Heterogeneity of sporadic Parkinson’s disease: molecular approach to solving the problem

Cover Page


Cite item

Abstract

We performed search for mutations in the LRRK2, PRKN (parkin) and SNCA (a-synuclein) genes in 359 patients of Slavonic ethnic origin (169 men and 190 women) with Parkinson’s disease, of whom 345 represented sporadic cases. Age at the disease onset was from 23 to 84 years, and patients with juvenile parkinsonism (debut of symptoms before 20 years) were excluded from enrollment. On study of a major mutation G2019S in the gene LRRK2 as well as of structural rearrangements in the PRKN and SNCA genes it was established that in Parkinson’s disease the frequency of these mutations is 7.5% (27 patients of 359). The mutation LRRK2-G2019S was found in 1.1% of patients, parkin gene exonic rearrangements in 5.8% (including 10.7% patients with an early form of Parkinson’s disease and 1.7% patients with a late form of the disease), and SNCA gene duplication in two patients. The performed analysis showed marked heterogeneity of the molecular structure of Parkinson’s disease in Russian population, which allows to consider this disorder not to be a unified form but rathera group of separate (although similar) neurodegenerative syndromes. The identification of inherited mutations in a part of sporadic cases of Parkinson’s disease changes significantly the familial prognosis and requires genetic counseling in persons from the ‘high risk’ group.

