G. KuhlenbåumerzF. StægbauerzE.B. RingelsteinzP. Young (Eds.)
Hereditary Peripheral Neuropathies
E.B. Ringelstein P. Young (Eds.)
Hereditary
Peripheral Neuropathies
With 32 Figures and 20 Tables
1 2
ISBN 3-7985-1453-4 Steinkopff Verlag Darmstadt
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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
Hereditary peripheral neuropathies are the most common in- herited 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 en- tities, particularly by defining their underlying genetic defect.
The first causative genetic alteration, i.e. the Charcot-Marie- Tooth 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 se- quence. 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 unravel- ing 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 avail- able yet, the progress in the genetics and biology of these dis- eases 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 appli- cable, yet compact book has been published in this field mak- ing 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, partic- ularly those just embarking on the journey to master this inno- vative field.
This book summarizes the clinical, genetic and biologic state of knowledge including the latest scientific advances. It is writ- ten for the clinician and the geneticist with a special interest in peripheral neuropathies, as well as the clinical and basic scien- tist 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 neuro- pathies containing chapters about the clinical and electrodiag- nostic 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 in- formation about genetic testing, including diagnostic algo- rithms, medical and surgical treatment, genetic counseling and animal models. Practical information about clinical and molec- ular diagnostic centers, self-help groups and frequently updated sources of information on the Internet are given in the appen- dix.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 heredi- tary neuropathies.
Mçnster, July 2005 E. Bernd Ringelstein, M.D., F.A.H.A z Preface
VI
z General part
1 Architecture of the peripheral nerve . . . 3
P. Young, M. Boentert Introduction . . . 3
1.1 Cellular components of the PNS . . . 3
1.2 Architecture of the myelin compartment . . 5
1.2.1 The internode . . . 6
1.2.2 The node of Ranvier . . . 8
1.2.3 The paranodal region . . . 8
1.2.4 The juxtaparanodal region . . . 9
1.3 Unmyelinated nerve fibers . . . 9
References . . . 10
z Approach to the patient with suspected hereditary neuropathy
2 Clinical evaluation and differential diagnosis . . . . 15R. Kiefer, E.B. Ringelstein Introduction . . . 15
2.1 General approach to the patient with peripheral neuropathy . . . 16
2.2 Specific features in the history of patients with hereditary neuropathies . . . 18
2.2.1 Chief complaint and functional deficits noted by the patient . . . 18
2.2.2 Onset and time course of disease . . . 20
2.2.3 Concomitant diseases . . . 21
2.2.4 Family history . . . 21
2.3 Specific features in the clinical examination of patients with suspected hereditary neuropathy . . . 22
2.3.1 Neurological examination . . . 22
2.3.2 General examination . . . 23
2.4 Differential diagnosis in patients with suspected hereditary neuropathy . . . . 24
2.4.1 Distal symmetric leg weakness with peroneal preponderance . . . 24
