Table of Contents 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... 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 bythepatient... 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
VIII z Table of Contents 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 evaluation of hereditary polyneuropathies... 29 M. Müller 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 Déjerine-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
Table of Contents z IX 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 Déjerine-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
X z Table of Contents 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. Kuhlenbäumer 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, LambertandCarney... 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
Table of Contents z XI 5.4.3 Congenital hypomyelinating neuropathy, central dysmyelination and intestinal (pseudo) obstruction (Waardenburg-Hirschsprung 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 10q24.1-q25.1 (OMIM 606483 or CMTDIA)... 133 7.2.2 DI-CMTB chromosome 19p12-p13.2 (OMIM 606482 or CMTDIB)... 134
XII z Table of Contents 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 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. Stögbauer, G. Kuhlenbäumer 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... 150 8.4 dhmn IV chromosome 11q13 (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 l-binding protein 2 (IGHMBP2) (OMIM 604320)... 152
Table of Contents z XIII 8.7 dhmn VIIa chromosome 2q14 (OMIM 158580)... 152 8.8 dhmn VIIb dynactin (DCTN) (OMIM 607641)... 153 8.9 dhmn pyramidal/amyotrophic 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. Kuhlenbäumer 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 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 9.2.5 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. Kuhlenbäumer 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
XIV z Table of Contents 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. Kuhlenbäumer 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
Table of Contents z XV 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
XVI z Table of Contents 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. Hünermund Subject Index... 255
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