2004) Mutations in the mitochondrial GTPase mitofusin 2 cause CharcotMarie-Tooth neuropathy type 2A. Nat Genet 36:449±451

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8 Distal hereditary motor neuropathies

(dHMN)

F. Stægbauer, G. Kuhlenbåumer

Introduction Hereditary motor neuropathies (dHMN) are predominantly characterized by the degeneration of lower motor neurons and are usually referred to as spinal muscular atrophies (SMA) [15]. According to the distribution of clinical symptoms, dHMN is classified as the proximal or the distal form. The proximal form is comprised mainly of typical SMA and will not be discussed further in this chapter, whereas distal dHMNs give rise to hereditary neuropathies and have been called progressive muscular atrophy or spinal forms of Charcot-Marie-Tooth disease (spinal CMT) [15]. dHMN accounts for about 10% of all cases of spinal muscular atrophy and is clinically and genetically heterogeneous [26]. Based on this heterogeneity, Harding (1993) proposed a classification into seven different subtypes (dHMN I±VII) [15]. Four of these are inherited autosomal dominantly and three autosomal recessively, whereas X-linked pedigrees have not been identified so far (Table 8.1). Electrophysiologic investigations of patients with dHMN are most helpful to differentiate between HMSN and dHMN but do not allow for discrimination between single dHMN subtypes. Sensory nerve conduction studies are normal with the exception of the dHMN V/CMT2D overlap type, in which sensory nerve conduction velocities (SNCV) and sensory nerve action potentials (SNAP) may be reduced [1, 8]. Motor NCV (MNCV) is usually within the normal range; in the presence of severe wasting it may be slightly reduced due to loss of large motor neurons [15]. Electromyography reveals signs of acute (spontaneous fibrillation and positive sharp waves) or chronic (largeamplitude motor unit potentials and polyphasic potentials) neurogenic alterations. Laboratory investigations are usually normal, in some patients, plasma creatine kinase may be moderately high [15]. The pathophysiological concept of dHMN includes degeneration of lower motor neurons in the anterior horn of the spinal cord with neurogenic muscular atrophy suggesting dying-forward atrophy. Consistently, in dHMN VI autopsy specimens revealed neurogenic atrophy of skeletal muscle without reinnervation [14]. The diameter of the anterior spinal roots was reduced and the remaining motor neurons showed chromatolysis. Morphometric and ultrastructural analyses of sural nerve biopsies are normal in most cases. Mild

upper limb predominance; with vocal cord paralysis

upper limb predominance and facial weakness; with vocal cord paralysis

lower limb predominance; with pyramidal features

dHMN VIIa

dHMN VIIb

dHMN Jerash type AR

AD

AD

AD AR

upper limb predominance

upper and lower limbs; with diaphragmatic paralysis

dHMN VI

AR

lower limb predominance

dHMN IV

dHMN V

AD AR

lower limb predominance

lower limb predominance

dHMN II

AD

lower limb predominance

dHMN I

dHMN III

Inheritance

Distribution

Type

Table 8.1. Clinical features of distal hereditary motor neuropathies

5 ± 10 y

10 ± 20 y

10±20 y

0±1 y

5±20 y

0±20 y

2±10 y

20±40 y

2±20 y

Age at onset

rare

rare

rare

never

rare

about 30 y

rare

rare

rare

Age unable to walk

probably normal

probably normal

probably normal

1y

normal

unknown

normal

normal

normal

Life expectancy

8 Distal hereditary motor neuropathies (dHMN) z

147

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F. Stægbauer, G. Kuhlenbåumer

Table 8.2. Genetic classification of distal hereditary motor neuropathies Type

Inheritance

Chromosomal Reference locus

Gene

Reference

dHMN II

AD

12q24.3

Timmerman et al. 1996 [31]

unknown

±

dHMN IV

AR

11q13

Viollet et al. 2002 [32]

unknown

±

dHMN V

AD

7p15

Christodoulou et al. 1995 [8]

GARS

Antonellis et al. 2003 [1]

dHMN VI

AR

11q13-q21

Grohmann et al. 1999 [14]

IGHMBP2

Grohmann et al. 2001 [13]

dHMN VIIa

AD

2q14

McEntagart et al. 2001 [22]

unknown

±

dHMN VIIb

AD

2p13

Puls et al. 2003 [28]

DCTN1

Puls et al. 2003 [28]

Jerash type

AR

9p21.1-p12

Christodoulou et al. 2000 [9]

unknown

±

loss of axons involving large and small myelinated fibers as well as minimal denervation in unmyelinated axons may be found. Muscle biopsy reveals signs of chronic denervation and mild secondary myopathy. To date seven genes and two additional chromosomal loci have been identified in dHMN (Table 8.2).

8.1 dHMN I ± small heat-shock protein 27 (HSP27 or HSBP1) (OMIM 608634) z Clinical features: The clinical presentation of dHMN I resembles classical HMSN with respect to muscle weakness and wasting but, in contrast, clinically apparent sensory loss is absent in nearly all cases [10, 16]. dHMN I is inherited autosomal dominantly and age at onset is before the age of twenty and usually in the first decade. Typically, the first clinical signs of dHMN I are distal weakness and wasting of the lower limbs, particularly of the anterior tibial and peroneal muscles. Pes cavus like foot deformity is frequently found and may be more prominent than in hereditary motor and sensory neuropathies (HMSN). About one quarter of the patients develop thoracolumbar scoliosis. Progression of motor symptoms to the proximal muscles of the lower limbs is not frequent. Involvement of the upper limbs is rare and can be found in about 20% of cases. Loss of deep tendon reflexes is less frequent than in HMSN, ankle jerks are absent in about

8 Distal hereditary motor neuropathies (dHMN)

z

30% of cases, but in over 60% knee jerks and upper limb reflexes are normal. The prognosis of dHMN I is generally good. The disorder is very slowly progressive and in some cases it appears to arrest in later stages. Fewer than half of the patients are able to walk unaided in adult or later adult life. z Genetics and pathomechanism: Very recently, missense mutations in the small heat-shock protein 27 gene (HSBP1 or HSP27) were identified in four families with clinical features matching the description of dHMN I ([12] and V. Timmerman, personal communication). It is not yet known whether the original families published by Harding are caused by mutations in HSP27 [16]. Mutations in HSP27 cause also CMT2F. HSP27 is induced by stress, like elevated temperature. It has antiapoptotic and cytoprotective properties, e.g., by inhibiting caspases [5, 19]. Upregulation of HSP27 is required for the survival of injured neurons and is overexpressed in Cu,Zn superoxide dismutase 1 (SOD1) transgenic mice, which are a model for amyotrophic lateral sclerosis (ALS) [3, 34]. HSP27 is also a suppressor of polyglutamine-induced cell death and plays a role in the organization of the neurofilament network. Transfection of HSP27 carrying mutations found in the dHMN families into eukaryotic cell lines lead to increased cell death and disturbances of neurofilament assembly [12].

8.2 dHMN II ± small heat-shock protein 22 (HSP22 or HSBP8) (OMIM 158590) z Clinical features: dHMN II is an autosomal dominantly inherited disease and is similar to dHMN I in terms of clinical expression, histological and electrophysiological features as well as prognosis. Both forms differ in the age at onset since dHMN II is the adult type with the development of clinical symptoms in the second to fourth decade [23]. The symptoms start in the extensor muscles of the great toe and later of the extensor muscles of the feet. The disease progresses rapidly and all distal muscles of the legs are completely paralyzed after five years. z Genetics and pathomechanism: In a large Belgian pedigree, the chromosomal locus of dHMN II was mapped to chromosome 12q24.3 [23, 31]. Recruitment of further families and reduction of the candidate region to 1.7 kb allowed the identification of missense mutations in the small heat-shock protein 22 gene (HSP22 also called: HSBP8) in four families [18]. All mutations resulted in an amino acid change at position 141 from lysine to two different amino acids. The mutation locates to the highly conserved so called alpha-crystalline domain which is common to a number of heatshock proteins. HSP22 interacts with HSP27 which is mutated in a form of

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HMN I discussed in the preceding paragraph. This interaction is strengthened if HSP22 is mutated and leads to formation of intracellular aggregates, thereby reducing cell viability through an unknown mechanism [18].

8.3 dHMN III ± chromosomal location unknown z Clinical features: In autosomal recessive dHMN III, clinical symptoms develop in the first decade. Patients are generally mildly affected and the course of the disease resembles dHMN I and dHMN II [16]. Based on electrophysiological and histological studies, these forms are not distinguishable definitely. z Genetics and pathomechanism: There are no studies available that confirm linkage of dHMN III to a single chromosomal locus.

8.4 dHMN IV ± chromosome 11q13 (OMIM 607088) z Clinical features: Autosomal recessive dHMN IV is much more severe than dHMN III. Age at onset is in the first to second decade and weakness and wasting is predominantly in the lower legs but, in contrast to the other forms, extends to the proximal muscles of the legs [26]. Progressive worsening during childhood and relative stabilization into adulthood has been reported [32]. In two affected persons from a Lebanese family, diaphragmatic paralysis was noted but this seems to be less frequent as in dHMN VI (see below). z Genetics and pathomechanism: Viollet et al. found linkage to markers on chromosome 11q13 in an inbred Lebanese family with the clinical characteristics of dHMN IV [32, 33]. dHMN IV was mapped to a region overlapping with the dHMN VI candidate region on chromosome 11q13. dHMN VI is caused by mutations in the immunoglobulin l-binding protein 2 gene (IGHMBP2) [13]. Mutations in this gene were not found in the dHMN IV family indicating that both diseases are caused by distinct genes located in the same chromosomal region.

8 Distal hereditary motor neuropathies (dHMN)

z

8.5 dHMN V a and b ± Va: glycyl tRNA synthetase gene (GARS) (OMIM 600749) ± Vb: Berardinelli Seip congenital muscular dystrophy gene (BSCL2) (OMIM 270685) z Clinical features: In autosomal dominant dHMN Va, muscle weakness and wasting is predominantly confined to the distal upper limbs. Lower limbs are involved only to a minor degree. Besides sporadic cases, few families have been described in which the disease was autosomal dominantly inherited [1, 8]. Most patients showed symmetrical weakness, while in others the distribution was strikingly asymmetrical. When present, clinical sensory loss was only a minor feature and pes cavus was frequent. In addition in some families mild spastic paraplegia was found. Interestingly, a similar phenotype was described in a family from Iowa in which sensory loss was common [17]. This disease was classified as axonal Charcot-Marie-Tooth type 2 and subcategorized as CMT type 2D. In a large Mongolian kinship, patients with features of dHMN Va and CMT2D were observed within one family [29]. Genetic studies revealed that dHMN Va and CMT2D are allelic and caused by mutations in the glycyl tRNA synthase (GARS) gene [1]. In a large Austrian family, clinical characteristics of dHMN V were found together with brisk tendon reflexes and slightly elevated muscle tone. This entity will be called dHMN V b in this book [2]. z Genetics and pathomechanism: Despite clinical heterogeneity, dHMN Va and CMT2D have been mapped to a single locus on chromosome 7p15 [1]. Further genetic analysis, revealed mutations in the glycyl tRNA synthetase (GARS) gene in five families with dHMN Va, CMT2D or an overlapping phenotype demonstrating that both diseases are allelic [1]. GARS is expressed in an ubiquitous fashion including brain and spinal cord and belongs to the family of aminoacyl-tRNA synthetases that perform an essential function in protein synthesis by catalyzing the esterification of an amino acid to its cognate tRNA. These enzymes are necessarily present in each cell and must properly recognize the tRNA and the amino acid in order to maintain fidelity of translation. The exact mechanism by which mutations in this ubiquitously expressed gene lead to the specific phenotype remains to be unraveled. dHMN 5b maps to chromosome 11q12-q24 and is caused by missense mutations in the Berardinelli-Seip congenital lipodystrophy gene (BSCL2) [35]. Silver syndrome is an entity which is usually classified as hereditary spastic paraplegia type 17 (SPG17) but it is clinically very similar if not identical to dHMN V b and is also caused by mutations in BSCL2 [25]. All mutations causing dHMN V b known to date destroy a Nglycosylation site, most likely resulting in protein misfolding. The mutated protein localizes to so called aggresomes while wildtype protein is evenly distributed in the cytoplasm [35].

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8.6 dHMN VI ± immunoglobulin l-binding protein 2 (IGHMBP2) (OMIM 604320) z Clinical features: dHMN VI is inherited autosomal recessive and the age of onset is in very early childhood (weeks to months) [4, 24]. The most prominent symptoms are severe respiratory distress resulting from diaphragmatic paralysis with eventration shown on chest X-ray and predominant involvement of the distal upper limbs. Muscle weakness spreads to involve proximal muscles and death may occur before the age of one year. Because of the diaphragmatic involvement, dHMN VI is also referred to as spinal muscular atrophy with respiratory distress (SMARD) [14]. z Genetics and pathomechanism: dHMN VI was mapped to chromosome 11q13-q21 in three families of Lebanese, German and Italian origin [13]. Subsequently mutations in the gene encoding immunoglobulin l-binding protein 2 (IGHMBP2) have been found in six families with dHMN VI [13]. IGHMBP2 was chosen as a candidate gene since the homologous gene in the mouse had been shown to be responsible for spinal muscular atrophy in the neuromuscular degeneration (pmn) mouse, whose phenotype resembles dHMN V [30]. IGHMBP2 is ubiquitously expressed with the highest levels in testis. The exact physiological function of IGHMBP2 is not known and its role in the development of dHMN VI remains to be clarified.

8.7 dHMN VIIa ± chromosome 2q14 (OMIM 158580) z Clinical features: dHMN VII was first reported in 1980 in a large Welsh kindred in which dHMN with vocal cord paralysis was inherited autosomal dominant [36]. Onset was most commonly in the second decade with weakness and wasting of the small hand muscles subsequently involving the distal muscles of the legs. Hoarseness was usually noted and laryngoscopy showed unilateral or bilateral vocal cord paralysis. Additional families were reported later [27]. Interestingly, there is a large overlap between dHMN VIIa and Charcot-Marie-Tooth syndrome type 2C (CMT2C). CMT2C is characterized by autosomal dominant inheritance, motor and sensory involvement of the limbs and progressive weakness of the vocal cords and the diaphragm and is distinguishable from dHMN VIIa by the sensory involvement [11]. z Genetics and pathomechanism: dHMN VIIa was mapped to chromosome 2q14 in the original Welsh and an additional family [22], while the phenotypical similar CMT2C was mapped to chromosome 12q23-q24 [20]. The causative genetic defects have not yet been identified.

8 Distal hereditary motor neuropathies (dHMN)

z

8.8 dHMN VIIb ± dynactin (DCTN) (OMIM 607641) z Clinical features: Recently a North American kindred with dHMN VII was reported in which additionally progressive facial weakness was observed [28]. This form is genetically different and should therefore be classified as dHMN VIIb, whereas the classic form should be termed dHMN VIIa. z Genetics and pathomechanism: dHMN VIIb has been localized to chromosome 12q13. A mutation in the dynactin-1 (DCTN1) gene, which is located in the linkage region, has been detected in one dHMN VIIb family [28]. The dynactin complex is required for dynein mediated retrograde transport of vesicles and organelles along microtubules. In transgenic mice, overexpression of dynamitin disrupts the dynactin complex and leads to late onset progressive motor neuron disease [21].

8.9 dHMN pyramidal/amyotrophic lateral sclerosis 4 (ALS4), senataxin (SETX) (OMIM 602433) z Clinical features: dHMN pyramidal is characterized by a variable age of onset between less than six months to 21 years of age. The main features are distal muscle weakness and atrophy, hyperreflexia and in some patients pyramidal signs [6]. The progression is slow and patients often become wheelchair bound in the fifth decade. Bulbar and respiratory muscles are spared and the life expectancy is not grossly reduced. z Genetics and pathomechanism: dHMN pyramidal was mapped to chromosome 9q34 and recently causative mutations were identified in the senataxin gene (SETX) [6, 7]. Senataxin contains a putative DNA/RNA helicase domain. DNA/RNA helicases are involved in DNA repair, replication as well as in transcription, transcript stability and translation initiation. Interestingly the IGHMBP2 gene which is mutated in dHMN VI also contains a DNA/RNA helicase domain and shows high homology to SETX. While missense mutations are causing dHMN pyramidal, homozygous nonsense mutations are responsible for the ataxia-oculomotor apraxia syndrome type 2 (AOA2, OMIM 606002). AOA2 is a complex syndrome involving cerebellar ataxia and atrophy, oculomotor apraxia, loss of tendon reflexes and a late onset peripheral neuropathy.

153

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8.10 dHMN Jerash type ± chromosome 9p21.1-p12 (OMIM 605726) z Clinical features: In 2000, Christodoulou et al. described seven consanguineous families from the Jerash region of Jordan in which dHMN was inherited autosomal recessive and age at onset was five to ten years [9]. Patients presented with symmetrical distal atrophy and weakness of the lower limbs and pyramidal features. Pes cavus was present in all affected persons. During the course of the disease involvement of the distal upper limbs was noticed. Sensory loss was not found. The authors classified this form of dHMN as Jerash type. z Genetics and pathomechanism: In the seven consanguineous families from Jordan, the Jerash type dHMN was mapped to chromosome 9p21.1-p12 [9]. This region includes the ciliary neurotrophic factor receptor (CNTFR) gene, which is expressed exclusively in the nervous system and skeletal muscle. Since mice lacking CNTFR display severe motor neuron deficits, this gene has been named as a functional candidate gene. Mutation analysis of CNTFR in the Jerash families has not been reported so far.

References 1. Antonellis A, Ellsworth RE, Sambuughin N, Puls I, Abel A, Lee-Lin SQ, et al. (2003) Glycyl tRNA Synthetase Mutations in Charcot-Marie-Tooth Disease Type 2D and Distal Spinal Muscular Atrophy Type V. Am J Hum Genet 72:1293±1299 2. Auer-Grumbach M, Loscher WN, Wagner K, Petek E, Korner E, Offenbacher H, et al. (2000) Phenotypic and genotypic heterogeneity in hereditary motor neuronopathy type V: a clinical, electrophysiological and genetic study. Brain 123:1612±1623 3. Benn SC, Perrelet D, Kato AC, Scholz J, Decosterd I, Mannion RJ, et al. (2002) Hsp27 upregulation and phosphorylation is required for injured sensory and motor neuron survival. Neuron 36:45±56 4. Bertini E, Gadisseux JL, Palmieri G, Ricci E, Di Capua M, Ferriere G, et al. (1989) Distal infantile spinal muscular atrophy associated with paralysis of the diaphragm: a variant of infantile spinal muscular atrophy. Am J Med Genet 33:328±335 5. Bruey JM, Ducasse C, Bonniaud P, Ravagnan L, Susin SA, Diaz-Latoud C, et al. (2000) Hsp27 negatively regulates cell death by interacting with cytochrome c. Nat Cell Biol 2:645±652 6. Chance PF, Rabin BA, Ryan SG, Ding Y, Scavina M, Crain B, et al. (1998) Linkage of the gene for an autosomal dominant form of juvenile amyotrophic lateral sclerosis to chromosome 9q34. Am J Hum Genet 62:633±640 7. Chen YZ, Bennett CL, Huynh HM, Blair IP, Puls I, Irobi J, et al. (2004) DNA/RNA Helicase Gene Mutations in a Form of Juvenile Amyotrophic Lateral Sclerosis (ALS4). Am J Hum Genet 74:1128±1135 8. Christodoulou K, Kyriakides T, Hristova AH, Georgiou DM, Kalaydjieva L, Yshpekova B, et al. (1995) Mapping of a distal form of spinal muscular atrophy with upper limb predominance to chromosome 7p. Hum Mol Genet 4:1629±1632

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z

9. Christodoulou K, Zamba E, Tsingis M, Mubaidin A, Horani K, Abu-Sheik S, et al. (2000) A novel form of distal hereditary motor neuronopathy maps to chromosome 9p21.1-p12. Ann Neurol 48:877±884 10. Davis CJ, Bradley WG, Madrid R (1978) The peroneal muscular atrophy syndrome: clinical, genetic, electrophysiological and nerve biopsy studies. I. Clinical, genetic and electrophysiological findings and classification. J Genet Hum 26:311±349 11. Dyck PJ, Litchy WJ, Minnerath S, Bird TD, Chance PF, Schaid DJ, et al. (1994) Hereditary motor and sensory neuropathy with diaphragm and vocal cord paresis. Ann Neurol 35:608±615 12. Evgrafov OV, Mersiyanova I, Irobi J, Van Den Bosch L, Dierick I, Leung CL, et al. (2004) Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy. Nat Genet 36:602±606 13. Grohmann K, Schuelke M, Diers A, Hoffmann K, Lucke B, Adams C, et al. (2001) Mutations in the gene encoding immunoglobulin mu-binding protein 2 cause spinal muscular atrophy with respiratory distress type 1. Nat Genet 29:75±77 14. Grohmann K, Wienker TF, Saar K, Rudnik-Schæneborn S, Stoltenburg-Didinger G, Rossi R, et al. (1999) Diaphragmatic spinal muscular atrophy with respiratory distress is heterogeneous, and one form is linked to chromosome 11q13-q21. Am J Hum Genet 65:1459±1462 15. Harding AE (1993) Inherited neuronal atrophy and degeneration predominantly of lower motor neurons. In: Dyck PJ, Thomas PK (eds) Peripheral Neuropathy. 3rd. Saunders, Philadelphia, pp 1051±1063 16. Harding AE, Thomas PK (1980) Hereditary distal spinal muscular atrophy. A report on 34 cases and a review of the literature. J Neurol Sci 45:337±348 17. Ionasescu V, Searby C, Sheffield V, Roklina T, Nishimura D, Ionasescu R (1996) Autosomal dominant Charcot-Marie-Tooth axonal neuropathy mapped on chromosome 7p (CMT2D). Hum Mol Genet 5:1373±1375 18. Irobi J, Van Impe K, Seeman P, Jordanova A, Dierick I, Verpoorten N, et al. (2004) Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy. Nat Genet 36:597±601 19. Kamradt MC, Chen F, Sam S, Cryns VL (2002) The small heat-shock protein alpha B-crystallin negatively regulates apoptosis during myogenic differentiation by inhibiting caspase-3 activation. J Biol Chem 277:38731±38736 20. Klein CJ, Cunningham JM, Atkinson EJ, Schaid DJ, Hebbring SJ, Anderson SA, et al. (2003) The gene for HMSN2C maps to 12q23-24: a region of neuromuscular disorders. Neurology 60:1151±1156 21. LaMonte BH, Wallace KE, Holloway BA, Shelly SS, Ascano J, Tokito M, et al. (2002) Disruption of dynein/dynactin inhibits axonal transport in motor neurons causing late-onset progressive degeneration. Neuron 34:715±727 22. McEntagart M, Norton N, Williams H, Teare MD, Dunstan M, Baker P, et al. (2001) Localization of the gene for distal hereditary motor neuronopathy VII (dHMN VII) to chromosome 2q14. Am J Hum Genet 68:1270±1276 23. McLeod JG, Prineas JW (1971) Distal type of chronic spinal muscular atrophy. Clinical, electrophysiological and pathological studies. Brain 94:703±714 24. Mellins RB, Hays AP, Gold AP, Berdon WE, Bowdler JD (1974) Respiratory distress as the initial manifestation of Werdnig-Hoffmann disease. Pediatrics 53:33±40 25. Patel H, Hart PE, Warner TT, Houlston RS, Patton MA, Jeffery S, et al. (2001) The Silver syndrome variant of hereditary spastic paraplegia maps to chromosome 11q12-q14, with evidence for genetic heterogeneity within this subtype. Am J Hum Genet 69:209±215 26. Pearn J, Hudgson P (1979) Distal spinal muscular atrophy. A clinical and genetic study of 8 kindreds. J Neurol Sci 43:183±191

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27. Pridmore C, Baraitser M, Brett EM, Harding AE (1992) Distal spinal muscular atrophy with vocal cord paralysis. J Med Genet 29:197±199 28. Puls I, Jonnakuty C, LaMonte BH, Holzbaur EL, Tokito M, Mann E, et al. (2003) Mutant dynactin in motor neuron disease. Nat Genet 33:455±456 29. Sambuughin N, Sivakumar K, Selenge B, Lee HS, Friedlich D, Baasanjav D, et al. (1998) Autosomal dominant distal spinal muscular atrophy type V (dSMA-V) and Charcot-Marie-Tooth disease type 2D (CMT2D) segregate within a single large kindred and map to a refined region on chromosome 7p15. J Neurol Sci 161:23± 28 30. Schmalbruch H, Jensen HJ, Bjaerg M, Kamieniecka Z, Kurland L (1991) A new mouse mutant with progressive motor neuronopathy. J Neuropathol Exp Neurol 50:192±204 31. Timmerman V, De Jonghe P, Simokovic S, Lofgren A, Beuten J, Nelis E, et al. (1996) Distal hereditary motor neuropathy type II (distal HMN II): mapping of a locus to chromosome 12q24. Hum Mol Genet 5:1065±1069 32. Viollet L, Barois A, Rebeiz JG, Rifai Z, Burlet P, Zarhrate M, et al. (2002) Mapping of autosomal recessive chronic distal spinal muscular atrophy to chromosome 11q13. Ann Neurol 51:585±592 33. Viollet L, Zarhrate M, Maystadt I, Estournet-Mathiaut B, Barois A, Desguerre I, et al. (2004) Refined genetic mapping of autosomal recessive chronic distal spinal muscular atrophy to chromosome 11q13.3 and evidence of linkage disequilibrium in European families. Eur J Hum Genet 12:483±488 34. Vleminckx V, Van Damme P, Goffin K, Delye H, Van Den Bosch L, Robberecht W (2002) Upregulation of HSP27 in a transgenic model of ALS. J Neuropathol Exp Neurol 61:968±974 35. Windpassinger C, Auer-Grumbach M, Irobi J, Patel H, Petek E, Horl G, et al. (2004) Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome. Nat Genet 36:271±276 36. Young ID, Harper PS (1980) Hereditary distal spinal muscular atrophy with vocal cord paralysis. J Neurol Neurosurg Psychiatry 43:413±418

9 Hereditary sensory

and autonomic neuropathies (HSAN) P. De Jonghe, G. Kuhlenbåumer

Introduction The terms HSAN and hereditary sensory neuropathy (HSN) are synonymous. Prominent sensory abnormalities and, in many forms, autonomic disturbances are the hallmark of HSANs. The HSANs have been classified into five subgroups by P. J. Dyck according to age of onset, mode of inheritance, clinical features, electrophysiological findings and pathology (Table 9.1) [12]. From the onset, it was clear that the subgroups do not represent genetic entities and that, i.e. an overlap between HSAN1 and some variants of hereditary motor and sensory neuropathies (HMSN) with prominent sensory features exists. We will review here the cardinal features of the five HSAN forms. HSAN1 is the only autosomal dominantly inherited form. It is also the mildest form and the only one with adult onset. Some HSAN1 patients do also show distal weakness and atrophy. In contrast, HSAN2 ± HSAN5 have a very early, often congenital onset and are autosomal recessively inherited. HSAN2 is characterized by congenital or early infantile onset sensory deficit affecting all modalities and the whole body. Mutilating ulcers and painless fractures are more common than in HSAN1. HSAN3, a very severe autosomal recessively inherited disease with prominent autonomic disturbances, has a high frequency of mutation carriers and affected children in Ashkenazi Jews. Prominent features of HSAN4 are repeated attacks of pyrexia due to the inability to sweat. Severe mutilations and mild mental retardation are additional clinical features. Histopathologic examination shows a prominent loss/absence of unmyelinated fibers in HSAN4. In contrast, severe loss of small myelinated fibers is found in patients with HSAN5. HSAN5 is clinically characterized by a selective loss of pain sensation mainly affecting the extremities. HSAN1 and HSAN3 are the most common HSAN types. Another neuropathy with prominent sensory features is CMT4F, an autosomal recessively inherited severe neuropathy with early onset caused by mutations in the periaxin (PRX) gene [7]. However, ulcerations are not a prominent feature of this neuropathy.

AR

AR

z HSAN3

congenitalinfancy

congenitalinfancy

involvement of pons, medulla oblongata, reticular formation, long tracts of the spinal cord; sural nerve: unmyelinated fibers severely decreased, normal number of myelinated fibers

absence of SNAPs, MNCV virtual absence of myelimay be slightly slowed and nated fibers and decrease of CMAPs reduced or absent unmyelinated fibers in sensory nerves at distal parts of extremities

predominantly Ashkenazi jews affected, MNCV might be mildly autonomic, sensory and motor involvement, slowed and CMAPs vomiting and poor feeding, defective decreased lacrimation, temperature control with pyrexia, excessive perspiration, skin blotching, emotional hypertension and postural hypotension, insensitivity to pain, but vibration/joint position sense often normal, CNS involvement, but no obvious mental retardation, kyphosis/ scoliosis, premature death, absence of fungiform papillae of the tongue

sensory loss affecting all modalities, legs > arms > trunk acral mutilation of feet and hands, tendon reflexes absent or weak

symmetrical loss of pain and temperature sense, legs > arms; ulceration of the feet, slowly progressive, sometimes lancinating pain

distal loss of myelinated fibers, increased number of Schwann-cell nuclei, degeneration of dorsal root ganglion cells

z HSAN2

20±40 MNCV and SNCV normal/ slightly reduced, SNAPs reduced or absent

AD or AR

z HSAN1

Histopathology

Mode of inheritance

Form Neurophysiology

P. De Jonghe, G. Kuhlenbåumer

Age of onset Main clinical features (years)

z

Table 9.1. Characteristics of the HSAN classification by P. J. Dyck

158

AR

AR

z HSAN4

z HSAN5

congenitalinfancy

congenitalinfancy

selective loss of pain sensation, affecting normal SNAPs mainly the extremities relatively preserved tactile, vibration, joint position sense, normal tendon reflexes and muscle strength, no mental retardation, sudomotor dysfunction in glove and stocking distribution

repeated episodes of pyrexia caused by high environmental temperature, sweat glands present but no sweating, no pain sensation: ulcerations and mutilations common, normal muscle strength and tendon reflexes, mild mental retardation (IQ *70) selective severe decrease of small myelinated fibers, small ± severe reduction in unmyelinated fibers in sural nerve biopsy

absence of unmyelinated axons, decrease in the number of small myelinated neurons. Sweat glands have a normal structure but are not innervated

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9.1 Assessment of HSANs with autonomic and neurophysiological examinations Only two tests, which are not commonly performed in daily clinical practice, are explained here. Other useful tests of autonomic dysfunction which are not described here are the Schellong test or the tilt table test, metronomic breathing, Valsalva's maneuver, carotid sinus massage, ninhydrin test (sweating of palms and soles), Minor sweat test (whole body) and the sympathetic skin response.

9.1.1 Quantitative testing of thermal perception Cutaneous cold receptors and nociceptors are innervated by small myelinated Ar-fibers, while warmth and heat pain receptors are connected to unmyelinated C-fibers. An adjustable thermal stimulator (e.g. Thermotest, Somedic, Stockholm, Sweden) is used to apply the thermal stimulus. This device contains a Peltier element capable of either heating or cooling the stimulator. The baseline temperature is set at 32 8C and the temperature change rate is set to 1 8C/s for warming and cooling and to 3 8C/s for heating. The stimulator is attached to the skin and the test person presses a button as soon as he feels the stimulus (ªmethod of limitsº) or until the stimulus becomes painful (heat stimulation). The difference between the baseline temperature and the perceived temperature is recorded. Normal data are available for several skin sites. Five successive measurements are averaged.

9.1.2 Histamine axonal flare test The histamine axonal flare test is a commonly used test to examine the innervation of the skin by non-myelinated C-type fibers. Diluted histamine is injected intradermally. Histamine causes a local reaction, but also reaches unmyelinated dermal C-fibers in which it induces an action potential traveling centrally to the point of division of the nerve. Here it is not only transmitted to the dorsal root ganglia but also antidromically to other branches of the nerve in the skin. It then reaches arterioles and causes vasodilatation and plasma exsudation through the release of vasoactive substances (neurogenic inflammation). Therefore, in healthy subjects, intradermal histamine injection causes a sharply demarcated local reaction surrounded by a less well demarcated area of hyperemia caused by the neurogenic inflammation, the so called axon flare. Patients with HSAN2, 3 and 4 display a lack of skin innervating C-fibers. The intradermal histamine injection is therefore not only painless but also does not induce the axon flare reaction.

9 Hereditary sensory and autonomic neuropathies (HSAN)

z

9.2 Forms of HSAN 9.2.1 HSAN1/HSN I ± serine palmitoyltransferase 1, long chain subunit 1 gene (SPTLC1) (OMIM 162400) z Clinical features: HSAN1 is the most common form of HSAN. The age of onset is usually between 15 and 40 years of age [12]. Spontaneous lancinating pain in the extremities, predominant severe loss of pain and temperature sensation compared to other sensory modalities and absence of autonomic nervous system involvement with the exception of disturbed sweating is characteristic for this type of HSAN [2]. The legs are more severely affected than the arms and the trunk and head are usually spared. Many patients develop painless ulcerations of the feet often complicated by osteomyelitis, which sometimes necessitates amputations. Disturbed sweating either hypo/anhidrosis or hyperhydrosis is common. In most HSAN1 patients the motor system is also affected leading to weakness and atrophy of the distal leg muscles [2]. The most important therapeutic measure is the prevention of foot ulcers. Patients should wear comfortable shoes and should inspect the inside of their shoes for foreign objects before putting them on. Activity requiring strenuous use of the feet like long walks should be avoided. Regular foot care and inspection is mandatory. If ulcers develop weight bearing should be avoided and radiographs of the feet, to rule out osteomyelitis, should be performed to initiate adequate treatment. Patients with CMT2B might show a similar clinical picture as HSAN1 patients, but in CMT2B patients all sensory modalities are usually equally affected, motor signs are more severe and the patients do not experience spontaneous lancinating pain [2]. Further differential diagnosis of spontaneous non-healing foot ulcers are given in Table 9.2. z Electrophysiology: Most patients show signs of an axonal neuropathy [2, 12]. Sensory nerves are primarily affected and the legs are more severely affected than the arms. Sensory nerve action potentials (SNAPs) are often absent in the sural nerve and reduced in amplitude in other nerves. Compound motor action potentials (CMAPs) can be reduced and slight slowing of motor nerve conduction velocities (MNCVs) may be present. z Pathology, genetics and pathomechanism: Histopathology shows distal loss, predominantly of small myelinated and unmyelinated fibers but also of larger myelinated fibers, an increase in the number of Schwann cell nuclei, thickened perineuria, a discontinuity of myelin and degeneration of dorsal root ganglia [12]. HSAN1 is genetically heterogeneous. About half of the HSAN1 families show mutations in the SPTLC1 gene on chromosome 9q22.1-q22.3 [4, 9]. A number of British HSAN1 families and Australian families of British extraction show a founder effect [23]. For the remainder

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Table 9.2. Common differential diagnosis of spontaneous foot ulcers z z z z z z z z

Diabetes mellitus Atherosclerosis Venous ulceration Syringomyelia Tabes dorsalis Neurotoxic peripheral neuropathy (e.g. chemotherapy, gold, isoniazid) Leprosy Amyloidosis

of families, no locus has yet been mapped. In addition, a mutation screen of the gene coding for the second subunit of serine palmitoyltransferase (SPTLC2) in 15 HSAN1 families without mutations in SPTLC1 did not yield any mutations, indicating that mutations in SPTLC2 are not a common course of HSAN1 [10]. Serine palmitoyltransferase transfers fatty acids to serine resulting in sphingosine. Addition of a second fatty acid leads to ceramide which in turn is a precursor of glycosphingolipids and sphingomyelin. SPTLC functions as a heterodimer composed of SPTLC1 and SPTLC2. Increased ceramide production causes apoptosis. The initial report of SPTLC1 mutations causing HSAN1 found elevated levels of ceramide in lymphoblasts of patients [9], suggesting ceramide induced apoptosis of peripheral nerve neurons as the pathomechanism. However, more detailed in vitro experiments demonstrated a reduction of serine-palmitoyltransferase activity of mutated alleles, suggesting a different pathomechanism for HSAN1 [5, 11].

z HSAN1 with cough and gastroesophageal reflux ± chromosome3p22-p24 (OMIM 608088) z Clinical features: This autosomal dominant disorder has been described in only one family. Patients experienced spontaneous lancinating pain and gastroesophageal reflux and/or cough due to minimal aspiration of the reflux [28]. Some patients also showed sensorineural hearing loss. z Electrophysiology: EMG shows signs of a predominant sensory peripheral neuropathy with undetectable SNAPs and normal or slightly reduced MNCVs. z Pathology, genetics and pathomechanism: Nerve biopsy showed loss of unmyelinated and myelinated axons [19]. The disorder has been mapped to chromosome 3p22-p24. The causative genetic defect remains to be identified [19].

9 Hereditary sensory and autonomic neuropathies (HSAN)

z

9.2.2 HSAN2 ± hereditary sensory neuropathy II gene (HSN2) (OMIM 201300) z Clinical description: HSAN2 is an infantile-onset or congenital, autosomal recessive severe sensory peripheral neuropathy [12]. All sensory modalities are affected but, in contrast to HSAN1, touch sensation is most severely reduced. The disease is not restricted to the extremities, but may affect the trunk as well. Tendon reflexes are often reduced. Ulcerations of the feet and hands as well as secondary osteomyelitis and Charcot's joints are much more common than in HSAN1. In some patients, autonomic nervous system disturbances such as tonic pupils, swallowing problems, hypotonia and apnea have been found [12], but they are not a feature in the families in which causative mutations in the HSN2 gene were recently found [21]. The central nervous system (CNS) is usually not affected. z Electrophysiology: SNAPs are absent. MNCVs and CMAPs may be reduced. z Pathology, genetics and pathomechanism: Examination of sensory nerve biopsy specimens shows severe loss of myelinated axons, some loss of nonmyelinated axons and the absence of cutaneous sensory receptors and nerve fibers [12, 21]. HSAN2 was recently mapped to chromosome 12p13.33. Three different mutations in a novel gene, HSN2, were detected in five Canadian families [21]. The function of this single exon gene is unknown. It is also not yet known how prevalent HSN2 mutations are in HSAN2.

9.2.3 HSAN3 ± (Syn: familial dysautonomia, Riley-Day syndrome) ± inhibitor of kappa light polypeptide gene (IKBKAP, protein IKAP) z Clinical features: HSAN3 is a severe autosomal recessive disease with infantile or congenital onset [25]. HSAN3 is nearly exclusively found in Ashkenazi Jews where the gene carrier frequency is estimated as 1 : 30 with a disease incidence of 1 : 3600 live births [3]. Current survival statistics indicate that newborns with HSAN3 have a *50% probability of reaching the age of 30 years. HSAN3 mainly affects the development and survival of autonomic and sensory neurons and to a lesser extent of the motor neurons [3]. Patients often present with a history of poor feeding, repeated episodes of vomiting, hypertension, tachycardia, excessive perspiration, cutis marmorata, irritability and insomnia. These features constitute a ªdysautonomic crisisº, which may appear in a cyclical fashion every month, week or even day. A dysautonomic crisis presumably results from catecholamines synthesized in the CNS acting on peripheral catecholamine receptors sensitized by the lack of peripheral catecholamine production. Due to the deficits in pain perception, ulcerations and other acral mutilations are common. Visceral pain perception however is preserved. Due to lack of

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corneal pain sensitivity and insufficient lacrimation, many patients develop corneal ulcers. Regular use of lubricating eye drops is mandatory. Most patients are of short stature and develop a kyphoscoliosis. Gastrointestinal dysfunction results in abnormal esophageal peristalsis, and gastroesophageal reflux. More than 50% of the patients require a gastrostomy or fundoplicatio, because reflux leads to recurrent aspiration and chronic lung disease [3]. Respiratory dysfunction is often due to recurrent aspiration, restrictive lung disease caused by kyphoscoliosis and chemoreceptor dysfunction aborting normal reactions to hypoxia and hypercapnia. Chemoreceptor dysfunction is dangerous in high altitude and during swimming and diving, because patients do not feel the urge to breath. Cardiovascular features include postural hypotension, sometimes leading to syncope and attacks of hypertension triggered by lying down or stress. Areflexia and ataxia are caused by the involvement of somatosensory nerves. Cardinal early clinical manifestations which are diagnostic are z no overflow tearing during crying, z absent fungiform papillae of the tongue, z depressed patellar reflexes (in 95% of patients), z abnormal histamine flare test and z patient is of Ashkenazi Jewish extraction [15]. Cranial magnetic resonance imaging (MRI) in older patients often shows signs of a generalized atrophy including the cerebellum, which may contribute to the ataxia. Older patients also experience progressive degeneration of the optic nerve. Specialized medical facilities familiar with all diagnostic as well as therapeutic aspects of the disease are available in the state of New York at the New York University School of Medicine and in Israel since *60% of the patients live in these two areas. It is interesting to note that a dysautonomic crisis and excessive hypertension are best treated with benzodiazepines and clonidine, the latter being a drug that lowers the central sympathetic tone. z Electrophysiology: SNAPs are reduced and MNCVs are also slightly reduced. Visual evoked potentials (VEP) may be delayed due to optic nerve degeneration. z Pathology, genetics and pathomechanism: HSAN3 is thought to be a developmental disorder mainly of the sensory and autonomic (especially sympathetic) system with further degenerative changes during life. Sural nerve biopsy specimens may show a severe reduction of unmyelinated fibers to 10±15% of normal controls but relative preservation of myelinated axons. Neurons in the spinal dorsal root ganglia, in the Gasserian ganglion and in the sympathetic ganglia are reduced. HSAN3 was mapped to chromosome 9q31 [6] and mutations in the IKBKAP gene were found in 2001 [1, 27]. Over 98% of the patients show allele sharing in the candidate region and carry the same 5' splice donor site mutation [1, 27]. This splice site mutation alters the

9 Hereditary sensory and autonomic neuropathies (HSAN)

z

splicing of IKBKAP in a tissue specific manner with very high levels of aberrantly spliced mRNA in the nervous tissue and comparatively low levels of aberrantly spliced mRNA in other tissues. The IKAP protein is part of the ªelongater complexº which is associated with elongating RNA-polymerase II. The exact pathomechanism remains to be elucidated.

9.2.4 HSAN4 ± neurotrophin receptor tyrosine kinase 1 gene (NTRK1) (OMIM 256800) z Clinical features: HSAN4 also called congenital insensitivity to pain and anhidrosis (CIPA) is an autosomal recessive disorder. Congenital onset, anhidrosis affecting the whole body, frequent bouts of pyrexia related to ambient temperature, absence of reaction to noxious stimuli and mild to severe mental retardation are the cardinal clinical features of this very rare disease [12, 18, 25]. Recurrent pyrexia is due to anhidrosis, which in turn is caused by lack of innervation of the cutaneous sweat glands [24]. Twenty percent of children succumb to hyperpyrexia in the first three years of life. Absence or severely impaired cutaneous as well as visceral pain perception, in combination with self mutilating behavior especially of young children leads to biting of the tongue resulting in a bifid or absent tongue, ulcerated fingertips, osteomyelitis and Charcot's joints. The children are often mentally retarded, labile, hyperactive and irritable. Peripheral motor and cranial nerve function are normal. Corneal ulcers appear in some cases. Except for anhidrosis, overt severe autonomic dysfunction is not a feature of the disease, but clinical tests reveal signs of autonomic dysfunction [18]. Patients do not develop bradycardia during carotid sinus massage or ocular pressure, the ciliospinal reflex is absent and abnormalities in pupillary function have been described. On examination the skin is warm, dry and thickened on the soles and palms. In contrast to HSAN3, fungiform papillae of the tongue are invariably present. Orthopedic deformities of the knee, elbow and ankle joints are common. Investigations like EEG, cranial MRI or CT are usually unremarkable. The histamine axon reflex shows a normal flare response. Specific treatment is not available. It is very important to prevent self-mutilation, treat hyperpyrexia promptly by physical cooling or acetaminophen and/or ibuprofen. Chlorpromazine or chloral hydrate is used to relax the children and prevent hyperactivity which worsens the pyrexia. z Electrophysiology: MNCVs, CMAPs, SNCVs and SNAPs are usually normal [12]. Somatosensory, visual and auditory brainstem evoked potentials are also normal. The sympathetic skin response (SSR) is absent. z Pathology, genetics and pathomechanism: Histopathological studies of the cutaneous branch of the radial nerve or the sural nerve show nearly complete absence of unmyelinated fibers and mild to severe loss of small myelinated fibers without degenerative or regenerative changes [14]. Skin biop-

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sies show morphologically normal sweat glands lacking innervation. Small neurons are absent in the dorsal root ganglia. Using a candidate gene approach, causative mutations were identified in the NTRK1 gene [17]. NTRK1 encodes a receptor tyrosine kinase for nerve growth factor (NGF) (reviewed in [18]). NGF signaling is mandatory for the survival of sympathetic ganglion neurons and nociceptive neurons during development but not for the development of large sensory or motor neurons, which are dependent on the action of other neurotrophins. NTRK1 protein dimerizes upon NGF binding to the extracellular domain leading to tyrosine autophosphorylation of the intracellular domain. The phosphorylated intracellular domain serves as an anchor for binding downstream signaling molecules. While nonsense mutations cause a loss of intact protein, the mechanism of action of missense mutations is more difficult to explain, but it has been shown for a number of missense mutations that they were aberrantly processed and most importantly had diminished autophosphorylation capacity [22]. In one Israeli-Bedouin family, linkage to NTRK1 locus was excluded suggesting that genetic heterogeneity is present [26].

9.2.5 HSAN5 ± in some cases: nerve growth factor beta (NGFB), neurotrophin receptor tyrosine kinase 1 gene (NTRK1) (OMIM 256800) z Clinical features: HSAN5 is an extremely rare and poorly characterized autosomal recessive or dominant disorder. It is clinically characterized by congenital indifference to pain often combined with mild anhidrosis in the distal parts of the legs and arms. Thermal sensation is preserved but heat might not be perceived as painful. Ulcerations and mutilations of the distal extremities as well as Charcot-joints are common. Signs of mild autonomic system involvement are cutis marmorata and mild to moderate postural hypotension found in some patients. All mechanoreceptor-dependent sensations are normal as well as muscle strength and tendon reflexes. All cognitive functions appear to be normal, too. z Electrophysiology: Standard electrophysiology including MNCVs, CMAPs, SNCVs and SNAPs are normal in most cases. z Pathology, genetics and pathomechanism: Sural nerve biopsy specimens showed a severe, selective decrease of small myelinated fibers with relative preservation of unmyelinated fibers and large myelinated fibers and no signs of de- or regeneration. Very recently mutations in the NGFB gene were found in an inbred family from northern Sweden with some characteristics of HSAN5 [13]. The onset of symptoms was in the first or second decade, which is rather late for HSAN5. Patients suffered from loss of pain perception and although they could feel heat, burns of the skin did not hurt. Joint problems were common and one patient reported repeated faint-

9 Hereditary sensory and autonomic neuropathies (HSAN)

z

ing on rising, problems when emptying the bladder as well as slight incontinence. The neurological examination did not show any other sensory or motor problems. Sural nerve biopsy specimens in the family carrying the NGFB mutation showed a prominent reduction of unmyelinated fibers and a much milder reduction of small myelinated fibers. It should be noted that this pattern is characteristic for HSAN4 but patients did not show the characteristic clinical HSAN4 phenotype. NGFB is a ligand for the NTRK1 protein, which is mutated in HSAN4. Because the HSAN5 phenotype presented here is much milder than the typical clinical picture of HSAN4, it seems likely that the NGFB missense mutation does not completely abolish its function. NGF deficient mice suffer from a very severe neuropathy [8]. Only one patient with some features of HSAN5 and a NTRK1 gene mutation, which causes the vast majority of HSAN4, has been reported [16]. The diagnosis was mainly based on a nerve biopsy showing predominant loss of unmyelinated fibers compared to small myelinated fibers. It is not proven that the patient described in this report does not suffer from a rather mild form of HSAN4 since he displayed generalized anhidrosis leading to recurrent attacks of severely elevated body temperature due to hot ambient temperatures which is not a feature of HSAN4. No mutations in NTRK1 were found in other patients with HSAN5 [29].

References 1. Anderson SL, Coli R, Daly IW, Kichula EA, Rork MJ, Volpi SA et al (2001) Familial dysautonomia is caused by mutations of the IKAP gene. Am J Hum Genet 68:753±758 2. Auer-Grumbach M, De Jonghe P, Verhoeven K, Timmerman V, Wagner K, Hartung HP, et al (2003) Autosomal dominant inherited neuropathies with prominent sensory loss and mutilations: a review. Arch Neurol 60:329±334 3. Axelrod FB (2002) Hereditary sensory and autonomic neuropathies. Familial dysautonomia and other HSANs. Clin Auton Res 12 (Suppl 1):I2±14 4. Bejaoui K, Wu C, Scheffler MD, Haan G, Ashby P, Wu L, et al (2001) SPTLC1 is mutated in hereditary sensory neuropathy, type 1. Nat Genet 27:261±262 5. Bejaoui K, Uchida Y, Yasuda S, Ho M, Nishijima M, Brown RH Jr, et al (2002) Hereditary sensory neuropathy type 1 mutations confer dominant negative effects on serine palmitoyltransferase, critical for sphingolipid synthesis. J Clin Invest 110:1301±1308 6. Blumenfeld A, Slaugenhaupt SA, Axelrod FB, Lucente DE, Maayan C, Liebert CB et al (1993) Localization of the gene for familial dysautonomia on chromosome 9 and definition of DNA markers for genetic diagnosis. Nat Genet 4:160±164 7. Boerkoel CF, Takashima H, Stankiewicz P, Garcia CA, Leber SM, Rhee-Morris L, et al (2001) Periaxin mutations cause recessive Dejerine-Sottas neuropathy. Am J Hum Genet 68:325±333 8. Crowley C, Spencer SD, Nishimura MC, Chen KS, Pitts-Meek S, Armanini MP et al (1994) Mice lacking nerve growth factor display perinatal loss of sensory and sympathetic neurons yet develop basal forebrain cholinergic neurons. Cell 76:1001±1011

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9. Dawkins JL, Hulme DJ, Brahmbhatt SB, Auer-Grumbach M, Nicholson GA (2001) Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I. Nat Genet 27:309±312 10. Dawkins JL, Brahmbhatt S, Auer-Grumbach M, Wagner K, Hartung HP, Verhoeven K et al (2002) Exclusion of serine palmitoyltransferase long chain base subunit 2 (SPTLC2) as a common cause for hereditary sensory neuropathy. Neuromuscul Disord 12:656±658 11. Dedov VN, Dedova IV, Merrill AH Jr, Nicholson GA (2004) Activity of partially inhibited serine palmitoyltransferase is sufficient for normal sphingolipid metabolism and viability of HSN1 patient cells. Biochim Biophys Acta 1688:168±175 12. Dyck PJ, Chance P, Lebo R, Carney JA (1993) Neuronal atrophy and degeneration predominantly affecting peripheral sensory and autonomic neurons. In: Dyck PJ, Thomas PK (eds) Peripheral neuropathy, 3rd edn. Saunders, Philadelphia, pp 1065±1093 13. Einarsdottir E, Carlsson A, Minde J, Toolanen G, Svensson O, Solders G et al (2004) A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception. Hum Mol Genet 13:799±805 14. Goebel HH, Veit S, Dyck PJ (1980) Confirmation of virtual unmyelinated fiber absence in hereditary sensory neuropathy type IV. J Neuropathol Exp Neurol 39:670±675 15. Hilz MJ (2002) Assessment and evaluation of hereditary sensory and autonomic neuropathies with autonomic and neurophysiological examinations. Clin Auton Res 12 Suppl 1:I33±43 16. Houlden H, King RH, Hashemi-Nejad A, Wood NW, Mathias CJ, Reilly M et al (2001) A novel TRK A (NTRK1) mutation associated with hereditary sensory and autonomic neuropathy type V. Ann Neurol 49:521±525 17. Indo Y, Tsuruta M, Hayashida Y, Karim MA, Ohta K, Kawano T et al (1996) Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis. Nat Genet 13:485±488 18. Indo Y (2002) Genetics of congenital insensitivity to pain with anhidrosis (CIPA) or hereditary sensory and autonomic neuropathy type IV. Clinical, biological and molecular aspects of mutations in TRKA(NTRK1) gene encoding the receptor tyrosine kinase for nerve growth factor. Clin Auton Res 12 (Suppl 1):I20±32 19. Kok C, Kennerson ML, Spring PJ, Ing AJ, Pollard JD, Nicholson GA (2003) A locus for hereditary sensory neuropathy with cough and gastroesophageal reflux on chromosome 3p22-p24. Am J Hum Genet 73:632±637 20. Kwon JM, Elliott JL, Yee WC, Ivanovich J, Scavarda NJ, Moolsintong PJ et al (1995) Assignment of a second Charcot-Marie-Tooth type II locus to chromosome 3q. Am J Hum Genet 57:853±858 21. Lafreniere RG, MacDonald ML, Dube MP, MacFarlane J, O'Driscoll M, Brais B et al (2004) Identification of a novel gene (HSN2) causing hereditary sensory and autonomic neuropathy type II through the Study of Canadian Genetic Isolates. Am J Hum Genet 74:1064±1073 22. Mardy S, Miura Y, Endo F, Matsuda I, Indo Y (2001) Congenital insensitivity to pain with anhidrosis (CIPA): effect of TRKA (NTRK1) missense mutations on autophosphorylation of the receptor tyrosine kinase for nerve growth factor. Hum Mol Genet 10:179±188 23. Nicholson GA, Dawkins JL, Blair IP, Auer-Grumbach M, Brahmbhatt SB, Hulme DJ (2001) Hereditary sensory neuropathy type I: haplotype analysis shows founders in southern England and Europe. Am J Hum Genet 69:655±659 24. Nolano M, Crisci C, Santoro L, Barbieri F, Casale R, Kennedy WR et al (2000) Absent innervation of skin and sweat glands in congenital insensitivity to pain with anhidrosis. Clin Neurophysiol 111:1596±1601

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25. Riley CM, Day RL, Greely D, Langford WS (1949) Central autonomic dysfunction with defective lacrimation. Pediatrics 3:468±447 26. Shatzky S, Moses S, Levy J, Pinsk V, Hershkovitz E, Herzog L, et al (2000) Congenital insensitivity to pain with anhidrosis (CIPA) in Israeli-Bedouins: genetic heterogeneity, novel mutations in the TRKA/NGF receptor gene, clinical findings, and results of nerve conduction studies. Am J Med Genet 92:353±360 27. Slaugenhaupt SA, Blumenfeld A, Gill SP, Leyne M, Mull J, Cuajungco MP et al (2001) Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. Am J Hum Genet 68:598±605 28. Spring PJ, Ing AJ, Nicholson G, Basset M, Kerlin P, Bowler S et al (2002) Autosomal dominant hereditary sensory neuropathy with gastro-oesophageal reflux and cough: clinical features of a family. J Neurol Sci Suppl 199:S64 29. Toscano E, Simonati A, Indo Y, Andria G (2002) No mutation in the TRKA (NTRK1) gene encoding a receptor tyrosine kinase for nerve growth factor in a patient with hereditary sensory and autonomic neuropathy type V. Ann Neurol 52:224±227

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10 Hereditary neuralgic amyotrophy (HNA) G. Kuhlenbåumer

Traditionally, HNA and hereditary neuropathy with liability to pressure palsy (HNPP) constituted the group of hereditary recurrent focal neuropathies, because both neuropathies show clinical signs that are restricted to certain anatomical structures as well as recurrent disease attacks. Nevertheless, most if not all HNPP cases show an underlying generalized demyelinating neuropathy of varying severity and are caused by a deletion on chromosome 17p11, which is the reciprocal event of the duplication accounting for CMT1A. Therefore, we decided to classify HNPP as a CMT1type neuropathy (see chapter ªCMT1º), leaving HNA as the only member of the group of hereditary focal neuropathies.

10.1 Clinical features HNA is a rare disease, but it has been reported in many different countries and ethnicities rendering worldwide occurrence very likely. HNA was first described by Dreschfeld in 1886 [8]. Approximately 25 reports of HNA families exist in the English-language literature [1±3, 6, 9±14, 16, 17, 20, 23±26, 30, 31, 33, 36, 38, 39]. The following description of HNA is based on these reports and our own unpublished clinical data. The inheritance is autosomal dominant and disease penetrance is 80±95%. HNA has a nonhereditary counterpart called idiopathic brachial plexus neuropathy which is ± with an incidence of approximately 1.64/100,000/year ± much more common than HNA [5]. The characteristic clinical manifestations of HNA are painful brachial plexus neuropathies. The disease may follow two distinct clinical courses: the classical remitting-relapsing course characterized by rapid onset of attacks and in most cases complete remission between attacks or a more protracted chronic undulating course with slower onset, chronic pain and often quite severe residual neurological deficits [3, 33]. Table 10.1 lists the clinical features of the different forms of brachial plexus neuropathy described here.

not known

as in remitting relapsing most patients recover completely Watts 2001 [36], Kuhlenbåumer 2001 [17]

infection, strenuous exercise, pregnancy/delivery, trauma

most patients recover completely

many, see body of text

z precipitating events

z prognosis

z references

Arts 1983 [3], van Alfen 2000 [33]

most patients show moderate to severe residual deficit

chronic undulating course

days to two years

absent

negative

mainly >10±70

Sporadic brachial plexus neuropathy

many, see body of text

most patients recover completely

as in remitting relapsing

days to two years

slowly increasing pain over rapid onset of pain weeks to months before onset of first severe attack

present (not specified)

positive

days to two years

absent in known families

z duration of attacks

positive

positive

present in most families

z family history

z dysmorphic features

not specified

rapid onset of pain

*4±45

*3±35

z age at onset

Chronic undulating HNA (not linked to Chr. 17q25)

z onset of attacks rapid onset of pain

Remitting-relapsing HNA (not linked to Chr. 17q25)

Remitting-relapsing HNA (linked to Chr. 17q25)

Feature

Table 10.1. Clinical features of the different forms of brachial plexus neuropathy

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10.1.1 Classical remitting-relapsing HNA The age of onset of classical HNA varies between 13 months and 45 years with an average age of onset in most series around 15±20 years. In nearly all cases, patients present with rapid onset of severe aching, burning or stabbing pain in one or both shoulders and often also in the arms which lasts for days to weeks. The pain is exacerbated by active and passive movement and cold. As the pain subsides, paresis of shoulder and arm muscles sets in. Paresis and atrophy most commonly affects the muscles of the shoulder girdle (deltoid, serratus anterior, rhomboids, supra- and infraspinatus) followed by the biceps and the extensors of the hand and fingers (Fig. 10.1). The pattern of muscle involvement can often not be explained by the affection of a single nerve or spinal root or a combination of either, but symptoms attributable to affection of a single nerve (e.g., long thoracic) have been found in a number of cases. Tendon reflexes are usually diminished or absent in affected limbs. The duration of paresis is extremely variable and can last only days but also up to two years. Recovery is in most cases functionally complete,

Fig. 10.1. Typical clinical appearance of classical remitting-relapsing HNA. Nine year old girl from a family with HNA showing linkage to the HNA locus on chromosome 17q25 during first HNA attack (A1 and A2). Notice the bilateral arm involvement. The right arm can not be abducted more than 20±308 due to weakness mainly of the right supraspinatus muscle (suprascapular nerve, C4±6) and to a lesser degree the deltoid muscle (axillary nerve, C5±6) (A2). Both hands demonstrate wrist drop due to paresis of the hand extensors (radial nerve, C7±8) (A1 and A2). On the right side, wrist drop is seen better in A2 because both arms are elevated in the saggital plane. A2 demonstrates additional winging of the scapula on both sides due to paresis of the serratus anterior muscle (long thoracic nerve, C5±7). (B) Nine months later. The girl has completely recovered

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z

Fig. 10.2. Facial dysmorphic features partially cosegregating with HNA in a family with classical remitting-relapsing HNA linked to the HNA locus on chromosome 17q25 locus. Thickly framed individuals are affected by HNA. II : 1, III : 1, III : 4 are affected and show hypotelorism (close set eyes) as well as epicanthal folds. III : 2 is affected and demonstrates hypotelorism but no epicanthal folds. II : 2 and III : 3 are not affected and exhibit neither hypotelorism nor epicanthal folds (photographs published with written permission of the family)

but even in these cases careful neurological examination might reveal minor degrees of residual atrophy or paresis. Moderate to severe residual deficits do occur in some cases. Sensory deficits are less prominent and commonly affect the areas supplied by the axillary nerve (over the deltoid muscle) and by the superficial radial nerve (radial forearm and hand). Involvement of the lumbosacral plexus occurs in 5±15% of the cases almost always together with attacks of brachial plexus neuritis. Hoarseness due to vocal cord paralysis and uni- or bilateral phrenic nerve palsy are also relatively frequent. In some cases, the facial nerve, the lower cranial nerves and the sympathetic nervous system (increased or decreased sweating in the affected limb, unilateral Horner's syndrome, *10% of attacks) are affected as well. Attacks are often (20± 70%) preceded by triggering events which can roughly be divided into two groups according to the duration until the onset of pain after the triggering event: strenuous use of the affected arm, trauma and cold are often followed by pain within hours while the interval between febrile infections and immunizations and the onset of pain tends to be days to weeks. Parturition is a particularly common antecedent event in women and attacks are not prevented

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by cesarean section [16]. The interval between birthing and the onset of pain is extremely variable (hours to weeks) and attacks may also be precipitated by pregnancy itself. Many reports describe dysmorphic features which in most but not all families segregate with the recurrent brachial plexus neuropathies (Fig. 10.2). The most common are hypotelorism (mean interpupillary distance 55.7 mm in HNA patients, 60.0 mm in controls, [14]), epicanthal folds, a short palpebral fissure and a small mouth. Cleft palate and syndactyly of the toes have been reported in a small number of cases only, but are clearly more common than in the general population. The average number of attacks during life is between 3 and 5 but varies widely (1?20). As a rule attacks become less frequent with increasing age.

10.1.2 Chronic undulating HNA The existence of a second clinically distinguishable type of HNA was first suggested by Arts et al. in 1983 [3]. Seventeen years later, a systematic study of HNA in the Netherlands including the family described by Arts et al. clearly demonstrated the existence of a second clinically distinct type of HNA that was named the chronic undulating form [33]. It is characterized by gradually increasing pain over a period of six weeks to two years before the onset of the first real attack with severe pain and paresis. In contrast to classical HNA, paresis and atrophy do not remit but remain nearly unchanged while pain does partially remit and recur. Exacerbations of pain sometimes herald new or increasing paresis. The long-term outcome seems less favorable than in remitting relapsing HNA with moderate to severe, sometimes disabling residual neurologic deficits in approximately 70% of patients. Hypotelorism was certainly present in one family. Two out of three existing reports suggest that chronic undulating and remitting-relapsing HNA may occur in the same family [3, 14].

10.1.3 Sporadic brachial plexus neuropathy (sBPN) (also called idiopathic brachial plexus neuritis, Parsonage-Turner syndrome) Several series between 1 and 136 patients with sBPN are described in the literature [22, 32]. The clinical features regarding the symptoms and course of individual attacks and triggering events are very similar to HNA. sBPN may occur in an endemic form which is related to poor hygienic conditions, but a specific pathogen has not been identified [4]. Some cases showed evidence of parvovirus B19 infection ([15] and references herein). The clinical differences between HNA and sBPN are: z sBPN shows a higher average age at onset (*30 years, 20±70 years), z sBPN is rare in the first decade of life, z sBPN patients do not show dysmorphic features, z sBPN patients have a lack of family history for BPN and

10 Hereditary neuralgic amyotrophy (HNA)

z

z recurrent attacks are infrequent in sBPN (*10% of patients have two attacks) [7, 22, 32]. The diagnosis of classical HNA attacks is relatively straightforward. The differential diagnosis includes shoulder injuries especially affecting the rotator cuff, cervical radiculopathies and, particularly if attacks show an atypical slow onset of pain, other conditions like neoplastic infiltration and radiation plexopathy (if applicable). HNPP may manifest as isolated brachial plexus neuropathy, but is easily distinguished by the absence of severe pain [21]. A causative treatment of HNA does not exist and data concerning symptomatic therapy are very limited. Pain therapy should employ nonsteroidal anti-inflammatory drugs and if necessary opiates (acute phase) or amitryptiline (chronic phase) [33]. Pain reduction under corticosteroid therapy (*50 mg of prednisone equivalent over weeks to months) has been reported in some cases, but most authors did not notice any benefit. Motor function did not improve with corticosteroid therapy in any of the cases [3, 25]. Pain might reoccur after discontinuation of steroid therapy [16]. One case report describes dramatic pain relief and motor improvement following intravenous immunoglobulin treatment (0.4 mg/kg bodyweight over 5 days) [2]. Physiotherapy, in the acute stage aiming at the preservation of joint mobility and later at improving muscle strength, is a mainstay of therapy.

