Skip to main content

Advertisement

SpringerLink
Log in

Increased severity over generations of Charcot-Marie-Tooth disease type 1A

  • ORIGINAL COMMUNICATION
  • Published:
Journal of Neurology Aims and scope Submit manuscript

Abstract

Background

Charcot-Marie-Tooth type 1A (CMT1A) is an autosomal dominant polyneuropathy due to a 1.5 Mb tandem duplication in chromosome 17p11.2, containing the PMP22 gene. This mutation is not modified during inheritance.

Objectives

We set forth to test the hypothesis that in a subgroup of CMT1A patients there is clinical anticipation, namely an increase in disease severity over generations.

Methods

Thirty-nine CMT1A mutation-positive patients in 16 families and 23 parent-offspring pairs were evaluated. This included 14 families with 2 generations and 2 families with 3 generations. Age of presentation was assessed by interviewing the patients and clinical severity was measured using the CMT neuropathy score (CMTNS).

Results

In 21/23 parent-child pairs and 14/16 families, there was an earlier age of presentation in children of genetically affected parents. The mean age of onset in the progeny was 12.61 years compared to 41.22 years in the parent generation, (p < 0.001).Mean severity in the younger generation was slightly higher than that of the parent generation. When corrected for the age difference, the trend for a worse phenotype in the younger generation became statistically significant (p < 0.02,Wilcoxon signed rank test).

Conclusions

Our findings suggest that in a subgroup of CMT1A patients there is an increase in clinical severity over generations. The mechanism responsible for this observation remains unknown. Our findings should be validated on a larger cohort of CMT1A families.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Shy ME (2004) Charcot-Marie-Tooth disease: an update. Curr Opin Neurol 17:579–585

    Article  PubMed  CAS  Google Scholar 

  2. Warner LE, Garcia CA, Lupski JR (1999) Hereditary peripheral neuropathies: clinical forms, genetics, and molecular mechanisms. Annu Rev Med 50:263–275

    Article  PubMed  CAS  Google Scholar 

  3. Lupski J, de Oca-Luna R, Slaugenhaupt S, et al. (1991) DNA duplication associated with Charcot-Marie-Tooth disease type 1A. Cell 66:219–232

    Article  PubMed  CAS  Google Scholar 

  4. Raeymaekers P, Timmerman V, Nelis E, De Jonghe P, Hoogendijk JE, Baas F, 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 

  5. Berger P, Young P, Suter U (2002) Molecular cell biology of Charcot-Marie-Tooth disease. Neurogenetics 4:1–15

    Article  PubMed  CAS  Google Scholar 

  6. Warner LE, Hilz MJ, 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 17:451–460

    Article  PubMed  CAS  Google Scholar 

  7. Dupre N, Bouchard JP, Cossette L, et al. (1999) Clinical and electrophysiological study in French-Canadian population with Charcot-Marie-tooth disease type 1A associated with 17p11. 2 duplication. Can J Neurol Sci 26:196–200

    PubMed  CAS  Google Scholar 

  8. Morocutti C, Colazza GB, Soldati G, et al. (2002) Charcot-Marie-Tooth disease in Molise, a central-southern region of Italy: an epidemiological study. Neuroepidemiology 21:241–245

    Article  PubMed  Google Scholar 

  9. Richards RI (2001) Dynamic mutations: a decade of unstable expanded repeats in human genetic disease. Hum Mol Genet 10:2187–2194

    Article  PubMed  CAS  Google Scholar 

  10. Lindblad K, Schalling M (1999) Expanded repeat sequences and disease. Semin Neurol 19:289–299

    Article  PubMed  CAS  Google Scholar 

  11. Rosenmann H, Kahana E, Korczyn AD, et al. (1999) Preliminary evidence for anticipation in genetic E200K Creutzfeldt-Jakob disease. Neurology 53:1328–1329

    PubMed  CAS  Google Scholar 

  12. Shirahama S, Miyahara A, Kitoh H, et al. (2003) Skewed X-chromosome inactivation causes intra-familial phenotypic variation of an EBP mutation in a family with X-linked dominant chondrodysplasia punctata. Hum Genet 112:78–83

