Genetics of Neuropathies

ABSTRACT

Charcot-Marie-Tooth disease (CMT) encompasses the heritable motor and sensory neuropathies that comprise most of the inherited peripheral neuropathies. Due to the great genetic heterogeneity of the condition, it can be difficult to determine what type of CMT a person has. The major phenotypic features of the CMT subtypes are delineated, as well as recommendations for focused genetic testing.

Peripheral neuropathy - inherited - Charcot-Marie-Tooth disease - genetic testing

REFERENCES

• 1 Skre H. Genetic and clinical aspects of Charcot-Marie-Tooth's disease.  Clin Genet. 1974;  6 (2) 98-118
• 2 Harding A E, Thomas P K. Genetic aspects of hereditary motor and sensory neuropathy (types I and II).  J Med Genet. 1980;  17 (5) 329-336
• 3 Harding A E, Thomas P K. The clinical features of hereditary motor and sensory neuropathy types I and II.  Brain. 1980;  103 (2) 259-280
• 4 Thomas P K, Harding A E. Inherited neuropathies: the interface between molecular genetics and pathology.  Brain Pathol. 1993;  3 (2) 129-133
• 5 Michels V V, Dyck P J. Mendelian inheritance and basis of classification of hereditary neuropathy with neuronal atrophy and degeneration. In: Dyck P, Thomas P K, Lambert E H, Bunge R eds.. Peripheral Neuropathy. 2nd ed. Philadelphia: WB Saunders; 1984: 1512-1524
• 6 Dubourg O, Tardieu S, Birouk N et al.. The frequency of 17p11.2 duplication and Connexin 32 mutations in 282 Charcot-Marie-Tooth families in relation to the mode of inheritance and motor nerve conduction velocity.  Neuromuscul Disord. 2001;  11 (5) 458-463
• 7 England J D, Gronseth G S, Franklin G American Academy of Neurology et al. Practice parameter: the evaluation of distal symmetric polyneuropathy: the role of laboratory and genetic testing (an evidence-based review). Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation.  PM R. 2009;  1 (1) 5-13
• 8 England J D, Gronseth G S, Franklin G American Academy of Neurology et al. Practice parameter: evaluation of distal symmetric polyneuropathy: role of laboratory and genetic testing (an evidence-based review). Report of the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation.  Neurology. 2009;  72 (2) 185-192
• 9 Burgunder J M, Schöls L, Baets J EFNS et al. EFNS guidelines for the molecular diagnosis of neurogenetic disorders: motoneuron, peripheral nerve and muscle disorders.  Eur J Neurol. 2011;  18 (2) 207-217
• 10 Saporta A S, Sottile S L, Miller L J, Feely S M, Siskind C E, Shy M E. Charcot-Marie-Tooth disease subtypes and genetic testing strategies.  Ann Neurol. 2011;  69 (1) 22-33
• 11 Feely S M, Laura M, Siskind C E et al.. MFN2 mutations cause severe phenotypes in most patients with CMT2A.  Neurology. 2011;  76 (20) 1690-1696
• 12 Krajewski K M, Shy M E. Genetic testing in neuromuscular disease.  Neurol Clin. 2004;  22 (3) 481-508, v v
• 13 Shy M E, Chen L, Swan E R et al.. Neuropathy progression in Charcot-Marie-Tooth disease type 1A.  Neurology. 2008;  70 (5) 378-383
• 14 Shy M E, Siskind C, Swan E R et al.. CMT1X phenotypes represent loss of GJB1 gene function.  Neurology. 2007;  68 (11) 849-855
• 15 Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. American Society of Human Genetics Board of Directors, American College of Medical Genetics Board of Directors.  Am J Hum Genet. 1995;  57 (5) 1233-1241
• 16 Lewis R A, Sumner A J, Shy M E. Electrophysiological features of inherited demyelinating neuropathies: A reappraisal in the era of molecular diagnosis.  Muscle Nerve. 2000;  23 (10) 1472-1487