10.2 Electrodiagnostic, laboratory and additional investigations Published data concerning electrodiagnostic features are sparse. Needle EMG usually shows pathologic spontaneous discharges as a sign of axonal damage in affected muscles during attacks [3, 16, 17]. Distal mNCVs and sNCVs are normal in most cases but slight slowing especially in nerves supplying affected muscles has also been observed. SNAPs from affected limbs are often reduced or absent indicating that the lesion is distal to the sensory root. Terminal latencies between Erb's point and proximal affected muscles (e.g., deltoid) are prolonged and CMAPs are reduced indicating a lesion within the brachial plexus [3, 18]. Electrophysiological signs of a generalized peripheral neuropathy in unaffected limbs are not found. Laboratory investigations including CSF are usually normal. An increased signal in the affected plexus on T2-weighted MRI has been described in very few cases, but was not found by other investigators [34].

10.3 Pathologic features Biopsies of peripheral nerves in unaffected limbs were either normal or demonstrated minimal loss of myelinated fibers. Four biopsies of clinically

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affected nerves have been reported (three superficial radial and one fascicle of the proximal median nerve). The biopsies showed epineurial and perivascular mononuclear infiltrates and in two cases marked axonal degeneration [16, 40].

10.4 Genetics and pathomechanism The major locus for classical remitting-relapsing HNA has been mapped to chromosome 17q25 to a region of approximately 1.5 mb between the STRmarkers D17S785 and D17S802 [19, 23, 28]. Allele sharing in American families suggests a likely further refinement to a candidate region of approximately 500 kb [37]. Despite an extensive search the causative mutations have still not been found. Four families not mapping to this locus demonstrate genetic heterogeneity of classical HNA [17, 36]. None of these families shows dysmorphic features. One family with the chronic undulating form of HNA does also not show linkage with the chromosome 17q25 locus [33]. Febrile infections and immunizations preceding attacks and mononuclear infiltrates in nerve biopsies suggest involvement of the immune system in this autosomal dominant hereditary condition. Similar biopsy findings as well as evidence for an autoimmune reaction against components of the brachial plexus has also been found in the sporadic brachial plexus neuropathy [27, 29, 35]. In summary, the causes of HNA still remain enigmatic. They have to account for a hereditary condition with remitting-relapsing course, dysmorphic features cosegregating with the attacks of brachial plexus neuropathies in some families but not in others and involvement of the immune system.

References 1. Airaksinen EM, Iivanainen M, Karli P, Sainio K, Haltia M (1985) Hereditary recurrent brachial plexus neuropathy with dysmorphic features. Acta Neurol Scand 71:309±316 2. Ardolino G, Barbieri S, Priori A (2003) High dose intravenous immune globulin in the treatment of hereditary recurrent brachial plexus neuropathy. J Neurol Neurosurg Psychiatry 74:550; author reply 550±551 3. Arts WF, Busch HF, den V, Brand H, Jennekens FG, Frants RR, et al. (1983) Hereditary neuralgic amyotrophy. Clinical, genetic, electrophysiological and histopathological studies. J Neurol Sci 62:261±279 4. Bardos V, Somodska V (1961) Epidemiologic study of a brachial plexus neuritis outbreak in northeast Czechoslovakia. World Neurol 2:973±979 5. Beghi E, Kurland LT, Mulder DW, Nicolosi A (1985) Brachial plexus neuropathy in the population of Rochester, Minnesota, 1970±1981. Ann Neurol 18:320±323

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z

6. Chance PF, Lensch MW, Lipe H, Brown RS, Brown RJ, Bird TD (1994) Hereditary neuralgic amyotrophy and hereditary neuropathy with liability to pressure palsies: two distinct genetic disorders. Neurology 44:2253±2257 7. Cruz-Martinez A, Barrio M, Arpa J (2002) Neuralgic amyotrophy: variable expression in 40 patients. J Peripher Nerv Syst 7:198±204 8. Dreschfeld J (1886) On some rarer forms of muscular atrophies. Brain 9:178±195 9. Dunn HG, Daube JR, Gomez MR (1978) Heredofamilial branchial plexus neuropathy (hereditary neuralgic amyotrophy with branchial predilection) in childhood. Dev Med Child Neurol 20:28±46 10. Erikson A (1974) Hereditary syndrome consisting in recurrent attacks resembling brachial plexus neuritis, special facial features, and cleft palate. Acta Paediatr Scand 63:885±888 11. Gardner JH, Maloney W (1968) Hereditary brachial and cranial neuritis genetically linked with ocular hypotelorism and syndactyly. Neurology 18:278 12. Geiger L, Mancall E, Penn A, Tucker S (1974) Familial neuralgic amyotrophy. Brain 97:87±102 13. Guillozet N, Mercer RD (1973) Hereditary recurrent brachial neuropathy. Am J Dis Child 125:884±887 14. Jeannet PY, Watts GD, Bird TD, Chance PF (2001) Craniofacial and cutaneous findings expand the phenotype of hereditary neuralgic amyotrophy. Neurology 57:1963±1968 15. Kirchhoff-Moradpour A, Huzly D, Korinthenberg R, Berner R (2001) Neuralgic amyotrophy associated with parvovirus B19 infection in a child. Eur J Pediatr 160:200±201 16. Klein CJ, Dyck PJ, Friedenberg SM, Burns TM, Windebank AJ (2002) Inflammation and neuropathic attacks in hereditary brachial plexus neuropathy. J Neurol Neurosurg Psychiatry 73:45±50 17. Kuhlenbåumer G, Meuleman J, De Jonghe P, Falck B, Young P, Hçnermund G et al. (2001) Hereditary neuralgic amyotrophy (HNA) is genetically heterogeneous. J Neurol 248:861±865 18. Lo YL, Mills KR (1999) Motor root conduction in neuralgic amyotrophy: evidence of proximal conduction block. J Neurol Neurosurg Psychiatry 66:586±590 19. Meuleman J, Kuhlenbåumer G, Schirmacher A, Wehnert M, De Jonghe P, De Vriendt E et al. (1999) Genetic refinement of the hereditary neuralgic amyotrophy (HNA) locus at chromosome 17q25. Eur J Hum Genet 7:920±927 20. Orstavik K, Ro H, Orstavik KH (1997) Recurrent brachial plexus neuropathy in a family with subtle dysmorphic features ± a case of hereditary neuralgic amyotrophy. Clin Genet 51:421±425 21. Orstavik K, Skard Heier M, Young P, Stægbauer F (2001) Brachial plexus involvement as the only expression of hereditary neuropathy with liability to pressure palsies. Muscle Nerve 24:1093±1096 22. Parsonage M, Turner J (1948) Neuralgic amyotrophy. The shoulder-girdle syndrome. Lancet June 26:973±978 23. Pellegrino JE, Rebbeck TR, Brown MJ, Bird TD, Chance PF (1996) Mapping of hereditary neuralgic amyotrophy (familial brachial plexus neuropathy) to distal chromosome 17q. Neurology 46:1128±1132 24. Phillips LH 2nd (1986) Familial long thoracic nerve palsy: a manifestation of brachial plexus neuropathy. Neurology 36:1251±1253 25. Poffenberger AL (1968) Heredofamilial neuritis with brachial predilection. The West Virginia Medical Journal 64:425±428 26. Roos D, Thygesen P (1972) Familial recurrent polyneuropathy. A family and a survey. Brain 95:235±248

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27. Sierra A, Prat J, Bas J, Romeu A, Montero J, Matos JA, et al. (1991) Blood lymphocytes are sensitized to branchial plexus nerves in patients with neuralgic amyotrophy. Acta Neurol Scand 83:183±186 28. Stægbauer F, Young P, Timmerman V, Spælders P, Ringelstein EB, Van Broeckhoven C, et al. (1997) Refinement of the hereditary neuralgic amyotrophy (HNA) locus to chromosome 17q24-q25. Hum Genet 99:685±687 29. Suarez GA, Giannini C, Bosch EP, Barohn RJ, Wodak J, Ebeling P, et al. (1996) Immune brachial plexus neuropathy: suggestive evidence for an inflammatory-immune pathogenesis. Neurology 46:559±561 30. Taylor R (1960) Heredofamilial mononeuritis multiplex with brachial plexus predeliction. Brain 82:113±137 31. Thomas PK, Ormerod IE (1993) Hereditary neuralgic amyotrophy associated with a relapsing multifocal sensory neuropathy. J Neurol Neurosurg Psychiatry 56:107± 109 32. Tsairis P, Dyck P, Mulder D (1972) Natural history of brachial plexus neuropathy. Arch Neurol 27:109±117 33. van Alfen N, van Engelen BG, Reinders JW, Kremer H, Gabreels FJ (2000) The natural history of hereditary neuralgic amyotrophy in the Dutch population: two distinct types? Brain 123:718±723 34. van Es HW (2001) MRI of the brachial plexus. Eur Radiol 11:325±336 35. Vriesendorp F, Dmytrenko G, Dietrich T, Koski C (1993) Anti-Peripheral Nerve Myelin Antibodies and Terminal Activation Products of Complement in Serum of Patients with Acute Brachial Plexus Neuropathy. Arch Neurol 50:1301±1303 36. Watts GD, O'Briant KC, Borreson TE, Windebank AJ, Chance PF (2001) Evidence for genetic heterogeneity in hereditary neuralgic amyotrophy. Neurology 56:675± 678 37. Watts GJ, O'Briant KC, Chance PF (2002) Evidence of a founder effect and refinement of the hereditary neuralgic amyotrophy (HNA) locus on 17q25 in American families. Hum Genet 110:166±172 38. Wehnert M, Timmerman V, Spoelders P, Meuleman J, Nelis E, Van Broeckhoven C (1997) Further evidence supporting linkage of hereditary neuralgic amyotrophy to chromosome 17q. Neurology 48:1719±1721 39. Wiederholt WC (1974) Hereditary brachial neuropathy. Report of two families. Arch Neurol 30:252±254 40. Windebank A (1993) Inherited recurrent focal neuropathies. In: Dyck P, Thomas P, Griffin J (eds) Peripheral neuropathy, 3rd edn. Saunders, Philadelphia, pp 1137±1148

11 Molecular genetic diagnosis

of hereditary neuropathies G. Kuhlenbåumer

This chapter is divided into two parts. The first provides a link between phenotypic characteristics and molecular genetic tests, allowing the clinician to order the appropriate genetic tests. This part will largely be presented as a decision tree (Fig. 11.1) for HMSN and a table (Table 11.1) listing characteristic and peculiar clinical features of the different forms of hereditary neuropathies and the corresponding most appropriate genetic tests. The second part presents the different molecular genetic testing methods themselves with special emphasis on the different principles used to detect the chromosome 17p CMT1A duplication and HNPP deletion. Ethical issues of molecular genetic testing are dealt with in a separate chapter. Centers offering molecular genetic tests are listed in the appendix of this book.

11.1 Molecular genetic testing strategies If the diagnosis hereditary neuropathy is suspected on the basis of typical clinical features and/or a positive family history, the following questions have to be answered before proceeding to molecular genetic tests: z Is the disease a pure peripheral neuropathy or do patients have additional symptoms or signs? Do they have features of CNS involvement? If CNS symptoms are present, or even prominent, a broad spectrum of other neurological diseases has to be considered, which includes numerous diseases not covered in this book. z Does the neuropathy involve the motor and sensory system (HMSN), is it a pure motor neuropathy (distal HMN) or a predominantly sensory and/or autonomic neuropathy (HSAN)? Hereditary neuropathy with liability to pressure palsy (HNPP) and hereditary neuralgic amyotrophy (HNA) can often be diagnosed on clinical grounds alone. The most important differential diagnosis of HNA is the much more common sporadic form of neuralgic amyotrophy most often manifesting as a monophasic plexopathy. At present, these diseases can only be differentiated by the family history and the usually monophasic course of the sporadic

Fig. 11.1. Ordering the appropriate molecular genetic test: a decision tree based approach

dHMN I dHMN II

(allelic to HMN V)

11.1

z

11.1

180 G. Kuhlenbåumer

11 Molecular genetic diagnosis of hereditary neuropathies

z

Table 11.1. Characteristic clinical features and genetic tests of non-HMSN hereditary peripheral neuropathies Clinical picture/other characteristic features Prominent/exclusive sensory symptoms z Prominent sensory symptoms, but also motor, early onset, sometimes focally folded myelin z Prominent sensory symptoms, but also motor, acral ulcerations z Lancinating pain, painless acral ulcerations, sensory deficit affects mainly pain and temperature z Neonatal onset, sweating, high blood pressure, sensory + motor, Ashkenazi Jews z ªCongenital insensitivity to painº (CIPA), fever, anhidrosis, mental retardation, reduced lifespan Prominent/exclusive motor symptoms z Upper limb preponderance, may be only motor or motor and sensory in the same family z Onset before 20 y, distal weakness, often scoliosis, slow progression z Adult onset, fast progression of distal weakness over *5 years z Congenital/very early onset, diaphragmatic/vocal cord involvement, reduced life expectancy z Early adult onset, prominent hand involvement, vocal cord/diaphragmatic involvement with breathing problems

IH

Form

Gene/Test

AR

CMT4F

PRX

AD

CMT2B

RAB7

AD

HSAN1

SPTLC1

AR

HSAN3

IKBKAP

AR

HSAN4/5

NTRK1

AD

CMT2D/HMN V

GARS

AD

dHMN I

HSPB1/HSP27

AD

dHMN II

HSPB8/HSP22

AR

dHMN VI

IGHMBP2

AD

dHMN VII

DCTN

CMT2D/HMN5

GARS

dHMN VII

DCTN

CMT4C1

LMNA

Predominant upper limb symptoms or upper limb symptoms earlier than lower limb symptoms z Upper limb preponderance, may be only motor AD or motor and sensory in the same family z Early adult onset, prominent hand involvement, AD vocal cord/diaphragmatic involvement with breathing problems Prominent proximal muscle involvement z Prominent proximal muscle involvement, North African families, severe neuropathy

AR

Sensorineural hearing loss or abnormal acoustically evoked potentials z Childhood onset, severe neuropathy, Bulgarian AR CMT4D/HMSN-L NDRG1 Gypsies z CMT with additional CNS signs: AEP abnormal, XCMTX GJB1 VEP abnormal, intellectual imp./cerebellar sy. linked

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Table 11.1 (continued) Clinical picture/other characteristic features

IH

Form

Gene/Test

z Severe, childhood onset, AEP prolonged I±III latency, focally folded myelin

AR

CMT4B1

MTMR2

Central nervous system abnormalities z AEP, VEP, intellectual impairment, cerebellar symptoms, MRI-T2 transient hyperint. possible z Cranial nerve involvement (not known whether of peripheral or central origin)

XCMTX linked AD/AR CMT1D/CMT4E

GJB1 EGR2

Vocal cord paralysis and/or respiratory problems z Early onset, severe neuropathy with vocal cord/ AD/AR CMT4A/CMT4C1 GDAP1 diaphragmatic involvement and wheelchair dependent in second decade z Congenital/very early onset, diaphragmatic/vocal AR dHMN6 IGHMBP2 cord involvement, reduced life expectancy dHMN7 DCTN z Early adult onset, prominent hand involvement, AD vocal cord/diaphragmatic involvement with breathing problems ªRestrictedº to certain ethnic groups z Childhood onset, severe neuropathy, Bulgarian AR Gypsies z Neonatal onset, sweating, high blood pressure, AR sensory + motor, Ashkenazi Jews z CCFDN ± congenital cataracts, facial dysmorphism AR and neuropathy, Wallachian Gypsies Peculiar myelin pathology z Focally folded myelin, severe, childhood onset, AEP prolonged I±III latency z Focally folded myelin, first decade onset z Sometimes focally folded myelin, early onset, prominent sensory symptoms, but also motor z Large cytoplasmic Schwann cell extensions, scoliosis in many patients Miscellaneous z No clinical symptoms, mild NCV slowing only (mNCV *37±42 m/s for median nerve) z Recurrent painless pressure palsies, entrapment syndromes

CMT4D/HMSN-L NDRG1 HSAN3

IKBKAP

CCFDN

CTDP1

AR

CMT4B1

MTMR2

AR AR

CMT4B2 CMT4F

MTMR13=SBF2 PRX

AR

CMT4C

KIAA1985

AD

DI-CMTD

ARHGEF10

AD

HNPP

Chr. 17p deletion

11 Molecular genetic diagnosis of hereditary neuropathies

z

form. A molecular genetic test is not available, because the genetic defect causing HNA is unknown. HNPP can also present with a CMT1-like clinical picture. z Which findings are revealed by the neurophysiological examination? In HMSN: mNCVs above 38±40 m/s argue strongly against the diagnosis CMT1, while mNCVs well below 38±40 m/s support this diagnosis. Intermediate to normal mNCVs are often found in CMTX patients with GJB1 mutations and in patients with certain MPZ mutations. The CMAPs are predominantly reduced in CMT2 but also often in CMT1, particularly in nerves with very low mNCVs. Patients with distal HMN have normal SNAPs and, in most cases, normal mNCVs and CMAPs, despite severe atrophy and signs of denervation in distal muscles on needle EMG examination. z What is the mode of inheritance? If half of the family members in more than one generation are affected, autosomal dominant inheritance with high penetrance is most likely, but X-chromosomal dominant inheritance can only be excluded if male-to-male transmission is present in the family. In some families and at first glance, CMTX might appear to be an X-chromosomal recessive disease, which means that female family members are not obviously affected, but half of their male offspring are. Closer clinical and electrophysiological examination of these female family members usually reveals signs of a mild subclinical neuropathy in CMTX families. Are the parents of the affected persons healthy? If a single child in an otherwise healthy family is affected, three possibilities have to be taken into account: (1) the disease is not heritable, (2) the mode of inheritance is autosomal recessive, (3) the disease is caused by a de-novo mutation. It is important to look for consanguinity of the parents. In our experience, sporadic cases with non-consanguineous parents are more likely to represent de novo mutations than true recessive cases. In contrast, if two or more children of healthy parents are the only affected family members, autosomal recessive mode of inheritance is more likely. z As soon as these questions are answered, focused molecular genetic diagnostic procedures should be applied. The autosomal dominant forms of HMSN are most common. The CMT1A duplication and the HNPP deletion account for the majority of all HMSN patients. Quantitative PCR methods make the molecular diagnosis of the duplication/deletion easier and cost effective. In most cases, the duplication/deletion analysis should be performed first. If no duplication or deletion is found, we proceed in most cases with sequence analysis of the GJB1 and MPZ genes. Only if X-chromosomal inheritance can reliably be excluded on the basis of male-to-male inheritance, the mutation analysis of GJB1 can be skipped. Figure 11.1 presents a more detailed decision tree explaining the molecular diagnostic proceeding for HMSNs. After a series of dichotomous decisions, a series of possible genetic defects/test (in italics and bold print) is pre-

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sented along with peculiar clinical features that can be caused by mutations in the corresponding gene. These features are intended to help choose the appropriate genetic tests. Table 11.1 presents a different view on the same problem. The subheadings (in bold print) present peculiar clinical features followed by a list of neuropathies and their corresponding genetic defects. This table is intended to help the clinician who has seen a patient with a possibly hereditary neuropathy, distinguished by a peculiar symptom or sign, e.g., vocal cord paralysis. All abbreviations, with the exception of the chromosome CMT1A duplication/HNPP deletion, correspond to genes that have to be analyzed for mutations. Nevertheless, the diagnostic and decision making aids presented here can only assist in arriving at the correct diagnosis. One always has to bear in mind that our knowledge about the molecular genetic basis of inherited disease is growing daily and that genotype/phenotype correlations will be subject to permanent refinement and change. In addition to phenotypic variation caused by mutations in different genes and different mutations in the same gene, large phenotypic variation is often even encountered in different patients with the same mutation. This is due to different individual genetic backgrounds and environmental influences. These factors, especially the influence of individual genetic background, are still largely unknown. Known environmental influences are mainly other factors, which might cause or aggravate peripheral neuropathies like diabetes mellitus or certain drugs like vincristin [12]. Applying all the phenotypical and molecular genetic knowledge available today, approximately 75±90% of all hereditary neuropathies can be reliably diagnosed. If despite all efforts a molecular diagnosis cannot be established, this can be due to a number of reasons. The two most important are (1) the defective gene causing the particular phenotype is not yet known. This will most likely hold true if the disease is clearly inherited. (2) The neuropathy is not heritable. This is most likely true in sporadic cases, especially if they present with a pure neuropathy without distinguishing additional features related to a particular genetic disease. Therefore, negative molecular genetic testing results in sporadic cases should prompt an intensive search for other, possibly treatable causes of the neuropathy. If genetic tests are ordered, it is usually desirable for the testing laboratory to have as much clinical information as possible, especially if the referring physician has not decided on a particular set of tests to be performed. The cost of genetic testing, a matter of much concern, is often not as high as suspected by many physicians. The chromosome CMT1A duplication/deletion test is less expensive than, e.g., the costs for a single MRI examination. For these reasons we think that the threshold, especially for chromosome CMT1A duplication/deletion testing should be low, because the incidence of CMT is rather high and this single test will be positive in *70% of all heritable cases with motor and sensory involvement [10].

11 Molecular genetic diagnosis of hereditary neuropathies

z

z Which kind of sample is required for molecular genetic testing? Most laboratories perform all genetic tests for inherited peripheral neuropathies on genomic DNA. Genomic DNA is usually isolated from peripheral blood leukocytes. In most cases, a 10±20 ml EDTA anticoagulated blood sample is appropriate. The blood sample must not be frozen nor refrigerated at any time because many methods are not able to isolate DNA from previously frozen samples. Refrigeration might cause undesirable clotting due to cold agglutinins. The blood sample can be sent to the laboratory by ordinary mail as long as it arrives within approximately four days. A 10 ml blood sample contains enough DNA for PCR based methods as well as Southern-blotting methods. Different sampling methods may be necessary for RNA-based analysis and fluorescence in situ hybridization (FISH). If in doubt, it is always advisable to contact the diagnostic lab before collecting the specimen. Prenatal testing and testing using archival paraffin embedded nerve biopsy material is possible [2, 3, 9].

11.2 Molecular genetic tests 11.2.1 Methods for the detection of the chromosome CMT1A duplication/HNPP deletion In most cases, this duplication encompasses around 1.5 ´ 106 bp and it is therefore too large to be detected with most methods employed to detect point mutations as well as small deletions/duplications and other types of mutations. Methods to detect the latter type of mutations are dealt with in the next section. The CMT1A duplication/HNPP deletion and the molecular architecture of the chromosomal region involved is described in detail in the chapter on ªCMT1Aº. For the understanding of the following methods, it is important to remember that duplication and deletion of the 17p11 region are reciprocal events during meiosis, creating one germ cell with a deletion and the other with a duplication of the 17p11 region. In the next generation, the duplication or deletion are stably inherited. Together with one copy of the unaffected parent, the affected child will have either three copies (CMT1A duplication) or one copy (HNPP deletion) of the duplicated/deleted region. The duplication/deletion arises due to unequal crossing over caused by misalignment of two highly homologous, but not identical regions ± the CMT1A distal and proximal repeat sequences (CMT1A-REPs). The CMT1A-REPs flank the duplicated/deleted chromosomal segment [14]. In some cases, smaller duplications/deletions have been found, but all of them contain the PMP22 gene [27]. Most (*80%) cross-over breakpoints are located within a 3.2 kb hotspot of recombination, which can be further

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refined to an interval of 1.7 kb and to a 741 bp sequence harboring approximately 75% and 60% of all recombinations [6, 17, 26]. Only the principles of the different genetic testing methods will be described, because the methods themselves are too numerous to be described in detail. Further detail can be found in the references or at the website of the European CMT consortium (http://molgen-www.uia.ac.be/CMT/Protocols/DefaultProtocols.cfm). All methods are based on three different principles: z Demonstration of DNA-sequence features unique to the duplication or deletion, e.g., additional restriction fragments. These methods are qualitative, meaning that the result is in most cases the presence or absence of an additional band after DNA electrophoresis. The main advantage of these methods is the unequivocal interpretation of the results. Most of these tests have the disadvantage that not all duplications/deletions are detected. With many of them rare, atypical smaller duplications or deletions are not detectable, because the specific DNA-sequence features, on which a particular test is based, may be absent in smaller duplications/ deletions. In addition, most of these tests require much more DNA than PCR-based quantitative tests and are time consuming and therefore expensive. z Demonstration of a gene dosage difference: These methods are quantitative. They measure the amount of genomic DNA at a given locus within the duplicated/deleted region in comparison to a non-duplicated locus outside the region. CMT1A patients harbor three copies of the PMP22 gene. Therefore, the gene dosage of PMP22 is increased by 50% compared to two copies in normal controls. HNPP patients harbor only one copy. The gene dosage is therefore reduced to one half of that of normal controls. The major disadvantage of all quantitative methods are the problems inherent to quantitative DNA measurement, sometimes resulting in equivocal test results. Today, most of these problems have been overcome by technical advances. z Direct visualization of three copies of the PMP22 gene in CMT1A patients and one copy in HNPP patients by FISH analysis. The CMT1A duplication was originally discovered using Southern blotting and pulsed field gel electrophoresis (PFGE) of genomic DNA as well as short-tandem-repeat (STR) analysis.

z Detection of the chromosome CMT1A duplication/HNPP deletion by pulsed field gel electrophoresis (PFGE) (e.g., [8, 25]) PFGE is a method to separate large DNA fragments (> 100 kb to more than 1 ´ 106 bp). Genomic DNA is digested with rare cutting restriction enzymes and after PFGE and Southern blotting hybridized with specific DNA probes. Methods to detect the CMT1A duplication/HNPP deletion by PFGE

11 Molecular genetic diagnosis of hereditary neuropathies

z

are based on the appearance of specific so called ªjunctionº fragments which are not present in normal controls. These junction fragments are created by the misalignment of the proximal CMT1A-REP of one chromosome with the distal CMT1A-REP of the other chromosome and subsequent crossing over during meiosis. The restriction sites flanking this junction fragment are also rearranged, enabling the detection of novel restriction fragments unique for the duplication or deletion. The main disadvantages of these very reliable methods are that they are time consuming, cumbersome and therefore expensive. They are still widely used in the United States of America by the company Athena diagnostics (Athena diagnostics, Worcester, MA, USA).

z Detection of the chromosome CMT1A duplication/HNPP deletion by Southern blotting of genomic DNA (e.g., [4, 15, 26]) One commonly used method uses digestion of genomic DNA with the restriction enzyme MSP1 followed by Southern transfer and detection with the probe pVAW409R3a, which is located close to the PMP22 gene and always contained in the duplication/deletion [15]. Three different alleles may be detected by this probe (2.8 kb ± 50%, 2.7 kb ± 44% and 1.9 kb ± 6%). Control individuals show two of these alleles, which may be the same or different ones (e.g., 2 ´ 2.8 kb = one band of 2.8 kb or 1 ´ 2.8 kb and 1 ´ 2.7 kb = 2 bands). Duplicated individuals show three alleles. The diagnosis is straightforward if three different alleles are present. If only two alleles are present, one of them shows a hybridization signal, which is twice as strong as the one of the other allele because it is represented in two copies. If only one allele is present, the hybridization signal is even stronger, but there is no other band to compare it with. In this case, the signal may be compared to that of a second unrelated probe, which recognizes a nonpolymorphic fragment outside the duplicated region. If the HNPP deletion is present, only one allele will be seen and comparison to the signal of a second unrelated probe is also necessary. The disadvantage of this method is that it relies in most cases on dosage difference. The analysis of dosage differences are subject to a number of technical influences and may be difficult to detect and interpret. The formation of unique junction fragments during the formation of the CMT1A duplication/HNPP deletion has been discussed above. This region carries restriction sites not present in the normal controls and can therefore be recognized by the presence of a specific novel fragment on hybridization of Southern blots with a probe derived from the CMT1A-REP region after digestion with appropriate restriction enzymes [26]. Unfortunately, the crossover does not always occur in the same place and depending on the method (enzymes and probes) junction fragments are not always detected. In these cases, the method has to rely again on dosage differences.

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z Detection of the chromosome CMT1A duplication/HNPP deletion by PCR methods employing special characteristics of the CMT1A repeat region (e.g., [22, 23])

These methods use PCR amplification of the 3.2 kb hotspot of recombination either alone or in combination with restriction digestion to demonstrate special features of the junction region on subsequent electrophoretic analysis. The main disadvantage of these methods is that only about 80% of cross-over breakpoints are located in this region restricting the sensitivity of these assays to a maximum of 80%. Advantages are simplicity and low cost.

z Detection of the chromosome CMT1A duplication/HNPP deletion by short-tandem-repeat (STR) analysis (e.g., [1, 5, 20]) STRs are di-, tri- and tetranucleotide repeats that are polymorphic due to different repeat length. These repeats are often highly polymorphic with 2?20 different alleles. The duplication is detected by the presence of three alleles of a particular STR located in the duplicated region, while the deletion is detected by hemizygosity of a number of markers in the deleted region. The sensitivity of the test depends on the heterozygosity and the number of markers used for the analysis. Recently published STR-marker panels of approximately 15 STRs are able to detect > 99% of all duplications. The detection of the HNPP deletion has to rely on statistical methods, calculating the likelihood that a certain number of seemingly homozygous (in reality hemizygous) STR markers occurred by chance versus the likelihood that they occurred because of the HNPP deletion, because homozygosity and hemizygosity of an STR marker cannot be reliably distinguished. The advantages of these tests are unequivocal readouts of the results and high sensitivity if the recently developed marker panels are used.

z Detection of the chromosome CMT1A duplication/HNPP deletion by fluorescent in situ hybridization on chromosome preparations (e.g., [16, 21]) FISH methods use in most cases hybridization of fluorescently labeled DNA probes encompassing the PMP22 gene. A number of variations exist. All methods directly visualize the presence of the duplication and deletion by the presence of an additional or missing hybridization signal. The main advantage of this method is the direct and unequivocal visualization of the results. Its main disadvantages are that it is comparatively time consuming, expensive and requires special equipment and expertise not present in many laboratories.

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z Detection of the chromosome CMT1A duplication/HNPP deletion by quantitative PCR assays (e.g., [7, 28, 30]) Quantitative PCR assays show gene dosage differences of the PMP22 gene itself. A number of different quantitative PCR assays exist that demonstrate 150% of the PMP22 gene dosage of normal controls in CMT1A patients and 50% of the normal gene dosage in HNPP patients. Modern methods developed in recent years mostly use so called real-time quantitative PCR methods. While these methods were initially mistrusted by many, they have in the meantime proven their sensitivity, reliability and efficiency. The major disadvantage are ambiguous results in some patients, which have to be reanalyzed by a different method. Major advantages are the high speed and relatively low price of most of these assays. Currently, the use of two different independent methods is regarded as the gold standard for the diagnosis of the CMT1A duplication/HNPP deletion.

11.2.2 Mutation detection methods for other genetic defects causing hereditary neuropathies All other genetic defects known to cause hereditary peripheral neuropathies are either point mutations or small rearrangements ± mostly duplications/deletion of one to a few bases ± which can be detected by ªconventionalº mutation detection methods which are also applicable to many other heritable diseases. The methodological details will not be discussed, because they are described in detail in standard textbooks of molecular genetics and laboratory methods [18]. All the following methods may either be used to analyze genomic DNA or cDNA generated by reverse transcription of the patient's RNA. For all genes known to be defective in hereditary neuropathies, mutation analysis on genomic DNA is usually preferred. Only three out of many mutation detection methods will be described here. They were chosen because they are widely used and are good examples to demonstrate the advantages and disadvantages of different methods. All methods presented here require amplification of the target sequences by polymerase chain reaction (PCR) prior to mutation analysis.

z Direct DNA-sequencing Today direct DNA-sequencing is (nearly) exclusively performed by the Sanger Dideoxy method [19]. Advantages of direct DNA sequencing are (1) very high sensitivity and (2) direct detection of the causative mutation. All other methods presented below screen only for the presence of a mutation in the target sequence but require subsequent DNA sequencing of positive samples to identify the exact mutation. Disadvantages of direct DNA se-

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quencing are that it is (1) more expensive and (2) slower than screening methods. These disadvantages play an important role if the yield of mutations is small compared to the number of samples. Another disadvantage (3): DNA sequences of patients still have to be compared visually to sequences of normal controls, because highly reliable automated mutation detection algorithms able to detect all visually detectable heterozygous mutations do not yet exist. This work is time-consuming and monotonous but requires at the same time a high amount of concentration, making it prone to examiner mistakes. PCR amplified DNA fragments of up to 400±600 bp can be reliably analyzed in a single sequencing reaction. It is essential to sequence both strands of the target DNA.

z Single strand conformational polymorphism (SSCP) analysis [13] Single stranded DNA adopts under nondenaturing conditions unique conformations dependent on its base sequence. In most cases, even single base changes introduce conformational changes that can be detected in PCR amplified target fragments of up to 200±300 bp by nondenaturing polyacrylamide (PAA) gel electrophoresis and subsequent silver staining of the gel. The major disadvantages of this so called single strand conformational polymorphism (SSCP) analysis are (1) the sensitivity of SSCP concerning point mutations is not higher than 70±80% at the most. (2) The reliability decreases with increasing size of the target fragment [11]. Small target fragments of not more than 250 bp are optimal. (3) SSCP positive samples require subsequent sequencing to identify the exact mutation. The main advantages of SSCP are its low price, speed and relatively easy handling. In our opinion SSCP should not be used anymore in the diagnostic setting, because negative results do not reliably exclude mutations.

z Denaturing high performance liquid chromatography (DHPLC) DHPLC is a relatively novel and highly sensitive mutation detection method [29]. It is based on the ability of a novel chromatography matrix to separate heteroduplex DNA molecules (= double stranded DNA with a single base pair mismatch) from homoduplex DNA molecules. PCR amplified DNA is first heat denatured and then slowly cooled to room temperature to allow heteroduplex formation if a mutation in one allele is present. The PCR product is heated again close to its melting temperature and separated on the column by elution with increasing concentrations of organic solvent. The sensitivity of DHPLC is highly dependent on the optimization of the DHPLC process with as many known mutations as possible, rendering it less suitable if DNAs with known mutations are not available in the lab or if the sample numbers are low. The main advantages are its low operating costs, the high sensitivity (> 95%) and the possibility to use fairly large PCR products up to 700±1000 bp [24].

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References 1. Badano JL, Inoue K, Katsanis N, Lupski JR (2001) New polymorphic short tandem repeats for PCR-based Charcot-Marie-Tooth disease type 1A duplication diagnosis. Clin Chem 47:838±843 2. Beckmann A, Schræder JM (2000) Screening for Charcot-Marie-Tooth type 1A and hereditary neuropathy with liability to pressure palsy in archival nerve biopsy samples by direct-double-differential PCR. Acta Neuropathol (Berl) 100:459±463 3. Bernard R, Labelle V, Negre P, Tardieu S, Azulay JP, Malzac P et al (2000) Prenatal detection of a 17p11.2 duplication resulting from a rare recombination event and novel PCR-based strategy for molecular identification of Charcot-Marie-Tooth disease type 1A. Eur J Hum Genet 8:229±235 4. Chance P, Alderson M, Leppig K, Lensch M, Matsunami N, Smith B et al (1993) DNA deletion associated with hereditary neuropathy with liability to pressure palsies. Cell 72:143±151 5. Latour P, Boutrand L, Levy N, Bernard R, Boyer A, Claustrat F et al (2001) Polymorphic short tandem repeats for diagnosis of the Charcot-Marie-Tooth 1A duplication. Clin Chem 47:829±837 6. Lopes J, Ravis N, Vandenberghe A, Palau F, Ionasescu V, Mayer M et al (1998) Fine mapping of de novo CMT1A and HNPP rearrangements within CMT1A-REPs evidences two distinct sex-dependent mechanisms and candidate sequences involved in recombination. Hum Mol Genet 7:141±148 7. Lorentzos P, Kaiser T, Kennerson ML, Nicholson GA (2003) A rapid and definitive test for Charcot-Marie-Tooth 1A and hereditary neuropathy with liability to pressure palsies using multiplexed real-time PCR. Genet Test 7:135±138 8. Lupski J, de Oca-Luna R, Slaugenhaupt S, Pentao L, Guzzetta V, Trask B et al (1991) DNA duplication associated with Charcot-Marie-Tooth disease type 1A. Cell 66:219±232 9. Navon R, Timmerman V, Læfgren A, Liang P, Nelis E, Zeitune M et al (1995) Prenatal diagnosis of Charcot-Marie-Tooth disease type 1A (CMT1A) using molecular genetic techniques. Prenat Diagn 15:633±640 10. Nelis E, Van Broeckhoven C, De JP, Læfgren A, Vandenberghe A, Latour P et al (1996) Estimation of the mutation frequencies in Charcot-Marie-Tooth disease type 1 and hereditary neuropathy with liability to pressure palsies: a European collaborative study. Eur J Hum Genet 4:25±33 11. Nelis E, Warner L, De Vriendt E, Chance P, Lupski J, Van Broeckhoven C (1996) Comparison of single-strand conformation polymorphism and heteroduplex analysis for the detection of mutations in Charcot-Marie-Tooth type 1 disease and related peripheral neuropathies. Eur J Hum Genet 4:329±333 12. Neumann Y, Toren A, Rechavi G, Seifried B, Shoham NG, Mandel M et al (1996) Vincristine treatment triggering the expression of asymptomatic Charcot-MarieTooth disease. Med Pediatr Oncol 26:280±283 13. Orita M, Suzuki Y, Sekiya T, Hayashi K (1989) Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction. Genomics 5:874±879 14. Pentao L, Wise C, Chinault A, Patel P, Lupski J (1992) Charcot-Marie-Tooth type 1A duplication appears to arise from recombination at repeat sequences flanking the 1.5 Mb monomer unit. Nat Genet 2:292±300 15. Raeymaekers P, Timmerman V, Nelis E, De Jonghe P, Hoogendijk JE, Baas F et al (1991) Duplication in chromosome 17p11.2 in Charcot-Marie-Tooth neuropathy type 1a (CMT 1a). The HMSN Collaborative Research Group. Neuromuscul Disord 1:93±97

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16. Rautenstrauss B, Fuchs C, Liehr T, Grehl H, Murakami T, Lupski J (1997) Visualization of the CMT1A Duplication and HNPP Deletion by FISH on Stretched Chromosome Fibers. JPNS 2:319±322 17. Reiter L, Murakami T, Koeuth T, Pentao L, Muzny D, Gibbs R et al (1996) A recombination hotspot responsible for two inherited peripheral neuropathies is located near a mariner transposon-like element. Nat Genet 12:288±297 18. Sambrook J, Fritsch EF, Maniatis T (2000) Molecular cloning: a laboratory manual, 3rd edn. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY 19. Sanger F, Nicklen S, Coulson AR (1977) DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci 74:5463±5467 20. Seeman P, Mazanec R, Zidar J, Hrusakova S, Ctvrteckova M, Rautenstrauss B (2000) Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP): reliable detection of the CMT1A duplication and HNPP deletion using 8 microsatellite markers in 2 multiplex PCRs. Int J Mol Med 6:421±426 21. Shaffer LG, Kennedy GM, Spikes AS, Lupski JR (1997) Diagnosis of CMT1A duplications and HNPP deletions by interphase FISH: implications for testing in the cytogenetics laboratory. Am J Med Genet 69:325±331 22. Stronach EA, Clark C, Bell C, Læfgren A, McKay NG, Timmerman V et al (1999) Novel PCR-based diagnostic tools for Charcot-Marie-Tooth type 1A and hereditary neuropathy with liability to pressure palsies. J Peripher Nerv Syst 4:117±122 23. Tachi N, Kozuka N, Ohya K, Chiba S (1999) Charcot-Marie-Tooth disease type 1A duplication by PCR analysis. Pediatr Neurol 20:360±363 24. Takashima H, Boerkoel CF, Lupski JR (2001) Screening for mutations in a genetically heterogeneous disorder: DHPLC versus DNA sequence for mutation detection in multiple genes causing Charcot-Marie-Tooth neuropathy. Genet Med 3:335±342 25. Timmerman V, Læfgren A, Le Guern E, Liang P, De Jonghe P, Martin J et al (1996) Molecular genetic analysis of the 17p11.2 region in patients with hereditary neuropathy with liability to pressure palsies (HNPP). Hum Genet 97:26±34 26. Timmerman V, Rautenstrauss B, Reiter L, Koeuth T, Læfgren A, Liehr T et al (1997) Detection of the CMT1A/HNPP recombination hotspot in unrelated patients of European descent. J Med Genet 34:43±49 27. Valentijn LJ, Baas F, Zorn I, Hensels GW, de Visser M, Bolhuis PA (1993) Alternatively sized duplication in Charcot-Marie-Tooth disease type 1A. Hum Mol Genet 2:2143±2146 28. Wilke K, Duman B, Horst J (2000) Diagnosis of haploidy and triploidy based on measurement of gene copy number by real-time PCR. Hum Mutat 16:431±436 29. Xiao W, Oefner PJ (2001) Denaturing high-performance liquid chromatography: A review. Hum Mutat 17:439±474 30. Young P, Stægbauer F, Wiebusch H, Læfgren A, Timmerman V, Van Broeckhoven C et al (1998) PCR-based strategy for the diagnosis of hereditary neuropathy with liability to pressure palsies and Charcot-Marie-Tooth disease type 1A. Neurology 50:760±763

12 Genetic counseling M. Hoeltzenbein

Introduction The number of genes known to be involved in pathogenesis of peripheral neuropathies is increasing rapidly. At the same time more and more, mostly exceedingly rare, disease entities and their genetic causes are discovered. Genetic conditions are different from other medical diagnoses as they might imply risks to other family members as well as to unborn children. In addition, a genetic diagnosis is permanent and currently often untreatable or incurable. In order to meet the specific needs and demands of patients and their relatives, a close collaboration between neurologists, clinical geneticists and molecular diagnostic laboratories is necessary. This chapter on genetic counseling was written based on the experience of the author in clinical genetics at university hospitals in Germany and therefore mainly reflects the situation in Germany.

12.1 Definition of genetic counseling and consequences The term genetic counseling was introduced in 1947 to describe the relationship between clinical geneticists and those to whom they provide information about the etiology, natural history, and recurrence risks of hereditary disorders [14]. In 1975 the American Society of Human Genetics defined genetic counseling as ªa communication process which deals with the human problems associated with the occurrence, or the risk of occurrence, of a genetic disorder in a family. This process involves an attempt by one or more appropriately trained persons to help the individual or family to z Comprehend the medical facts, including the diagnosis, probable course of the disorder, and the available management, z Appreciate the way heredity contributes to the disorder, and the risk of recurrence in specified relatives, z Understand the alternatives for dealing with the risk of recurrence, z Choose the course of action which seems to them appropriate in view of their risk, their family goals, and their ethical and religious standards, and to act in accordance with that decision, and

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z Make the best possible adjustment to the disorder in an affected family member and/or to the risk of recurrence of that disorder.º [1] Especially with respect to genetic diagnosis consequent implementation of these guidelines for practical genetic counseling means z Genetic counseling has to be voluntary for the client, z All diagnostic tests should be preceded by individual counseling, z Prenatal diagnostic testing does not preclude termination of pregnancy in case of a pathological result, and z Family planning and reproductive decisions are entirely in the hands of the consulters [4, 11]. Genetic counseling is provided by clinical geneticists. Access to genetic counseling is open to everybody interested in or at risk of a genetic disorder. Persons seeking such advice are called counselees or clients. The main reasons for referral to a department of medical genetics are z Diagnosis or risk of a genetic disease in the consulter or in a relative, z Congenital birth defects, z Mental retardation, z Down syndrome or other chromosomal alterations, z Frequent miscarriages or previous stillbirth, z Advanced maternal age, and z Request of information on possibilities of prenatal diagnostics.

12.2 Course and general principles of genetic counseling Genetic counseling of patients with neurologic diseases is often performed when a molecular diagnosis is wanted or the results of genetic tests have to be discussed. Even if there is no possibility of genetic confirmation of a disease, counseling can be important to explain risk figures in case of a clearly inherited disorder or a high probability of a genetic disease. Genetic counseling starts with careful listening to the family's wishes or concerns. A construction of a three-generation pedigree is followed by taking medical history, additional clinical assessments or initiation of investigations. After reviewing medical records and gathering necessary information about the family history, further diagnostic options like molecular testing are discussed. Frequently, a diagnosis has to be searched for over a longer period of time in clinical genetics. Finally, after diagnosis and confirmation of etiology all biological and medical facts including the relevance and consequences for the family can be discussed with the client. Accurate diagnosis and knowledge about etiology is of utmost importance for further genetic counseling. It is generally agreed upon that contact to other family members at risk should not be made directly by the counselor, but only through the client

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himself. Clients often feel guilty or stigmatized after diagnosis of a genetic disease in the family and it is important to recognize and allay this apprehension. In addition, common misconceptions on heredity may also need to be resolved. For about 30 years non-directiveness has remained central to the practice of genetic counseling, particularly when issues of family planning and reproductive decisions are being made in order to prevent consulters from taking over pre-determined decisions from their counselors. However, during recent years it became more and more evident that strict employment of the term non-directiveness is not always possible, on the other hand not always helpful or wanted in the counseling process [15]. In addition, surveys suggest that, regardless of the mode of genetic counseling, the encounter fails to alter previously made reproductive decisions [9]. Therefore, it has been recommended to acknowledge the autonomy of the individual and interpret non-directiveness in a broader sense.

12.3 Diagnostic/molecular testing Whereas initially molecular analysis of neurologic diseases was only performed in departments of medical genetics, more and more molecular laboratories are set up in departments of neurology for research purpose, performing molecular analysis of their own patients. In contrast to Huntington's disease, where clinical diagnosis can be confirmed by detection of the trinucleotide expansion, the situation for the hereditary neuropathies is different. Genetic heterogeneity and mutations in different genes that can often be associated with a remarkable phenotypic overlap often necessitate analysis of several genes, before the disease causing mutation can be identified. Based on the family history and neurological findings, including nerve conduction and EMG studies, molecular genetic testing can be initiated after informed consent of the patient. This is easily possible for the frequent HMSN I/CMT1 with about 70% of affected patients carrying a duplication of a part of chromosome 17p and also for CMTX caused by mutations in the small gene encoding the gap junction protein beta 1 (GJB1) [7]. Mutation or linkage analysis of other known genes involved in recessive and dominant CMT diseases can in most cases be offered either on a diagnostic or on a research basis now.

12.3.1 Predictive testing of late-onset disorders Genetic analysis of a person at risk for a late-onset disease will allow a statement about the future risk to develop a certain disease. Experiences gained with predictive testing in Huntington's disease have been suggested to be a model for the study of other late-onset disorders. International

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guidelines have been developed and found useful by patients or at risk persons [8]. Detailed counseling by an experienced geneticist is required and psychosocial support is usually offered before genetic testing can be performed in late-onset disorders. Pfeiffer et al. [12] asked adult patients with HMSN I/CMT1 for their relevant disability and found a similar psychosocial burden as patients with stroke and a similar disability. Of the interviewed patients with HMSN I/ CMT1, 36% voted against childbearing, if the prospective child would have a similar disability. Due to the broad spectrum of clinical symptoms, general guidelines for counseling patients with hereditary peripheral neuropathies cannot be given. For most autosomal-dominantly inherited neuropathies, the situation is often different from Chorea Huntington. Symptoms might already be present in young adults and nerve conduction studies would usually reveal, if a person at risk is affected or not, so that molecular analysis in this situation would no longer be a predictive test. Parents often ask for testing of their healthy children and it is important to understand and think about their needs. Among geneticists, there is currently a consensus that children should not be tested for late-onset neurological disorders in the absence of treatment or prophylactic measurements and that this decision should be deferred until the individual is of sufficient intellectual and emotional maturity [2]. However, if the child has a disorder that requires a diagnosis, genetic testing might be the most appropriate investigation. For further details on predictive testing referring to the ªStellungnahme zur postnatalen prådiktiven genetischen Diagnostikº [10] and ªRichtlinien zur prådiktiven genetischen Diagnostik der Bundesårztekammerº [3], or similar documents published by the association of medical geneticists of the respective countries is recommended.

12.3.2 Prenatal testing Prenatal testing has been developed and is employed mainly for early onset and untreatable diseases with severe mental and/or physical disability. As a prerequisite accurate diagnosis and direct or indirect molecular or biochemical test options have to be available. Routinely performed is chorionic villus sampling at about 12 weeks and amniocentesis around 16 weeks of pregnancy. Both procedures have a small risk of miscarriage. Therefore, it is very important to offer counseling already before a planned pregnancy. Requests for prenatal testing for typically adult-onset conditions such as autosomal-dominant or X-linked neuropathies are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination. Although most centers would consider decisions about prenatal testing to be the choice of the parents, careful discussion of these issues is appropriate.

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12.3.3 Preimplantation diagnostics Prenatal diagnosis of CMT1A might be a difficult issue for future parents. In order to avoid termination of pregnancy in case of an affected child, in some countries preimplantation diagnosis for CMT1A is offered and has been performed in individual cases [6]. However, preimplantation diagnosis is not allowed in Germany at the moment, although there is an ongoing discussion about this.

12.4 Special issues of genetic counseling A major task for clinical genetics is dealing with neuropathies as one feature of a complex disease associated with further symptoms. These could be specific syndromes that are associated with further symptoms like Fabry's disease or Refsum's syndrome or new disease entities or other complex phenotypes not yet classified, like neuropathies with X-linked mental retardation or deafness [13]. Cytogenetic aberrations, which are not routinely detected by molecular analysis, should be excluded in the presence of mental retardation or frequent miscarriages in the affected patient or his family. For example, larger duplications of chromosome 17p11 might cause a more severe phenotype with mental retardation. In addition, balanced chromosomal rearrangements like translocations or inversions segregating with a specific neuropathy in a family would allow further molecular-cytogenetic work up and finally identification of a the disease causing gene [5].

References 1. Ad Hoc Committee on Genetic Counseling (1975) Am J Hum Genet 27:240±241 2. American Academy of Pediatrics: Committee on Bioethics (2001) Ethical Issues with genetic testing in pediatrics. Pediatrics 107:1451±1455 3. Bekanntmachungen der Bundesårztekammer (2003) Richtlinien zur prådiktiven genetischen Diagnostik. Dtsch Ørztebl 6 A:277±285 4. Berufsverband Medizinische Genetik eV (1996) Leitlinien zur Erbringung humangenetischer Leistungen: 1. Leitlinien zur Genetischen Beratung. Medgen 8, Sonderbeilage, pp 1±2 5. Bugge M, Bruun-Petersen G, Brondum-Nielsen K, Friedrich U, Hansen J, Jensen G, Jensen PK, Kristoffersson U, Lundsteen C, Niebuhr E, Rasmussen KR, Rasmussen K, Tommerup N (2000) Disease associated balanced chromosome rearrangements: a resource for large scale genotype-phenotype delineation in man. J Med Genet 37:858±865 6. De Vos A, Sermon K, Van de Velde H, Joris H, Vandervorst M, Lissens W, Mortier G, De Sutter P, Lofgren A, Van Broeckhoven C, Liebaers I, Van Steirteghem A

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7. 8.

9. 10. 11. 12. 13. 14. 15.

(1998) Pregnancy after preimplantation genetic diagnosis for Charcot-Marie-Tooth disease type 1A. Mol Hum Reproduction 4:978±984 Europåische Leitlinien zur molekulargenetischen Diagnostik der Charcot-MarieTooth'schen Erkrankung des Typs 1A sowie der tomakulæsen Neuropathie (2001) Medgen 13:309±314 International Huntington Association (IHA) and the World Federation of Neurology (WFN) Research Group on Huntington's Chorea (1994) Guidelines for the molecular genetics predictive test in Huntington's disease. Neurology 44:1533± 1536 Kessler S (1992) Psychological aspects of genetic counseling VII: Thoughts on directiveness. J Genet Counsel 1:9±17 Kommission fçr Úffentlichkeitsarbeit und ethische Fragen der Gesellschaft fçr Humangenetik e.V. (2000) Stellungnahme zur postnatalen prådiktiven genetischen Diagnostik. Medgen 12:376±377 Murken J, Cleve H (1996) Humangenetik, 6th edn. Enke, Stuttgart Pfeiffer G, Wicklein EM, Ratusinski T, Schmitt L, Kunze K (2001) Disability and quality of life in Charcot-Marie-Tooth disease type 1. J Neurol Neurosurg Psychiatry 70:548±550 Priest JM, Fischbeck KH, Nouri N, Keats BJ (1995) A locus for axonal motor-sensory neuropathy with deafness and mental retardation maps to Xq24-q26. Genomics 29:409±412 Reed S (1975) A short history of genetic counseling. Soc Biol 21:332±339 Wolff G, Jung C (1995) Nondirectiveness and genetic counseling. J Genet Counseling 4:3±25

13 Medical treatment

of hereditary neuropathies P. Young

Introduction The clinical features of inherited neuropathies are either caused by demyelination of the peripheral nerve and the consecutive axonal degeneration, or by the primary axonal damage caused by the specific genetic defect. The types of neurological deficits depend on the neurologic system that is predominantly affected and might be either motor, sensory or autonomic [37]. Although we have learned much about the molecular genetic basis of inherited neuropathies over the last 15 years, the biological consequences of the specific genetic alteration remain largely uncovered so far [23]. Furthermore, the glial-axonal interactions which may be disturbed by specific mutations are in most forms of inherited neuropathies not sufficiently understood to serve as a basis for therapeutic interventions. Up to now, causative treatment approaches could not be developed for any form of inherited neuropathy [33]. Based on theoretical and experimental considerations, some trials were undertaken using either antioxidant or immunomodulating agents [33]. The outcome was measured by using clinical scales or electrophysiological methods to evaluate progression of the peripheral neuropathy. These trials were mainly performed in small groups of patients suffering from the most frequent form of inherited neuropathies, the Charcot-Marie-Tooth disease type 1 (CMT1A) which is caused by a duplication on chromosome 17p11.2 harboring the peripheral myelin protein 22 gene (PMP22). The most prominent symptom in all forms of inherited neuropathies is the progressive wasting of distal muscles, especially the peroneal muscles, and the small intrinsic muscles of the feet resulting in weakness while walking and, in the majority of cases, in foot deformities. Sensory symptoms include tingling, burning or aching of feet, legs and sometimes hands. The autonomic system is not primarily affected; thus, autonomic dysfunction is not associated with CMT1. Erectile dysfunction may also be present due to progressive involvement of motor and sensory nerves (e.g., pudendal nerve). CMT2 and CMTX do not differ from CMT1 concerning these main features. However, the severity of symptoms can differ between the subtypes.

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Table 13.1. Medical treatment Medical treatment in humans Agent z Corticosteroids z Lipoic acid in CMT1 z Vitamin E in CMT1

Comment [reference] No significant improvement in CMT1 [12] Slight effect on motor deficit [15, 16, 36]

Experimental treatment in animal models z Neurotrophin3 in P0 mutant mice Decreased demyelination [19] z Progesterone antagonist in PMP22 Improvement in behavioral tests, decreased overexpressing rats demyelination, reduction of PMP22 mRNA overexpression [34] z Vitamin C in PMP22 overexpressing mice Improvement in behavioral tests, improvement of nerve conduction velocity [30] z RNA interference Not evaluated in vivo in mice [3,10]

A summary of treatment approaches in humans and experimental animals is given in Table 13.1.

13.1 Causative therapy 13.1.1 Genetic treatment Attempts to treat the underlying genetic defects in CMT have to face some principal considerations as the aim should be either to correct gene dosage or to correct the change of function caused by the mutated gene, which may either be a loss of function or a toxic gain of function. Further, genetic therapeutical approaches have to overcome the poor accessibility of the PNS at the right time point [38] before demyelination or primary or secondary axonal degeneration has started. The most frequent form of inherited neuropathies is CMT1A. This syndrome is caused by the overexpression of PMP22 protein in Schwann cells resulting in an impaired trafficking and accumulation of intracellular PMP22 protein [26, 27]. Thus, a reduction of the overexpression of PMP22 could be an aim of therapeutic approaches since it was shown in mice that the demyelinating phenotype can be reversed if the expression of PMP22 is normalized [31]. But how can normalization of inborn PMP22 overexpression be achieved?

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z RNA interference Small interfering RNAs (siRNAs) were shown to block translation in vitro and in vivo [3, 10]. Thus, it may be possible to regulate cellular PMP22 expression by using siRNAs aimed at reducing PMP22 overexpression. Experimental data showing successful use of siRNAs in the PNS are still lacking. Many unsolved problems have to be taken into account like the manner of administering siRNAs in vivo and how to ensure that the peripheral nerve and especially the Schwann cells are specifically targeted by the siRNAs. Furthermore, PMP22 is a dosage sensitive gene meaning that iatrogenic underexpression implicates the risk of a pathological state as seen in hereditary neuropathy with liability to pressure palsy (HNPP) caused by the loss of one allele of PMP22 [22].

z Adenoviral gene transfer It was shown that by using adenoviral vectors as potential vehicles to reach Schwann cells of the PNS in vivo [19] strong incurable immune responses as seen after adenoviral injection can be circumvented. However, appropriate gene constructs are lacking and future clinical approaches have not been established. Suitable animal models will help to develop adenoviral approaches further.

13.1.2 Prevention of axonal degeneration The pathobiological hallmarks of hereditary neuropathies are either demyelination and secondary axonal damage, or primary axonal loss with consecutive muscle atrophy. Medical treatment could aim at preventing the axon from degenerating [24]. Another aim in therapeutic approaches could be the rescue of the axon and possibly the neuron, too [8]. Survival of the demyelinated axon resulting in reduced progression of muscular atrophy and paresis would be an approach of choice in several forms of hereditary neuropathies in which demyelination is the primary pathogenetic step.

z Neurotrophic factors Several neurotrophic factors are known to rescue neurons and their axons from degeneration [17]. The usefulness of neurotrophic factors to prevent axonal degeneration was shown by adenoviral transfer of neurotrophin3 in MPZ deficient mice [19]. Local application like intramuscular injection was shown to be efficient in reducing progressive motor neuropathy in a mouse model for spinal muscular atrophy [35]. Therapeutic problems resulting from systemic use are not solved. One has to take into account that systemic application of neurotrophic factors may have severe side effects which can be more harmful than the symptoms of hereditary neuropathies.

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As it was shown in the development of therapeutic strategies in amyotrophic lateral sclerosis (ALS), the systemic use of brain derived neurotrophic factors had unpredictable side effects [28].

z Antioxidant reagents There are a few reports in which antioxidants were used in patients suffering from CMT1 and CMT2 [15, 16, 36]. The rationale for this approach was to prevent the axon from degeneration by reducing oxidative stress. The size of these studies is too small to show that these therapeutic strategies can be used as a standard therapy in CMT syndromes. As antioxidant reagents, lipoic acid and vitamin E were used analogous to the treatment of ALS [2]. Therapy with vitamin C has become a new perspective based on the observation that a mouse model of CMT1A improved significantly under high dosage vitamin C treatment. In how far this therapy regimen is successful in humans suffering from CMT1A has to be evaluated in future studies [30].

z Immunotherapeutics In the early 1980s, two small studies evaluated the benefit of corticosteroids in CMT1 patients [12]. These studies showed no consistent results regarding the improvement of CMT1 symptoms in these patients. Temporary improvement was not stable and muscle wasting could not be stopped by the treatment regimen used. Further studies have not been initiated so far. Recently, the observation that, in CMT1B and CMTX mouse models, the immune system has an influence on the degree of demyelination [6, 25] led to the question if suppression of the immune system could improve the symptoms of patients suffering from CMT1B caused by mutations in MPZ and CMTX patients carrying mutations in GJB1. Up to now no studies have been started.

z Progesterone antagonists In a rat model of CMT1A, it was shown that the use of the progesterone antagonist onapristone reduced demyelination and even improved histopathological changes [34]. This improvement could be correlated with the reduction of PMP22 mRNA and protein. Besides morphological improvements behavioral tasks were also improved, giving hope that clinically detectable parameters of patients with hereditary neuropathies might improve as well. Although using progesterone antagonists in human CMT1A syndrome is still at the first step, it is feasible to think about using it in selected patients [5, 9].

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13.2 Symptomatic therapy 13.2.1 Neuropathic pain As for acquired neuropathies, membrane stabilizing (antiepileptic) drugs like gabapentin and carbamazepine can also be used to reduce neuropathic pain in patients suffering from inherited neuropathies. Furthermore, antidepressive agents such as desipramine, amitriptyline and a number of other agents can be used to reduce neuropathic pain in patients with hereditary neuropathies [11]. The response of patients suffering from different forms of hereditary neuropathies has not yet been evaluated in controlled studies. Recommended dosages are equivalent to the dosages used in acquired neuropathies like diabetic or paraneoplastic neuropathies [29].

13.2.2 Autonomic dysfunction Autonomic dysfunction is the main feature of hereditary sensory and autonomic neuropathies (HSAN), but patients with a HMSN/CMT syndrome may in some cases also suffer from moderate autonomic dysfunction. The most frequent autonomic symptom in patients with HMSN/CMT is erectile dysfunction. Besides hereditary neuropathies which affect mainly the autonomic nervous system like HSAN/HSN, patients with a HMSN/CMT syndrome also rarely suffer from moderate autonomic dysfunction. The therapy of erectile dysfunction in patients with hereditary neuropathies does not differ from therapies in patients with other neuropathies, e.g. diabetic neuropathy. Phosphodiesterase-5 inhibitors like sildenafil and its derivates are medications of choice with regard to possible contraindications and side effects [4, 7, 20]. In CMTX, excessive sweating can be observed in some patients. Like in noninherited neuropathies, local injections of botulinum toxin is the therapy of choice [21, 32]. Botulinum toxin should be used by physicians who are experienced in its administration. Side effects like initial weakness of arm muscles after axillary injection should be monitored carefully.

13.2.3 Surgery of foot deformities Some CMT syndromes are associated with foot deformities which lead to further immobilization. Especially early manifestation of pes cavus and shortened Achilles tendon can lead to severe handicaps reducing mobility in young patients. Thus, besides conservative orthopedic treatment, surgery of foot muscles and tendons of leg muscles may be an appropriate method. After completion of length growth in adolescence, orthopedic surgery can be recommended for achieving better stability and improvement of walking [13,

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14, 18]. Some studies were published showing a clear benefit from surgical correction of foot deformities in different CMT syndromes if associated with pes cavus [28]. Further details can be found in chapter 14 in this book.

