Genetics of Hereditary Neuropathies

  • G. L. Mancardi
Part of the Topics in Neuroscience book series (TOPNEURO)


Hereditary motor and sensory neuropathies (HMSN) have been previously classified on the basis of clinical course, mode of inheritance and neuropathological findings [1]. In the past years, considerable advances in the knowledge of this heterogeneous group of disorders have been made due to genetic studies demonstrating that duplication, deletion or mutation of specific genes of the peripheral myelin are the most common causes of HMSN. The classification of HMSN and of related disorders, from now forward called with the eponymous Charcot-Marie-Tooth disease (CMT), is continuously evolving. CMT has a prevalence of 1 case every 2500 [1] and is divided into CMT1 and CMT2 according to neurophysio-logic and neuropathologic findings. In fact, in CMT1 the motor nerve conduction velocity (MNCV) of the median nerve is < 38 m/s. Nerve biopsy shows hypertrophy of the nerve, demyelination and remyelination of the nerve fibers, and Schwann cell proliferation around the demyelinated fibers in an “onion bulb” fashion. In contrast, in CMT2 MNCV is only slightly lowered (> 38 m/s) and sural nerve biopsy shows signs of primary axonal involvement with minimal signs of myelin sufferance. CMT1 and CMT2 are usually inherited as dominant disorders and are clinically indistinguishable. A severe form of CMT called Dejerine-Sottas syndrome (DSS) has onset in early childhood and a progressive and disabling clinical course.


Myelin Sheath Myelin Protein Onion Bulb Motor Nerve Conduction Velocity Sural Nerve Biopsy 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Dyck PJ, Chance PF, Lebo RV, Carney JA (1993) Hereditary motor and sensory neuropathies. Peripheral neuropathy, 3rd edn. WB Saunders, Philadelphia, pp 1094–1136Google Scholar
  2. 2.
    Lupski JR, Montes de Oca-Luna R., Slaugenhaupt S et al. (1991) DNA duplication associated with Charcot-Marie-Tooth disease type 1A. Cell 66: 219–232PubMedCrossRefGoogle Scholar
  3. 3.
    Raeymaekers P, Timmerman V, Nelis E et al. (1991) Duplication in chromosome 17p11.2 in Charcot-Marie-Tooth neuropathy type 1A. Neuromusc Dis 1: 93–97PubMedCrossRefGoogle Scholar
  4. 4.
    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 1:171–175PubMedCrossRefGoogle Scholar
  5. 5.
    Crespi V, Fabrizi G, Mandich P et al. (1999) Proposal of guide-lines for diagnosis of Charcot-Marie-Tooth disease and related neuropathies. It J Neurol Sci (in press)Google Scholar
  6. 6.
    Hayasaka K, Himoro M, Sato W et al. (1993) Charcot-Marie-Tooth neuropathy type 1B associated with mutations in the myelin protein zero gene. Nat Genet 5: 31–34PubMedCrossRefGoogle Scholar
  7. 7.
    Bergoffen J, Scherer SS, Wang S et al. (1993) Connexin mutations in X-linked Charcot-Marie-Tooth disease. Science 262: 2039–2042PubMedCrossRefGoogle Scholar
  8. 8.
    Ben Othmane K, Middleton LT, Loprest LJ et al. (1993) Localization of a gene (CMT2A) for autosomal dominant Charcot-Marie-Tooth disease type 2 to chromosome 1p and evidence of genetic heterogeneity. Genomics 17: 370–375PubMedCrossRefGoogle Scholar
  9. 9.
    Kwon JM, Elliot JL, Yee WC et al. (1995) Assignment of a second Charcot-Marie-Tooth type II locus to chromosome 3q. Am J Hum Genet 57: 853–858PubMedGoogle Scholar
  10. 10.
    Ionasescu V, Searby C, Sheffield VC et al. (1996) Autosomal dominant Charcot-Marie-Tooth axonal neuropathy mapped on chromosome 7p (CMT2D). Hum Mol Genet 5: 1373–1375PubMedCrossRefGoogle Scholar
  11. 11.
    Marrosu MG, Vaccargiu S, Marrosu G et al. (1998) Charcot-Marie-Tooth disease type 2 associated with mutation of the myelin protein zero gene. Neurology 50:1397–1401PubMedCrossRefGoogle Scholar
  12. 12.
    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: 269–273PubMedCrossRefGoogle Scholar
  13. 13.
    Hayasaka K, Himoro M, Sawaishy Y et al. (1993) De novo mutation in the myelin P0 gene in Dejerine-Sottas disease. Nat Genet 5: 266–268PubMedCrossRefGoogle Scholar
  14. 14.
    Warner LE, Hilz M J, Appel SH et al. (1996) Clinical phenotypes of different MPZ (P0) mutations may include Charcot-Marie-Tooth type 1B, Dejerine-Sottas, and congenital hypomyelination. Neuron 17:451–460PubMedCrossRefGoogle Scholar
  15. 15.
    Warner LE, Mandas P, Butler IJ et al. (1998) Mutations in the early growth response 2 (EGR2) gene are associated with hereditary myelinopathies. Nat Genet 18: 382–384PubMedCrossRefGoogle Scholar
  16. 16.
    Mancardi GL, Mandich P, Nassani S et al. (1995) Progressive sensory-motor polyneuropathy with tomaculous changes is associated to 17p11.2 deletion. J Neurol Sci 131:30–34PubMedCrossRefGoogle Scholar
  17. 17.
    Chance PF, Alderson MK, Leppig KA et al. (1993) DNA deletion associated with hereditary neuropathy with liability to pressure palsies. Cell 72: 143–151PubMedCrossRefGoogle Scholar
  18. 18.
    Pareyson D, Taroni F (1996) Deletion of the PMP 22 gene and hereditary neuropathy with liability to pressure palsies. Curr Opin Neurol 9: 348–354PubMedCrossRefGoogle Scholar
  19. 19.
    Ben Othmane K, Hentati F, Lennon F et al. (1993) Linkage of a locus (CMT 4A) for autosomal recessive Charcot-Marie-Tooth disease to chromosome 8q. Hum Mol Genet 2:1625–1628PubMedCrossRefGoogle Scholar
  20. 20.
    Ohnishi A, Yoshiyuki M, Ikeda M et al. (1989) Autosomal recessive motor and sensory neuropathy with excessive myelin outfolding. Muscle Nerve 12: 568–575CrossRefGoogle Scholar
  21. 21.
    Schenone A, Abbruzzese M, Uccelli A et al. (1994) Hereditary motor and sensory neuropathy with myelin outfolding: clinical, genetic and neuropathological study of three cases. J Neurol Sci 122: 20–27PubMedCrossRefGoogle Scholar
  22. 22.
    Bolino A, Brancolini V, Bono F et al. (1996) Localization of a gene responsible for autosomal recessive demyelinating neuropathy with focally folded myelin sheaths to chromosome 11q23 by homozygosity mapping and haplotype sharing. Hum Mol Genet 5:1051–1054PubMedCrossRefGoogle Scholar
  23. 23.
    McLeod JG, Low PA, Morgan JA (1978) Charcot-Marie -Tooth disease with Leber optic atrophy. Neurology 28:179–184PubMedCrossRefGoogle Scholar
  24. 24.
    Massion-Verniory L, Dumont E, Potuin A (1946) Retinite pigmentaire familiale complique d’une amyotrophic neurale. Rev Neurol 78: 561–571Google Scholar
  25. 25.
    Satya-Murti S, Cacace AT, Hanson PA (1979) Abnormal auditory evoked potentials in hereditary motor-sensory neuropathy. Ann Neurol 5: 445–448PubMedCrossRefGoogle Scholar
  26. 26.
    Rosenberg RN, Chutorian A (1967) Familial optico-acoustic nerve degeneration and polyneuropathy. Neurology 17: 827–832PubMedCrossRefGoogle Scholar
  27. 27.
    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: 307–315PubMedCrossRefGoogle Scholar
  28. 28.
    Mancardi GL, Di Rocco M, Schenone A et al. (1992) Hereditary motor and sensory neuropathy with deafness, mental retardation and absence of large myelinated fibers. J Neurol Sci 110:121–130PubMedCrossRefGoogle Scholar
  29. 29.
    Scherer SS (1997) The biology and pathobiology of Schwann cells. Curr Opin Neurol 10: 386–397PubMedCrossRefGoogle Scholar
  30. 30.
    Pentao L, Wise CA, Chinault AC et al. (1992) Charcot-Marie-Tooth type 1A duplication appears to arise from recombination at repeat sequences flanking the 1.5 Mb monomer unit. Nat Genet 2: 292–300PubMedCrossRefGoogle Scholar
  31. 31.
    Vallat JM, Sindou P, Preux PMP et al. (1996) Ultrustructural PMP-22 expression in inherited demyelinating neuropathies. Ann Neurol 39: 813–817PubMedCrossRefGoogle Scholar
  32. 32.
    Hanemann CO, Stoll G, D’Urso D et al. (1994) Peripheral myelin protein-22 expression in Charcot-Marie-Tooth disease type la sural nerve biopsies. J Neurosci Res 37: 654–659PubMedCrossRefGoogle Scholar
  33. 33.
    Schenone A, Nobbio L, Mandich P et al. (1997) Underexpression of messenger RNA for peripheral myelin protein 22 in hereditary neuropathy with liability to pressure palsies. Neurology 48: 445–449.PubMedCrossRefGoogle Scholar
  34. 34.
    Scherer SS, Yi-Tian Xu, Nelles R et al. (1998) Connexin 32-null mice develop demyelinating peripheral neuropathy. Glia 24: 8–20PubMedCrossRefGoogle Scholar
  35. 35.
    Sereda M, Griffiths I, Puhlhofer A et al. (1996) A transgenic rat model of Charcot-Marie-Tooth disease. Neuron 16: 1049–1060PubMedCrossRefGoogle Scholar
  36. 36.
    Martini R, Zielasek J, Toyka KV (1998) Inherited demyelinating neuropathies: from gene to disease. Curr Opin Neurol 11: 545–556PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia 1999

Authors and Affiliations

  • G. L. Mancardi
    • 1
  1. 1.Department of Neurological SciencesUniversity of GenoaGenoaItaly

Personalised recommendations