• 17 Kamholz J, Menichella D, Jani A et al.. Charcot-Marie-Tooth disease type 1: molecular pathogenesis to gene therapy.  Brain. 2000;  123 (Pt 2) 222-233
• 18 Lupski J R, de Oca-Luna R M, Slaugenhaupt S et al.. DNA duplication associated with Charcot-Marie-Tooth disease type 1A.  Cell. 1991;  66 (2) 219-232
• 19 Raeymaekers P, Timmerman V, Nelis E The HMSN Collaborative Research Group et al. Duplication in chromosome 17p11.2 in Charcot-Marie-Tooth neuropathy type 1a (CMT 1a).  Neuromuscul Disord. 1991;  1 (2) 93-97
• 20 Sheth S, Francies K, Siskind C E, Feely S M, Lewis R A, Shy M E. Diabetes mellitus exacerbates motor and sensory impairment in CMT1A.  J Peripher Nerv Syst. 2008;  13 (4) 299-304
• 21 Blair I P, Nash J, Gordon M J, Nicholson G A. Prevalence and origin of de novo duplications in Charcot-Marie-Tooth disease type 1A: first report of a de novo duplication with a maternal origin.  Am J Hum Genet. 1996;  58 (3) 472-476
• 22 Passage E, Norreel J C, Noack-Fraissignes P et al.. Ascorbic acid treatment corrects the phenotype of a mouse model of Charcot-Marie-Tooth disease.  Nat Med. 2004;  10 (4) 396-401
• 23 Verhamme C, de Haan R J, Vermeulen M, Baas F, de Visser M, van Schaik I N. Oral high dose ascorbic acid treatment for one year in young CMT1A patients: a randomised, double-blind, placebo-controlled phase II trial.  BMC Med. 2009;  7 70
• 24 Burns J, Ouvrier R A, Yiu E M et al.. Ascorbic acid for Charcot-Marie-Tooth disease type 1A in children: a randomised, double-blind, placebo-controlled, safety and efficacy trial.  Lancet Neurol. 2009;  8 (6) 537-544
• 25 Micallef J, Attarian S, Dubourg O et al.. Effect of ascorbic acid in patients with Charcot-Marie-Tooth disease type 1A: a multicentre, randomised, double-blind, placebo-controlled trial.  Lancet Neurol. 2009;  8 (12) 1103-1110
• 26 Pareyson D, Reilly M M, Schenone A CMT-TRIAAL et al. Ascorbic acid in Charcot-Marie-Tooth disease type 1A (CMT-TRIAAL and CMT-TRAUK): a double-blind randomised trial.  Lancet Neurol. 2011;  10 (4) 320-328
• 27 Chance P F, Alderson M K, Leppig K A et al.. DNA deletion associated with hereditary neuropathy with liability to pressure palsies.  Cell. 1993;  72 (1) 143-151
• 28 Infante J, García A, Combarros O et al.. Diagnostic strategy for familial and sporadic cases of neuropathy associated with 17p11.2 deletion.  Muscle Nerve. 2001;  24 (9) 1149-1155
• 29 Stögbauer F, Young P, Kuhlenbäumer G, De Jonghe P, Timmerman V. Hereditary recurrent focal neuropathies: clinical and molecular features.  Neurology. 2000;  54 (3) 546-551
• 30 Andersson P B, Yuen E, Parko K, So Y T. Electrodiagnostic features of hereditary neuropathy with liability to pressure palsies.  Neurology. 2000;  54 (1) 40-44
• 31 Li J, Krajewski K, Shy M E, Lewis R A. Hereditary neuropathy with liability to pressure palsy: the electrophysiology fits the name.  Neurology. 2002;  58 (12) 1769-1773
• 32 Hayasaka K, Himoro M, Sato W et al.. Charcot-Marie-Tooth neuropathy type 1B is associated with mutations of the myelin P0 gene.  Nat Genet. 1993;  5 (1) 31-34
• 33 Street V A, Bennett C L, Goldy J D et al.. Mutation of a putative protein degradation gene LITAF/SIMPLE in Charcot-Marie-Tooth disease 1C.  Neurology. 2003;  60 (1) 22-26
• 34 Latour P, Gonnaud P M, Ollagnon E et al.. SIMPLE mutation analysis in dominant demyelinating Charcot-Marie-Tooth disease: three novel mutations.  J Peripher Nerv Syst. 2006;  11 (2) 148-155
• 35 Saifi G M, Szigeti K, Wiszniewski W et al.. SIMPLE mutations in Charcot-Marie-Tooth disease and the potential role of its protein product in protein degradation.  Hum Mutat. 2005;  25 (4) 372-383