References 1. The BDNF study group. (Phase 3) (1999) A controlled trial of recombinant methionyl human BDNF in ALS. Neurology 52:1427±1433 2. Bains JS, Shaw CA (1997) Neurodegenerative disorders in humans: the role of glutathione in oxidative stress-mediated neuronal death. Brain Res Brain Res Rev 25:335±358 3. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281±297 4. Bella AJ, Brock GB (2003) Tadalafil in the treatment of erectile dysfunction. Curr Urol Rep 4:472±478 5. Bradbury J (2004) Antiprogesterone hope for inherited neuropathy. Lancet Neurol 3:6 6. Carenini S, Maurer M, Werner A, Blazyca H, Toyka KV, Schmid CD, Raivich G, Martini R (2001) The role of macrophages in demyelinating peripheral nervous system of mice heterozygously deficient in p0. J Cell Biol 152:301±308 7. Carson CC, 3rd (2003) Sildenafil: a 4-year update in the treatment of 20 million erectile dysfunction patients. Curr Urol Rep 4:488±496 8. Coleman M, Perry V (2002) Axon pathology in neurological disease: a neglected therapeutic target. Trends Neurosci 25:532 9. De Jonghe P, Timmerman V (2003) Anti-steroid takes aim at neuropathy. Nat Med 9:1457±1458 10. Devroe E, Silver PA (2004) Therapeutic potential of retroviral RNAi vectors. Expert Opin Biol Ther 4:319±327 11. Duby JJ, Campbell RK, Setter SM, White JR, Rasmussen KA (2004) Diabetic neuropathy: an intensive review. Am J Health Syst Pharm 61:160±173; quiz 175±166 12. Dyck PJ, Swanson CJ, Low PA, Bartleson JD, Lambert EH (1982) Prednisone-responsive hereditary motor and sensory neuropathy. Mayo Clin Proc 57:239±246 13. Fenton CF, 3rd, McGlamry ED, Perrone M (1982) Severe pes cavus deformity secondary to Charcot-Marie-Tooth disease: a case report. J Am Podiatry Assoc 72:171±175 14. Fenton CF, 3rd, Schlefman BS, McGlamry ED (1984) Surgical considerations in the presence of Charcot-Marie-Tooth disease. J Am Podiatry Assoc 74:490±498 15. Folkers K, Simonsen R (1995) Two successful double-blind trials with coenzyme Q10 (vitamin Q10) on muscular dystrophies and neurogenic atrophies. Biochim Biophys Acta 1271:281±286 16. Folkers K, Wolaniuk J, Simonsen R, Morishita M, Vadhanavikit S (1985) Biochemical rationale and the cardiac response of patients with muscle disease to therapy with coenzyme Q10. Proc Natl Acad Sci U S A 82:4513±4516 17. Frostick SP, Yin Q, Kemp GJ (1998) Schwann cells, neurotrophic factors, and peripheral nerve regeneration. Microsurgery 18:397±405 18. Gould N (1984) Surgery in advanced Charcot-Marie-Tooth disease. Foot Ankle 4:267±273 19. Guenard V, Schweitzer B, Flechsig E, Hemmi S, Martini R, Suter U, Schachner M (1999) Effective gene transfer of lacZ and P0 into Schwann cells of P0-deficient mice. Glia 25:165±178

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20. Hellstrom WJ (2003) Vardenafil: a new approach to the treatment of erectile dysfunction. Curr Urol Rep 4:479±487 21. Low PA (2002) Autonomic neuropathies. Curr Opin Neurol 15:605±609 22. Lupski J, Wise C, Kuwano A, Pentao L, Parke J, Glaze D, Ledbetter D, Greenberg F, Patel P (1992) Gene dosage is a mechanism for Charcot-Marie-Tooth disease type 1A. Nat Genet 1:29±33 23. Maier M, Berger P, Suter U (2002) Understanding Schwann cell-neurone interactions: the key to Charcot-Marie-Tooth disease? J Anat 200:357±366 24. Martini R (2001) The effect of myelinating Schwann cells on axons. Muscle Nerve 24:456±466 25. Maurer M, Kobsar I, Berghoff M, Schmid CD, Carenini S, Martini R (2002) Role of immune cells in animal models for inherited neuropathies: facts and visions. J Anat 200:405±414 26. Naef R, Adlkofer K, Lescher B, Suter U (1997) Aberrant protein trafficking in Trembler suggests a disease mechanism for hereditary human peripheral neuropathies. Mol Cell Neurosci 9:13±25 27. Naef R, Suter U (1999) Impaired intracellular trafficking is a common disease mechanism of PMP22 point mutations in peripheral neuropathies. Neurobiol Dis 6:1±14 28. Ochs G, Penn RD, York M, Giess R, Beck M, Tonn J, Haigh J, Malta E, Traub M, Sendtner M, Toyka KV (2000) A phase I/II trial of recombinant methionyl human brain derived neurotrophic factor administered by intrathecal infusion to patients with amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 1:201±206 29. Pappagallo M (2003) Newer antiepileptic drugs: possible uses in the treatment of neuropathic pain and migraine. Clin Ther 25:2506±2538 30. Passage E, Norreel JC, Noack-Fraissignes P, Sanguedolce V, Pizant J, Thirion X, Robaglia-Schlupp A, Pellissier JF, Fontes M (2004) Ascorbic acid treatment corrects the phenotype of a mouse model of Charcot-Marie-Tooth disease. Nat Med 10:396±401 31. Perea J, Robertson A, Tolmachova T, Muddle J, King RH, Ponsford S, Thomas PK, Huxley C (2001) Induced myelination and demyelination in a conditional mouse model of Charcot-Marie-Tooth disease type 1A. Hum Mol Genet 10:1007±1018 32. Rusciani L, Severino E, Rusciani A (2002) Type A botulinum toxin: a new treatment for axillary and palmar hyperhidrosis. J Drugs Dermatol 1:147±151 33. Saifi GM, Szigeti K, Snipes GJ, Garcia CA, Lupski JR (2003) Molecular mechanisms, diagnosis, and rational approaches to management of and therapy for Charcot-Marie-Tooth disease and related peripheral neuropathies. J Investig Med 51:261±283 34. Sereda MW, Meyer zu Horste G, Suter U, Uzma N, Nave KA (2003) Therapeutic administration of progesterone antagonist in a model of Charcot-Marie-Tooth disease (CMT-1A). Nat Med 9:1533±1537 35. Wagey R, Lurot S, Perrelet D, Pelech SL, Sagot Y, Krieger C (2001) Phosphatidylinositol 3-kinase activity in murine motoneuron disease: the progressive motor neuropathy mouse. Neuroscience 103:257±266 36. Williams LL, O'Dougherty MM, Wright FS, Bobulski RJ, Horrocks LA (1986) Dietary essential fatty acids, vitamin E, and Charcot-Marie-Tooth disease. Neurology 36:1200±1205 37. Young P, Suter U (2003) The causes of Charcot-Marie-Tooth disease. Cell Mol Life Sci 60:2547±2560 38. Young P, Suter U (2001) Disease mechanisms and potential therapeutic strategies in Charcot-Marie-Tooth disease. Brain Res Brain Res Rev 36:213±221

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clinical management and therapy of CMT patients R. Forst, A. Ingenhorst

Introduction In the clinical routine treatment of CMT patients, the orthopedic surgeon is confronted predominantly with the nearly constant presence of equinocavovarus deformity of the foot. The equinocavovarus deformity requires in many cases a complex operative treatment taking into account the individual pathology. Problems with hand function, scoliosis, hip dysplasia and recurring luxations of the patella require in some cases orthopedic attention [20]. Consistent physio- and/or occupational therapy, assisted by different procedures of physical therapy is recommended to supplement operative treatment. The main goal of conservative rehabilitation is the improvement of muscle strength and hand function, prevention of joint deformities, promotion of mobility, prevention of falls, resolution of psychologic problems, as well as prevention and therapy of pain [65]. Rehabilitative concepts specific for CMT are missing in the current literature. Siegel [69] recommends the use of an elastic bandage on the ankle joint to compensate the kineceptive (sensory/proprioceptive) loss due to CMT for improvement of the stance ± and gait confidence. In a case report [21], the positive effect of transcutaneous electric nerve stimulation (TENS) in alleviating muscle atrophy has been described. An improvement of ankle joint stability and function, a reduction of hand and foot fatigue, advancement of grip strength and improvement in activities of daily living were achieved with daily treatment. Due to progressive resistance training of the proximal leg muscles for several weeks, a significant increase of strength similar to healthy persons has been observed. By using a surface EMG and measuring the maximum voluntary isometric contraction, the increase of muscle strength and leg-related functional performance was found to be based initially on neural factors (additional recruitment of motor units), later on the resulting muscle hypertrophy [28, 29].

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14.1 Upper extremities (Fig. 14.1) CMT is the most common inherited degenerative peripheral neuropathy affecting the upper extremities. About one-half to two-thirds of patients show hand symptoms after a mean disease period of 19 years, which typically occur later than the involvement of the lower extremities. The shoulder and elbow function are only affected in the most severe cases. The majority of the patients report motor deficits with loss of muscle strength (50%), loss of dexterity (15.6%), trembling (4.7%), cramping (4.7%) and in 23% sensory changes [38]. When the disorder involves the upper extremities during the disease progress, most of the strength deterioration occurs in the first five to ten years. A relative stable phase with less progression follows. In contrast, the sensibility and dexterity worsen continuously over time. Interestingly, CMT patients are able to adapt and regulate fine motor movements despite the sensory loss: familiar movement patterns can be carried out without significant differences to healthy persons while novel motor patterns are very difficult to perform, especially if visual control is absent [40]. Clinically, mixed median and ulnar nerve palsies (radial nerve is usually not affected) develop and result in a weakness of the intrinsic muscles of the hand with fingerclawing [70] (Fig. 14.1). The failure of the interossei muscles, such as the primary metacarpophalangeal (MCP) flexors, leads to a hyperextension of the MCP joints due to the overload of the extensors. The dominance of the long finger flexors induces a flexion of the interphalangeal joints. Because of the paresis of the interossei muscles, the lateral finger mobility is also lost. Extrinsic muscles, which can be involved at a later time in the disease process, adopt the intrinsic muscle function only at a physiologic joint position. Therefore, the M. extensor digitorum communis becomes an extensor of the interphalangeal joints only if the MCP joints are not hyperextended.

Fig. 14.1. An 8-year old girl with CMT1: severe hand manifestation and atrophy of the intrinsic muscles

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Table 14.1. Surgical treatment of upper limb deformities. APL abductor pollicis longus, EDC extensor digitorum communis, EI extensor indicis, EPB extensor pollicis brevis, EPL extensor pollicis longus, FDS flexor digitorum superficialis indicis, PL palmaris longus [9, 30, 36, 38, 52, 70] Problem

Procedure

Comment

z decreased conduction velo- carpal tunnel release city of the median nerve (carpal tunnel compression)

long-term-effect? ± progression of the neuropathy!

z lack of opposition

opponensplasty using FDS or EPB or EI or EDC + EPL

different techniques

z weak pinch

MCP1 joint fusion combined with transfer of EPB or APL transfer EI

z clawing of the fingers

lasso loop operation using flexor digitorum superficialis (FDS) volar plate tenodese transfer of palmaris longus (PL) prolonged with palmar aponeurosis

Because many of the patients compensate the functional loss well, an operative treatment is rarely required. The various possibilities of treatment with orthopedic support devices, e.g., braces, can efficiently facilitate daily and professional activities [38]. Surgical treatment is only useful in exceptional cases of advanced clawhand deformities with lack of a vigorous grip and thumb-index pinch, as well as thumb opposition. Different operation techniques are described in the actual literature, among them especially the activity improving tendon transfers (Table 14.1). Before an operative intervention, it has to be taken into consideration that the optimal timing and selection of a motor donor unit to transfer is complicated by the impossibility to predict the individual course of the disease. In addition, the effect of increasing the activity of a motor unit by tendon transfers on the progress of disease is not clear. For this reason, the tendon transfer should be performed in a stable phase of the disease defined by minimal progress [38]. In a study by Mackin et al. [30], it is recommended to carry out an EMG examination before tendon transfers in addition to the clinical examination and biomechanical considerations to optimize the selection of donor muscles. Interestingly, important differences among partially denervated donor muscles have been observed, which could not be detected in the physical examination by experienced clinical examiners. In every case, a postoperative training therapy has to follow to achieve the maximum of function of the transferred muscle [30].

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14.2 Spine The incidence of scoliosis in CMT patients vacillates between 10% and 50% in older children. A thoracic curvature of the spine and an increased risk for girls has been described and attributed to their more rapid growth compared to boys. CMT1 patients are more frequently involved than patients with type 2, due to the usually earlier onset of the disease and the in most cases more rapidly progressive course of the disease. Scoliosis is also often associated with Djerine-Sottas syndrome (DSS also called CMT3) [61]. The degree of the deformity is normally mild to moderate (according to Daher et al. [11] average 198 Cobb; Walker et al. [67] 65% between 10± 208 Cobb) and an increased kyphosis occurs in 38% of the patients [67]. Usually, the therapeutical management of these spinal deformities is the same as for patients with idiopathic scoliosis. Only in a few cases is dorsal stabilization necessary [6, 11, 67]. The development of compression syndromes caused by hypertrophic nerve roots is described as a possible but rare complication of CMT [49, 53]. In these cases the clinical findings consist in myelo-/radiculopathy, spinal claudication or conus medullaris-, cauda equina symptoms. Hypertrophy of the lumbosacral intradural nerve root, signal abnormalities and enhancement have been described in MRI, correlating with an increased amount of onion bulbs in sural nerve biopsies [8]. Conservative procedures and operative treatment (laminectomy with duraplasty) are performed. An MRI examination is recommended if CMT patients complain about persistent back or spinal pain!

14.3 Hip joint An association between partially severe hip dysplasias and CMT in older children and adolescents has been observed with an incidence of 10%, in particular in CMT1 [33, 48, 66]. Often initially asymptomatic, the problem remains unrecognized over years. The pathology affects both the femoral and the acetabular component. Different techniques are described for an operative treatment: an isolated varisation osteotomy, an additional Chiari osteotomy, isolated Chiari osteotomy or a primary triple, double or Salter osteotomy [16, 26, 46±48]. To avoid peripheral nerve lesions, the sensitive peripheral sciatic and peroneal nerves of CMT patients have to be protected against pressure and positional damages perioperatively and during casting. According to the results of Kumar et al. [26], two of ten operated children developed a paresis of the ischiatic nerve with only partial recovery. Because of these findings it was necessary to treat the foot paresis in one case with a Lambrinudi triple osteotomy, in the other case with a triple osteotomy in combination with a tibialis posterior transfer.

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In addition, there are indications of an increased risk for postoperative avascular necrosis of the femoral heads for unknown reasons. Therefore, reconstructive operations of the hip should only be performed in symptomatic patients or in cases with radiological proof of progress of the hip dysplasia or subluxation [6]. Because of the considerable therapeutical consequences, Kumar et al. [26] recommend an X-ray screening for all children affected by CMT respectively to rule out a CMT in children affected by a dysplastic hip.

14.4 Knee joint Contrary to our own observations, there is only one publication in the current literature concerning an increased incidence of recurrent luxations of the patella [20]. In particular the changed axis of the leg due to the foot deformity (external rotation of the malleolus) and the necessity for gait stabilization (see below) with spontaneous compensatory adaptation in hip and knee joints (flexion) as well as in the pelvic region (increased anteversion) can influence patella centralization. An additional cause could be a primary muscular destabilization due to a weakness of the M. quadriceps femoris. Therapy consists both of conservative muscular stabilizing methods as physiotherapy and bandages and also established operative procedures as reconstructive soft tissue techniques or a tuberosity transfer.

14.5 Ankle joint and foot 14.5.1 Clinical basics A wide intrafamilial variability, which does not allow reliable prediction of the disease process, and a bilateral, but usually asymmetric foot affection is typical for CMT [17]. For the orthopedic surgeon, the type of CMT is less important than the current grade of paresis in the different muscles and the allocation of the sensomotoric changes. A pes cavus or cavovarus can usually be assessed in an early stage of the disease. Often this deformity is the first reason for a medical examination. Etiologically, the cause for the typical pes cavovarus is a dysbalance between intrinsic foot muscles and extrinsic muscles of the lower leg. In contrast, patients having no active muscle strength below the knee, show a flat, but well balanced foot [61]. In CMT, an imbalance exists between important antagonistic muscles with predominance of the posterior tibial over the peroneus brevis and of the peroneus longus over the anterior tibial resulting in a weakness of eversion and dorsiflexion. Com-

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pared with other muscles, these deficits are explained by their early involvement in the disease process and functionally by their more distal insertion points. Considering their lower muscle volume, they are also weaker in healthy people. Initially, the deformity is supple, in later stages of the disease soft tissue contractures occur and bone growth contributes to the altered foot position [61]. The fascial structures crossing the cavus deformity thicken and serve as a deforming force, resulting in a continuous worsening of the foot deformity creating a vicious cycle. Consequently, not only the progress of the neurological disease but also the secondary mechanical factors are important. The distal marked paresis often results in the clinical picture called `stork legs' or `inverted champagne bottle legs' [22]. Rarely a planovalgus deformity can occur, especially in the infant period. According to an investigation of Exner [13], all affected children have a delayed start of walking, so that in such constellations the diagnosis of a hereditary neuropathy has to be confirmed and other neuromuscular diseases have to be ruled out before planning operative treatment. In the examination of Ghanem et al. [17], 17% (of 66 examined CMT children) have a pes valgus or planovalgus, which converts spontaneously in approximate half of the cases to a pes cavovarus. The majority of CMT patients have foot and ankle problems. In a study conducted by Birouk et al. [7], a foot deformity was observed in 95% of the examined CMT1A patients (according to Ghanem et al. [17] 96%). An early disease onset is predictive for a rapid progress: 50% of the patients develop already in the first decade, 70% before the second decade a symptomatic involvement of the foot [45]. Foot pain, pressure ulcers and development of calluses caused by ill-fitting shoes [42], growing in of toenails, increasing instability (45% [17]), frequent falls, recurrent ankle distorsions, tiptoe gait, decreased strength and conditions with restriction of the maximal and painless walking distance, impossibility of barefoot walking, difficulties regarding shoe shopping and a progressive deformity have been reported as subjective complaints. Often flexible or rigid clawtoes exist.

14.5.2 Pathogenesis of the deformities Two different models explaining the pathogenesis of foot deformities exist in the current literature. According to Sabir and Lyttle [55, 56], the muscles supplied by the longest axons of the sciatic nerve are affected first. Muscles above the knee joint are rarely involved. Muscles with small volume become weak faster, e.g., the peroneal muscles are involved before the triceps surae is affected. Degeneration follows a centripetal pattern beginning in the intrinsic foot muscles (especially the musculi lumbricales) and later the flexor digitorum longus and brevis, flexor hallucis longus, extensor hallucis longus and brevis, finally the peroneal muscles, extensor hallucis longus and brevis, tibialis posterior and tibialis anterior will be affected.

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Mann and Missirian [32] found in muscle function tests divergent results: a marked weakness of the anterior tibial, peroneus brevis and the intrinsic foot muscles, as well as a good to normal strength of the posterior calf muscles, the peroneus longus and the long foot flexors has been observed. In the development of the paresis, the peroneal and intrinsic muscles, the tibialis anterior, extensor digitorum longus and then all other foot muscles are affected in succession. The specific pattern of paresis leads to the structural deformity, which is characterized by the unopposed action of the peroneus longus (= forefoot equinus with first ray plantarflexion) caused by relative weakness of the anterior tibial and the functional loss of the peroneus brevis which permits the tibialis posterior (= hindfoot varus) to act unopposed. The deformity is enhanced by the progressive contracture of the intrinsic foot muscles and the plantar fascia. The absence of prospective, longitudinal data makes the interpretation of those discrepant results difficult. Perhaps the problem will be solved with the help of techniques examining the recruitment of motor units and the use of imaging Table 14.2. Pathogenesis of isolated foot-deformities in Charcot-Marie-Tooth disease Deformity

Pathogenesis

z Pes cavus

Unopposed peroneus longus (weak tibialis anterior) causes first ray plantarflexion, forefoot equinus and clinical-cavus and leads to forefoot pronation ± probably all metatarsales are involved (= global anterior cavus) / an additional contracture of the gastrocnemii a hindfoot equinus Overweight of the tibialis posterior (weak peroneus brevis) with inversion of the subtalar joint Fibrosis and shortening of the short plantar muscles and secondary contracture of the plantar fascia (increase the rigidity of the deformity)

z Pes adductus

Overpower of the tibialis posterior and long toe-flexors (forefoot adduction is found in the metatarsal joints or in the transverse tarsal joint (talonavicular/calcaneocuboid)

z Hindfoot varus

Overweight of the tibialis posterior and long toe-flexors As a secondary deformity: a fixed forefoot pronation (due to the first ray plantarflexion) leads obligatory to a compensatory hindfoot varus in stance (tripod effect) and increases the plantar pressure on the lateral border of the foot

z Clawtoes

Weak musculi lumbricales/interossei with preponderance of the long extensors and flexors lead to MTP extension and IP flexion Deformity worsens in swing phase due to the function of the long toe-extensors as an additional ankle-extensor

z Ankle instability

Weak peroneus brevis Hindfoot varus results in an increased risk for lateral ankle inversiontype injuries

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techniques. In comparison to the peroneus brevis, the soleus and gastrocnemii muscles remain stronger for a long time because more motor units exist in cross-section [22]. MRI examinations show a relative increase of the size of the peroneal compartment in comparison to the anterior compartment, which can be interpreted as dominance of the peroneus longus over the anterior tibial muscle. The components which play a role in the pathogenesis of the typical foot deformities are summarized in Table 14.2.

14.5.3 Special diagnostic tests In gait analysis, a complex disturbance of the gait pattern has been described [32, 56]. The existing foot drop, the muscle weakness, the sensory alterations and a decreased proprioception have to be compensated while walking. Patients do often not show a typical steppage, but a marionette gait. During the swing phase, a pelvic shift and elevation combined with a moderate hip and knee flexion to regulate the foot drop has to be compensated by a lateral bending of the upper trunk to the stance side for balancing. In addition, a hyperextension in the metatarsophalangeal (MTP) joints (at MT1 corresponding to the cock-up deformity) and a recruitment of the long extensor muscles supporting the dorsal flexion appear. Due to the foot drop, heel strike is impossible. Different grades of lateral ankle instability with a tendency for inverting the hindfoot have been observed during walking and, in addition, the midfoot and the subtarsal joints were blocked. In differentiated gait pattern analysis, during tiptoe walking an early inversion of the foot and heel, during heel walking a weakness of dorsalflexors and evertors have been observed. The patients walk on the lateral side of the fifth ray and the sole. A deformity persisting in stance indicates that secondary structural bone and tendon deformities have developed [61]. At the beginning, it is only visible during active dorsal flexion. Regarding the pathogenesis the ground reaction forces on the loaded foot have to be taken into consideration. The restricted muscular stabilization of the foot skeleton during weight-bearing leads to further deformities, intensified by motion induced thrust and shear forces [12]. The importance of the toe function in walking also has to be pointed out. A reduced contact time of the toes and consequently a diminished area taking load increase the pressure under the metatarsal heads [35]. Additional indications exist for an often detectable weakness of the hip abductor muscles, which causes asymmetric hip moments (= vector sum of forces acting at the joint) and a truncal instability in the mediolateral plane during ambulation [27]. The dynamic pedobarography is an additional diagnostic technique for analyzing mild to moderate foot deformities which is helpful in planning and assessment of therapy. The gait line, contact areas, peak pressures and pressure time integral can be determined. The reliability of this method is limited in severe foot deformities and marked muscular discoordination, and the cause of increased or decreased peak plantar pressure remains still undeterminable [10]. It is impossible to distinguish between flexible and

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Fig. 14.2 a, b. Lateral block test: correction of the heel varus demonstrates the flexibility of the hindfoot

fixed deformities. Metaxiotis et al. [35] examined 15 CMT patients preand postoperatively and separated them into three groups: z ªantegrade walkerº with heel-toe pattern (clinically predominant cavus foot), z ªretrograde walkerº with toe-heel pattern (clinically predominant forefoot equinus) and z ªinversion contact patternº with main load under the fifth metatarsal bone (clinically predominant hindfoot varus). A physiological antegrade heel-toe pattern with increased contact areas could be restored postoperatively by different operative procedures and in a few cases over corrections were detected [35]. The reliability of X-ray diagnosis is also considerably restricted in comparing pre- and postoperative metric analysis, because as a result of the variability of the foot deformity it is not possible to define a reproducible standardized view. Regardless of these findings in the current literature a lateral radiograph is taken in the weight bearing technique to assess the medial arc, an a.p. projection to assess the forefoot adduction and a posterior projection to assess the heel varus. In the lateral standing radiograph, the calcaneus pitch, instep, MT1-inclination, inferior cortex of calcaneusMT1, talo-MT1 (Meary's angle), talo-calcaneal, tibio-calcaneal, tibio-talar, first-fifth-MT angles and additionally the height of the longtitudinal arch can be measured. In the lateral radiograph the fibula stands relatively posterior to the tibia, which is related to a rotation of the tibia caused by the hindfoot varus. A calcaneo-cavus is atypical for the CMT disease and therefore the calcaneus pitch angle is below 308. The standing a.p. radiograph allows evaluation of the talo-MT1, talo-MT2, calcaneo-MT1 and the calcaneo-MT2 angles [1±3, 35, 58±59, 61, 69].

14 Orthopedic aspects in diagnosis, clinical management and therapy of CMT patients

z

Table 14.3. Subjects of the decision-making process in the management of foot deformities in Charcot-Marie-Tooth disease Problem

Strategy ± Consideration

z Is CMT responsible for the deformity?

Demand for an exact differential diagnosis ± necessary especially in young patients with progressive foot deformities before therapy The ªidiopathicº cavus foot is rare and probably the only symptom of a non-classified neurologic disorder. 2/3 pes cavus patients have neurologic problems, 50% of them are CMT disease [2, 61, 69]

z Is the deformity fixed or flexible? Primary or secondary?

Need for a careful examination and analysis of function! The typical pes cavovaro-adductus consists of several components: ± lateral view: the heel does not touch the floor ± dorsal: calcaneus inversion, prominence of the lateral malleolus, forefoot adduction ± ventral: forefoot adduction, clawtoes ± medial: cavus and supination of the foot Demand for an isolated inspection of the ankle (flexion/extension), subtalar joint (inversion/eversion), transverse tarsal joint (abduction/adduction), MTP and IP joints. The ªlateral block testº (Coleman and Chesnut, Fig. 14.2) differentiates a flexible from a fixed hindfoot varus. An equinus deformity is often the result from a forefoot seldom a hindfoot equinus. Clavus develop normally at the plantar basis of the V. MT and caput ossis metatarsales Demand for a pre-operative exact clinical examination and strength testing to identify powerful muscles to be transferred and to balance the foot ± no routine tendon transfers! Fixed bony deformities can be themselves deforming forces (1st ray plantarflexion ± hindfoot varus)

z What are the deforming forces and the deficits?

z Are the clawtoes Fixed toe-deformities require bony and soft tissue procedures fixed or flexible? z Is the ankle unstable? z What are the patient's goals?

Individual conditions of life have to be respected

14.5.4 Therapy A careful clinical and neurological foot examination with an independent assessment of the fore-, mid- and hindfoot in weight-bearing and nonweight-bearing position, survey of the vascular status, documentation of the plantar callosities, check-up of the integrity of the metatarsal fat pad and radiographs are necessary prior to therapeutical interventions [54, 61]. In some studies, a standardized questionnaire, e.g., Maryland Foot Score (MFS), is used for pre- and postoperative evaluation. Different questions, which have to be taken into consideration before the decision about operative procedures is made, are compiled in Table 14.3 [2, 22, 24, 32].

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z Conservative therapy High ankle-foot orthoses (below the knee) can be used to compensate the foot drop and prevent the fatigue of the leg muscles in patients with marked ataxia or abnormal position sense [61]. Some authors recommend night-splinting to avoid fixed deformities [17] and extra-deep shoes to compensate clawtoes with support to unload the metatarsal heads. Metatarsalgias can also be soothed by soft bedding and using a surface material for insoles like for diabetic patients. Patients with a plantar-flexed first ray and compensatory flexible hindfoot varus may benefit from lateral support at the forefoot (in shoes or inserts), which pronates the foot and stabilizes the lateral ankle area [2]. Additionally pressure relief below the MT1 head decreases pressure and reduces the longitudinal arch. In advanced cases orthopedic shoes may be useful. In long-term observations, a lack of durable prophylaxis of foot deformities by conservative treatment is described as well as the impossibility to correct the basic deformity [22, 58].

z Operative therapy (Fig. 14.3) Because of the variable complexity of the deformity, no standardized therapeutic algorithm exists [19]. The decision for an operative treatment has to be made considering the following individual factors: age of the patient, flexibility of the deformity, severity and vector of the deforming forces and the sensory status. Dæderlein [12] points out the trias ªcorrect ± stabilize ± balanceº for the treatment of neuromuscular foot deformities. In children the operative goal is, apart from recovering a plantigrade foot position with good function, the prevention of a progress or the development of a fixed deformity. Soft tissue procedures are used isolated or in combination with bony procedures [17]. In flexible foot deformities, an early soft tissue release and tendon transfers are advantageous because the remaining foot deformities are less marked if the operation is performed before skeletal maturity is reached. An early intervention leads not only to the preservation of the normal biomechanics and foot position, but also avoids an even more invasive treatment. On the other hand, it is impossible to correct fixed deformities only with dynamic tendon transfers. The performance of tendon transfers in an imbalanced paresis can lead to unexpected results. A tendon that is transferred will lose one grade in muscle power [58]. Ghanem et al. [17] propose an age-related concept for therapy: avoidance of clawtoe surgery before the age of six; in severe deformities performance of a medial and plantar release combined with an osteotomy before reaching the age of 10, in addition, a tibialis posterior transfer in cases with peroneal muscle atrophy; above the age of 14 indication to tarsectomy under following conditions: experienced surgeon, reducible hindfoot varus, absence of subtalar instability and normal form. Around the age of 40, an atrophy of the plantar fat pad often occurs and consecutively painful calluses develop under

14 Orthopedic aspects in diagnosis, clinical management and therapy of CMT patients

z

Fig. 14.3 a±d. A 25-year old man with CMT1: pre- (a, b) and postoperative (c, d) clinical and radiological findings after correction of a rigid pes cavovaro-adductus by an Imhåuser osteotomy

the metatarsal heads. At this stage every kind of an operative correction is no longer optimal. For these cases an individualized shoe- and/or orthosis support should be preferred. The cavus deformity due to CMT is among all cavus feet the most difficult to treat and the most prone to recurrence because of the progressive nature of the muscular imbalance [2]. Generally, an increasing rigid foot deformity requires complex corrective surgery. To ensure optimal patient management, it should be pointed out to the patient preoperatively that perhaps in a later stage of the disease additional operative treatment may be necessary. Results of an operative intervention are difficult to interpret due to the wide spectrum of neurological dysfunctions, the lack of standardized assessment criteria and the number of possible surgical procedures. Regular controls of the disease progress, in at least yearly intervals, are necessary because of the risk of recurrence or deterioration especially during the growth period [12]. An overview of the operative soft tissue and bony procedures for correction of the individual foot deformity is shown in Table 14.4 a and b.

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Table 14.4 a. Soft tissue procedures to correct foot-deformities in Charcot-Marie-Tooth disease Deformity

Procedure

Comment

z Plantar fascia contracture

Plantar (fascia) release

Usually additional; a compensation in the lateral block test demonstrates the hindfoot flexibilty ± in this case, it is possible to achieve a spontaneous correction of the hindfoot with an isolated correction of the forefoot. Samilson [37] recommend for a fixed varus deformity a radical posteromedial plantar and selectively a medial tarsal release. In children, Olney [24] corrects a marked proximal cavus using a dome-osteotomy combined with a plantar release (plantar fascia, abductor hallucis, abductor digiti quinti, plantar intrinsic muscles, short and long plantar ligaments)

z Reduced ankle- Achilles tendon lengthening extension (Achilles tendon shortening) z Flexible clawtoes II±IV

z Flexible clawtoe I

Often combined with tendon transfers or bony procedures Resulting from foot drop and contracture of the triceps surae due to the muscular imbalance between extensors and flexors [22, 35, 61±62, 68] The possibility of spontaneous correction of flexible clawtoes after midfoot osteotomies has to be considered [2] Improves ankle dorsiflexion; sometimes combined Hibbs procedure with interphalangeal (IP) joint fusions (= extensor digit. long. transfer to 3rd cuneiform) Lengthening of extensors Lengthening of flexors Plantar flexortenotomies, dermotomies Dorsal capsulotomy of MTP joints

Improves ankle dorsiflexion and eliminates its deJones procedure (= extensor hallucis forming force in hallux MTP extension deformity longus transfer to 1st MTP neck) Flexor hall. longus lengthening Flexor to extensor transfer

14 Orthopedic aspects in diagnosis, clinical management and therapy of CMT patients

z

Table 14.4 a (contiuned) Deformity

Procedure

Comment

z Flexible pes cavovaroadductus

Peroneus longus to brevis transfer

Strengthens eversion and eliminates 1st ray plantarflexing force; rare indication for transfer of peroneus longus to achilles tendon Strengthens ankle dorsiflexion, reduces cavusproducing vector, stabilizes hindfoot. Best effect in early stages of the deformity [37, 72]; seldom indication for a split transfer [15, 35] Not advisable due to a greater involvement of the muscle and the disease progress

Tibialis posterior transfer Tibialis anterior transfer

Table 14.4 b. Bony procedures to correct foot-deformities in Charcot-Marie-Tooth disease Deformity

Procedure

Comment

z Fixed clawtoes Interphalangeal fusion (PIP joint)

Arthrodesis of the Vth toe has to be avoided due to the risk of pressure problems in unyielding shoes [14] Fusion of the great toe with 2 crossing Kirschner wires or one screw [5], in some cases combined with metatarsophalangeal capsulotomies and extensor tendon lengthening, in marked deformities of young patients with flexor to extensor transfer, can be combined also with the Jones procedure [62] Hohmann procedure Decreases pressure under metatarsal heads [35] (toe II±V) Helal procedure (toe II±V)

z Fixed hindfoot Dwyer (lateral No influence of the deforming pathology; enlarges varus (childclosing wedge) contact area hood) calcaneal osteotomy Used to correct skeletally immature patients as young as 7 years old without influence on heel growth and sometimes with amelioration of the cavus deformity. Children younger than 10 years with mild deformities should be operated without wedge resection, in older children or in marked deformities a lateral closing wedge osteotomy would be useful. Skeletally matured patients with pes cavovaro-adductus should be treated with a dorsal wedge intertarsal osteotomy and a Dwyer procedure [61±62] Siegel [63] combines a modified Dwyer osteotomy with a Mitchell procedure (plantar fasciotomy with proximal displacement of calcaneal osteotomy) in order to lengthen the heel and facilitate the fitting for a shoe or brace. Gould [18] adds proximal dorsal closing wedge metatarsal osteotomies

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Table 14.4 b (continued) Deformity

Procedure

Comment

Superolateral sliding No disadvantages in midtarsal or tarsometatarsal calcaneal osteotomy function, it is combined with a metatarsal dorsolateral closing wedge osteotomy (always MT1, optionally other metatarsalia) and a plantar release. Advantages: full joint mobility and flexibility, full shock absorbing function. A non-union, delayed union and degenerative intertarsal joint diseases postoperatively were rarely found [59] (Of the MT1 alone or of all metatarsalia); corrects a z Fixed metatar- Metatarsal sus adductus osteotomies: metatarsus adductus or a rigid forefoot equinus [5, (fixed mild pes Proximal dorsal 18, 35, 61±62]; at toe II±V without fixation (plantar closing wedge cavovarocontinuity), the osteotomy of toe I will be performed adductus) greenstick at last and stabilized with a screw. It has to be metatarsal considered that this procedure does not reach the osteotomies deformity center and is able to increase the pressure on the head of the 2nd MT. Risk: overcorrection (forefoot ªrockerbottomº) and painful callosities Dorsal wedge Osteotomy concerning the tarsometatarsal joints, osteotomy Jahss removes more bone from the 2nd and 3rd metatarsal bases than from the 1st metatarsocunei(Jahss procedure) form, 4th- and 5th- tarsometatarsal joint. The bone wedges are obtained proximal to painful callus and should be taken from painful, stiff, arthritic, unstable or functionless joints [24]. Risk: overcorrection with abduction malposition and forefoot ªrockerbottomº [58]. Additional disadvantage: loss of motion and shock absorbing effect of the metatarsal-cuneiform-cuboid complex [59] z Fixed pes cavovaroadductus (adult)

Midfoot (mid-tarsal) Disadvantage of all mid-tarsal osteotomies: they osteotomies: span the navicular-cuneiform-cuboid complex and reduce the midtarsal joint motion [59]. In mild deformities, a plantar-based opening wedge osteotomy of the medial cuneiform without the need for an internal fixation may be combined with the shortening of the lateral column or procedures of the medial column ± advantage of this procedure: full motion of the subtalar joint [39] Removal of a dorsally and slightly laterally based Dorsal wedge wedge (proximal cut through naviculare and cuintertarsal boid, distal cut through cuboid and the cuneiforosteotomy mia); corrects a mild or moderate cavus and adductus deformity [62]

14 Orthopedic aspects in diagnosis, clinical management and therapy of CMT patients Table 14.4 b (continued) Deformity

Procedure

Comment

Imhåuser osteotomy

Possibility of a total correction of all deformity components: dorsally and laterally based wedge resection of the Chopart joint, in marked cases an entire navicular resection has to be done; the procedure leads to an elevation of the forefoot, reduces the cavus and corrects the forefoot adduction. In most cases the clawtoes straighten themselves spontaneously, sometimes postoperatively patients are able to wear ready-made shoes; additional tendon transfers should be useful (tibialis posterior, peroneus longus) [23] ± Steindler: dorsally based osteotomy including the talar neck combined with a plantar release ± Cole: anterior tarsal wedge osteotomy (great risk (30%) of pseudarthrosis and early arthropathy) ± Wilcox: midtarsal dome-osteotomy ± Japas: V-shaped-osteotomy, corrects nearly the apex of the deformity

Other mid-tarsal osteotomies (Steindler, Cole, Wilcox, Japas)

z Severe pes cavovaroadductus (adult)

Triple arthrodesis (fusion of the talonavicular-, subtalar-, calcaneocuboid joint; e.g. Ryerson, Lambrinudi)

Salvage procedure! Reserved for older patients Long-term outcome: often deteriorates with time due to the development of late-onset complications. In recent studies, the average age at surgery was 12± 19 years [31, 41, 58]. Often, other procedures were performed before without total correction and sometimes soft tissue procedures were added to a triple arthrodesis before or afterwards. Most surgeons use this method in advanced, rigid and matured cavovarus. A discrepancy between the patient satisfaction and the objective assessment in longterm follow-ups has been described [4, 22, 41]. Independently of the chosen method, in the follow-up >10±20 years the operation may lead to the development of late-onset lesions [4, 60, 71]. In several studies, the postoperative result was classified by the surgeon as fair or poor in 28±47% [4, 41, 68] The problem is usually functional impairment and the necessity for postoperative bracing [62]. A high incidence of degenerative changes in the ankle and midfoot (up to 100% 44 years postoperatively [57]), pseudarthrosis (up to 23% [4]) or delayed fusions, avascular necrosis of the talus and residual deformities (up to 62% [4]) with need for revision (8% [31]), neuropathic ankle [34, 68], instability, pain and callosities were described. A very rigid equinovarus preoperatively leads to the worst results. A risk of under- or overcorrection (up to 60% [71]) and foot

z

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Table 14.4 b (continued) Deformity

Procedure

External fixators

Comment shortening [18, 58] was found. Patients with painful pseudarthrosis, recurrent or residual deformities received additional foot or ankle joint fusions. The good result of the study of Saltzman et al. 1999 was explained with the inhomogeneity of the patient collective (high percentage (55%) of polio patients with a stabile foot situation, muscle balance and lack of progression and sensory lesions, not comparable to CMT). The reduced tarsal joint motion increased by the progressive loss of proprioception and balance stresses the ankle and leads to osteoarthritic changes and ligamental laxity Raikin 2002 recommends the avoidance of excessive bony or wedge resection and the use of rigid internal fixation to diminish the pseudarthrosis and deformity recurrence rate. Alternative procedures like the Imhåuser osteotomy permit a more flexible plantigrade foot position and treat the main apex of the deformity There is a need for a preventive therapeutical strategy with early soft tissue procedures and probably bracing to avoid triple arthrodesis; this implies continuous patient care in order to detect deformities prior to need for treatment Volkov-Oganesyan-Povarov hinged distraction apparatus: corrects 3-dimensionally a severe equinocavovarus deformity in an average distraction time of 3±13 weeks depending on the rigidity and severity of the deformity, secondary changes in the joints and soft tissue and patient tolerance. In cases with reduced or absent ankle motion, an additional ankle compression can be used for a non-invasive fusion. Advantages: slowly and gradual distraction of foot capsules and ligaments, avoidance of an open procedure and of wedge resection with maintenance of the original foot length. Disadvantages: long therapy duration, risk of pin track infection, osteomyelitis with precocious apparatus removal, skin problems, reduction of ankle motion, reduced success rate in CMT due to the disease progression, difficult technique [43, 44] Ilizarov method: combined with V-shaped osteotomy, sometimes with additional procedures; advantages: obtainment of a stable, plantigrade painless foot, correction of all deformity components; disadvantages: pin tract problems, skin necrosis with residual deformity, toe contractures, technically difficult [25]

14 Orthopedic aspects in diagnosis, clinical management and therapy of CMT patients

z

14.6 Fractures In the present literature, no systematic studies exist about the incidence and therapy of fractures in CMT. It has to be presumed that in advanced disease stages with considerable restriction of the mobility an osteoporosis caused by inactivity occurs, leading to an increased risk of fractures. In a case report Quintart et al. [50] described a pathologic tibia fracture of a CMT patient. On the X-rays a narrowing of the shaft with thinning of the cortex, rarefaction at the end of long bones and a relative widening of the medullary cavity were observed. The muscular atrophy was made responsible for these radiographic bony changes. It is important to consider that consolidation of fractures require approximately the same time as in healthy individuals and that the fracture should be immobilized as short as possible, just as in other patients with neuromuscular disease.

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60. Santavirta S, Turunen V, Ylinen P, Konttinen YT, Tallroth K (1993) Foot and ankle fusions in Charcot-Marie-Tooth disease. Arch Orthop Trauma Surg 112:175±179 61. Shapiro F, Bresnan MJ (1982) Orthopaedic management of childhood neuromuscular disease. Part II: peripheral neuropathies, Friedreich's ataxia, and arthrogryposis multiplex congenita. J Bone Joint Surg [Am] 64:949±953 62. Shapiro F, Specht L (1993) The diagnosis and orthopaedic treatment of childhood spinal muscular atrophy, peripheral neuropathy, Friedreich ataxia, and arthrogryposis. J Bone Joint Surg [Am] 75:1699±1714 63. Siegel IM (1989) Neuropathic ankle in CMT disease [letter]. Orthop Rev 18:267 64. Siegel IM (1994) Management of kineceptive loss in CMT with an elastic ankle support. Muscle Nerve 17:827 65. Vinci P, Perelli SL (2002) Footdrop, foot rotation, and plantarflexor failure in Charcot-Marie-Tooth disease. Arch Phys Med Rehabil 83:513±516 66. Walker JL, Nelson KR, Heavilon JA, Stevens DB, Lubicky JP, Ogden JA, VandenBrink KA (1994) Hip abnormalities in children with Charcot-Marie-Tooth disease. J Pediatr Orthop 14:54±59 67. Walker JL, Nelson KR, Stevens DB, Lubicky JP, Ogden JA, VandenBrink KD (1994) Spinal deformity in Charcot-Marie-Tooth disease. Spine 19:1044±1047 68. Wetmore RS, Drennan JC (1989) Long-term results of triple arthrodesis in Charcot-Marie-Tooth disease. J Bone Joint Surg [Am] 71:417±422 69. Windhager R, Lack W, Kutschera H, Wimberger W, Mayr M (1989) Clinical and radiologic comparison of ªidiopathicº and ªneurogenicº pes cavus. Z Orthop Ihre Grenzgeb 127:169±173 70. Wood VE, Huene D, Nguyen J (1995) Treatment of the upper limb in CharcotMarie-Tooth disease. J Hand Surg [Br] 20:511±518 71. Wukich DK, Bowen JR (1989) A long-term study of triple arthrodesis for correction of pes cavovarus in Charcot-Marie-Tooth disease. J Pediatr Orthop 9:433±437 72. Zwipp H, Rammelt S, Dahlen C, Reichmann H (1999) The Charcot joint. Orthopåde 28:550±558

15 Animal models

of hereditary neuropathies P. Young, U. Suter

Introduction On the basis of new insights into the genetic basis of different types of hereditary neuropathies, several animal models have been generated using transgenic and gene targeting techniques in mice and rats. Animal models are excellent tools to learn more about the biological function of specific proteins involved in myelin maintenance, glia/axon interactions and, in general, about cellular mechanisms of inherited neuropathies. Furthermore, these models reflect the human disease and provide the opportunity to establish therapeutic strategies. Up to now, the available animals are mainly models for the group of hereditary motor and sensory neuropathies (Charcot-Marie-Tooth disease; CMT). The scientific and therapeutical value of each of theses models must be carefully evaluated since transgenic mice and rats carrying comparable mutations or genetic defects as in humans may not always reflect the human disease per se in all facets. In this chapter, a list of available animal models of hereditary neuropathies and their specific clinical and histopathological features are presented. From a histopathologic and electrophysiologic point of view, two main different types of CMT can be distinguished. Primary demyelination is the basis of CMT1, CMT4 and Djerine Sottas syndrome (DSS), while in CMT2 primary axonal degeneration causes the clinical phenotype [28]. In this chapter, gene symbols are given in capitalized italics for the human genes. Mice or rat genes are indicated in non-capitalized italics.

15.1 Models for demyelinating CMT1A: peripheral myelin 22 (pmp22) 15.1.1 pmp22 transgenic rats z Genetic defect: These rats overexpress pmp22 protein (pmp22) because they carry extra copies of the pmp22 gene (pmp22) [24].

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z Phenotype: Behavioral symptoms appear at about 60 days after birth. Heterozygous pmp22 overexpressing rats show deficits in their front limb grip force and in their capability to walk on a round horizontal bar (bar test). Nerve conduction velocities of peripheral nerves are decreased. Demyelinated and amyelinated large axons are detectable within the second postnatal month. Homozygous pmp22 overexpressing rats are affected more severely than the heterozygous animals. For unknown reasons they show severe spasticity and seizures. Histopathologically these homozygous animals completely lack myelinated fibers. z Corresponding CMT syndrome: Heterozygous pmp22 overexpressing rats reflect the clinical, electrophysiological and histopathological changes in CMT1A patients. Homozygous pmp22 overexpressing rats do not have a direct human counterpart but it should be noted that a homozygous duplication on chromosome 17p11.2 causes a severe hereditary neuropathy in humans [14]. With the aid of this animal model, the positive therapeutic effect of the progesterone antagonist onapristone has been shown (see also chapter 13) [25].

15.1.2 pmp22 transgenic mice z Genetic defect: Transgenic mice carrying varying copy numbers of pmp22 were created by different groups [9, 15]. z Phenotype: pmp22 overexpressing transgenic mice show histopathological changes that are correlated with the gene copy number and severity of the clinical phenotype [10]. Mice with a high copy number of the pmp22 transgene show demyelinated and amyelinated nerve fibers within the PNS earlier than mice with low copy numbers. There is strong evidence that the phenotypic expression in these transgenic mice results not only from Schwann cell pathology but also from axonal and neuronal changes [19, 21, 22]. z Corresponding CMT syndrome: pmp22 overexpressing mice reflect some clinical and histopathological features of CMT1A.

15.1.3 Inducible pmp22 transgenic mice z Genetic defect: Transgenic mice carrying the pmp22 transgene under a regulatory tetracycline inducible promoter. In this animal model pmp22 expression ceases when tetracycline is administered with the food [20].

15 Animal models of hereditary neuropathies

z

z Phenotype: These mice show the same phenotype as straight pmp22 overexpressing mice (as long as they are not fed tetracycline with their chow). This phenotype is reverted when tetracycline is given and a reduction of the demyelination of the peripheral nerves can be observed. z Corresponding CMT syndrome: In the case of pmp22 overexpression, mice are comparable to human CMT1A. Reduction of pmp22 expression after addition of tetracycline to the food results in decreased demyelination, but complete reversion of the CMT1A-like phenotype is not achieved.

15.1.4 pmp22 knockout mice z Genetic defect: pmp22 deficient mice were generated by classical gene targeting techniques [1, 2]. z Phenotype: Homozygous pmp22 deficient mice show early onset of demyelination within the peripheral nervous system (PNS) resulting in an early onset of paresis and muscular atrophy in the hind limbs [2]. Clinically these mice also exhibit inducible myotonia-like symptoms [30]. Electrophysiologically, reduced nerve conduction velocities (NCVs) of the peripheral nerves are observed. Histopathologically, focally hypermyelinated fibers (so called tomacula) are found in younger animals followed by demyelination (Fig. 15.1) [2]. Clinically, heterozygous pmp22 deficient mice show a very mild phenotype without significant paresis or muscular atrophy [1]. Microscopic changes in the PNS resemble the human condition of hereditary neuropathy with liability to pressure palsy (HNPP) with longitudinally oriented hypermyelinated stretches (tomacula) as histopathological hallmarks [1]. z Corresponding CMT syndrome: Homozygous pmp22 deficient mice can be seen as a model for severe forms of demyelinating neuropathies. Histopathologically, heterozygous pmp22 deficient mice resemble the human HNPP phenotype. As in HNPP, these mice develop a mild progressive demyelinating neuropathy in later ages.

15.1.5 Mice carrying point mutations in pmp22 trembler, trembler J, Tr-m1H, Tr-m2H z Genetic defect: A spontaneous point mutation in the pmp22 gene causing an amino acid exchange from glycine to aspartic acid at codon 150 was found in trembler mice [29]. Trembler-J mice carry a point mutation in pmp22 causing an amino acid exchange from leucine to proline at codon 16 [27]. Tr-m1H and Tr-m2H mice were generated in the course of a genome-wide, phenotype-driven, large-scale N-ethyl-N-nitrosourea (ENU)

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Fig. 15.1. Cross section of sciatic nerves from a PMP22 wildtype mouse (a, PMP22 wt/wt), PMP22 heterozygous deficient mouse (b, PMP22 0/wt) and a PMP22 overexpressing mouse mutant (c, PMP22 over). In b most prominent is a fiber with thickened myelin caused by supernumerous myelin lamellae and reduced axon size (asterisk). This structure corresponds to the so called tomacula in HNPP. The arrow indicates a fiber which is almost void of myelin. c shows a significant loss of myelinated nerve fibers. Myelin thickness is reduced in most fibers. (Courtesy of Dr. Sara Sancho, Fribourg, Switzerland)

mutagenesis screen [11]. In Tr-m1H, the mutation causes an amino acid exchange at codon 12 (histidine to arginine), while in Tr-m2H the amino acid exchange is a codon 153 tyrosine substitution for a stop codon. These four different mutations in mice are dominant. z Phenotype: All four mice lines exhibit a severe form of hypo- and demyelination. Most nerve fibers are found to be hypomyelinated while few fibers show demyelination. Focal ineffective remyelination ± causing so called onion bulb myelin formations ± is rare. A typical feature is the trembling observed from early postnatal stages onwards. Muscle wasting starts as early as six weeks of age [16]. z Corresponding CMT syndrome: Mice carrying point mutations reflect the situation of severely affected CMT1A patients carrying PMP22 point mutations. Mutations corresponding to the trembler-J mutation and the trembler mutation in mice were also found in very severely affected CMT1 pa-

15 Animal models of hereditary neuropathies

z

tients [31]. Thus, trembler-J and trembler mice are accepted as animal models for CMT1A caused by PMP22 point mutations. Tr-m2H also serves as a model for CMT1A, however, extended histopathological analysis is not available [11, 12]. Analogous to the Tr-m1H mutation, a mutation of codon 12 (histidine to glutamine) has been identified in a patient with a severe form of CMT (Djerine-Sottas syndrome) [32] (see also: Inherited Peripheral Neuropathies Mutation Database (IPNMD) at: http://molgen-www.uia. ac.be/CMTMutations/ for human mutations).

15.2 Models for demyelinating CMT1B: myelin protein zero (mpz) knockout mice z Genetic defect: Disruption of mpz encoding the p0 protein by gene targeting techniques. Homozygous and heterozygous animals have been generated resulting in different levels of p0 expression [7]. z Phenotype: Homozygous p0 deficient mice exhibit a severe muscle atrophy at early stages of postnatal development [17]. Most nerve fibers are amyelinated. Heterozygous mice show mild motor behavioral deficits and mild tremor [17]. Heterozygous animals show much milder alterations of myelinated nerve fibers such as dysmyelination, onion bulb formation and mild axonal loss starting at four months of age [17]. In these mice a peculiar type of nerve fibers is found showing patchy demyelination leading to the formation of so called heminodes along the axon. Heminodes are characterized by the histopathological feature of nodes of Ranvier which show paranodal organization on the side of the nodal and paranodal region while the paranodal formations are lacking on the other side. z Corresponding CMT phenotype: Homozygous p0 deficient mice do not reflect the broad spectrum of human MPZ associated CMT phenotypes. They are comparable to congenital hypomyelination or very severe cases of CMT, also called Djerine-Sottas syndrome (DSS). Heterozygous p0 deficient mice resemble the human demyelinating phenotype of CMT1B associated with point mutations in MPZ. However, some CMT1B patients show a more axonal phenotype which is not reflected by the accompanying axonal loss caused by demyelination in heterozygous p0 deficient mice. These patients can be diagnosed as CMT2 or dominant intermediate CMT (DI-CMT) by clinical, electrophysiological and genetic measures [5, 33].

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15.3 Models for demyelinating and axonal CMTX: gap junction protein beta 1 (gjb1) knockout mice z Genetic defect: Gene disruption by gene targeting techniques resulting in deficiency for the protein Cx32. Homozygous and heterozygous mice have been generated [18, 23]. z Phenotype: Homozygous Cx32 deficient mice exhibit a peripheral neuropathy after approximately five months [23]. Histopathologically demyelination is a typical feature with thinning of compacted myelin layers and onion bulb formation. Strikingly, periaxonal collars are thickened, a feature not observed in other demyelinating CMT syndromes [3, 23]. z Corresponding CMT syndrome: In CMTX, clinical and histopathological features are heterogeneous [33] due to the fact that some patients present with a predominantly demyelinating neuropathy while others suffer from a predominantly axonal neuropathy. A third group presents a mixture of demyelination and axonal pathology [8, 33]. In contrast to the human disease, axonal degeneration is less prominent in Cx32 deficient mice [3, 23].

15.4 Model for demyelinating CMT4F: periaxin (prx) knockout mice z Genetic defect: prx is a constituent of the dystroglycan-dystrophin-related protein-2 complex, which links the Schwann cell cytoskeleton to the extracellular matrix. prx null mutants have been generated by gene targeting techniques [26]. z Phenotype: prx deficient mice develop difficulties in walking at six to nine months of age accompanied by neuropathic pain [26]. Demyelination and tomacula-like structures can be found in these mutant animals although myelination initially is normal. z Corresponding CMT syndrome: CMT4F is an autosomal recessive CMT syndrome, which is characterized by demyelination and excessive neuropathic pain. The similarity between the histopathological and clinical features of prx deficient mice and the corresponding features of CMT4F patients lead to the identification of PRX as a candidate gene for CMT4F. Therefore, prx deficient mice represent an excellent model of CMT4F.

15 Animal models of hereditary neuropathies

z

15.5 Model for axonal CMT2A2: kinesin motor protein 1 beta (kif1b) knockout mice z Genetic defect: Classical gene targeting and disruption of the kif1b locus. Homozygous mice are not viable. Heterozygous mice are viable and show reduced kif1b protein levels [36]. z Phenotype: Heterozygous kif1b deficient mice develop progressive muscle weakness and atrophy of the hind limbs [36]. Axonal degeneration is not a striking phenotypic feature of kif1b deficient mice but axonal transport via synaptic vesicles is disturbed. z Corresponding CMT syndrome: CMT2A2 is characterized by primary axonal loss and degeneration. Heterozygous kif1b deficient mice mimic the human CMT2A2 phenotype clinically and histopathologically.

15.6 Model for axonal CMT2E: neurofilament light chain (nefl) knockout mice z Genetic defect: Mouse lines have been generated in which nefl has been disrupted by gene targeting strategies [13, 37]. z Phenotype: Mice deficient for nefl show no striking axonal loss or degeneration. Axonal regeneration is delayed which is not observed in the human situation [37]. z Corresponding CMT syndrome: CMT2E caused by mutations in NEFL is not reflected by nefl deficient mice.

15.7 Model for recessive CMT4C1: lamin A/C (lmna) knockout mice z Genetic defect: lmna deficient mice were generated by gene targeting techniques [6]. z Phenotype: Ultrastructural exploration of sciatic nerves of lmna deficient mice revealed reduction of axon density, axonal enlargement, and the presence of non myelinated axons [6].

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z Corresponding CMT phenotype: Autosomal recessive CMT2 (CMT2B1) is caused by mutations in LMNA. Histopathological and clinical findings in these patients resemble the changes found in lmna deficient mice [6].

15.8 Conclusions Animal models exist for some demyelinating and some axonal CMT syndromes. With the aid of these models, approaches for therapeutic strategies can be further developed in the future. Additional models have to be and will be generated to mimic human CMT syndromes that have no appropriate model. Newly discovered hereditary neuropathy genes and animal models will provide the basis for a deeper view into the molecular mechanisms which lead to the clinical phenotype and syndrome. The establishment of causative treatment strategies is critically dependent on appropriate models in which axonal and glial function can be dissected (see also for review [4, 16, 28, 34, 35].

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8. Hattori N, Yamamoto M, Yoshihara T, Koike H, Nakagawa M, Yoshikawa H, Ohnishi A, Hayasaka K, Onodera O, Baba M, Yasuda H, Saito T, Nakashima K, Kira J, Kaji R, Oka N, Sobue G (2003) Demyelinating and axonal features of CharcotMarie-Tooth disease with mutations of myelin-related proteins (PMP22, MPZ and Cx32): a clinicopathological study of 205 Japanese patients. Brain 126:134±151 9. Huxley C, Passage E, Manson A, Putzu G, Figarella-Branger D, Pellissier JF, Fontes M (1996) Construction of a mouse model of Charcot-Marie-Tooth disease type 1A by pronuclear injection of human YAC DNA. Hum Mol Genet 5:563±569 10. Huxley C, Passage E, Robertson AM, Youl B, Huston S, Manson A, Saberan-Djoniedi D, Figarella-Branger D, Pellissier JF, Thomas PK, Fontes M (1998) Correlation between varying levels of PMP22 expression and the degree of demyelination and reduction in nerve conduction velocity in transgenic mice. Hum Mol Genet 7:449±458 11. Isaacs AM, Davies KE, Hunter AJ, Nolan PM, Vizor L, Peters J, Gale DG, Kelsell DP, Latham ID, Chase JM, Fisher EM, Bouzyk MM, Potter A, Masih M, Walsh FS, Sims MA, Doncaster KE, Parsons CA, Martin J, Brown SD, Rastan S, Spurr NK, Gray IC (2000) Identification of two new Pmp22 mouse mutants using large-scale mutagenesis and a novel rapid mapping strategy. Hum Mol Genet 9:1865±1871 12. Isaacs AM, Jeans A, Oliver PL, Vizor L, Brown SD, Hunter AJ, Davies KE (2002) Identification of a new Pmp22 mouse mutant and trafficking analysis of a Pmp22 allelic series suggesting that protein aggregates may be protective in Pmp22-associated peripheral neuropathy. Mol Cell Neurosci 21:114±125 13. Lee MK, Cleveland DW (1994) Neurofilament function and dysfunction: involvement in axonal growth and neuronal disease. Curr Opin Cell Biol 6:34±40 14. LeGuern E, Gouider R, Mabin D, Tardieu S, Birouk N, Parent P, Bouche P, Brice A (1997) Patients homozygous for the 17p11.2 duplication in Charcot-Marie-Tooth type 1A disease. Ann Neurol 41:104±108 15. Magyar J, Martini R, Ruelicke T, Aguzzi A, Adlkofer K, Dembic Z, Zielasek J, Toyka K, Suter U (1996) Impaired differentiation of Schwann cells in transgenic mice with increased PMP22 gene dosage. J Neurosci 16:5351±5360 16. Maier M, Berger P, Suter U (2002) Understanding Schwann cell-neurone interactions: the key to Charcot- Marie-Tooth disease? J Anat 200:357±366 17. Martini R, Zielasek J, Toyka K, Giese P, Schachner M (1995) Protein zero (P0)-deficient mice show myelin degeneration in peripheral nerves characteristic of inherited human neuropathies. Nat Genet 11:281±286 18. Nelles E, Butzler C, Jung D, Temme A, Gabriel HD, Dahl U, Traub O, Stumpel F, Jungermann K, Zielasek J, Toyka KV, Dermietzel R, Willecke K (1996) Defective propagation of signals generated by sympathetic nerve stimulation in the liver of connexin32-deficient mice. Proc Natl Acad Sci USA 93:9565±9570 19. Norreel JC, Vinay L, Fontes M, Clarac F (2003) Close relationship between motor impairments and loss of functional motoneurons in a Charcot-Marie-Tooth type 1A model. Neuroscience 116:695±703 20. Perea J, Robertson A, Tolmachova T, Muddle J, King RH, Ponsford S, Thomas PK, Huxley C (2001) Induced myelination and demyelination in a conditional mouse model of Charcot-Marie-Tooth disease type 1A. Hum Mol Genet 10:1007±1018 21. Sancho S, Magyar JP, Aguzzi A, Suter U (1999) Distal axonopathy in peripheral nerves of PMP22-mutant mice. Brain 122:1563±1577 22. Sancho S, Young P, Suter U (2001) Regulation of Schwann cell proliferation and apoptosis in PMP22-deficient mice and mouse models of Charcot-Marie-Tooth disease type 1A. Brain 124:2177±2187 23. Scherer SS, Xu YT, Nelles E, Fischbeck K, Willecke K, Bone LJ (1998) Connexin32-null mice develop demyelinating peripheral neuropathy. Glia 24:8±20

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24. Sereda M, Griffiths I, Puhlhofer A, Stewart H, Rossner MJ, Zimmerman F, Magyar JP, Schneider A, Hund E, Meinck HM, Suter U, Nave KA (1996) A transgenic rat model of Charcot-Marie-Tooth disease. Neuron 16:1049±1060 25. Sereda MW, Meyer zu Horste G, Suter U, Uzma N, Nave KA (2003) Therapeutic administration of progesterone antagonist in a model of Charcot-Marie-Tooth disease (CMT-1A). Nat Med 9:1533±1537 26. Sherman DL, Fabrizi C, Gillespie CS, Brophy PJ (2001) Specific disruption of a schwann cell dystrophin-related protein complex in a demyelinating neuropathy. Neuron 30:677±687 27. Suter U, Moskow JJ, Welcher AA, Snipes GJ, Kosaras B, Sidman RL, Buchberg AM, Shooter EM (1992) A leucine-to-proline mutation in the putative first transmembrane domain of the 22-kDa peripheral myelin protein in the trembler-J mouse. Proc Natl Acad Sci USA 89:4382±4386 28. Suter U, Scherer SS (2003) Disease mechanisms in inherited neuropathies. Nat Rev Neurosci 4:714±726 29. Suter U, Welcher AA, Ozcelik T, Snipes GJ, Kosaras B, Francke U, Billings-Gagliardi S, Sidman RL, Shooter EM (1992) Trembler mouse carries a point mutation in a myelin gene. Nature 356:241±244 30. Toyka KV, Zielasek J, Ricker K, Adlkofer K, Suter U (1997) Hereditary neuromyotonia: a mouse model associated with deficiency or increased gene dosage of the PMP22 gene. J Neurol Neurosurg Psychiatry 63:812±813 31. Valentijn L, Baas F, Wolterman R, Hoogendijk J, Van den Bosch H (1992) Identical point mutations of PMP-22 in Trembler-J mouse and Charcot-Marie-Tooth disease type 1A. Nat Genet 2:288±290 32. Valentijn LJ, Ouvrier RA, van den Bosch NH, Bolhuis PA, Baas F, Nicholson GA (1995) Dejerine-Sottas neuropathy is associated with a de novo PMP22 mutation. Hum Mutat 5:76±80 33. Young P, Grote K, Kuhlenbaumer G, Debus O, Kurlemann H, Halfter H, Funke H, Ringelstein EB, Stogbauer F (2001) Mutation analysis in Chariot-Marie Tooth disease type 1: point mutations in the MPZ gene and the GJB1 gene cause comparable phenotypic heterogeneity. J Neurol 248:410±415 34. Young P, Suter U (2003) The causes of Charcot-Marie-Tooth disease. Cell Mol Life Sci 60:2547±2560 35. Young P, Suter U (2001) Disease mechanisms and potential therapeutic strategies in Charcot-Marie-Tooth disease. Brain Res Brain Res Rev 36:213±221 36. Zhao C, Takita J, Tanaka Y, Setou M, Nakagawa T, Takeda S, Yang HW, Terada S, Nakata T, Takei Y, Saito M, Tsuji S, Hayashi Y, Hirokawa N (2001) Charcot-MarieTooth disease type 2A caused by mutation in a microtubule motor KIF1Bbeta. Cell 105:587±597 37. Zhu Q, Couillard-Despres S, Julien JP (1997) Delayed maturation of regenerating myelinated axons in mice lacking neurofilaments. Exp Neurol 148:299±316

Appendix: genetic testing laboratories and support groups G. Hçnermund

Although concentrated in Australia, Europe, Japan and Northern America, facilities performing genetic testing for hereditary neuropathies exist virtually worldwide. So do support groups. In the tables listing the facilities, mere laboratories without clinical facilities, on the one hand, are differentiated from clinical departments running their own laboratories, on the other hand. This determination seems reasonable because the latter combine clinical as well as genetic engineering knowledge. Therefore, both groups might be contacted for different reasons. With regard to support groups, many people worldwide address themselves to the aim of providing information and help to affected persons. Sometimes they are organized in large societies with their own homepages and sometimes they only form local networks. In either case the available information is listed. Evidently, support groups for hereditary neuropathies do not exist in every country. Alternatively, if available, information about neuromuscular support groups is given. All available and necessary information for the contact of the particular facility or support group is listed in the tables. The institutions are arranged alphabetically by country. The tables provide the name and postal address of the institution as well as a contact person, their homepage and potentially an overview of the feasible genetic testing. To obtain the depicted information, clinical departments and laboratories were contacted throughout the world. Nevertheless, it is obviously impossible to give a complete worldwide overview. In case of countries with various testing facilities, the ones with the broadest range of genes were chosen. All websites and e-mail addresses were fully functional at the time of manuscript writing. However, due to the fast changing internet some of them might change. If so entering the name of the institution into a search engine should supply the up-to-date information. z Table 1 lists clinical departments performing genetic testing. z Table 2 displays laboratories performing genetic testing. z Table 3 provides information about support groups.

HÖpital Piti-Salpžtri re, INSERM U289, 47, Bd de l'HÖpital, 75651 Paris Cedex 13, France

Department of Neurology, University Hospital, University of Mçnster, AlbertSchweitzer-Str. 33, 48149 Mçnster, Germany

z France

z Germany

Director: Bernd Ringelstein, MD, Prof. Co-Contact: Gregor Kuhlenbåumer, MD, E-mail: [email protected] Phone: (+49) ± 251-83-48197/-48196, Fax: (+49) ± 251-83-48181 Website: neurologie.uni-muenster.de Remark: Further genes on research base

Contact: Eric LeGuern, MD E-mail: [email protected] Website: www.ap-hop-paris.fr/hopitaux/pitie_salpetriere.htm

Department of Pediatrics, Zagreb University Contact: Nina Barisic, MD E-mail: [email protected] Hospital Center, Kispaticeva 12, 10000 Zagreb, Croatia

z Croatia

Children's Hospital of Eastern Ontario, Molecular Genetics Diagnostic Laboratory, Ottawa, Ontario, Canada Hospital for Sick Children, Molecular Genetics Laboratory, Toronto, Ontario, Canada

EGR2, GAN, GJB1, MPZ, PMP22-Del, PMP22-Dup

Information not given

Information not given

IKBKAP

PMP22-Del, PMP22-Dup

GJB1, MPZ, PMP22-Del, PMP22-Dup

Alberta Children's Hospital, Molecular Diagnostic Laboratory, Calgary, Alberta, Canada

z Canada

Director: Peter Bridge, PhD, FCCMG, FACMG Contact: E-mail: [email protected] Phone: (+403) ± 943-7026, Fax: (+403) ± 943-7624 Website: www.fp.ucalgary.ca/medicalgenetics Director: Nancy Carson, PhD, FCCMG, E-mail: [email protected] Phone: (+613) ± 737-7600 ext 3282, Fax: (+613) ± 738-4822 Website: www.cheori.org/html/molecular.html Co-Directors: Peter N Ray, PhD; Tracy L Stockley, PhD Contact: Leslie Steele, MSc, E-mail: [email protected] Phone: (+416) ± 813-6590, Fax: (+416) ± 813-7732 Website: www.sickkids.ca/molecular

Institution and postal address

Country Tested genes

G. Hçnermund

Director, contact person(s), website (http://...), remarks

z

Table 1. Clinical departments performing genetic testing for hereditary neuropathies

238

Director: Mordechai Shohat, MD Co-Contact: Inbal Kedar, MSc, E-mail: [email protected] Co-Contact: Ellen Taub, MSc, E-mail: [email protected] Phone: (+972) ± 3-937-7659, Fax: (+972) ± 3-937-7660 Website: www.clalit.org.il/rabin/Content/Content.asp? CID=185&u=576 Wolfson Medical Center, Molecular Genetics Director: Esther Leshinsky-Silver, PhD Laboratory, 62 Halohamim Tel Giborim, E-mail: [email protected] Holon, Israel Phone: (+972) ± 3-5028692, Fax: (+972) ± 3-5028693

Department of Neurology, Nagoya University, Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya 466-8550, Japan

z Japan

Contact: Gen Sobue, MD, PhD E-mail: [email protected] Phone: (+81) 52-744-2385, Fax: (+81) 52-744-2384 Website: www.med.nagoya-u.ac.jp/uc.html

Rabin Medical Center, Molecular Genetics, Petah Tikva, Israel

z Israel

Cx32, MPZ, PMP22-Del, PMP22-Dup

IKBKAP

IKBKAP

Cx32, PMP22Del, PMP22-Dup

Director: Demetris Vassilopoulos, MD, Prof. Contact: Marios Panas, MD, E-mail: [email protected] Phone: (+30) ± 010/7289289, Fax: (+30) ± 010/7289289 Website: www.uoa.gr/uoauk/uoaindex.htm

Neurogenetic Unit, Department of Neurology, Athens National University, Eginition Hospital, 74 Vs. Sophias Av., 11528 Athens, Greece

EGR2, GJB1, MPZ, PMP22Del, PMP22-Dup

Director: Reiner Benecke, MD, Prof. Contact: Arndt Rolfs, MD, Prof., E-mail: [email protected] Phone: (+49) ± 381 494-9514, Fax: (+49) 381 494-9512 Website: neurologie.med.uni-rostock.de/index.html

z Greece

Department of Neurology, Neurobiologisches Labor, University of Rostock, Gehlsheimer Straûe 20, 18147 Rostock, Germany

Appendix: genetic testing laboratories and support groups z

239

MPZ, PMP22Del, PMP22-Dup

Information not given GJB1, MPZ, PMP22 (sequence analysis only) Cx32, MPZ, PMP22-Del, PMP22-Dup GJB1, MPZ, NGDR1, PMP22Dup, PMP22-Del

Co-Contact: Saiko Kurihara, PhD, E-mail: [email protected] Co-Contact: Yoshi Adachi, PhD, E-mail: [email protected] Phone: (+81) ± 859 34 8032, Fax: (+81) ± 859 34 8083 Website: neurol.med.tottori-u.ac.jp Contact: Kiyoshi Hayasaka, MD E-mail: [email protected] Director: Masanori Nakagawa, MD, Prof. E-mail: [email protected] Phone: (+81) ± 75-251-5793, Fax: (+81) ± 75-211-8645 Website: www2.kpu_m.ac.jp/~neurolog Contact: Andrzej Kochaski MD, PhD, E-mail: [email protected] Phone/Fax: (+48) ± 22 658 45 01 Website: www.cmdik.pan.pl/index_eng.html

Department of Neurology, Faculty of Medicine, Tottori University, 36-1 Nishimachi, Yonago, Tottori 683-8504, Japan

Director: Francesc Palau, MD, PhD Co-Contact: Javier Garcia-Planells, MSc, E-mail: [email protected] Co-Contact: Ana Cuesta Peredo, E-mail: [email protected] Phone: (+34) ± 96-317-7821, Fax: (+34) ± 96-317-7870 Website: www.igem.es

PMP22-Del, Director: Aurea Mira, MsC, PhD Contact: Eugenia Monros, MsC, PhD, E-mail: [email protected] PMP22-Dup Phone: (+34) ± 93-253-2103, Fax: (+34) ± 93-280-3626 Website: www.hsjdbcn.org/index.html

Neuromuscular Unit, Medical Research Centre, Banacha 1a, 02-098, Warsaw, Poland

Institut de Gen tica M dica i Molecular (IGEM), Hospital NISA Virgen del Consuelo, C/Callosa d'Ensarri—, 12, 46007 Valencia, Spain

Hospital Sant Joan de Deu Molecular Genetics, Esplugues (Barcelona), Spain

z Poland

z Spain

Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan Department of Neurology and Gerontology, Kyoto Prefectural University of Medicine, Kawaramachi Hirokoji, Kamikyo-ku, Kyoto 602, Japan

Tested genes

Country Director, contact person(s), website (http://...), remarks

G. Hçnermund

Institution and postal address

z

Table 1 (continued)

240

PMP22-Dup Duplication or point mutation screening for PMP22 PMP22-Del Deletion screening for PMP22

Mount Sinai School of Medicine Genetic Testing Laboratory (DNA Division), New York, NY, USA

Henry Ford Hospital, DNA Diagnostic Laboratory, Detroit, MI, USA

IKBKAP Director: Toni R Prezant, PhD Contact: William J Childers, MT, E-mail: [email protected] Phone: (+1) 323 669-2271, Fax: (+1) 323 660-7072 Website: www.childrenshospitalla.org Director: Kristin G Monaghan, PhD, FACMG, IKBKAP E-mail: [email protected] Phone: (+1) ± 313 916-7681, Fax: (+1) ± 313 916-9476 Website: www.henryfordhealth.org/1310.cfm Co-Directors: Ruth Kornreich, PhD, Margaret M McGovern, MD, PhD IKBKAP Contact: Jane Robinowitz, MS, E-mail: [email protected] Phone: (+1) ± 212 241-6947, Fax: (+1) ± 212 860-3316 Website: www.mssm.edu

Children's Hospital Los Angeles, University Children's Genetic Laboratory, Los Angeles, CA, USA

z USA

GJB1, MPZ, PMP22-Del, PMP22-Dup

Director: Sabina Gallati, PhD, Prof. E-mail: [email protected] Phone: (+4131) 632 94 93 / 94, Fax: (+4131) 632 94 84 Website: www.cx.unibe.ch/dkf2/Humangenet/humgenet1.htm

Children's University Hospital G2/811, Human Molecular Genetics Bern, Switzerland

z Switzerland

Appendix: genetic testing laboratories and support groups z

241

z Austria

Co-Director: Luba Kalaydjieva, MD, PhD E-mail: [email protected] Phone: (+61) ± 8-9400-5684, Fax: (+61) ± 8-9400-5851 Co-Director: Tamara Rogers, PhD, E-mail: [email protected] Phone: (+61) ± 8-9400-5107, Fax: (+61) ± 8-9400-5851 Website: www.chg.ecu.edu.au/home.html Contact: Luba Kalaydjieva, E-mail: [email protected] Website: www.uwa.edu.au

Department of Medical Biology and Human Director: Klaus Wagner, MD, Prof. Genetics, Karl-Franzens-Universitåt Graz, Contacts: Michaela Auer-Grumbach, MD Harrachgasse 21/8, 8010 Graz, Austria E-mail: [email protected] Klaus Wagner, MD, Prof., Peter Kroisel, MD, Prof., Hannelore Zierler, MD, Prof. Phone.: (+43) ± 316-380-4111, Fax: (+43) ± 380-9605 Website: www.kfunigraz.ac.at/imhwww

Western Australian Institute for Medical Research, The University of Western Australia, ªBº Block QE II Medical Centre, Hospital Avenue, Nedlands WA 6008, Australia

Edith Cowan University, Centre for Human Genetics Perth, Australia

DCTN1, EGR2, GARS, GDAP1, GARS, GJB1, IGHMBP2, IKBKAP, KIF1B, LITAF/SIMPLE, LMNA, MPZ, NEFL, NDRG1, NTRK1, PMP22, PRX, RAB7, SBF2, SPTLC1

CMT4B2, EGR2, GDAP1, MTMR2, NDRG1, PRX (Research testing for MTMR13, SBF2) Information not given

GENDA, Ciudad autonoma de Buenos Aires, Co-Director: Viviana Bernath, PhD, E-mail: [email protected] PMP22-Dup Argentina Phone: (+54) ± 11-4780-4800, Fax: (+54) ± 11-4780-4800 Co-Director: Mariana Herrera, PhD, E-mail: [email protected] Phone: (+54) ± 11-4780-4800, Fax: (+54) ± 11-4780-4800 Website: www.genda.com.ar

z Argentina

z Australia

Institution and Postal Address

Country Tested Genes

G. Hçnermund

Director, Contact Persons, Website (http://...)

z

Table 2. Laboratories without clinical departments performing genetic testing for hereditary neuropathies

242

z Canada

z Belgium

Co-Contact: Vinciane Dideberg, MD E-mail: [email protected] Co-Contact: Karin Segers MDV, PhD, E-mail: [email protected] Phone: (+32) ± 43 66 24 78, Fax : (+32) ± 43 66 22 81 Website: http://www.chuliege.be

Genetique Moleculaire, Bat B23 +3 p20, CHU Sart Tilman, 4000 Liege, Belgium

Director: Elizabeth L Spriggs, PhD, FCCMG Health Sciences Centre, Molecular Diagnostic Laboratory, Winnipeg, Manitoba, Contact: Margaret Gibb, E-mail: [email protected] Phone: (+1) ± 204 787-1024, Fax: (+1) ± 204 787-3846 Canada Website: www.hsc.mb.ca/corporate

Director: Christine Van Broeckhoven, PhD, Prof. Contact: Peter De Jonghe, MD, PhD, Prof. E-mail: [email protected] Phone: (+32) ± 3-8202499, Fax: (+32) ± 3-8202541 Website: molgen-www.uia.ac.be

Director: Gerd Utermann, MD, Prof., E-mail: [email protected] Phone: (+43) ± 512 507-3451, Fax: (+43) ± 512 507-2861 Co-contact: Andreas Janecke, MD, E-mail: [email protected] Phone: (+43) ± 512 507-3469, Fax: (+43) ± 512-507-2861 Website: info.uibk.ac.at/c/c5/c503/medbiolneu/index.html

Molecular Genetics Department (VIB8), University of Antwerp, Universiteitsplein 1, 2610 Antwerpen, Belgium

Department of Medical Biology and Human Genetics, Leopold-Franzens-University of Innsbruck, Schæpfstr. 41, 6020 Innsbruck, Austria

PMP22-Del, PMP22-Dup

EGR2, GJB1, MPZ, PMP22Del, PMP22-Dup, (further genes on research base) PMP22-Del, PMP22-Dup

EGR2, GJB1, MPZ, PMP22Dup

Appendix: genetic testing laboratories and support groups z

243

2nd School of Medicine, Charles University, DNA Laboratory, Praha 5, Czech Republic

z Czech Republic

Director: Pavel Seeman, MD; E-mail: [email protected] Phone: (+42) ± 02-2443-3300-2, Fax: (+42 ) ± 02-2443-3322 Contact: Radim Mazanec, MD; E-mail: [email protected] Phone: (+42) ± 02-2443-6866 Website: camelot.lf2.cuni.cz/funkovai/ublg/english.html

Cyprus Institute of Neurology and Genetics, Director: Kyproula Christodoulou, BSc, MSc, PhD Molecular Genetics Department, Nicosia, E-mail: [email protected] Cyprus Phone: (+357) ± 2-392649, Fax: (+357) ± 2-358238 Website. www.cing.ac.cy

GJB1, PMP22Del, PMP22-Dup

GJB1, MPZ, PMP22-Del, PMP22-Dup

Information not given

Director: Grskovic, MD, Prof., E-mail: [email protected]

z Cyprus

IKBKAP

Director: Charles Strom, MD, PhD Contact: Joy B Redman, MS, E-mail: [email protected] Phones: (+1) ± 949 728-4279, (800) 642-4657/-4279 Fax: (949) 728-4874, Website: www.questdiagnostics.com

Quest Diagnostics, Inc., Nichols Institute, San Juan Capistrano, Canada

Clinical Institute of Laboratory Diagnosis, Zagreb University School of Medicine and Clinical Hospital Center, Croatia

GJB1, SPTLC1

Director: Peter J Ainsworth, BSc, PhD, MBChB, FRCPC E-mail: [email protected] Co-Contact: J Alan Stuart, BSc, CMLTO, E-mail: [email protected] Phone: (+1) ± 519 685-8122, Fax: (+1) ± 519 685-8279 Website: www.lhsc.on.ca

London Health Sciences Centre, Molecular Diagnostic Laboratory, London, Ontario, Canada

z Croatia

Tested Genes

Country Director, Contact Persons, Website (http://...)

G. Hçnermund

Institution and Postal Address

z

Table 2 (continued)

244

Saint Joseph University, Medical Genetics Unit, Paris, France

Ruhr University, Human Genetics, Bochum, Germany

z France

z Germany

Director: Andre Megarbane, MD, PhD Contact: Valerie Delague, PhD, E-mail: [email protected] Phone: (+961) 1-614046, Fax: (+961) 1-614054 Website: http://www.usj.edu.lb

Director: Anders Bùrglum, MD, PhD, Prof. E-mail: [email protected] Phone: (+45) ± 8942 1676, Fax: (+45) ± 8612 3173 Website: www.humgen.au.dk

Director: Joerg Thomas Epplen, MD, Prof. Contact: Wolfram Klein, MD, E-mail: [email protected] Phone: (+49) ± 234-32-25764, Fax: (+49) ± 234-32-14196 Website: www.ruhr-uni-bochum.de/mhg Institute of Human Genetics, Universitåtskli- Director: Peter Propping, MD, Prof. nikum Bonn, Wilhelmstr. 31, 53111 Bonn, Contact: Brunhilde Wirth, PhD, Prof., E-mail: [email protected] Phone: (+49) ± 0228-287-2344, Fax: (+49) ± 0228-287-2380 Germany Website: www.meb.uni-bonn.de/humgen/institut.htm Director: Prof. Dr. med. Andr Reis Institute of Human Genetics, FriedrichAlexander-University, Schwabachanlage 10, Contact: Cornelia Kraus, MD, 91054 Erlangen, Germany E-mail: [email protected] Phone: (+49) ± 9131-852-6587, Fax: (+49) ± 9131/209297 Co-Contact: Bernd Rautenstrauss, PhD, E-mail: [email protected] Phone: (+49) ± 9131-852-2352, Fax: (+49) ± 9131-209297 Website: www.humgenet.uni-erlangen.de/englisch/home.html

Department of Human Genetics, The Bartholin Building, University of Aarhus, 8000 Aarhus C, Denmark

z Denmark

EGR2, GJB1, MPZ, PMP22Del, PMP22-Dup (further genes on research base)

GJB1, MPZ, PMP22-Dup

EGR2, GJB1, MPZ, PMP22Del, PMP22-Dup

EGR2, GDAP1, MTMR2, NDRG1, PMP22-Dup, PRX (further genes on research base)

Information not given

Appendix: genetic testing laboratories and support groups z

245

Samsung Medical Center, Department of Laboratory Medicine, Genetics Laboratory, Seoul 135-710, Korea

Medical Genetics Unit Saint-Joseph University, Damas street, PO BOX 11-5076, Riad El Solh 1107 2180, Beirut-Lebanon

Academic Medical Center DNA Diagnostics Laboratory Amsterdam, The Netherlands

Neuromuscular Unit, Medical Research Center, Polish Academy of Sciences, ul. Banacha 1a, 02-097 Warsaw, Poland

z Korea

z Lebanon

z Netherlands

z Poland

Laboratorio di Genetica Umana, Dipartimento di Biologia, Universita di Padova, Padova, Italy

PMP22-Del, PMP22-Dup

Information not given

IKBKAP

Information not given

Director: Marcel Mannens, PhD, E-mail: [email protected] Co-Contact: Egbert J.W. Redeker, PhD Phone: (+31) ± 20-566-7899, Fax: (+31) ± 20-691-8626 Website: www.amc.nl/index.cfm?sid=1 Director: Andrzej KochanÂski, MD, PhD, E-mail: [email protected] Fax: (+48) ± 22 658 45 01

Contact: Andr Mgarban, MD, PhD, E-mail: [email protected] PMP22-Dup, Phone: (+961) ± 1.614-046, Fax: (+961) ± 1-614.054 PRX Website: www.usj.edu.lb

Co-Directors: Sun Hee Kim, MD, PhD, Jong-Won Kim, MD, PhD Contact: Chang-Seok Ki, MD, E-mail: [email protected] Phone: (+82) ± 2-3410-2709, Fax: (+82) ± 2-3410-2719 Website: www.genetics.or.kr

Director: Paola Mandich, MD, Prof., E-mail: [email protected] Co-Contact: Emily Bellone, MD, E-mail: [email protected] Phone: (+39) ± 010 35378600/3537957, Fax: (+39) ± 010 3538978 Website: en.unige.it Contact: E-mail: [email protected]

Information not given EGR2, GDAP1, GJB1, LITAF, MPZ, PMP22Del, PMP22-Dup

Department of Biology, University of Padua, U. Bassi St. 58/B, 35121 Padova, Italy Dept. of Neuroscience, Ophthalmology and Genetics, Section of Medical Genetics and Service of Medical Genetics, c/o DIMI, Viale Benedetto XV, 6, 16132 Genova, Italy

z Italy Director: A. Cassini, PhD, Prof.

Institution and Postal Address Tested Genes

G. Hçnermund

Country Director, Contact Persons, Website (http://...)

z

Table 2 (continued)

246

z United Kingdom Department of Molecular and Cell Biology, Director: Kevin Docherty, PhD, Prof., E-mail: [email protected] University of Aberdeen, Institute of Medical Phone: (+44) ± 1224 555872, Fax: (+44) ± 1224 555844 Website: mcb1.ims.abdn.ac.uk/mcb.htm Sciences, Foresterhill, Aberdeen Scotland AB25 2ZD, UK

Information not given

Information not given

Human Molecular Genetics, Department of Clinical Research and Department of Pediatrics (G2, Lab 811), University of Bern, Inselspital, 3010 Bern, Switzerland

Director: Sabina Gallati, Prof., PhD, E-mail: [email protected] Phone: (+41) ± 31-632 94 46, Fax: (+41) ± 31-632 94 84 Website: www.cx.unibe.ch/dkf2/Humangenet/MolHum.htm

Information not given

Department of Medical Genetics, University Director: Albert Schinzel, Prof., MD, E-mail: [email protected] of Zurich, Schorenstr. 16, Phone: (+41) ± 1 655 7051, Fax: (+41) ± 1 655 7220 8603 Schwerzenbach, Switzerland Website: www.medgen.unizh.ch

GDAP1

Contact: Francesc Palau, MD, E-mail: [email protected] Co-Contact: Carmen EspinÕs, MD Phone: (+34) ± 96-339-3773, Fax: (+34) ± 96-369-0800 Website: http://www.csic.es

Laboratory of Genetics and Molecular Medicine, Instituto de Biomedicina, CSIC, C/Jaume Roig, 11, 46010 Valencia, Spain

z Switzerland

PMP22-Dup

Director: Jose I Lao, MD, E-mail: [email protected] Phone: (+34) ± 93-496-4444, Fax: (+34) ± 93-215-4838 Website: www.echevarne.com

Lab. ªDr. F. Echevarneº Department of Genetics Barcelona, Spain

GJB1, PMP22Dup

z Spain

Co-Directors: Alexander Polyakov, PhD, E-mail: [email protected] Svetlana Tverskaya, PhD, E-mail: [email protected] Phones: (+7) ± 095-727-9502, (+7) ± 095-504-3166

Research Center for Medical Genetics, DNA Diagnostics Department, Moscow, Russia

z Russia

Appendix: genetic testing laboratories and support groups z

247

Director: William K Seltzer, PhD, FACMG Contact: Kara Houde Ng, MS, E-mail: [email protected] Phone: (+1) ± 508 756-2886 ext. 3021, Fax: (+1) ± 508 753-5601 Website: http://www.athenadiagnostics.com/site/content/index.asp Director: Sau W. Cheung, PhD Contacts: Patricia Robbins-Furman, MPH, Patricia A Ward, MS, Eric S Schmitt, MS, PhD E-mail: [email protected] Phones: (800) 411-GENE, (+1) ± 713 798-6555, Fax: (+1) ± 713 798-6584 Website: www.imgen.bcm.tmc.edu/medgen/ klebergcytogenetics.htm Director: Aubrey Milunsky, MD, DSc Contact: Maureen Flynn, MS Phone: (+1) ± 617 638-7083, Fax: (+1) ± 617 638-7092, Website: www.bumc.bu.edu/Departments/HomeMain.asp? DepartmentID=118 Co-Directors: D Alexa Sirko-Osadsa, PhD, FACMG, Elizabeth Rohlfs, PhD, Lynne Rosenblum-Vos, PhD, Stephanie Hallam, PhD Contacts: Jennifer D Teicher, MS, CGC, Amy Merrill, MS, CGC Phone: (1-800) 255-7357, Fax: (+1) ± 508 389-5549 Website: www.genzymegenetics.com

Athena Diagnostics, Inc., Reference Lab, Worcester, MA, USA

z USA

Genzyme Genetics, Molecular Diagnostic Laboratory, Westborough, MA

Boston University School of Medicine, Center for Human Genetics, Boston, MA, USA

Baylor College of Medicine, Kleberg Cytogenetics Laboratory Houston, TX, USA

Director, Contact Persons, Website (http://...)

Institution and Postal Address

IKBKAP

IKBKAP, PMP22Del, MPZ

EGR2, GJB1, MPZ, NEFL, PMP22-Del, PMP22-Dup, PRX IKBKAP, PMP22Del, PMP22-Dup

G. Hçnermund

Country Tested Genes

z

Table 2 (continued)

248

Director: Jeffery M Vance, MD, PhD Contact: Jeffrey Mark Stajich, PA-C, E-mail: [email protected] Phones: (800) 283-4316 opt 8, then 3, (+1) ± 919 684-0622, Fax: (+1) ± 919 684-0950 Website: wwwchg.mc.duke.edu

PMP22-Dup Duplication or point mutation screening for PMP22 PMP22-Del Deletion screening for PMP22

New York University Medical Center, Molecular Genetics Laboratory New York, NY, USA

Director: Harry Ostrer, MD Contact: Elsa Reich, MS, E-mail: [email protected] Phone: (+1) ± 212 263-6603, Fax: (+1) ± 212 263-7590 Website: www.med.nyu.edu/genetics Director: Warren G Sanger, PhD University of Nebraska Medical Center, Human Genetics Laboratory, Munroe-Meyer Contact: Bhavana J Dave, PhD, E-mail: [email protected] Phone: (+1) ± 402 559-9914, Fax: (+1) ± 402 559-7248 Institute, Omaha, NE, USA Website: www.unmc.edu/services/geneticslab

Duke University Medical Center, Center for Human Genetics, Durham, NC, USA

PMP22-Dup

EGR2, GARS, GDAP1, KIF1B, MTMR2, NEFL, NDRG1, PRX, RAB7 (Research testing: CMT4B2 (MTMR13| SBF2) IKBKAP

Appendix: genetic testing laboratories and support groups z

249

Address: 1 Springbank Dr., St. Catharines, Ontario, Canada L2S 2K1, Contact: Linda Crabtree Phone: (+61) ± 905-687-3630, Fax: (+61) ± 905-687-8753, E-mail: [email protected] Website: www.cmtint.org

Address: 132 Ontario St, Guelph, Ontario N1E 3B4, Canada Phone: (+1) 519-821-0300, Fax: (+1) 519-821-1330, E-mail: [email protected] Contact: Manon Labelle, Address: 964, Dosquet, Longueuil, Quebec, J4L 3V5, Canada Phone: (+1) ± 514 679-8261

Charcot-Marie-Tooth International

Charcot-Marie-Tooth Association Australia Inc. (CMTAA)

Steirische Gesellschaft fçr Muskelkranke

CMT-Belgium

Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth Quebec

z International

z Australia

z Austria

z Belgium

z Canada

Muskelsvindfonden

Contact, Website (http://...)

Institution

Country

z Denmark

G. Hçnermund

Address: Kongsvang Alle 23, 8000 ârhus C, Denmark Phone: (+45) ± 8948 2222, Fax: (+45) ± 8948 2212, E-mail: [email protected] Website: www.muskelsvindfonden.dk

President: Nelly Cools, Address: Quinten Matsijslaan 33, 2280 Grobbendonk, Belgium Phone: (+32) ± 14 51 79 44 Co-Contact: Alexander Leysen, Address: Lievevrouwestraat 27, 2520 Ranst, Belgium Phone: (+03) ± 4751271 Secretary: Maria Saey, Address: Bareldreef 100, B2880 Bornem, Belgium Phone/Fax: (+32) ± 3 889 03 99

Co-Contact: Mag. Sabine Bayer, Address: Pomisgasse 13/2, 8010 Graz, Austria Phone/Fax: (+43) ± 316 81 43 84, E-mail: [email protected] Co-Contact: Elke Trummer, Mçhlgasse 6, 8330 Feldbach, Austria Phone: (+43) ± 31 52 27 22, Fax: (+43) ± 31 52 43 40 16, E-mail: [email protected] Website: www.krv.at/muskel

Address: Building 51, Concord Hospital, Concord 2139 NSW, Australia Phone: (+02) ± 97675105, Fax: (+02) ± 97675167, E-mail: [email protected] Website: e-bility.com/cmtaa/index.php

z

Table 3. Support organizations, foundations and Internet resources

250

Muscular Dystrophy Ireland

CMT International Israel

President: Fiorenzo Pavanati, E-mail: [email protected] Vice-President: Rita Ricco, E-mail: [email protected] Secretary: Dario Ceroni, E-mail: [email protected] Phone: (+39) ± 445-396127, Website: www.acmt-rete.it/pãcmt-rete/acm_000_main.html Associazione Italiana malattia President: Paolo Vinci, M.D., E-mail: [email protected] Co-Contact: E-mail: [email protected] di Charcot Marie Tooth Website: utenti.lycos.it/cmt99/index.htm (A.I.C.M.T.)

z Ireland

z Israel

z Italy

Associazione Charcot Marie Tooth (ACMT) ± Rete

CMT Germany www.hmsn.de www.hmsn.org

z Germany

Contact: Elana Shapiro, Address: Hagome 14/36 Gilo, Jerusalem, Israel 93856

Address: Coleraine House, Coleraine Street, Dublin 7, Ireland, Phone/Fax: (+353) ± 1 872 1501 E-mail: [email protected], Website: www.mdi.ie

Contact: Werner Stecher, Address: Warthestr. 32, 31582 Nienburg, Germany Contact: Sandra Conze, Address: Aachen, Germany, E-mail: [email protected] Contact: Gerhard Wenske, Address: Vor dem Nordhees 2, 38644 Goslar, Germany E-mail: [email protected], Website: www.hmsn.de

Address: Låntinen Pitkåkatu 35, 20100 Turku, Finland Phone: (+358) ± 2 273 9700, Fax: (+358) ± 2 273 9701, E-mail: [email protected] Website: www.lihastautiliitto.fi

Finnish Muscular Disorders Association

z Finland

Address: 7 rue du Pied des Fourches, 23270 Chatelus Malvaleix, France Co-Contact: Bernadine Robert, Address: 39 Rue de la Foret, 41200 Romorantin, France Phone/Fax (+33) ± 54 76 39 62, E-mail: [email protected] Co-Contact: Philippe de Maisonneuve, Address: 32, rue de la Grande Mauffinee, 49240 Avrille, France, E-mail: [email protected] Website: crealinks.net/cmt-france

CMT France

z France

Appendix: genetic testing laboratories and support groups z

251

CMT International New Zealand Muscular Dystrophy Association of New Zealand Inc.

Muscular Dystrophy Founda- Address: PO Box 1535, Pinegowrie 2123, Phone/Fax: (+27) ± 011 789-7634 Website: www.mdsa.org.za tion of South Africa

Associacion Espanola Address: Gran via de Les Corts Catalanes, 562 Pral 2, 08011 Barcelona, Spain De Enfermedades Musculares Phone: (+93) ± 451 65 44, Fax: (+93) 451 69 04 (ASEM) Contact: Manuel Becerra, Address: Francisco Navacerrada no 12, 28028 Madrid, Spain Phone: (+93) ± 91 361 38 95

z New Zealand

z South Africa

z Spain

Contact: Gaile Fornusek, Address: P.O. Box 260, Thames, New Zealand Phone/Fax: (+64) ± 7 8687677, E-mail: [email protected] Address: 7A Taylors Road, Morningside, PO Box 16-238, Sandringham, Auckland 1030, New Zealand, Phone: 0800 800337, (+09) ± 815 0247, Fax: (+09) ± 815 7260, E-mail: [email protected] Website: www.mda.org.nz

Address: Vredehofstraat 31, 3761 HA Soestdijk, The Netherlands Phone: 035-6034040, Fax: 035-6027440 Website: www.vsop.nl Address: Lt.Gen. van Heutszlaan 6, 3743 JN Baarn, The Netherlands Phone: (+31) ± 35-548 04 80, Fax: (+31) ± 35-548 04 99, E-mail: [email protected] Website: www.vsn.nl/index.html

Vereniging Samenwerkende Ouder- en PatiŸntenorganisaties Dutch Neuromuscular Diseases Association, Vereniging Spierziekten Nederland (VSN)

z Netherlands

Address: c/o Muscular Dystrophy Group-Malta, 4 Gzira Road, Gzira GZR 04, Malta Phone: (+356) ± 21 346 688, Fax: (+356) ± 21 318 024 Website: www.eamda.com

European Alliance of Neuromuscular Disorders Associations (EAMDA)

z Malta

Address: Direzione Nazionale, Via P.P. Vergerio, 17, 35126 Padova, Italy Phone: (+39) ± 4949-757361, Fax: (+39) 49-757033 Vice-President: Catello Labriola, E-mail: [email protected] Website: www.uildm.org

Unione Italiana Lotta Alla Distrofia Muscolare (U.I.L.D.M.)

Country Contact, Website (http://...)