2.4.2 Pes cavus and hammertoes . . . 25
2.4.3 The HNPP phenotype . . . 26
2.4.4 The HNA phenotype . . . 26
2.4.5Pain and the sensory abnormalities of HSAN . . . 27
2.4.6 Nerve hypertrophy . . . 27
References . . . 27
3 Electrodiagnostic evaluation of hereditary polyneuropathies . . . 29
M. Mçller 3.1 General considerations . . . 29
3.2 Electrodiagnostic evaluation of hereditary polyneuropathies . . . 29
3.3 Electrodiagnostic features and differential diagnosis of different forms of hereditary polyneuropathies . . . 32
3.3.1 Charcot-Marie-Tooth disease type 1 and 4 (CMT1/CMT4) . . . 32
3.3.2 Charcot-Marie-Tooth disease type 2 (CMT2) 33 3.3.3 Dominant intermediate CMT (DI-CMT) . . . 34
3.3.4 Charcot-Marie-Tooth disease X chromosomal (CMTX) . . . 34
3.3.5Djerine-Sottas syndrome (DSS) . . . 34
3.3.6 Congenital hypomyelination (CH) . . . 35
3.3.7 Hereditary motor neuropathies (dHMN) . . . 35
3.3.8 Hereditary sensory and autonomic neuro- pathies (HSAN)/hereditary sensory neuro- pathies (HSN) . . . 35
3.3.9 Hereditary neuropathy with liability to pressure palsy (HNPP) . . . 37
3.3.10 Hereditary neuralgic amyotrophy (HNA) . . . 37
3.3.11 Giant axonal neuropathy (GAN) . . . 38
References . . . 38 z Table of Contents
VIII
4 Principles of pathology and nerve biopsy . . . 41 A. Schenone
Introduction . . . 41 4.1 Charcot-Marie-Tooth disease type 1
(CMT1) . . . 44 4.1.1 Charcot-Marie-Tooth disease type 1A
(CMT1A) . . . 44 4.1.2 Charcot-Marie-Tooth disease type 1B
(CMT1B) . . . 46 4.1.3 Charcot-Marie-Tooth disease type 1C
(CMT1C) . . . 48 4.1.4 Charcot-Marie-Tooth disease type 1D
(CMT1D) . . . 48 4.1.5Djerine-Sottas syndrome (DSS) . . . 48 4.1.6 Congenital hypomyelination (CH) . . . 49 4.1.7 Hereditary neuropathy with liability
to pressure palsy (HNPP) . . . 5 0 4.2 Charcot-Marie-Tooth disease type 4
(CMT4) . . . 5 2 4.2.1 Charcot-Marie-Tooth disease type 4A
(CMT4A) . . . 5 2 4.2.2 Charcot-Marie-Tooth disease type 4B1
and 4B2 (CMT4B1, CMT4B2) . . . 5 3 4.2.3 Charcot-Marie-Tooth disease type 4C
(CMT4C) . . . 5 5 4.2.4 Charcot-Marie-Tooth disease type 4D
(CMT4D) . . . 5 5 4.2.5Charcot-Marie-Tooth disease type 4E
(CMT4E) . . . 5 6 4.2.6 Charcot-Marie-Tooth disease type 4F
(CMT4F) . . . 5 6 4.3 X-linked Charcot-Marie-Tooth disease
(CMTX) . . . 5 6 4.4 Charcot-Marie-Tooth disease type 2
(CMT2) . . . 5 8 4.5 Hereditary sensory and autonomic
neuropathies (HSAN) . . . 5 9 4.5.1 Hereditary sensory and autonomic
neuropathy type 1 (HSAN1) . . . 5 9 4.5.2 Hereditary sensory and autonomic
neuropathy type 2 (HSAN2) . . . 60 4.5.3 Hereditary sensory and autonomic
neuropathy type 3 (HSAN3) . . . 61
4.5.4 Hereditary sensory and autonomic neuropathy type 4 and 5
(HSAN4 and HSAN5) . . . 61 4.6 Hereditary motor neuropathies (HMN) . . . 62 4.7 Giant axonal neuropathy (GAN) . . . 62 4.8 Hereditary neuralgic amyotrophy (HNA) . . 63 References . . . 63
z Specific neuropathies, treatment and counseling
5 Overview of the classification and genetics of hereditary peripheral neuropathies and rare
unclassified forms . . . 73 G. Kuhlenbåumer
5.1 History . . . 73 5.2 Clinical and electrophysiological pheno-
type of hereditary motor and sensory
neuropathies (HMSNs) . . . 74 5.3 Classification of hereditary neuropathies . . 75 5.3.1 The HMSN classification by Dyck, Chance,
Lambert and Carney . . . 75 5.3.2 Classification of primary hereditary
neuropathies according to clinical subgroups and genetic entities . . . 83 5.4 Rare forms of hereditary peripheral neuro-
pathies which do not fit into the current
classification schemes . . . 85 5.4.1 Giant axonal neuropathy ± gigaxonin (GAN)
(OMIM 256850) . . . 85 5.4.2 Agenesis of the corpus callosum with
peripheral neuropathy (ACCPN) or Ander- man syndrome or hereditary motor and sen- sory neuropathy with agenesis of the
corpus callosum (HMSN/ACC) ± solute carrier family 12 member 6 gene (SLC12A6 coding for the protein: KCC3)
(OMIM 218000) . . . 86 z Table of Contents
X
5.4.3 Congenital hypomyelinating neuropathy, central dysmyelination and intestinal (pseudo) obstruction (Waardenburg-Hirsch- sprung disease) ± SRY like box 10 tran-
scription factor (SOX10) (OMIM 602229) . . 87
5.4.4 Hereditary peripheral neuropathy and deafness ± gap junction protein 3 (GJB3 or connexin31) . . . 87
5.4.5 Minifascicular peripheral neuropathy, partial gonadal dysgenesis ± desert hedgehog (DHH) (OMIM 607080) . . . 88
References . . . 88
6 Charcot-Marie-Tooth disease type 1 (CMT1) and hereditary neuropathy with liability to pressure palsy (HNPP) . . . 92
E. Nelis, P. de Jonghe, V. Timmerman 6.1 Autosomal dominant CMT1 and HNPP . . . 92
6.1.1 Clinical features . . . 92
6.1.2 Electrodiagnostic and laboratory features . . 94
6.1.3 Pathological features . . . 95
6.1.4 Genetics and pathomechanism . . . 96
6.2 Autosomal recessive demyelinating CMT or CMT4 . . . 103
6.2.1 Clinical features . . . 103
6.2.2 Electrodiagnostic features . . . 104
6.2.3 Pathological features . . . 104
6.2.4 Genetics and pathomechanism . . . 105
References . . . 109
7 CMT2, dominant intermediate CMT and CMTX . . . . 121
M.C. Hannibal, P.F. Chance Introduction . . . 121
7.1 Charcot-Marie-Tooth neuropathy type 2 . . . 121
7.1.1 Autosomal dominant CMT2 . . . 121
7.1.2 Autosomal recessive CMT2 . . . 131
7.2 DI-CMT: dominant intermediate Charcot-Marie-Tooth neuropathy . . . 133
7.2.1 DI-CMTA ± chromosome 10q24.1-q25.1 (OMIM 606483 or CMTDIA) . . . 133
7.2.2 DI-CMTB ± chromosome 19p12-p13.2 (OMIM 606482 or CMTDIB) . . . 134
7.2.3 DI-CMTC ± chromosome 1p34-p35
(OMIM 608323, CMTDIC) . . . 134 7.2.4 DI-CMTD ± myelin protein zero (MPZ)
(OMIM 607791, CMTDID) . . . 135 7.2.5DI-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) . . . 135 7.2.6 HMSN-P ± chromosome 3p14.1-q13
(OMIM 604484, HMSNO or Okinawa type) . 136 7.3 CMTX: Charcot-Marie-Tooth neuropathy,
X-linked types . . . 136 7.3.1 CMTX1 ± gap junction protein beta 1 gene
(GJB1, formerly connexin 32 (Cx32)
(OMIM 302800) . . . 137 7.3.2 CMTX2 ± chromosome Xp22.2
(OMIM 302801) . . . 138 7.3.3 CMTX3 ± chromosome Xq26
(OMIM 302802) . . . 139 7.3.4 CMTX4 ± chromosome Xq24-26.1 (OMIM
310490, Cowchock syndrome or neuropathy, axonal motor-sensory with deafness and
mental retardation, NAMSD) . . . 139 References . . . 139 8 Distal hereditary motor neuropathies (dHMN) . . . 146
F. Stægbauer, G. Kuhlenbåumer
Introduction . . . 146 8.1 dHMN I ± small heat shock protein 27
(HSP27 or HSBP1) (OMIM 608634) . . . 148 8.2 dHMN II ± small heat shock protein 22
(HSP22 or HSBP8) (OMIM 158590) . . . 149 8.3 dHMN III ± chromosomal location
unknown . . . 15 0 8.4 dHMN IV ± chromosome 11q13
(OMIM 607088) . . . 15 0 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) . . 151 8.6 dHMN VI ± immunoglobulin l-binding