• 36 Warner L E, Mancias P, Butler I J et al.. Mutations in the early growth response 2 (EGR2) gene are associated with hereditary myelinopathies.  Nat Genet. 1998;  18 (4) 382-384
• 37 Vandenberghe N, Upadhyaya M, Gatignol A et al.. Frequency of mutations in the early growth response 2 gene associated with peripheral demyelinating neuropathies.  J Med Genet. 2002;  39 (12) e81
• 38 Pareyson D, Taroni F, Botti S et al.. Cranial nerve involvement in CMT disease type 1 due to early growth response 2 gene mutation.  Neurology. 2000;  54 (8) 1696-1698
• 39 Boerkoel C F, Takashima H, Garcia C A et al.. Charcot-Marie-Tooth disease and related neuropathies: mutation distribution and genotype-phenotype correlation.  Ann Neurol. 2002;  51 (2) 190-201
• 40 Russo M, Laurá M, Polke J M et al.. Variable phenotypes are associated with PMP22 missense mutations.  Neuromuscul Disord. 2011;  21 (2) 106-114
• 41 Züchner S, Mersiyanova I V, Muglia M et al.. Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A.  Nat Genet. 2004;  36 (5) 449-451
• 42 Verhoeven K, De Jonghe P, Coen K et al.. Mutations in the small GTP-ase late endosomal protein RAB7 cause Charcot-Marie-Tooth type 2B neuropathy.  Am J Hum Genet. 2003;  72 (3) 722-727
• 43 Auer-Grumbach M, De Jonghe P, Wagner K, Verhoeven K, Hartung H P, Timmerman V. Phenotype-genotype correlations in a CMT2B family with refined 3q13-q22 locus.  Neurology. 2000;  55 (10) 1552-1557
• 44 De Jonghe P, Timmerman V, FitzPatrick D, Spoelders P, Martin J J, Van Broeckhoven C. Mutilating neuropathic ulcerations in a chromosome 3q13-q22 linked Charcot-Marie-Tooth disease type 2B family.  J Neurol Neurosurg Psychiatry. 1997;  62 (6) 570-573
• 45 Kwon J M, Elliott J L, Yee W C et al.. Assignment of a second Charcot-Marie-Tooth type II locus to chromosome 3q.  Am J Hum Genet. 1995;  57 (4) 853-858
• 46 Landouré G, Zdebik A A, Martinez T L et al.. Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C.  Nat Genet. 2010;  42 (2) 170-174
• 47 Chen D H, Sul Y, Weiss M et al.. CMT2C with vocal cord paresis associated with short stature and mutations in the TRPV4 gene.  Neurology. 2010;  75 (22) 1968-1975
• 48 Deng H X, Klein C J, Yan J et al.. Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4.  Nat Genet. 2010;  42 (2) 165-169
• 49 Dyck P J, Litchy W J, Minnerath S et al.. Hereditary motor and sensory neuropathy with diaphragm and vocal cord paresis.  Ann Neurol. 1994;  35 (5) 608-615
• 50 Klein C J, Cunningham J M, Atkinson E J et al.. The gene for HMSN2C maps to 12q23-24: a region of neuromuscular disorders.  Neurology. 2003;  60 (7) 1151-1156
• 51 Antonellis A, Ellsworth R E, Sambuughin N et al.. Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V.  Am J Hum Genet. 2003;  72 (5) 1293-1299
• 52 Sivakumar K, Kyriakides T, Puls I et al.. Phenotypic spectrum of disorders associated with glycyl-tRNA synthetase mutations.  Brain. 2005;  128 (Pt 10) 2304-2314
• 53 Mersiyanova I V, Perepelov A V, Polyakov A V et al.. A new variant of Charcot-Marie-Tooth disease type 2 is probably the result of a mutation in the neurofilament-light gene.  Am J Hum Genet. 2000;  67 (1) 37-46
• 54 Georgiou D M, Zidar J, Korosec M, Middleton L T, Kyriakides T, Christodoulou K. A novel NF-L mutation Pro22Ser is associated with CMT2 in a large Slovenian family.  Neurogenetics. 2002;  4 (2) 93-96
• 55 Yoshihara T, Yamamoto M, Hattori N et al.. Identification of novel sequence variants in the neurofilament-light gene in a Japanese population: analysis of Charcot-Marie-Tooth disease patients and normal individuals.  J Peripher Nerv Syst. 2002;  7 (4) 221-224
• 56 Jordanova A, De Jonghe P, Boerkoel C F et al.. Mutations in the neurofilament light chain gene (NEFL) cause early onset severe Charcot-Marie-Tooth disease.  Brain. 2003;  126 (Pt 3) 590-597
• 57 Perez-Olle R, Leung C L, Liem R K. Effects of Charcot-Marie-Tooth-linked mutations of the neurofilament light subunit on intermediate filament formation.  J Cell Sci. 2002;  115 (Pt 24) 4937-4946
• 58 Evgrafov O V, Mersiyanova I, Irobi J et al.. Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy.  Nat Genet. 2004;  36 (6) 602-606
• 59 Chung K W, Kim S B, Cho S Y et al.. Distal hereditary motor neuropathy in Korean patients with a small heat shock protein 27 mutation.  Exp Mol Med. 2008;  40 (3) 304-312
• 60 Houlden H, Laura M, Wavrant-De Vrièze F et al.. Mutations in the HSP27 (HSPB1) gene cause dominant, recessive, and sporadic distal HMN/CMT type 2.  Neurology. 2008;  71 (21) 1660-1668
• 61 Solla P, Vannelli A, Bolino A et al.. Heat shock protein 27 R127W mutation: evidence of a continuum between axonal Charcot-Marie-Tooth and distal hereditary motor neuropathy.  J Neurol Neurosurg Psychiatry. 2010;  81 (9) 958-962
• 62 Tang B S, Zhao G H, Luo W et al.. Small heat-shock protein 22 mutated in autosomal dominant Charcot-Marie-Tooth disease type 2L.  Hum Genet. 2005;  116 (3) 222-224
• 63 Irobi J, Van Impe K, Seeman P et al.. Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy.  Nat Genet. 2004;  36 (6) 597-601
• 64 Tang B S, Luo W, Xia K et al.. A new locus for autosomal dominant Charcot-Marie-Tooth disease type 2 (CMT2L) maps to chromosome 12q24.  Hum Genet. 2004;  114 (6) 527-533
• 65 Baxter R V, Ben Othmane K, Rochelle J M et al.. Ganglioside-induced differentiation-associated protein-1 is mutant in Charcot-Marie-Tooth disease type 4A/8q21.  Nat Genet. 2002;  30 (1) 21-22
• 66 Sivera R, Espinós C, Vílchez J J et al.. Phenotypical features of the p.R120W mutation in the GDAP1 gene causing autosomal dominant Charcot-Marie-Tooth disease.  J Peripher Nerv Syst. 2010;  15 (4) 334-344
• 67 Claramunt R, Pedrola L, Sevilla T et al.. Genetics of Charcot-Marie-Tooth disease type 4A: mutations, inheritance, phenotypic variability, and founder effect.  J Med Genet. 2005;  42 (4) 358-365
• 68 Crimella C, Tonelli A, Airoldi G et al.. The GST domain of GDAP1 is a frequent target of mutations in the dominant form of axonal Charcot Marie Tooth type 2K.  J Med Genet. 2010;  47 (10) 712-716
• 69 Senderek J, Bergmann C, Ramaekers V T et al.. Mutations in the ganglioside-induced differentiation-associated protein-1 (GDAP1) gene in intermediate type autosomal recessive Charcot-Marie-Tooth neuropathy.  Brain. 2003;  126 (Pt 3) 642-649
• 70 Nelis E, Erdem S, Van Den Bergh P Y et al.. Mutations in GDAP1: autosomal recessive CMT with demyelination and axonopathy.  Neurology. 2002;  59 (12) 1865-1872
• 71 Sevilla T, Cuesta A, Chumillas M J et al.. Clinical, electrophysiological and morphological findings of Charcot-Marie-Tooth neuropathy with vocal cord palsy and mutations in the GDAP1 gene.  Brain. 2003;  126 (Pt 9) 2023-2033
• 72 Boerkoel C F, Takashima H, Nakagawa M et al.. CMT4A: identification of a Hispanic GDAP1 founder mutation.  Ann Neurol. 2003;  53 (3) 400-405
• 73 Bolino A, Muglia M, Conforti F L et al.. Charcot-Marie-Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2.  Nat Genet. 2000;  25 (1) 17-19
• 74 Houlden H, King R H, Wood N W, Thomas P K, Reilly M M. Mutations in the 5′ region of the myotubularin-related protein 2 (MTMR2) gene in autosomal recessive hereditary neuropathy with focally folded myelin.  Brain. 2001;  124 (Pt 5) 907-915
