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Genetik der Neuropathien

Genetics of neuropathies

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Zusammenfassung

Hereditäre Neuropathien gehören zu den häufigsten neurogenetischen Erkrankungen. Sie treten meist als sensible und motorische Neuropathien auf, es gibt aber auch rein sensible und rein motorische sowie sensible und autonome hereditäre Neuropathien. In der klinischen Praxis ist eine Kenntnis der hereditären Neuropathien wichtig, um sie unter den Polyneuropathien erkennen und einer erfolgreichen genetischen Diagnostik zuführen zu können. Die Molekulargenetik der hereditären Neuropathien ist äußerst heterogen mit mittlerweile mehr als 40 bekannten krankheitsverursachenden Genen. Die 4 häufigsten Gene machen dabei fast 90% der genetisch diagnostizierten hereditären Neuropathien aus. Wir geben in diesem Übersichtsartikel einen Überblick über die derzeit bekannten Gene und stellen einen rationalen gendiagnostischen Algorithmus zur Diagnostik der häufigsten Varianten vor.

Summary

Hereditary neuropathies belong to the most common neurogenetic disorders. They appear mostly as sensory and motor neuropathies but there are also pure sensory, pure motor as well as sensory and autonomic hereditary neuropathies. In clinical practice, knowledge of hereditary neuropathies is important in order to recognize them among polyneuropathies and achieve a successful genetic diagnosis. The molecular genetics of hereditary neuropathies are very heterogeneous with currently more than 40 known disease-causing genes. The 4 most common genes account for almost 90% of the genetically diagnosed hereditary neuropathies. In this review article we provide an overview of the currently known genes and propose a rational genetic work-up protocol of the most common genes.

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  1. Anonymous (1999) 4th Workshop of the European CMT-Consortium – 62nd ENMC International Workshop: rare forms of Charcot-Marie-Tooth disease and related disorders 16–18 October 1998, Soestduinen, The Netherlands. Neuromuscul Disord 9:279–287

    Article  Google Scholar 

  2. Antonellis A, Ellsworth Re, Sambuughin N et al (2003) Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V. Am J Hum Genet 72:1293–1299

    Article  PubMed  CAS  Google Scholar 

  3. Auer-Grumbach M (2008) Hereditary sensory neuropathy type I. Orphanet J Rare Dis 3:7

    Article  PubMed  Google Scholar 

  4. Auer-Grumbach M, Olschewski A, Papic L et al (2010) Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C. Nat Genet 42:160–164

    Article  PubMed  CAS  Google Scholar 

  5. Axelrod FB, Gold-Von Simson G (2007) Hereditary sensory and autonomic neuropathies: types II, III, and IV. Orphanet J Rare Dis 2:39

    Article  PubMed  Google Scholar 

  6. Azzedine H, Bolino A, Taieb T et al (2003) 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 72:1141–1153

    Article  PubMed  CAS  Google Scholar 

  7. Baxter RV, Ben Othmane K, Rochelle JM et al (2002) Ganglioside-induced differentiation-associated protein-1 is mutant in Charcot-Marie-Tooth disease type 4A/8q21. Nat Genet 30:21–22

    Article  PubMed  CAS  Google Scholar 

  8. Bird TD (2012) Charcot-Marie-Tooth hereditary neuropathy overview. In: Pagon RA, Bird TD, Dolan CR (Hrsg) GeneReviews™ [Internet]. University of Washington, Seattle

  9. Bolino A, Muglia M, Conforti Fl et al (2000) Charcot-Marie-Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2. Nat Genet 25:17–19

    Article  PubMed  CAS  Google Scholar 

  10. Calvo J, Funalot B, Ouvrier RA et al (2009) Genotype-phenotype correlations in Charcot-Marie-tooth disease type 2 caused by mitofusin 2 mutations. Arch Neurol 66:1511–1516

    Article  PubMed  Google Scholar 

  11. Chance PF, Alderson MK, Leppig KA et al (1993) DNA deletion associated with hereditary neuropathy with liability to pressure palsies. Cell 72:143–151