G. Hçnermund

Institution

z

Table 3 (contiuned)

252

Website: users.rcn.com/smith.ma.ultranet/CMTneto.html Address: Crozer Mills Enterprise Center, 601 Upland Avenue, Upland, PA 19015, USA Phone: (+1) ± 610-499-7486 or 800-606-CMTA, E-mail: [email protected] or [email protected] Website: www.charcot-marie-tooth.org/site/content/index.asp Address: P.O. Box 287103, New York, NY 10128, USA, Website: www.hereditaryneuropathy.org Contact: [email protected], Website: www.hnpp.org/index.htm

CMTnet Charcot-Marie-Tooth Association

z USA

Hereditary Neuropathy Foundation hnpp.org

CMT International UK

Secretary: Karen Butcher, Address: PO Box 5089, Christchurch, BH23 2WJ, UK Phone: 0870 7744 314, E-mail: [email protected], Website: www.cmt.org.uk Adress: 121 Lavernock Road, Penarth, South Glamorgan Wales, CF64 3QG, UK Phone: (+44) ± 1222 709537, E-mail: [email protected] Secretary: Mrs. Margaret Read, Phone (+44) ± 1222 709537 Contact: Annette Masser, Address: 11 Brinsons Close, Burton, Christchurch, Hants BH23 7HS, UK Phone (+44) ± 1202 476334

CMT United Kingdom

z UK

Contact: Trudi Sulzberger, Address: Beatrice Wege 11, 3600 Thun, Switzerland Phone: (+41) ± 033 2228142 Contact: Karin Oberhansli, Address: Winterthurerstrasse 30, 8610 Uster, Switzerland Phone: (+41) ± 01 940-5072

CMT Regionalgruppe Bern und Umgebung CMT Regionalgruppe Zçrich und Ostschweiz

z Switzerland

Appendix: genetic testing laboratories and support groups z

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Subject Index

A Abductor hallucis longus muscle 32 Abductor pollicis longus muscle 208 ACCPN, see Anderman syndrome Achilles tendon 25 Acoustically evoked potentials, see AEP Adherens junction 9 AEP 33, 34, 86, 137, 181, 182 Agenesis of the corpus callosum with peripheral neuropathy (ACCPN), see Anderman syndrome ALS, see amyotrophic lateral sclerosis Amitriptyline 203 Amniocentesis 196 Amyloidosis 162 Amyotrophic lateral sclerosis 149, 202 Anderman syndrome 82, 86 Angiokeratoma, cutaneous 27 Anhidrosis 161, 165±167, 181 Ankyrin G 8 Anterior horn 62, 136 ± of the medulla 58 Anterior tibial muscle 75 Antioxidants 202 Antiprogesterone 200, 202 AOA2, see Ataxia-oculomotor apraxia syndrome type 2 Apnea 163 AR-CMT2 59, 126 ARHGEF10 gene 77, 124, 135, 182 Arrhythmia, cardiac 24 27 Arthropathy, neurogenic 24 Ascorbic acid 74 Ataxia 93, 103, 164, 216 Ataxia-oculomotor apraxia syndrome type 2 153 Atherosclerosis 162 Autonomic dysfunction 3 Autosomal recessive CMT2, see AR-CMT2

Axillary nerve Axon 4

33, 170, 173

B Berardinelli-Seip congenital lipodystrophy gene, see BSCL2 gene Beta-catenin 7±9 Blink reflex 32 Botulinum toxin 203 Brachial plexus neuropathy (BPN), see also sporadic brachial plexus neuropath 174 Brachial plexus 26, 37, 93, 170, 173±175 Brainstem 3, 15 BSCL2 gene 80, 151 Bungner's bands 134 C Cadherin/catenin complex 9 Calcaneocuboid joint 212 Calnexin 99 Carbamazepine 203 Carotid sinus massage 160 Carpal tunnel 26, 93, 208 ± syndrome 19, 94 Caspr1 8, 9 Caspr2 9 Cataract 182 Cauda equina 209 CCFDN 77, 104, 105, 107, 108, 182 Central nervous system 6, 8, 15, 22, 25, 33, 38, 62, 85, 137, 158, 163, 179, 181 Cerebellum 164 Cerebrospinal fluid, see CSF CH 30, 35, 48±50, 56, 77, 82, 93±95, 100, 101, 106, 107 CH and Hirschsprung disease 82, 87 Charcot, J. M. 73

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Subject Index

Charcot's joints 163 Charcot-Marie-Tooth disease, see CMT Charcot-Marie-Tooth disease type I, see CMT1 Chiari osteotomy 209 Chopart's joints 221 Chorea Huntington 196 Chorionic villous sampling 196 Chronic inflammatory demyelinating polyneuropathy (CIDP) 26, 30, 37, 41, 95 Ciliary neurotrophic factor receptor gene, see CNTFR gene CIPA (Congenital insensitivity to pain and anhidrosis) 165, 181 CK, see creatine kinase Claudin 9 Clawhand 208 Claw-like hands 132 Clawtoes (see also hammertoes) 74, 92, 211, 216, 218, 221 Cleft palate 26, 174 Clonidine 164 CMAP 30±32, 34±37, 75, 86, 88, 94, 95, 104, 129, 130, 132, 137, 161, 163, 165, 166, 175, 183 CMD1A (Cardiomyopathy with atrioventricular conduction defect) 131 CMT 16, 18, 20, 22, 24, 25, 41, 48, 92, 94, 209 CMT Russe, see also HMSN Russe (HMSN-R) 108 CMT1 20, 21, 23, 27, 30±32, 34, 44, 48, 49, 51, 74±76, 92±96, 100, 101, 103, 107, 108, 121, 129, 133, 134, 137, 183, 195, 196, 199, 200, 202, 207, 209, 217 CMT1A 18, 22, 44±48, 74, 76, 92, 95±98, 102, 126, 136, 170,184±186, 188, 189, 199, 200, 202, 211, 227, 229±231 CMT1A-REP 97, 98, 185, 187 CMT1B 18, 46, 47, 76, 92, 94±96, 100, 102, 126, 202 CMT1C 48, 76, 92, 94±96 CMT1D 48, 76, 92, 93, 95, 96, 182 CMT1F 76, 93, 129 CMT2 18, 20, 23, 30, 32±34, 58, 59, 63, 75, 78, 86, 96, 100, 121, 126, 133, 134, 137, 183, 199, 202 CMT2A 33, 122, 127 CMT2A1 78, 126, 127 CMT2A2 78, 126, 233 CMT2B 23, 78, 122, 127, 161, 181, CMT2B1 79, 123, 131, 234

CMT2B2 79, 123, 131 CMT2C 22, 78, 122, 128, 152 CMT2D 19, 22, 78, 122, 128, 151, 181 ± overlap type 146 CMT2E 33, 59, 63, 78, 101, 106, 122, 128, 133, 233 CMT2F 78 ,122, 129, 149 CMT2G 78, 123, 130 CMT2H 79, 123, 131 CMT2I 79, 123, 130 CMT2J 79, 123, 130, 133, 135 CMT2K 79, 123, 131 CMT2L 79, 130 CMT3 121 CMT4 18, 20, 22, 24, 32, 46, 52, 76, 121 CMT4A 52, 53, 76, 104, 105, 132, 133, 182 CMT4B 55, 104, 105 CMT4B1 52, 53, 76, 106, 182 CMT4B2 53, 76, 106, 182 CMT4C 55, 77, 104±106, 126, 131, 133, 182 CMT4C1 79, 123, 131, 181, 182, 233 CMT4C2 79, 123, 131 CMT4C3 79, 132 CMT4C4 79, 105, 123, 126, 132 CMT4C5 123 CMT4D 55, 77, 104, 105, 107, 181, 182 CMT4E 56, 77, 104, 105, 107, 182 CMT4F 56, 77, 104, 105, 107, 157, 181, 182, 232 CMTDI1 124 CMTDI2 124 CMTDI3 124 CMTX 18, 20, 22, 23, 30, 33, 34, 53, 56, 79, 121, 126, 136, 181±183, 195, 199, 202, 203, 232 CMTX1 56, 57, 79, 125, 137 CMTX2 57, 79, 125, 138 CMTX3 79, 125, 139 CMTX4 79, 125, 139 CNS, see central nervous system CNTFR gene 154 CNX, see calnexin Compacted myelin 5±7 Complex repetitive discharges 33 Compound motor action potential, see CMAP Conduction block 37, 95 Congenital cataract facial dysmorphism neuropathy, see CCFDN Congenital hypomyelination, see CH

Subject Index Congenital insensitivity to pain and anhidrosis, see CIPA Connexin 31, see GJB3 Connexin 32, see GJB1 Contactin 7, 8 Contactin-associated protein 1, see Caspr1 Contactin-associated protein 2, see Caspr2 Conus medullaris 209 Corneal ulcers 164 Corticosteroids 200, 202 Cost of genetic testing 184 Cough 162 Cowchock syndrome (see also CMTX4) 79, 125, 139 Cramps 73, 124 Cranial nerve 101, 123, 165, 173, 182 Cranial nerve hypertrophy 93 Creatine kinase 124, 136, 146 Crossing over 185, 187 CSF 75, 94, 175 CTDP1 gene (C-terminal domain phosphatase of RNA polymerase II gene) 77, 102, 107, 182 Cutis marmorata 163, 166 Cx31, see GJB3 Cx32, see GJB1 D DCTN1 gene 80, 147, 153, 181, 182 Deafness (see also hearing loss) 87, 92, 94, 130, 137 Deep peroneal nerve 61 Djerine-Sottas syndrome, see DSS Delayed rectifying potassium channels (Kv1.1, Kv1.2) 9 Deltoid muscle 170 Dementia 85 Demyelination 16, 45, 46, 51, 57±59, 61, 95, 126, 134, 135, 200±202, 229±232 Denaturating high performance chromatography, see DHPLC Desipramine 203 DHH gene (desert hedgehog gene) 82, 88 dHMN 146, 179 dHMN I 147±150, 181 dHMN II 147, 149, 150, 181 dHMN III 147, 150 dHMN IV 147, 150

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dHMN V 147, 181 dHMN Va 151 dHMN Vb 151 dHMN VI 146, 147, 150, 152, 153, 181, 182 dHMN VII 181, 182 dHMN VIIa 147, 152 dHMN VIIb 147, 153 dHMN Jerash type 147, 154 dHMN pyramidal 153 DHPLC 190 Diabetes mellitus 124, 136, 162, 184 Diabetic neuropathy 27 Diaphragm 32, 122, 147, 150, 152, 181, 182 DI-CMT 34, 77, 121, 124, 133, 231 DI-CMTA 77, 124, 134 DI-CMTB 77, 124 DI-CMTC 77, 124, 134 DI-CMTD 77, 135, 182 Dilated cardiomyopathy with atrioventricular conduction defect, see CMD1A DI-slowed nerve conduction velocities without CMT neuropathy 135 Distal HMN, see dHMN and HMN Distal motor latency (DML) 33, 34 DNA sequencing 189 Dome-osteotomy 218 Dominant Dunnigan type familial partial lipodystrophy, see FPL Dominant intermediate CMT, see DI-CMT Dominant limb girdle muscular dystrophy type 1 B, see LGMDB1 Dorsal funiculus 136 Dorsal root ganglion 3, 58, 60, 87, 130, 136, 158, 161, 164, 166 Dorsal stabilization 209 DSS 18, 20, 22, 23, 24, 27, 30, 34, 35, 44, 48, 49, 56, 73, 93±95, 100±102, 108, 121, 209, 231 Dunnigan type familial partial lipodystrophy, see FPL Dwyer calcaneal osteotomy 219 Dynactin-1 gene, s. DCTN1 gene Dynamic pedography 213 Dynein 153 Dysarthria 136 Dysmyelination 231 Dysphagia 136 Dystroglycan-dystrophin related protein2 complex 107

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Subject Index

E Early growth response element 2 gene, see EGR2 gene E-cadherin 5, 7±9 EDMD2 131 EEG 86 EGR2 gene 49, 50, 56, 76, 77, 93, 96, 100, 101, 102, 107, 182 EGR zinc-finger transcription factor 48 Electromyography 31, 32, 35±37, 104, 126, 130, 146, 162, 175, 183, 195, 206, 208 Emery-Dreifuss muscular dystrophy, see EDMD2 EMG, see electromyography 86 Endoplasmatic reticulum 98 Epicanthal folds 26, 173, 174 Equinocavovarus deformity 206 Erb's point 175 Erectile dysfunction 199, 203 ERM proteins (ezrin, radixin, moesin) 8 Evoked potentials 31 Extensor digitorum brevis muscle 25, 32 Extensor digitorum communis muscle 208 Extensor digitorum longus muscle 212 Extensor hallucis brevis muscle 211 Extensor hallucis longus muscle 211, 218 Extensor indicis muscle 208 Extensor pollicis brevis muscle 208 Extensor pollicis longus muscle 208 External fixators 222 F F-actin 8 F-waves 31, 32 Fabry's disease 27, 197 Facial dysmorphism 182 Facial nerve 32, 33, 173 Facioscapulohumeral muscular dystrophy 25 Familial amyloid polyneuropathy, see FAP 42 Familial dysautonomia (FD), see HSAN3 FAP 44 Fasciculations 33, 73, 136

Fibrillation potential 31, 33, 35, 36 Fibroblast 4, 42 FISH 185, 186, 188 Flexor digitorum brevis muscle 211 Flexor digitorum longus muscle 211 Flexor digitorum superficialis muscle 208 Flexor hallucis longus muscle 211, 218 Fluorescence in situ hybridisation, see FISH 185 Friedreich ataxia 25 Fundoplicatio 164 G Gabapentin 203 Gait analysis 213 GAN 23, 24, 38, 62, 63, 81, 85, 86 Ganglioside-induced differentiation associated protein 1 gene see GDAP1 gene Gap junction protein beta 1, see GJB1 Gap junction protein beta 1 gene, see GJB1 gene Gap junction protein beta 3, see GJB3 Gap junction protein beta 3 gene, see GJB3 gene GARS gene 58, 78, 80, 122, 128, 148, 181 Gas3 gene, see PMP22 gene Gasserian ganglion 164 Gastrocnemii muscles 212 Gastrotomy 164 GDAP1 gene 52, 53, 59, 76, 79, 102, 105, 106, 121, 123, 124, 126, 132, 133, 182 Gene dosage 98, 186, 187 Gene targeting 227, 229, 232, 233 Giant axonal neuropathy, see GAN Giant axons 59, 63, 86 Gigaxonin (see also GAN) 62, 85, 86 GJB1 gene 8, 34, 56, 57, 79, 101, 121, 125, 126, 136, 137, 181, 183, 192, 195, 202, 232 GJB3 gene 82, 87, 88 Glucosyl-ceramide 60 Glutathione S-transferase 106 Glycyl-tRNA synthetase gene, see GARS gene Golgi apparatus 98, 99 g-ratio 44, 49, 51, 53 Great auricular nerve 92 Growth arrest-specific 3 gene, see Gas3 gene

Subject Index GTPase mitofusin 2 gene, see MFN2 gene 33, 58 Guillain-Barr syndrome 16 H Hammertoes (see also clawtoes) 16, 20, 23±26, 139 Hearing loss (see also deafness) 22, 24, 87, 123, 139, 162 Heat shock protein 27 gene, see HSP27 gene Helal procedure 219 Hepatomegaly 27 Hereditary motor and sensory neuropathy proximal type, see HMSN-P Hereditary motor and sensory neuropathy, see HMSN Hereditary motor neuropathy, see HMN (dHMN) 19 Hereditary motor neuropathy type 5, see HMN (dHMN) V Hereditary neuralgic amyotrophy, see HNA Hereditary neuropathy with liability to pressure palsy, see HNPP Hereditary sensory and autonomic neuropathy, see HSAN Hereditary sensory and autonomic neuropathy type 1, see HSAN1 Hereditary sensory neuropathy 2 gene, see HSN2 gene Hereditary spastic paraplegia 25 Hereditary spastic paraplegia type 17 151 Hip dysplasia 206, 209 Histamine axonal flare test 160 HIV-associated neuropathy 27 HMN (dHMN) I 80 HMN (dHMN) II 80 HMN (dHMN) IV 80 HMN (dHMN) Jerash type 80 HMN (dHMN) pyramidal/ALS4 80 HMN (dHMN) V 19, 22 HMN (dHMN) Va 80 HMN (dHMN) Vb 80 HMN (dHMN) VI 80 HMN (dHMN) VIIA 80 HMN (dHMN) VIIB 19, 22, 80 HMN (dHMN) 20, 22, 23, 25, 62 HMSN 19, 34, 35, 37, 44, 179 HMSN I 74, 92, 195, 196 HMSN II, see CMT2 74, 83

HMSN III, see DSS 73, 75, 93 HMSN IV, see Refsum's disease HMSN V 83 HMSN VI 83 HMSN VII 83 HMSN/ACC see Anderman syndrome HMSN-L (HMSN-Lom), see CMT4D HMSNO 124 HMSN-P 18, 22, 78, 124, 136 HMSN-Russe (HMSN-R) 77, 104, 105 HNA 19±22; 26, 37, 63, 81, 170, 175, 179, 183 HNPP 16, 18±23, 26, 30, 37, 44, 50±52, 63, 70, 76, 93, 94, 96±98, 175, 179, 182±189, 201, 229 Hoarseness 33, 152, 173 Hohmann procedure 219 HSAN 20, 27, 30, 35, 59, 81, 122, 127, 157, 179, 203 HSAN1 20, 23, 27, 36, 59, 60, 81, 157, 158, 161, 162, 181 HSAN2 23, 24, 60, 81, 157, 158, 160, 163 HSAN3 23, 36, 61, 81, 157, 158, 160, 163, 164, 181, 182 HSAN4 23, 36, 61, 81, 157, 159, 160, 165, 167, 181 HSAN5 36, 61, 157, 159, 166, 167, 181 HSBP1 gene, see HSP27 gene HSBP8 gene, see HSP22 gene HSN 35, 81, 157, 203 HSN1 81 HSN2 gene 81, 163 HSP 83 HSP22 gene 79, 80, 130, 131, 149, 181 HSP27 gene 58, 78, 80, 129, 148, 149, 181 Huntington's disease, see Chorea Huntington Hypercapnia 164 Hyperhidrosis 161 Hyperlipidemia 124, 136 Hypermyelination 56 Hyperpyrexia 165 Hypertension 158, 163 Hypertrophic neuropathy 23 Hypertrophy of peripheral nerves 92 Hypoglossal nerve 93 Hypohydrosis 16 Hypotelorism 26, 173, 174 Hypotension 158, 164, 166 Hypotonia 163 Hypoxia 164

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Subject Index I

Ichthyosis 24 IGHMBP2 gene 80, 147, 150, 152, 153, 181, 182 IKBKAP gene 61, 81, 164, 165, 181, 182 Ilizarov method 222 Imhåuser osteotomy 217, 221 Immunoglobulin l-binding protein 2 gene, see IGHMBP2 gene Immunotherapy 18 Infantile neuroaxonal dystrophy 85 Inhibitor of kappa light polypeptide gene, see IKBKAP gene Inner mesaxon 7 Insomnia 163 Intellectual impairment (see also mental retardation) 137, 181, 182 Intermediate line 6 Internodal segment 50 Internode 5, 6, 7, 43, 46, 58 Interossei muscles 207, 212 Interphalangeal joints 207 Intertarsal joint 220 Intraperiod line 99 IP joint 215, 218 Ischiatic nerve 87 J Jahss procedure 220 Jones procedure 218, 219 Juxtaparanodal region 5, 9 K KIAA1985 gene 102, 106, 182 KIF1B(b) gene 58, 59, 78, 122, 127, 232 Kinesin motor protein 1 B gene, see KIF1B(b) gene Krox20 gene 100, 101 Kyphoscoliosis (see also scoliosis) 24, 131, 164 Kyphosis 209 L Lacrimation 158, 164 Lambrinudi triple osteotomy 209 LaMiN A/C gene, see LMNA gene Laminectomy 209 Large motor unit potentials 33 Lasso loop operation 208

Lepromateous neuropathy 27 Leprosy 26, 162 LGMDB1 131 Limb girdle muscular dystrophy type 1 B, see LGMDB1 Lipoic acid 200, 202 Lipopolysaccharide-induced tumor necrosis factor gene, see LITAF/ SIMPLE gene LITAF/SIMPLE gene 48, 76, 92, 96, 100, 102 LMNA gene 59, 79, 123, 131, 181, 233, 234 Long thoracic nerve 22, 26, 170 L-periaxin 56, 107 Lumbosacral plexus 173 Lumbricales muscles 212 Lymphomatous polyneuropathy 26 M MAG gene 4, 99, 101 Major dense line 6, 99 Marinesco-Sjogren syndrome 108 Maryland Foot Score (MFS) 215 MBP gene 6, 99, 101 MCP joint fusion 208 MCP joints 207 Median nerve 26, 29, 34, 45, 94, 104, 128, 129, 175, 207, 208 Medulla oblongata 158 Meiosis 185, 187 Menkes disease 85 Mental retardation (see also intellectual impairment) 125, 138, 139, 157, 159, 181, 197 MEP 34 Merlin 8 Mesaxon 52 Metacarpophalangeal joints, see MCP joints Metachromatic leukodystrophy 85 Metatarsal joints 212 Metatarsophalangeal joints, see MTP joints Metronomic breathing 160 MFN2 gene 33, 58, 78, 126, 127 Minifascicular neuropathy 82 Minor sweat test 160 Mitchell procedure 219 MITE, mariner transposon-like element 97 Mitofusin 2 gene, see MFN2 gene

Subject Index MNCV 32, 34, 36, 37, 73, 74, 86, 94, 95, 104, 121, 126, 128, 130, 131, 133, 134, 137, 146, 161±166, 175, 183 Monoclonal gammopathy 44 Morphometry 44 Motor evoked potentials, see MEP Motor nerve conduction velocity, see MNCV Motor neuron disease 15 Motor unit action potential, see MUAP MPZ gene 6, 46, 49, 50, 58, 76, 77, 87, 97, 92, 96, 99, 100±102, 108, 121, 123, 124, 126, 130, 133, 135, 183, 200, 201, 202, 231 MRI (magnetic resonance imaging) 137, 164, 165, 175, 182, 184, 209, 213 MTM1 gene 106 MTMR2 gene 53, 76, 102, 106, 182 MTMR13 gene 53, 76, 102, 106, 182 MTP joints 213, 215 MUAP 38 Multifocal acquired demyelinating sensory and motor neuropathy 26 Multifocal motor neuropathy 26 Multiple mononeuropathy 16 Muscle atrophy 22 Muscle biopsy 32, 147 Muscle cramps 124, 136 Myelin 3, 5, 46, 47, 49, 52, 53, 56, 58, 59, 85, 95, 98±100, 105, 107, 134, 137, 138, 161, 181, 182, 227 Myelin associated glycoprotein, see MAG Myelin basic protein, see MBP Myelin outfoldings 545 Myelin protein zero (P0), see MPZ Myelin sheath 4, 6±8, 43, 44, 46, 47, 49, 50, 52, 55, 57, 58, 105, 107, 135 Myelination 4, 6, 99, 100, 102 Myopathy 15 Myotonia 229 Myotonic dystrophy 25 Myotubularin related protein-2 gene, see MTMR2 gene Myotubularin related protein-13 gene, see MTMR13 gene N NCV 30±33, 35, 37, 38, 44, 74, 86, 88, 94, 102, 104, 121, 124, 129, 132, 138, 182, 200, 228, 229 NDRG1 gene 77, 102, 107, 181, 182

z

NEFL gene 33, 58, 59, 63, 76, 78, 93±96, 101, 102, 106, 121, 122, 126, 129, 133, 233 Nerve biopsy (see also sural nerve biopsy) 18, 41, 62, 86, 95, 104, 105, 131, 134, 135, 162, 163, 175, 185 Nerve conduction studies 29, 31, 36, 37 Nerve conduction velocity, see NCV Nerve growth factor, see NGF Neurofibromatosis 2 gene 8 Neurofilament light chain gene, see NEFL gene Neurofilament 50, 62, 102, 129, 149 Neuromuscular junction 9 Neuropathy, acquired amyloid 27 ±, diabetic 27 ±, HIV-associated 27 ±, lepromateous 27 ±, minifascicular 82 ±, Neuropathy, toxic 63 ±, transthyretin amyloid 27 ±, vasculitic 27 Neurotrophin receptor tyrosine kinase 1 gene, see NTRK1 gene Neurotrophin3 200, 201 NGF 61, 166, 167 NGF high affinity receptor TRK1 gene 61 NGF beta gene, see NGFB gene NGFB gene 61, 81, 166, 167 n-hexane 85 Ninhydrin test 160 N-myc downstream regulated gene 1, see NDRG1 gene Nodal region 5, 8, 57 Node of Ranvier 5, 8, 43, 56, 57, 138 Nonaka myopathy 25 NTRK1 gene 61, 81, 165, 166, 167, 181 Nystagmus 85 O Onapristone 202 Onion bulb 44±46, 48, 49, 51±53, 55±58, 95, 104, 126, 134±136, 209, 230, 231 Opponensplasty 208 Optic atrophy 22, 24 Optic nerve 164 Osteolysis 24 Osteomyelitis 24, 161, 163, 165 Osteotomy 209, 216 Outer mesaxon 7

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Subject Index

P P0 (myelin protein zero), see MPZ Pain, neuropathic 18 Palmaris longus muscle 208 Palmitoyltransferase-1 gene, see SPTLC1 gene Papillary dysfunction 123 Paranodal region 5, 8, 9, 56, 57, 134 Paranodal segment 50 Parsonage-Turner syndrome, see sporadic brachial plexus neuropathy Parvovirus B19 170 Patella 210 PCR 185, 188, 189 Pedography, dynamic 213 Periaxin gene, see PRX gene Peripheral myelin protein 22, see PMP22 Peroneal muscles 22, 73, 74, 211, 216 Peroneal nerve 26, 29, 36, 37, 104, 209 Peroneus brevis muscle 210, 212, 219 Peroneus longus muscle 210, 211, 219 Perspiration 158, 163 Pes cavovaroadductus 219, 220 Pes cavovarus 210 Pes cavus 16, 20, 23±26, 74, 92, 94, 126, 128, 138, 139, 148, 151, 154, 203, 204, 210, 215 Pes planovalgus 211 Pes valgus 211 PFGE 186 Phrenic nerve 32, 33, 173 Physiotherapy 18 Phytanic acid 83 Planovalgus deformity 211 PLP, see Proteolipoproteine PMP22 6, 41, 51, 52, 87, 98, 99, 137, 186, 200±202, 228, 229 PMP22 gene 6, 41, 46, 49±52, 76, 87, 92, 94, 96, 98, 99, 101, 102, 108, 126, 137, 185±189, 199±202, 227±231 Polyacrylamide 85 Polymerase chain reaction, see PCR Polyneuropathy 15 Polyphasic motor unit action potential 36 Pons 158 Positive sharp waves 31, 33, 35 Potassium channels 9 Prenatal testing 185, 196 Progesterone 74 Proteolipidproteine (PLP) 87

PRX gene 49, 56, 77, 101, 102, 107, 157, 181, 182, 232 Pseudoarthrosis 221 Pudendal nerve 199 Pulsed field gel electrophoresis, see PFGE Pyrexia 157±159, 165 Q Quadriceps femoris muscle

210

R RAB7 gene 58, 78, 122, 127, 181 Radial cutaneous nerve 41 Radial nerve 37, 165, 207 RAS-related GTP binding protein 7 gene, see RAB7 gene Recessive intermediate CMT, see RI-CMT Reflux, gastroesophageal 162, 164 Refsum's disease 24, 25, 27, 83, 197 Rehabilitation 206 Remyelination 45, 51, 52, 59, 61, 95, 107, 134, 135, 230 Renal failure 27 Repetitive discharges 35 Respiratory failure 22 Reticular formation 158 Retinitis pigmentosa 24, 83 Reverse transcription 189 Rho guanine nucleotide exchange factor 10 gene, see ARHGEF10 gene RI-CMT 124 Riley-Day syndrome, see HSAN3 RLS, see Roussy-Levy syndrome Romberg sign 93 Roussy-Levy syndrome 93, 102 S Salter osteotomy 209 Sanger Dideoxy method 189 Sarcoidosis 26 SBF2 gene 76, 102, 106, 182 sBPN, see sporadic brachial plexus neuropathy Scapula 170 Scapula, winging of (Scapula alata) 22 Schellong test 160 Schmidt-Lanterman incisures 4, 5, 7, 56, 57, 134, 138

Subject Index Schwann cell 3, 6, 7±9, 15, 42, 44, 45, 49, 52, 53, 55±57, 61, 88, 95, 99±101, 105, 107, 138, 158, 161, 182, 200, 201, 228, 232 Sciatic nerve 46, 51, 106, 107, 131, 209, 211, 230 Scoliosis 94, 132, 148, 158, 181, 182, 206, 209 Seipin 80 Seitelberger disease, see infantile neuroaxonal dystrophy Senataxin, see SETX Sensory nerve action potential, see SNAP Sensory nerve conduction velocity, see SNCV Septate-like junction 8, 9, 105 Serine palmitoyltransferase 1, long chain subunit 1 gene, see SPTLC1 gene Serine palmitoyltransferase 1, long chain subunit 2, see SPTLC2 Serratus anterior muscle 170 Set binding factor 2 (SBF2), see MTMR13 SETX gene 80, 153 Short-tandem-repeat analysis, see STR analysis Shoulder girdle 170 Sildenafil 203 Silver syndrome 151 Single stranded conformational polymorphism analysis, see SSCP analysis siRNA 201 Skeletal abnormalities 23 Skin biopsy 18, 165 Skin changes 23 SLC12A6 gene 82, 86, 87 SMA, see spinal muscular atrophy Small heat shock protein 22 gene, see HSP22 gene Small heat shock protein 27 gene, see HSP27 gene Small integral membrane protein of lysosome/late endosome, see LITAF/ SIMPLE gene Small interfering RNA, see siRNA SNAP 30, 32±36, 38, 75, 86, 88, 94, 127, 130, 132, 146, 161±164, 166, 175 SNCV 34, 146, 165, 166, 175 SOD1 gene 149 Soleus muscle 212 SOX10 gene 82, 87

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Spartin gene 83 Spectrin 8 S-periaxin 56 Spinal claudication 209 Spinal cord 3, 158 Spinal muscular atrophy 146, 201 Sporadic brachial plexus neuropathy 26, 174, 175 SPTLC1 gene 59, 60, 81, 161, 162, 181 SPTLC2 162 SSCP analysis 190 SSEP 33, 37, 86 SSR 35, 160, 165 STR analysis 186, 188 Subtalar joint 212 Subtarsal joint 213 Superficial peroneal nerve 41 Superficial radial nerve 173 Superoxide dismutase 1 gene, see SOD1 gene Supraspinatus muscle 170 Sural nerve 29, 41, 43, 44, 51, 60, 61, 96, 158, 165 Sural nerve biopsy 45±63, 74, 86, 88, 105, 130, 134, 136, 146, 159, 164, 166, 167, 209 Sweating 181, 203 Sympathetic skin response, see SSR Syncope 164 Syndactyly 174 Syringomyelia 162 T Tabes dorsalis 162 Tachycardia 163 Talonavicular joint 212 Tangier disease 26, 27 Teased fiber preparation 42, 45, 46, 50, 57, 58 Tendon transfer 208, 216 TENS 206 Tetracycline 228 Tibial nerve 16, 29, 31, 94, 104, 136 Tibialis anterior muscle 32, 210±212 Tibialis posterior muscle 210±212, 219 Tight junction 8, 9 Tilt table 160 Tomacula 50±52, 56, 63, 95, 96, 105, 229, 232 Tomaculous neuropathy, see also HNPP 93 Tongue atrophy 136

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Subject Index

Transcutaneous electric nerve stimulation, see TENS Transthyretin amyloid neuropathy 27 Transverse tarsal joint 212 Trembler mice 229, 231 Trembler-J mice 99, 229, 231 Tremor 23, 93, 103, 231 Triceps surae muscle 211 Triple arthrodesis 221 Troyer's syndrome 83 U Ulnar nerve 29, 31, 34, 37, 104, 207 Ulnar sulcus, see sulcus ulnaris 93 Uncompacted myelin 7, 8 V Valsalva's maneuver 160 Varisation osteotomy 209 Vasculitis 16, 26

VEP 33, 34, 86, 137, 164, 181, 182 Vincristin 184 Visually evoked potentials, see VEP Vitamin C 200, 202 Vitamin E 200, 202 Vocal cord 92, 105, 122, 123, 126, 132, 133, 147, 152, 173, 181, 182, 184 Vocal cord paralysis 22 Volar plate tenodese 208 Volkov-Oganesyan-Povarov hinged distraction apparatus 222 Vomiting 163 W Waardenburg-Hirschsprung disease Wallerian degeneration 43 White matter lesions 137 X X chromosomal CMT, see CMTX

87