About the authors

S. N. Illarioshkin

Research Center of Neurology

Author for correspondence.
Email: platonova@neurology.ru
Russian Federation

P. A. Slominsky

Institute of Molecular Genetics, Russian Academy of Sciences, Moscow

Email: platonova@neurology.ru
Russian Federation

M. I. Shadrina

Institute of Molecular Genetics, Russian Academy of Sciences, Moscow

Email: platonova@neurology.ru
Russian Federation

G. Kh. Bagyeva

Research Center of Neurology

Email: platonova@neurology.ru
Russian Federation

T. B. Zagorovskaya

Research Center of Neurology

Email: platonova@neurology.ru
Russian Federation

E. D. Markova

Research Center of Neurology

Email: platonova@neurology.ru
Russian Federation

A. V. Karabanov

Research Center of Neurology

Email: platonova@neurology.ru
Russian Federation

V. V. Poleshchuk

Research Center of Neurology

Email: platonova@neurology.ru
Russian Federation

E. V. Polevaya

Research Center of Neurology

Email: platonova@neurology.ru
Russian Federation

N. V. Fedorova

Russian Medical Academy of Postgraduate Education, Moscow

Email: platonova@neurology.ru
Russian Federation

S. A. Limborskaya

Institute of Molecular Genetics, Russian Academy of Sciences, Moscow

Email: platonova@neurology.ru
Russian Federation

I. A. Ivanova-Smolenskaya

Research Center of Neurology

Email: platonova@neurology.ru
Russian Federation

References

  1. Загоровская Т.Б., Иллариошкин С.Н., Сломинский П.А. и др. Клинико-генетический анализ ювенильного паркинсонизма в России. Журн. неврол. и психиатрии им. С.С. Корсакова 2004; 8: 66–72.
  2. Иванова-Смоленская И.А., Маркова Е.Д., Загоровская Т.Б., Иллариошкин С.Н. Семейные случаи болезни Паркинсона (клиникоогенетический анализ). Мед. генетика 2002; 5: 234–237.
  3. Иллариошкин С.Н. Конформационные болезни мозга. М.: Янус К, 2003.
  4. Иллариошкин С.Н., Загоровская И.А., Иванова-Смоленская И.А., Маркова Е.Д. Генетические аспекты болезни Паркинсона. Неврол. журн. 2002; 5: 47–51.
  5. Левин О.С., Докадина Л.В. Эпидемиология паркинсонизма и болезни Паркинсона. Неврол. журн. 2005; 5: 41–49.
  6. Berg D., Schweitzer K.J., Leitner P. et al. Type and frequency of mutations in the LRRK2 gene in familial and sporadic Parkinson’s disease. Brain 2005; 128: 3000–3011.
  7. DeRijk M.C., Breteler M.M., Graveland G.A. et al. Prevalence of Parkinson’s disease in the elderly: the Rotterdam study. Neurology 1995; 45: 2143–2146.
  8. Di Fonzo A., Tassorelli C., De Mari M. et al. Comprehensive analysis of the LRRK2 gene in sixty families with Parkinson’s disease. Eur. J. Hum. Genet. 2006; 14: 322–331.
  9. Elbaz A., Grigoletto F., Balderschi M. et al. Familial aggregation of Parkinson’s disease: A population-based case-control study in Europe. Neurology 1999; 52: 1876–1882.
  10. Farrer M., Kachergus J., Forno L. еt al. Comparison of kindreds with familial parkinsonism and ббsynuclein genomic multiplications. Ann. Neurol. 2004; 55: 174–179.
  11. Farrer M., Stone J., Mata I.F. et al. LRRK2 mutations in Parkinson disease. Neurology 2005; 65: 738–740.
  12. Foroud T. LRRK2: both a cause and a risk factor for Parkinson’s disease? Neurology 2005; 65: 664–665.
  13. Foroud T., Uniacke S.K., Liu L. et al. Heterozygosity for a mutation in the parkin gene leads to later onset Parkinson disease. Neurology 2003; 60: 796–801.
  14. Gilks W.P., Abou-Sleiman P.M., Gandhi S. et al. A common LRRK2 mutation in idiopathic Parkinson’s disease. Lancet 2005; 365: 415–416.
  15. Golbe L.I. Young onset Parkinson’s disease: a clinical review. Neurology 1991; 41: 168–173.
  16. Golbe L.I. Alpha-synuclein and Parkinson’s disease. Mov. Disord. 1999; 14: 6–9.
  17. Hernandez D.G., Paisan Ruiz C., McInerney Leo A. et al. Clinical and positron emission tomography of Parkinson’s disease caused by LRRK2. Ann. Neurol. 2005; 57: 453–456.
  18. Hilker R., Klein C., Hedrich K. et al. The striatal dopaminergic deficit is dependent on the number of mutant alleles in a family with mutations in the parkin gene: evidence for enzymatic function in humans. Neurosci. Lett. 2002; 323: 50–54.
  19. Hughes A.J., Daniel S.E., Kilford L., Lees A.J. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J. Neurol. Neurosurg. Psychiatry 1992; 55: 181–184.
  20. Illarioshkin S.N., Ivanova-Smolenskaya I.A., Markova E.D. et al. Lack of a-synuclein gene mutations in families with autosomal dominant Parkinson’s disease. J. Neurol. 2000; 247: 968–969.
  21. Khan N.L., Graham E., Critchley P. et al. Parkin disease: a phenotypic study of a large series of cases. Brain 2003; 126: 1279–1292.
  22. Kitada T., Asakawa S., Hattori N. et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 1998; 392: 605–608.
  23. Kruger R., Vieira-Saecker A., Kuhn W. et al. Increased susceptibility to sporadic Parkinson’s disease by a certain combined бб synuclein/apolipoprotein E genotype. Ann. Neurol. 1999; 45: 611–617.
  24. Leroy E., Boyer R., Auburger G. et al. The ubiquitin pathway in Parkinson’s disease. Nature 1998; 395: 451–452.
  25. Lesage S., Diirr A., Tazir M. et al. LRRK2 G2019S as a cause of Parkinson’s disease in North African Arabs. New Engl. J. Med. 2006; 354: 422–423.
  26. Liicking C.B., Diirr A., Bonifati V. et al. Association between early-onset Parkinson’s disease and mutations in the parkin gene. New Engl. J. Med. 2000; 342: 1560–1567.
  27. Mata I.F., Lockhart P.J., Farrer M.J. Parkin genetics: one model for Parkinson’s disease. Hum. Mol. Genet. 2004; 13: 127–133.
  28. Mata I.F., Ross O.A., Kachergus J. et al. LRRK2 mutations are a common cause of Parkinson’s disease in Spain. Eur. J. Neurol. 2006; 13: 391–394.
  29. Morrison K.E. Parkin mutations and early onset parkinsonism. Brain 2003; 126: 1250–1251.
  30. Mouradian M.M. Recent advances in the genetics and pathogenesis of Parkinson disease. Neurology 2002; 58: 179–185.
  31. Ozelius L.J., Senthil G., Saunders Pullman R. et al. LRRK2 G2019S as a cause of Parkinson’s disease in Ashkenazi Jews. New Engl. J. Med. 2006; 354: 424–425.
  32. Paisan-Ruiz C., Jain S., Evans E.W. et al. Cloning of the gene containing mutations that cause PARK88linked Parkinson’s disease. Neurol. 2004; 44: 595–600.
  33. Paisan-Ruiz C., Lang A.E., Kawarai T. et al. LRRK2 gene in Parkinson disease: mutation analysis and case control association study. Neurology 2005; 65: 696–700.
  34. Piccini P., Burn D.J., Ceravolo R. et al. The role of inheritance in sporadic Parkinson’s disease: evidence from a longitudinal study of dopaminergic function in twins. Ann. Neurol. 1999; 45: 577–582.
  35. Singleton A.B., Farrer M., Johnson J. et al. Alpha-synuclein locus triplication causes Parkinson’s disease. Science 2003; 302: 841.
  36. Tan E.K., Khajavi M., Thoronby J.I. et al. Variability and validity of polymorphism association studies in Parkinson’s disease. Neurology 2000; 55: 533–538.
  37. Veldman B., Wijn A., Knoers N. et al. Genetic and environmental risk factors in Parkinson’s disease. Clin. Neurol. Neurosurg. 1998; 100: 15–26.
  38. Vieregge P., Hagenah J., Heberlein I. et al. Parkinson’s disease in twins: a follow-up study. Neurology 1999; 53: 566–572.
  39. Vila M., Przedborski S. Genetic clues to the pathogenesis of Parkinson’s disease. Nat. Med. 2004; 10 (Suppl.): S58–S62.
  40. West A., Periquet M., Lincoln S. et al. Complex relationship between parkin mutations and Parkinson disease. Am. J. Med. Genet. 2002; 114: 584–591.
  41. Wszolek Z.K., Pfeiffer R.F., Tsuboi Y. et al. Autosomal dominant parkinsonism associated with variable synuclein and tau pathology. Neurology 2004; 62: 161991622.
  42. Zabetian C.P., Samii A., Mosley A.D. et al. A clinic based study of the LRRK2 gene in Parkinson disease yields new mutations. Ibid. 2005; 65: 741–744.
  43. Zimprich A., Biskup S., Leitner P. et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron. 2004; 44: 601–607.

Copyright (c) 2007 Illarioshkin S.N., Slominsky P.A., Shadrina M.I., Bagyeva G.K., Zagorovskaya T.B., Markova E.D., Karabanov A.V., Poleshchuk V.V., Polevaya E.V., Fedorova N.V., Limborskaya S.A., Ivanova-Smolenskaya I.A.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77-83204 от 12.05.2022.


This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies