ISBN: 37985
TITLE: Hereditary Peripheral Neuropathies
AUTHOR: Kuhlenbumer et al.
TOC:

1 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
1 Approach to the patient with suspected hereditary neuropathy
2 Clinical evaluation and differential diagnosis 15
R. 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
2.4.5 Pain and the sensory abnormalities of HSAN 27
2.4.6 Nerve hypertrophy 27
References 27
3 Electrodiagnostic evaluationof hereditary polyneuropathies 29
M. MLLER
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
3.3.5 Djerine-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 neuropathies (HSAN)/hereditary sensory neuropathies (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
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
4.1.5 Djerine-Sottas syndrome (DSS) 48
4.1.6 Congenital hypomyelination (CH) 49
4.1.7 Hereditary neuropathy with liability to pressure palsy (HNPP) 50
4.2 Charcot-Marie-Tooth disease type 4 (CMT4) 52
4.2.1 Charcot-Marie-Tooth disease type 4A (CMT4A) 52
4.2.2 Charcot-Marie-Tooth disease type 4B1 and 4B2 (CMT4B1, CMT4B2) 53
4.2.3 Charcot-Marie-Tooth disease type 4C (CMT4C) 55
4.2.4 Charcot-Marie-Tooth disease type 4D (CMT4D) 55
4.2.5 Charcot-Marie-Tooth disease type 4E (CMT4E) 56
4.2.6 Charcot-Marie-Tooth disease type 4F (CMT4F) 56
4.3 X-linked Charcot-Marie-Tooth disease (CMTX) 56
4.4 Charcot-Marie-Tooth disease type 2 (CMT2) 58
4.5 Hereditary sensory and autonomic neuropathies (HSAN) 59
4.5.1 Hereditary sensory and autonomic neuropathy type 1 (HSAN1) 59
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
Specific neuropathies, treatment and counseling
5 Overview of the dassification and genetics of hereditary peripheral neuropathies and rare undassified forms 73
G. KUHLENBUMER
5.1 History 73
5.2 Clinical and electrophysiological phenotype 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 neuropathies 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 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) 86
5.4.3 Congenital hypomyelinating neuropathy, central dysmyelination and intestinal (pseudo) obstruction (Waardenburg-Hirsch sprung disease) - SRY like box 10 transcription 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 10g24.1-825.1 (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
7.2.5 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) 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 Xg26 (OMIM 302802) 139
7.3.4 CMTX4 - chromosome Xg24-26.1 (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. STGBAUER, G. KUHLENBUMER
Introduction 146
8.1 dHMN I - small heat shock protein 27 (HSP27 or HSBPl) (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 150
8.4 dHMN IV - chromosome llg13 (OMIM 607088) 150
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 u-binding protein 2 (IGHMBP2) (OMIM 604320) 152
8.7 dHMN VIIa - chromosome 2814 (OMIM 158580) 152
8.8 dHMN VIIb - dynactin (DCTN) (OMIM 607641) 153
8.9 dHMN pyramidallamyotrophic lateral sclerosis 4 (ALS4), senataxin (SETX) (OMIM 602433) 153
8.10 dHMN Jerash type - chromosome 9p21.1-p12 (OMIM 605726) 154
References 154
9 Hereditary sensory and autonomic neuropathies (HSAN) 157
P DE JONGHE, G. KUHLENBUMER
Introduction 157
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 HSANVHSN I - serine palmitoyltransferase 1, long chain subunit 1 gene (SPTLCl) (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
9.2.5 HSAN5 - 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. KUHLENBUMER
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. KUHLENBUMER
11.1 Molecular genetic testing strategies 179
11.2 Molecular genetic tests 185
11.2.1 Methods for the detection of the chromosome 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
13.2.3 Surgery of foot deformities 203
References 204
14 Orthopedic aspects in diagnosis, dinical 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: myelinprotein zero (mpz) knockout mice 231
15.3 Models for demyelinating and axonal CMTX: gap-junction-protein beta 1 (gibl) 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 (kiflb) 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 supportgroups 237
G. HNERMUND
SubjectIndex 255
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