• 75 Parman Y, Battaloglu E, Baris I et al.. Clinicopathological and genetic study of early-onset demyelinating neuropathy.  Brain. 2004;  127 (Pt 11) 2540-2550
• 76 Tyson J, Ellis D, Fairbrother U et al.. Hereditary demyelinating neuropathy of infancy. A genetically complex syndrome.  Brain. 1997;  120 (Pt 1) 47-63
• 77 Verny C, Ravisé N, Leutenegger A L et al.. Coincidence of two genetic forms of Charcot-Marie-Tooth disease in a single family.  Neurology. 2004;  63 (8) 1527-1529
• 78 Senderek J, Bergmann C, Weber S et al.. Mutation of the SBF2 gene, encoding a novel member of the myotubularin family, in Charcot-Marie-Tooth neuropathy type 4B2/11p15.  Hum Mol Genet. 2003;  12 (3) 349-356
• 79 Azzedine H, Bolino A, Taïeb T et al.. Mutations in MTMR13, a new pseudophosphatase homologue of MTMR2 and Sbf1, in two families with an autosomal recessive demyelinating form of Charcot-Marie-Tooth disease associated with early-onset glaucoma.  Am J Hum Genet. 2003;  72 (5) 1141-1153
• 80 Senderek J, Bergmann C, Stendel C et al.. Mutations in a gene encoding a novel SH3/TPR domain protein cause autosomal recessive Charcot-Marie-Tooth type 4C neuropathy.  Am J Hum Genet. 2003;  73 (5) 1106-1119
• 81 Gooding R, Colomer J, King R et al.. A novel gypsy founder mutation, p.Arg1109X in the CMT4C gene, causes variable peripheral neuropathy phenotypes.  J Med Genet. 2005;  42 (12) e69
• 82 Colomer J, Gooding R, Angelicheva D et al.. Clinical spectrum of CMT4C disease in patients homozygous for the p.Arg1109X mutation in SH3TC2.  Neuromuscul Disord. 2006;  16 (7) 449-453
• 83 Azzedine H, Ravisé N, Verny C et al.. Spine deformities in Charcot-Marie-Tooth 4C caused by SH3TC2 gene mutations.  Neurology. 2006;  67 (4) 602-606
• 84 Laššuthová P, Mazanec R, Vondráček P et al.. High frequency of SH3TC2 mutations in Czech HMSN I patients.  Clin Genet. 2011;  80 334-345
• 85 Houlden H, Laura M, Ginsberg L et al.. The phenotype of Charcot-Marie-Tooth disease type 4C due to SH3TC2 mutations and possible predisposition to an inflammatory neuropathy.  Neuromuscul Disord. 2009;  19 (4) 264-269
• 86 Boerkoel C F, Takashima H, Stankiewicz P et al.. Periaxin mutations cause recessive Dejerine-Sottas neuropathy.  Am J Hum Genet. 2001;  68 (2) 325-333
• 87 Guilbot A, Williams A, Ravisé N et al.. A mutation in periaxin is responsible for CMT4F, an autosomal recessive form of Charcot-Marie-Tooth disease.  Hum Mol Genet. 2001;  10 (4) 415-421
• 88 Marchesi C, Milani M, Morbin M et al.. Four novel cases of periaxin-related neuropathy and review of the literature.  Neurology. 2010;  75 (20) 1830-1838
• 89 Kabzinska D, Drac H, Sherman D L et al.. Charcot-Marie-Tooth type 4F disease caused by S399fsx410 mutation in the PRX gene.  Neurology. 2006;  66 (5) 745-747
• 90 Chow C Y, Zhang Y, Dowling J J et al.. Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J.  Nature. 2007;  448 (7149) 68-72
• 91 Zhang X, Chow C Y, Sahenk Z, Shy M E, Meisler M H, Li J. Mutation of FIG4 causes a rapidly progressive, asymmetric neuronal degeneration.  Brain. 2008;  131 (Pt 8) 1990-2001
• 92 Bergoffen J, Scherer S S, Wang S et al.. Connexin mutations in X-linked Charcot-Marie-Tooth disease.  Science. 1993;  262 (5142) 2039-2042
• 93 Siskind C E, Murphy S M, Ovens R, Polke J, Reilly M M, Shy M E. Phenotype expression in women with CMT1X.  J Peripher Nerv Syst. 2011;  16 (2) 102-107
• 94 Siskind C, Feely S M, Bernes S, Shy M E, Garbern J Y. Persistent CNS dysfunction in a boy with CMT1X.  J Neurol Sci. 2009;  279 (1-2) 109-113
• 95 Reilly M M, Shy M E. Diagnosis and new treatments in genetic neuropathies.  JNNP. 2009;  80 (12) 1304-1314