protein 2 (IGHMBP2) (OMIM 604320) . . . . 15 2 z Table of Contents
XII
8.7 dHMN VIIa ± chromosome 2q14
(OMIM 158580) . . . 15 2 8.8 dHMN VIIb ± dynactin (DCTN)
(OMIM 607641) . . . 15 3 8.9 dHMN pyramidal/amyotrophic lateral
sclerosis 4 (ALS4), senataxin (SETX)
(OMIM 602433) . . . 15 3 8.10 dHMN Jerash type ± chromosome
9p21.1-p12 (OMIM 605726) . . . 15 4 References . . . 15 4 9 Hereditary sensory and autonomic neuropathies
(HSAN) . . . 15 7 P. De Jonghe, G. Kuhlenbåumer
Introduction . . . 15 7 9.1 Assessment of HSANs with autonomic
and neurophysiological examinations . . . 160 9.1.1 Quantitative testing of thermal perception . 160 9.1.2 Histamine axonal flare test . . . 160 9.2 Forms of HSAN . . . 161 9.2.1 HSAN1/HSN I ± serine palmitoyltransferase
1, long chain subunit 1 gene (SPTLC1)
(OMIM 162400) . . . 161 9.2.2 HSAN2 ± hereditary sensory neuropathy II
gene (HSN2) (OMIM 201300) . . . 163 9.2.3 HSAN3 ± (Syn: familial dysautonomia, Riley-
Day syndrome) ± inhibitor of kappa light
polypeptide gene (IKBKAP, protein IKAP) . . 163 9.2.4 HSAN4 ± neurotrophin receptor tyrosine
kinase 1 gene (NTRK1) (OMIM 256800) . . . 165 9.2.5HSAN5± in some cases: nerve growth factor
beta (NGFB), neurotrophin receptor tyrosine kinase 1 gene (NTRK1) (OMIM 256800) . . . 166 References . . . 167 10 Hereditary neuralgic amyotrophy (HNA) . . . 170
G. Kuhlenbåumer
10.1 Clinical features . . . 170 10.1.1 Classical remitting-relapsing HNA . . . 172 10.1.2 Chronic undulating HNA . . . 174 10.1.3 Sporadic brachial plexus neuropathy (sBPN)
(also called idiopathic brachial plexus
neuritis, Parsonage-Turner syndrome) . . . . 174
10.2 Electrodiagnostic, laboratory and additional
investigatons . . . 175
10.3 Pathologic features . . . 175
10.4 Genetics and pathomechanism . . . 176
References . . . 176
11 Molecular genetic diagnosis of hereditary neuropathies . . . 179
G. Kuhlenbåumer 11.1 Molecular genetic testing strategies . . . 179
11.2 Molecular genetic tests . . . 185
11.2.1 Methods for the detection of the chromo- some CMT1A duplication/HNPP deletion . . 185
11.2.2 Mutation detection methods for other genetic defects causing hereditary neuropathies . . . 189
References . . . 191
12 Genetic counseling . . . 193
M. Hoeltzenbein Introduction . . . 193
12.1 Definition of genetic counseling and consequences . . . 193
12.2 Course and general principles of genetic counseling . . . 194
12.3 Diagnostic/molecular testing . . . 195
12.3.1 Predictive testing of late-onset disorders . . . 195
12.3.2 Prenatal testing . . . 196
12.3.3 Preimplantation diagnostics . . . 197
12.4 Special issues of genetic counseling . . . 197
References . . . 197
13 Medical treatment of hereditary neuropathies . . . 199
P. Young Introduction . . . 199
13.1 Causative therapy . . . 200
13.1.1 Genetic treatment . . . 200
13.1.2 Prevention of axonal degeneration . . . 201
13.2 Symptomatic therapy . . . 203
13.2.1 Neuropathic pain . . . 203
13.2.2 Autonomic dysfunction . . . 203 z Table of Contents
XIV
13.2.3 Surgery of foot deformities . . . 203
References . . . 204
14 Orthopedic aspects in diagnosis, clinical management and therapy of CMT patients . . . 206
R. Forst, A. Ingenhorst Introduction . . . 206
14.1 Upper extremities . . . 207
14.2 Spine . . . 209
14.3 Hip joint . . . 209
14.4 Knee joint . . . 210
14.5 Ankle joint and foot . . . 210
14.5.1 Clinical basics . . . 210
14.5.2 Pathogenesis of the deformities . . . 211
14.5.3 Special diagnostic tests . . . 213
14.5.4 Therapy . . . 215
14.6 Fractures . . . 223
References . . . 223
15 Animal models of hereditary neuropathies . . . 227
P. Young, U. Sueter Introduction . . . 227
15.1 Models for demyelinating CMT1A: peripheral myelin protein 22 (pmp22) . . . . 227
15.1.1 pmp22 transgenic rats . . . 227
15.1.2 pmp22 transgenic mice . . . 228
15.1.3 Inducible pmp22 transgenic mice . . . 228
15.1.4 pmp22 knockout mice . . . 229
15.1.5 Mice carrying point mutations in pmp22: trembler, trembler J, Tr-m1H, Tr-m2H . . . 229
15.2 Models for demyelinating CMT1B: myelin protein zero (mpz) knockout mice . . . 231
15.3 Models for demyelinating and axonal CMTX: gap-junction-protein beta 1 (gjb1) knockout mice . . . 232
15.4 Model for demyelinating CMT4F: periaxin (prx) knockout mice . . . 232
15.5 Model for axonal CMT2A2: kinesin motor protein 1 beta (kif1b) knockout mice . . . 233
15.6 Model for axonal CMT2E: neurofilament light chain (nefl) knockout mice . . . 233
15.7 Model for recessive CMT4C1: lamin A/C
(lmna) knockout mice . . . 233 15.8 Conclusions . . . 234 References . . . 234 Appendix: genetic testing laboratories
and support groups . . . 237 G. Hçnermund
Subject Index . . . 25 5 z Table of Contents
XVI
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
14195Berlin 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
z Authors' addresses XVIII
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
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 dys- function 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 depen- dent on the correct morphological and molecular organization of the pe- ripheral nerve fiber.
1.1 Cellular components of the PNS
The two major cellular components of peripheral nerves are (1) axons orig- inating 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 myelinat- ing cells. Unmyelinating Schwann cells are responsible for the correct en- sheathing 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
Architecture of the peripheral nerve
P. Young, M. Boentert
1
of an axon in a 1:1 relation [12, 27]. The process of myelination is character- ized by the formation of a defined number of wraps of compacted cell mem- brane 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 pres- ence of extracellular matrix receptors (ECM) [22]. The adaxonal compart- ment is characterized by the presence of molecules which mediate cell adhe- sion 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 periph- eral nerve diseases and axonal degeneration is not fully elucidated.
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 bycompacted myelin (M). Arrow heads indi- cate the adaxonal compartment of the Schwann cell cytoplasm while the abaxonal compart- ment is indicated bySCC
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 conduc- tion 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 com- pacted myelin sheath is further regularly seen in regions called Schmidt- Lanterman incisures consisting of uncompacted myelin. The myelin seg- ments which extend between two nodes of Ranvier are called internodal re- gions of the peripheral myelinated nerve fiber (Fig. 1.2).
