Huntington´s Disease: Experience with Genetic Testing within 1994 – 2005

Czech version

Authors: J. Židovská ¹; J. Klempíř ²; V. Kebrdlová ¹; T. Uhrová ³; J. Koblihová ⁴; M. Anders ³; P. Doubek ³; J. Vevera ³; J. Roth ²
Authors‘ workplace: Ústav biologie a lékařské genetiky 1. LF UK a VFN, Praha ¹; Neurologická klinika 1. LF UK a VFN, Praha ²; Psychiatrická klinika 1. LF UK a VFN, Praha ³; Ústřední vojenská nemocnice, Praha ⁴
Published in: Cesk Slov Neurol N 2007; 70/103(1): 72-77
Category: Short Communication

Práce vznikla za podpory grantu IGA MZ ČR 7623-3 Autoři děkují za spolupráci všem doporučujícím neurologickým, psychiatrickým a genetickým pracovištím a Společnosti pro pomoc při Huntingtonově chorobě (www.huntington.cz).

Overview

The aim of research is to present clinico-genetic characteristics of Huntington´s disease in a representative sample of Czech population, and to show the benefit of genetic testing and its difficulties.

Huntington´s disease (HD) is an autosomally dominant hereditary neurodegenerative disease with its onset in adulthood conditioned by the expansion of CAG repetition in the coding area of gene IT 15. Since 1994, there have been carried out 629 genetic tests: 567 diagnostic, 61 presymptomatic and one prenatal tests. The diagnostic test confirmed the clinical diagnosis of HD in 72.5 % patients. A new mutation was demonstrated in two cases. With positive familial history, the diagnosis was confirmed in 95 % patients, in the absent familial occurrence the test was positive in 18 % patients, in the case of unclear anamnestic data HD was the problem in 60 %. That has shown the benefit of DNA analysis as a masterful tool in differential diagnostics.

The presymptomatic test was completed by about 1/3 of applicants in the risk of HD development. The result was positive in 40 %. The acceptance of presymptomatic test made 4 % of supposed risky population, prenatal diagnostics was required quite exceptionally. The low utilization of predictive test is caused by the discrepancy between the possibility of precise molecular-genetic diagnostics and non-existence of an effective therapy for HD.

Key-words:
Huntington´s disease, CAG repetition, DNA analysis, diagnostic testing.

Sources

1. Harper PS. The epidemiology of Huntington´s disease. J Med Genet 1992; 89: 365-72.

2. The Huntington´s Disease Colaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington´s disease chromosomes. Cell 1993; 72: 971-83.

3. Koeppen AH. The hereditary ataxias. J Neuropathol Exp Neurol 1998; 57: 531-43.

4. Kremer B, Almquist E, Theilmann J et al. A world-wide study of the Huntington´s disease mutation. N Engl J Med 1994; 30: 1401-6.

5. Rubinsztein DC, Leggo J, Voles R et al. Phenotypic characterization of individuals with 30-40 CAG repeats in the Huntingtion disease (HD) gene reveals HD cases with 36 repeats and apparently normal eldery individuals with 36-39 repeats. Am J Hum Genet 1996; 59: 16-22.

6. McNeil SM, Novelletto A, Srindhi J et al. Reduced penetrance of the Huntington´s disease mutation. Hum Mol Genet 1997; 6: 775-9.

7. Nance MA. Huntington disease – another chapter rewritten. Am J Hum Genet 1996; 59: 1-8.

8. Brinkman RR, Mezei MM, Theilmann J et al. The likelihood of beening affected with Huntington disease by a particular age, for a specific CAG size, Am J Hum Genet 1997; 60: 1202-10.

9. Soebel SK, Brokes Cowan D. Impact of genetic testing for Huntington disease on the familysystem. Am J Med Genet 2000; 90: 49-59.