    Article  PubMed  CAS  Google Scholar 

  12. Claeys KG, Zuchner S, Kennerson M et al (2009) Phenotypic spectrum of dynamin 2 mutations in Charcot-Marie-Tooth neuropathy. Brain 132:1741–1752

    Article  PubMed  Google Scholar 

  13. Cowchock FS, Duckett SW, Streletz LJ et al (1985) X-linked motor-sensory neuropathy type-II with deafness and mental retardation: a new disorder. Am J Med Genet 20:307–315

    Article  PubMed  CAS  Google Scholar 

  14. Cuesta A, Pedrola L, Sevilla T et al (2002) The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot-Marie-Tooth type 4A disease. Nat Genet 30:22–25

    Article  PubMed  CAS  Google Scholar 

  15. De Sandre-Giovannoli A, Chaouch M, Kozlov S et al (2002) Homozygous defects in LMNA, encoding lamin A/C nuclear-envelope proteins, cause autosomal recessive axonal neuropathy in human (Charcot-Marie-Tooth disorder type 2) and mouse. Am J Hum Genet 70:726–736

    Article  Google Scholar 

  16. Delague V, Bareil C, Tuffery S et al (2000) Mapping of a new locus for autosomal recessive demyelinating Charcot-Marie-Tooth disease to 19q13.1–13.3 in a large consanguineous Lebanese family: exclusion of MAG as a candidate gene. Am J Hum Genet 67:236–243

    Article  PubMed  CAS  Google Scholar 

  17. Delague V, Jacquier A, Hamadouche T et al (2007) Mutations in FGD4 encoding the Rho GDP/GTP exchange factor FRABIN cause autosomal recessive Charcot-Marie-Tooth type 4H. Am J Hum Genet 81:1–16

    Article  PubMed  CAS  Google Scholar 

  18. Deng HX, Klein CJ, Yan J et al (2010) Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4. Nat Genet 42:165–169

    Article  PubMed  CAS  Google Scholar 

  19. Dubourg O, Tardieu S, Birouk N et al (2001) Clinical, electrophysiological and molecular genetic characteristics of 93 patients with X-linked Charcot-Marie-Tooth disease. Brain 124:1958–1967

    Article  PubMed  CAS  Google Scholar 

  20. Dyck PJ, Chance PF, Lebo R et al (1993) Hereditary motor and sensory neuropathies. In: Dyck PJ, Thomas PK, Griffin JW et al (Hrsg) Peripheral neuropathy. WB Saunders, Philadelphia, S 1116–1117

  21. Fabrizi GM, Cavallaro T, Angiari C et al (2007) Charcot-Marie-Tooth disease type 2E, a disorder of the cytoskeleton. Brain 130:394–403

    Article  PubMed  Google Scholar 

  22. Fabrizi GM, Taioli F, Cavallaro T et al (2009) Further evidence that mutations in FGD4/frabin cause Charcot-Marie-Tooth disease type 4H. Neurology 72:1160–1164

    Article  PubMed  CAS  Google Scholar 

  23. Gess B, Jeibmann A, Schirmacher A et al (2011) Report of a novel mutation in the PMP22 gene causing an axonal neuropathy. Muscle Nerve 43:605–609

    Article  PubMed  Google Scholar 

  24. Guilbot A, Williams A, Ravise N et al (2001) A mutation in periaxin is responsible for CMT4F, an autosomal recessive form of Charcot-Marie-Tooth disease. Hum Mol Genet 10:415–421

    Article  PubMed  CAS  Google Scholar 

  25. Gullapalli RR, Lyons-Weiler M, Petrosko P et al (2012) Clinical integration of next-generation sequencing technology. Clin Lab Med 32:585–599

    Article  PubMed  CAS  Google Scholar 

  26. Harding AE, Thomas PK (1980) The clinical features of hereditary motor and sensory neuropathy types I and II. Brain 103:259–280

    Article  PubMed  CAS  Google Scholar 

  27. Hayasaka K, Himoro M, Sato W et al (1993) Charcot-Marie-Tooth neuropathy type 1B is associated with mutations of the myelin P0 gene. Nat Genet 5:31–34