1 Architecture of the peripheral nerve z 5
Fig. 1.2. Morphologyand 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 bythe paranodal re- gion (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 byarrows)
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 fi- bers [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 re- sulting 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 sepa- rated 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 maxi- mum of 19 nm (in unfixed tissue). The number of periods is strictly re- lated 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 re- ceptor 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 galacto- cerebrosides 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 com- partment 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 extra- cellular domain and has a highly positively charged intracellular domain [17]. This combination is postulated to be a prerequisite for myelin com- paction. With the aid of the extracellular domains homophilically interact- ing 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 ma- jor 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 depen- dency 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 ex- pressed 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.
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 adhe- rens 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 inter- rupted by uncompacted myelin bridges called Schmidt-Lanterman inci-
1 Architecture of the peripheral nerve z 7
Fig. 1.3. Immunohistochemical staining with an antibody against E-cadherin on a myelinated nerve fiber. E-cadher- in is expressed in the myelated nerve fiber in the uncom- pacted myelin compartment at the paranodal region of the node of Ranvier (arrow), the Schmidt-Lanterman inci- sures (asterisks) and the outer mesaxon (arrow heads)
sures. These incisures show an accumulation of potassium channels, E-cad- herin, beta-catenin, caspr and several tight junction markers. The function of the incisures is yet not fully understood but the expression of gap junc- tion forming gap junction protein beta 1 (GJB1) in these structures sug- gests 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 fami- ly. 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 lat- eral end of myelinating Schwann cells. The microvilli are in close contact with the axonal cytoskeleton [14]. The diameter of the axon itself is re- duced at the nodal region. Microvilli contain F-actin and proteins like ez- rin, 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 char- acterized 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-
tion of potassium channels in the juxtaparanodal region which is the re- gion adjacent to the paranodal region, providing evidence that the correct formation of septate like junctions is the basis for correct potassium chan- nel 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-cate- nin 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 lo- calization 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 potas- sium channels at the juxtaparanodal region are necessary for normal im- pulse 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 con- trast to the myelinated fiber bundles unmyelinated fiber bundles are ac- companied by a single Schwann cell. Unmyelinated fibers lack the above described organization of proteins found in myelinated fibers. Unmyeli- nated fibers are packed into bundles by unmyelinating Schwann cells. Ac- cumulation of ion channels is not observed and proteins which take part in fiber bundling are not well described so far.
1 Architecture of the peripheral nerve z 9
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Approach to the patient
with suspected hereditary
neuropathy
Introduction
Many clinicians experience the evaluation of patients with peripheral neuro- pathy as challenging and sometimes non-rewarding. While the clinical diag- nosis of a length-dependent sensorimotor peripheral neuropathy is easily made by experienced neurologists, the cause of the disorder may remain un- resolved in many cases despite extensive workup. Furthermore, some periph- eral neuropathies may present with clinical features which are not easily rec- ognized to be derived from disorders of the peripheral nerve at all. Thus, mul- tifocal and pure motor neuropathic syndromes may be confused with myopa- thies 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 com- ponents 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 longi- tudinally 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 pre- sentation of peripheral neuropathy which makes the differential diagnosis appear difficult to many.
However, not all peripheral neuropathies look the same. A careful clini- cal 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 gen- eral approach to the patient with peripheral neuropathy, elaborates on spe- cific aspects of the history and clinical examination of patients with var- ious forms of hereditary neuropathies, and suggests a logical approach to establish a differential diagnosis in these patients [3, 5, 7].
and differential diagnosis
R. Kiefer, E.B. Ringelstein
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 provid- ing 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-neuro- logical 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 sym- metric weakness, with little sensory involvement, without other affected family members, and with a preceding diarrhea may suffer from Guillain- Barr syndrome. Another person with subacute onset of weakness and sen- sory 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 vas- culitis, to name just one possible cause of this syndrome. In contrast, if the onset of the multiple mononeuropathy started years ago, the course was re- lapsing-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 syn- drome 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 dis- tribution 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.
z R. Kiefer, E.B. Ringelstein 16
The role of clinical neurophysiology is discussed in detail in the next chap- ter. Once the neurophysiological examination is completed, a clearer pic- ture 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- Table 2.1. Important clinical features for the initial categorization of a patient's neuropathy
Item 1: Age at onset Item 2: Course
z birth z infancy z childhood z adolescence z young adulthood z midlife
z advanced age
z acute z subacute
z chronic-progressive z lifelong
z 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 autosomal dominant z autosomal recessive z X-linked
z none
Item 5: Distribution of deficits Item 6: Concomitant conditions z length-dependent (distal-symmetric)
z proximal symmetric z marked asymmetry
z one nerve or multiple individual nerves z radicular
z nerve plexus z cranial nerves
z additional CNS symptoms and signs z combinations of the above
z diabetes mellitus z renal or liver disease
z rheumatic disease and vasculitis z malignancy
z gastrointestinal disorders z malnutrition
z ocular disorders z hearing loss
z alcohol and drug abuse z neurotoxic drugs z others
vestigations of other organ systems to determine concomitant disease, ge- netic 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 di- agnosis [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 neuro- pathiesº 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 pa- tient. 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 al- ways 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 neuropa- thy is disturbance of gait. Gait may be impaired due to weakness, proprio- ceptive 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 Djerine-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.
z R. Kiefer, E.B. Ringelstein 18
Weakness of the hands with difficulties in writing, turning a key or grasp- ing 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 af- fected, and quadriceps weakness is not a usual feature of this disease. Pa- tients 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 af- fected 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 dis- turbance which are accentuated in the dark. Sensory loss may, however, go Table 2.2. Common presenting complaints in patients with hereditaryneuropathies
CMT and distal HMN phenotype z Disturbance of gait
z Weakness
z Sensoryloss (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 familymembers
unnoticed for many patients with CMT, particularly in CMT2. Some pa- tients may even insist on feeling normal sensation despite having total loss of vibration sense at the toes and severe sensory abnormalities on neuro- physiological testing. The history alone may therefore not provide the nec- essary 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 fol- lowed by weakness. Specific questioning may reveal similar episodes in the past.
Loss of pain and distal loss of sweating are characteristics of HSAN ex- cept 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 fre- quent 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 ill- ness 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 retrospec- tively be recognized when specifically asked for. In neuropathy patients with suspected hereditary neuropathy, it is therefore very important to spe- cifically ask for early symptoms during childhood and adolescence and in- quire about indirect hints for abnormal function. Low physical activity as z R. Kiefer, E.B. Ringelstein
20
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 re- membered 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 ex- plore 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 ab- sence 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 muta- tion and therefore the patient is the first affected member of the family.
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 respi- ratory problems and additional CNS features are rare but nevertheless rep- resent important and informative findings in classifying hereditary neuro- pathy.
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 re- spiratory failure.
Weakness and muscle atrophy in CMT occurs typically in a length-de- pendent pattern and shows a preponderance of peroneal muscles. The small muscles of the foot and the peroneal muscles of the lower leg are af- fected 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 ex- amination is required to recognize asymmetry in such patients and to de- tect 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 de- tailed 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 distribu- tion of weakness in CMT and HNPP. In CMT, there is a length dependent loss of all modalities. Perception of vibration sense is reduced first, fol- lowed 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.
z R. Kiefer, E.B. Ringelstein 22
Pain and temperature sensation are preferentially lost in HSAN1 and CMT2B, and are selectively absent in HSAN4. In contrast, all sensory mo- dalities 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 ul- nar 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 long- er. 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. Alter- nating 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 to- gether. Absence of foot deformities makes CMT unlikely but does not en- tirely exclude the diagnosis. The reason for these deformities are tone im-