10. International Huntington Association (IHA) and the World Federation of Neurology (WFN) Research Group on Huntington´s Chorea. Guidelines for the molecular genetics predictive test in Huntington´s disease. Neurology 1994; 44: 1533-6.

11. Mullenbach R. An efficient salt-chloroform extraction of DNA from blood and tissues. Trends Genet 1998; 5: 391.

12. Warner JP, Barron L H, Brock DJ. A new polymerase chain reaction (PCR) assay for the trinucleotide repeat that is unstable and expanded on Huntington´s disease chromosomes. Mol Cell Probes 1993; 235-9.

13. Losekoot M, Bakker B, Laconne F et al. A European pilot quality assessment scheme for molecular diagnosis of Huntington´s disease. Eur J Hum Genet 1999; 7: 217-22.

14. Potter NT, Spector EB, Prior TW. Technical standards and guidelines for Huntington disease testing. Genet Med 2004; 6: 61-5.

15. ACMG/ASHG statement. Laboratory guidelines for Huntington disease genetic testing. Am J Hum Genet 1998; 62: 1243-7.

16. Laccone F, Engel U, Holinski-Feder E et al. DNA analysis of Huntington´s disease: Five years of experience in Germany, Austria, and Switzerland. Neurology 1999; 53: 801-6.

17. Falush D, Almquist EW, Brinkman RR et al. Measurement od Mutation flow implies both a high new-mutation rate for Huntington disease and substantial underascertainment of late-onset cases. Am J Med Genet 2000; 68: 373-85.

18. Xiang F, Almquist W, Huq M et al. A Huntington disease-like neurodegenerative disorder maps to chromosome 20. Am J Med Genet 1998; 1431-8.

19. Ramos-Arroyo MA, Moreno S, Valiente A. Incidence and mutation rates of Huntington´s disease in Spain: experience of 9 years of direct genetic testing. J Neurol Neurosurg Psychiatry 2005; 76: 337-42.

20. Do Carmo Costa M, Magalhaes P, Ferreirinha F et al. Molecular diagnosis of Huntington disease in Portugal: implications for genetic counselling and clinical practice. Eur J Hum Genet 2003;11: 872-8.

21. Akbas F, Erginhel-Unaltun N. DNA testing for Huntington disease in the Turkish population. Eur Neurol 2003; 50: 20-4.

22. Jakab K, Gárdián G, Endreffy E et al. Analysis of CAG repeat expansion in Huntington´s disease gene (IT 15) in a Hungarian population. Eur Neurol 1999; 41: 107-10

23. Codori AM, Hanson R, Brandt J. Self-selection in predictive testing for Huntington´s disease. Am J Med Genet, 1994; 54: 167-73.

24. Stern HJ, Harton GL, Sisson ME et al. Non-disclosing preimplantation genetic diagnosis for Huntington´s disease. Prenat Diagn 20002; 22: 503-7.

25. Mandich P, Jacopini G, Di Maria E et al. Predictive testing for Huntington´s disease: ten years´experience in two Italian centres. Ital J Neurol Sci 1998; 9: 68-74.

26. Harper P S, Lim C, Craufurd D. Ten years of presymptomatic testing for Huntington´s disease: the experience of the UK Huntington´s Disease Predictive Consortium. J Med Genet 2000; 37: 567-71.

27. Maat-Kievit A, Vegter-van der Vlis M, Zoeteweij M et al. Experience in prenatal testing for Huntington´s disease in The Netherlands: procedures, results and guidelines (1987-1997). Prenat Diagn 1999; 19: 450-7.

28. Almquist EW, Bloch M, Brinkman R et al. A Worldwide Assessment od the frequency of suicide, suicide attempts, or psychiatric hospitalization after predictive testing for Huntinton disease. Am J Hum Genet 1999; 64: 1293-304.

29. Timman R, Roos R, Maat-Kievit A. Adverse effects of predictive testing for Huntington disease underestimated: long-term effects 7-10 years after the test. Health Psychol 2004; 23: 189-97.