    Article  PubMed  CAS  Google Scholar 

  28. Ionasescu V, Searby C, Ionasescu R (1994) Point mutations of the connexin32 (GJB1) gene in X-linked dominant Charcot-Marie-Tooth neuropathy. Hum Mol Genet 3:355–358

    Article  PubMed  CAS  Google Scholar 

  29. Ionasescu VV, Trofatter J, Haines Jl et al (1991) Heterogeneity in X-linked recessive Charcot-Marie-Tooth neuropathy. Am J Hum Genet 48:1075–1083

    PubMed  CAS  Google Scholar 

  30. Ionasescu VV, Trofatter J, Haines Jl et al (1992) X-linked recessive Charcot-Marie-Tooth neuropathy: clinical and genetic study. Muscle Nerve 15:368–373

    Article  PubMed  CAS  Google Scholar 

  31. Ito D (2012) BSCL2-related neurologic disorders/seipinopathy. In: Pagon RA, Bird TD, Dolan CR (Hrsg) GeneReviews™ [Internet]. University of Washington

  32. Jansen GA, Waterham HR, Wanders RJ (2004) Molecular basis of Refsum disease: sequence variations in phytanoyl-CoA hydroxylase (PHYH) and the PTS2 receptor (PEX7). Hum Mutat 23:209–218

    Article  PubMed  CAS  Google Scholar 

  33. Jordanova A, Irobi J, Thomas FP et al (2006) Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy. Nat Genet 38:197–202

    Article  PubMed  CAS  Google Scholar 

  34. Kalaydjieva L, Gresham D, Gooding R et al (2000) N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lom. Am J Hum Genet 67:47–58

    Article  PubMed  CAS  Google Scholar 

  35. Kalaydjieva L, Hallmayer J, Chandler D et al (1996) Gene mapping in Gypsies identifies a novel demyelinating neuropathy on chromosome 8q24. Nat Genet 14:214–217

    Article  PubMed  CAS  Google Scholar 

  36. Kim HJ, Sohn KM, Shy ME et al (2007) Mutations in PRPS1, which encodes the phosphoribosyl pyrophosphate synthetase enzyme critical for nucleotide biosynthesis, cause hereditary peripheral neuropathy with hearing loss and optic neuropathy (cmtx5). Am J Hum Genet 81:552–558

    Article  PubMed  CAS  Google Scholar 

  37. Kleffner I, Schirmacher A, Gess B et al (2010) Four novel mutations of the myelin protein zero gene presenting as a mild and late-onset polyneuropathy. J Neurol 257:1864–1868

    Article  PubMed  Google Scholar 

  38. Kuhlenbaumer G, Hannibal MC, Nelis E et al (2005) Mutations in SEPT9 cause hereditary neuralgic amyotrophy. Nat Genet 37:1044–1046

    Article  PubMed  Google Scholar 

  39. Landoure G, Zdebik AA, Martinez Tl et al (2010) Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C. Nat Genet 42:170–174

    Article  PubMed  CAS  Google Scholar 

  40. Lupski JR, De Oca-Luna RM, Slaugenhaupt S et al (1991) DNA duplication associated with Charcot-Marie-Tooth disease type 1A. Cell 66:219–232

    Article  PubMed  CAS  Google Scholar 

  41. Matsunami N, Smith B, Ballard L et al (1992) Peripheral myelin protein-22 gene maps in the duplication in chromosome 17p11.2 associated with Charcot-Marie-Tooth 1A. Nat Genet 1:176–179

    Article  PubMed  CAS  Google Scholar 

  42. Mersiyanova IV, Perepelov AV, Polyakov AV et al (2000) 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 67:37–46

    Article  PubMed  CAS  Google Scholar 

  43. Misko Al, Sasaki Y, Tuck E et al (2012) Mitofusin2 mutations disrupt axonal mitochondrial positioning and promote axon degeneration. J Neurosci 32:4145–4155

    Article  PubMed  CAS  Google Scholar 

  44. Murphy SM, Laura M, Fawcett K et al (2012) Charcot-Marie-Tooth disease: frequency of genetic subtypes and guidelines for genetic testing. J Neurol Neurosurg Psych 83:706–710

    Article  Google Scholar 

  45. Ohnishi A, Murai Y, Ikeda M et al (1989) Autosomal recessive motor and sensory neuropathy with excessive myelin outfolding. Muscle Nerve 12:568–575

    Article  PubMed  CAS  Google Scholar 

  46. Patel H, Cross H, Proukakis C et al (2002) SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia. Nat Genet 31:347–348

    PubMed  CAS  Google Scholar 

  47. Patel PI, Roa BB, Welcher AA et al (1992) The gene for the peripheral myelin protein PMP-22 is a candidate for Charcot-Marie-Tooth disease type 1A. Nat Genet 1:159–165

    Article  PubMed  CAS  Google Scholar 

  48. Plante-Bordeneuve V, Said G (2011) Familial amyloid polyneuropathy. Lancet Neurol 10:1086–1097

    Article  PubMed  CAS  Google Scholar 

  49. Quattrone A, Gambardella A, Bono F et al (1996) Autosomal recessive hereditary motor and sensory neuropathy with focally folded myelin sheaths: clinical, electrophysiologic, and genetic aspects of a large family. Neurology 46:1318–1324

    Article  PubMed  CAS  Google Scholar 

  50. Raeymaekers P, Timmerman V, Nelis E et al (1991) Duplication in chromosome 17p11.2 in Charcot-Marie-Tooth neuropathy type 1a (CMT 1a). The HMSN Collaborative Research Group. Neuromuscul Disord 1:93–97

    Article  PubMed  CAS  Google Scholar 

  51. Roa BB, Dyck PJ, Marks HG et al (1993) Dejerine-Sottas syndrome associated with point mutation in the peripheral myelin protein 22 (PMP22) gene. Nat Genet 5:269–273

    Article  PubMed  CAS  Google Scholar 

  52. Roa BB, Garcia CA, Suter U et al (1993) Charcot-Marie-Tooth disease type 1A. Association with a spontaneous point mutation in the PMP22 gene. N Engl J Med 329:96–101

    Article  PubMed  CAS  Google Scholar 

  53. Rossor AM, Kalmar B, Greensmith L et al (2011) The distal hereditary motor neuropathies. J Neurol Neurosurg Psych 83:6–14

    Article  Google Scholar 

  54. Rotthier A, Baets J, Timmerman V et al (2012) Mechanisms of disease in hereditary sensory and autonomic neuropathies. Nat Rev 8:73–85

    CAS  Google Scholar 

  55. Russo M, Laura M, Polke JM et al (2011) Variable phenotypes are associated with PMP22 missense mutations. Neuromuscul Disord 21:106–114

    Article  PubMed  CAS  Google Scholar 

  56. Said G, Grippon S, Kirkpatrick P (2012) Tafamidis. Nat Rev Drug Discov 11:185–186

    Article  PubMed  CAS  Google Scholar 

  57. Saporta AS, Sottile Sl, Miller LJ et al (2011) Charcot-Marie-Tooth disease subtypes and genetic testing strategies. Ann Neurol 69:22–33

    Article  PubMed  Google Scholar 

  58. Senderek J, Bergmann C, Stendel C et al (2003) Mutations in a gene encoding a novel SH3/TPR domain protein cause autosomal recessive Charcot-Marie-Tooth type 4C neuropathy. Am J Hum Genet 73:1106–1119

    Article  PubMed  CAS  Google Scholar 

  59. Shy ME, Jani A, Krajewski K et al (2004) Phenotypic clustering in MPZ mutations. Brain 127:371–384

    Article  PubMed  Google Scholar 

  60. Stendel C, Roos A, Deconinck T et al (2007) Peripheral nerve demyelination caused by a mutant Rho GTPase guanine nucleotide exchange factor, frabin/FGD4. Am J Hum Genet 81:158–164

    Article  PubMed  CAS  Google Scholar 

  61. Street VA, Bennett Cl, Goldy JD et al (2003) Mutation of a putative protein degradation gene LITAF/SIMPLE in Charcot-Marie-Tooth disease 1C. Neurology 60:22–26

    Article  PubMed  CAS  Google Scholar 

  62. Takashima H, Nakagawa M, Umehara F et al (2003) Gap junction protein beta 1 (GJB1) mutations and central nervous system symptoms in X-linked Charcot-Marie-Tooth disease. Acta Neurol Scand 107:31–37

    Article  PubMed  CAS  Google Scholar 

  63. Timmerman V, Nelis E, Van Hul W et al (1992) The peripheral myelin protein gene PMP-22 is contained within the Charcot-Marie-Tooth disease type 1A duplication. Nat Genet 1:171–175

    Article  PubMed  CAS  Google Scholar 

  64. Valentijn LJ, Bolhuis PA, Zorn I et al (1992) The peripheral myelin gene PMP-22/GAS-3 is duplicated in Charcot-Marie-Tooth disease type 1A. Nat Genet 1:166–170

    Article  PubMed  CAS  Google Scholar 

  65. Vance JM, Nicholson GA, Yamaoka LH et al (1989) Linkage of Charcot-Marie-Tooth neuropathy type 1a to chromosome 17. Exp Neurol 104:186–189

    Article  PubMed  CAS  Google Scholar 

  66. Verhoeven K, Claeys KG, Zuchner S et al (2006) MFN2 mutation distribution and genotype/phenotype correlation in Charcot-Marie-Tooth type 2. Brain 129:2093–2102

    Article  PubMed  Google Scholar 

  67. Verhoeven K, De Jonghe P, Coen K et al (2003) Mutations in the small GTP-ase late endosomal protein RAB7 cause Charcot-Marie-Tooth type 2B neuropathy. Am J Hum Genet 72:722–727

    Article  PubMed  CAS  Google Scholar 

  68. Warner LE, Mancias P, Butler IJ et al (1998) Mutations in the early growth response 2 (EGR2) gene are associated with hereditary myelinopathies. Nat Genet 18:382–384

    Article  PubMed  CAS  Google Scholar 

  69. Wierzbicki AS, Lloyd MD, Schofield CJ et al (2002) Refsum’s disease: a peroxisomal disorder affecting phytanic acid alpha-oxidation. J Neurochem 80:727–735

    Article  PubMed  CAS  Google Scholar 

  70. Yiu EM, Geevasinga N, Nicholson GA et al (2011) A retrospective review of X-linked Charcot-Marie-Tooth disease in childhood. Neurology 76:461–466

    Article  PubMed  CAS  Google Scholar 

  71. Zimon M, Baets J, Fabrizi GM et al (2011) Dominant GDAP1 mutations cause predominantly mild CMT phenotypes. Neurology 77:540–548

    Article  PubMed  CAS  Google Scholar 

  72. Zuchner S (2010) Peripheral neuropathies: whole genome sequencing identifies causal variants in CMT. Nat Rev 6:424–425

    Article  Google Scholar 

  73. Zuchner S, Mersiyanova IV, Muglia M et al (2004) Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat Genet 36:449–451

    Article  PubMed  Google Scholar 

  74. Zuchner S, Noureddine M, Kennerson M et al (2005) Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth disease. Nat Genet 37:289–294

    Article  PubMed  Google Scholar 

  75. Zuchner S, Vorgerd M, Sindern E et al (2004) The novel neurofilament light (NEFL) mutation Glu397Lys is associated with a clinically and morphologically heterogeneous type of Charcot-Marie-Tooth neuropathy. Neuromuscul Disord 14:147–157

    Article  PubMed  Google Scholar 

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  1. Klinik für Neurologie, Sektion für Schlafmedizin und ambulante Neurologie, Universitätsklinikum Münster, Albert-Schweitzer Campus 1, Gebäude A1, 48149, Münster, Deutschland

    B. Gess, A. Schirmacher & P. Young

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  1. B. Gess
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Gess, B., Schirmacher, A. & Young, P. Genetik der Neuropathien. Nervenarzt 84, 157–165 (2013). https://doi.org/10.1007/s00115-012-3640-4

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