    Article  PubMed  Google Scholar 

  13. Trkova M, Hladikova M, Kasal P, Goetz P, Sedlacek Z (2002) Is there anticipation in the age at onset of cancer in families with Li-Fraumeni syndrome? J Hum Genet 47:381–386

    Article  PubMed  Google Scholar 

  14. Cavallini MC, Albertazzi M, Bianchi L, Bellodi L (2002) Anticipation of age at onset of obsessive-compulsive spectrum disorders in patients with obsessivecompulsive disorder. Psychiatry Res 111:1–9

    Article  PubMed  Google Scholar 

  15. Freeman HJ (2002) Familial Crohn’s disease in single or multiple first-degree relatives. J Clin Gastroenterol 35:9–13

    Article  PubMed  Google Scholar 

  16. Shy ME, Blake J, Krajewski K, et al. (2005) Reliability and validity of the CMT neuropathy score as a measure of disability. Neurology 64:1209–1214

    PubMed  CAS  Google Scholar 

  17. Cornblath DR, Chaudhry V, Carter K, et al. (1999) Total neuropathy score: validation and reliability study. Neurology 53:1660–1664

    PubMed  CAS  Google Scholar 

  18. Lopes J, LeGuern E, Gouider R, Brice A, et al. (1996) Recombination hot spot in a 3. 2-kb region of the Charcot-Marie-Tooth type 1A repeat sequences: new tools for molecular diagnosis of hereditary neuropathy with liability to pressure palsies and of Charcot-Marie- Tooth type 1A. French CMT Collaborative Research Group. American Journal of Human Genetics 58:1223–1230

    PubMed  CAS  Google Scholar 

  19. Ashizawa T, Conneally PM (1999) Repeats may not be everything in anticipation. Neurology 53:1164–1164

    PubMed  CAS  Google Scholar 

  20. Goncalves A, da Salva JB (1977) Brothers affected by the Charcot-Marie-Tooth peroneal muscular atrophy with a positive variant of the anticipation phenomenon (Article in Portuguese). Arq Neuropsiquiatr 35:167–171

    PubMed  CAS  Google Scholar 

  21. Thornton C (1999) The myotonic dystrophies. Semin Neurol 19:25–33

    Article  PubMed  CAS  Google Scholar 

  22. Bertram L, Tanzi RE (2005) The genetic epidemiology of neurodegenerative disease. J Clin Invest 115:1449–1457. Review

    Article  PubMed  CAS  Google Scholar 

  23. Harley HG, Rundle SA, MacMillan JC, et al. (1993) Size of the unstable CTG repeat sequence in relation to phenotype and parental transmission in myotonic dystrophy. Am J Hum Genet 52:1164–1174

    PubMed  CAS  Google Scholar 

  24. Snell RG, MacMillan JC, Cheadle JP, et al. (1993) Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington’s disease. Nat Genet 4:393–397

    Article  PubMed  CAS  Google Scholar 

  25. Benton CS, de Silva R, Rutledge SL, et al. (1998) Molecular and clinical studies in SCA-7 define a broad clinical spectrum and the infantile phenotype. Neurology 51:1081–1086

    PubMed  CAS  Google Scholar 

  26. MacDonald ME, Vonsattel JP, Shrinidhi J, et al. (1999) Evidence for the GluR6 gene associated with younger onset age of Huntington’s disease. Neurology 53:1330–1332

    PubMed  CAS  Google Scholar 

  27. Inoue K, Dewar K, Katsanis N, et al. (2001) The 1. 4-Mb CMT1A duplication/ HNPP deletion genomic region reveals unique genome architectural features and provides insights into the recent evolution of new genes. Genome Res 11:1018–1033

    Article  PubMed  CAS  Google Scholar 

  28. Presciuttini S, Varesco L, Sala P, et al. (1994) Age of onset in familial adenomatous polyposis: heterogeneity within families and among APC mutations. Ann Hum Genet 58:331–342

    Article  PubMed  CAS  Google Scholar 

  29. Goldberg JM, Piver MS, Jishi MF, Blumenson L (1997) Age at onset of ovarian cancer in women with a strong family history of ovarian cancer. Gynecol Oncol 66:3–9

    Article  PubMed  CAS  Google Scholar 

  30. Hsu L, Zhao LP, Malone KE, Daling JR (2000) Assessing changes in ages at onset over successive generation: an application to breast cancer. Genet Epidemiol 18:17–32

    Article  PubMed  CAS  Google Scholar 

  31. Shugart YY, Hemminki K, Vaittinen P, Kingman A, Dong C (2000) A genetic study of Hodgkin’s lymphoma: an estimate of heritability and anticipation based on the familial cancer database in Sweden. Hum Genet 106:553–556

    Article  PubMed  CAS  Google Scholar 

  32. Gorwood P, Leboyer M, Falissard B, Rouillon MJF, Feingold J (1996) Anticipation in schizophrenia: new light on a controversial problem. Am J Psych 153:1173–1177

    CAS  Google Scholar 

  33. Iwai K, Yamamoto M, Yoshihara T, Sobue G (2002) Anticipation in familial amyotrophic lateral sclerosis with SOD1-G93S mutation. J Neurol Neurosurg Psych 72:819–820

    Article  CAS  Google Scholar 

  34. Misu K, Hattori N, Ando Y, Ikeda S, Sobue G (2000) Anticipation in earlybut not late-onset familial amyloid polyneuropathy (TTR Met30) in Japan. Neurology 55:451–452

    PubMed  CAS  Google Scholar 

  35. Kovach MJ, Campbell KC, Herman K, et al. (2002) Anticipation in a unique family with Charcot-Marie-Tooth syndrome and deafness: delineation of the clinical features and review of the literature. Am J Med Genet 108:295–303

    Article  PubMed  CAS  Google Scholar 

  36. Höweler CJ, Busch HFM, Geraedts JPM, Niermeijer MF, Staal A (1989) Anticipation in myotonic dystrophy: fact or fiction? Brain 112:779–797

    Article  PubMed  Google Scholar 

  37. Tawil R, Forrester J, Griggs RC, et al. (1996) Evidence for anticipation and association of deletion size with severity in facioscapulohumeral muscular dystrophy. The FSH-DY Group. Ann Neurol 39:744–748

    Article  PubMed  CAS  Google Scholar 

  38. Chauvenet AR, Shashi V, Selsky C, et al. (2003) Vincristine-induced neuropathy as the initial presentation of Charcot-Marie-Tooth disease in acute lymphoblastic leukemia: a pediatric oncology group study. J Ped Hemat Oncol 25:316–320

    Article  Google Scholar 

  39. Pulst SM, Santos N, Wang D, et al. (2005) Spinocerebellar ataxia type 2: polyQ repeat variation in the CACNA1A calcium channel modifies age of onset. Brain 128:2297–2303

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Neurological Sciences Unit, Hadassah University Hospital, Mount Scopus, 24035, Jerusalem, 91240, Israel

    I. Steiner MD

  2. Dept. of Neurology, Hadassah University Hospital, Ein-Karem, Jerusalem

    M. Gotkine MD, I. Biran ND & Z. Argov MD

  3. Dept. of Neurology, Shaare Zedek Hospital, Ein-Karem, Jerusalem

    B. Steiner-Birmanns MD

  4. Dept. of Human Genetics, Hadassah University Hospital, Ein-Karem, Jerusalem

    S. Silverstein MSc & D. Abeliovich PhD

  5. Dept. of Neurology, Soroka Medical Center, Ben Gurion University, Faculty of Health Sciences, Beer Sheva, Israel

    I. Wirguin MD

Authors
  1. I. Steiner MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Gotkine MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. B. Steiner-Birmanns MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. I. Biran ND
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S. Silverstein MSc
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D. Abeliovich PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Z. Argov MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. I. Wirguin MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to I. Steiner MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Steiner, I., Gotkine, M., Steiner-Birmanns, B. et al. Increased severity over generations of Charcot-Marie-Tooth disease type 1A. J Neurol 255, 813–819 (2008). https://doi.org/10.1007/s00415-008-0693-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-008-0693-1

Key words

Search

Navigation