The Genetic Aetiology of Late-onset Chronic Progressive Cerebellar Ataxia. A Population-based Study

Overview

Journal J Neurol

Specialty Neurology

Date 2009 Mar 5

PMID 19259763

Citations 13

Authors

Mark Wardle

Elisa Majounie

Mustapha B Muzaimi

Nigel M Williams

Huw R Morris

Neil P Robertson

Affiliations

Soon will be listed here.

Abstract

Background: An increasing number of dominant and recessive disorders have been associated with late onset chronic progressive ataxia (LOCA) complicating the formulation of a rational diagnostic strategy. Furthermore, there is marked geographic and ethnic variation in the relative importance of these individual disorders and the cause of such observed variation remains unexplained.

Methods: We have systematically investigated a population-based cohort of patients with chronic progressive LOCA for SCA 1, 2, 3, 6, 7, 8, 10, 12, 17, FXTAS and FRDA. In addition we have examined repeat length polymorphism in chromosomes from a genetically homogeneous and representative control population to investigate the association of high-normal repeats and disease prevalence.

Results: A total of 178 patients including 55 familial cases segregating in 38 kindreds and 123 sporadic were investigated. Pathological expansions were identified in 11/38 (28.9 %) of families and in 5/123 (4.1 %) of sporadic patients. The most frequent diagnoses were SCA6 (6 families and 1 sporadic patient), DRPLA (4 families) and SCA8 (1 family). In addition, one elderly female patient was identified with "possible FXTAS". Six (2 %) control patients were noted to have expanded SCA8 alleles.

Conclusions: SCA6 and DRPLA were the most frequent genetic diagnoses identified. Patterns of high-normal allele frequency in this UK population were distinct compared to other ethnic groups but this was poorly predictive of the distribution of disease in this region. The relative contribution of new mutation formation and founder effects to the prevalence of familial ataxia is uncertain, and further exploration of these factors will require detailed analysis of disease allele haplotypes and meiotic instability of intermediate length alleles.

Citing Articles

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Epidemiology of Spinocerebellar Ataxias in Europe.

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DRPLA: understanding the natural history and developing biomarkers to accelerate therapeutic trials in a globally rare repeat expansion disorder.

Chaudhry A, Anthanasiou-Fragkouli A, Houlden H J Neurol. 2020; 268(8):3031-3041.

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References

Imbert G, Kretz C, Johnson K, Mandel J . Origin of the expansion mutation in myotonic dystrophy. Nat Genet. 1993; 4(1):72-6. DOI: 10.1038/ng0593-72. View

Hagerman P, Hagerman R . The fragile-X premutation: a maturing perspective. Am J Hum Genet. 2004; 74(5):805-16. PMC: 1181976. DOI: 10.1086/386296. View

Giunti P, Sabbadini G, Sweeney M, Davis M, Veneziano L, Mantuano E . The role of the SCA2 trinucleotide repeat expansion in 89 autosomal dominant cerebellar ataxia families. Frequency, clinical and genetic correlates. Brain. 1998; 121 ( Pt 3):459-67. DOI: 10.1093/brain/121.3.459. View

Schols L, Szymanski S, Peters S, Przuntek H, Epplen J, Hardt C . Genetic background of apparently idiopathic sporadic cerebellar ataxia. Hum Genet. 2000; 107(2):132-7. DOI: 10.1007/s004390000346. View

Worth P, Houlden H, Giunti P, Davis M, Wood N . Large, expanded repeats in SCA8 are not confined to patients with cerebellar ataxia. Nat Genet. 2000; 24(3):214-5. DOI: 10.1038/73411. View

Maruyama H, Izumi Y, Morino H, Oda M, Toji H, Nakamura S . Difference in disease-free survival curve and regional distribution according to subtype of spinocerebellar ataxia: a study of 1,286 Japanese patients. Am J Med Genet. 2002; 114(5):578-83. DOI: 10.1002/ajmg.10514. View

Hagerman R, Leehey M, Heinrichs W, Tassone F, Wilson R, Hills J . Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology. 2001; 57(1):127-30. DOI: 10.1212/wnl.57.1.127. View

Juvonen V, Hietala M, Kairisto V, Savontaus M . The occurrence of dominant spinocerebellar ataxias among 251 Finnish ataxia patients and the role of predisposing large normal alleles in a genetically isolated population. Acta Neurol Scand. 2005; 111(3):154-62. DOI: 10.1111/j.1600-0404.2005.00349.x. View

Onodera Y, Aoki M, Tsuda T, Kato H, Nagata T, Kameya T . High prevalence of spinocerebellar ataxia type 1 (SCA1) in an isolated region of Japan. J Neurol Sci. 2000; 178(2):153-8. DOI: 10.1016/s0022-510x(00)00390-7. View

10.

Leggo J, Dalton A, Morrison P, Dodge A, Connarty M, Kotze M . Analysis of spinocerebellar ataxia types 1, 2, 3, and 6, dentatorubral-pallidoluysian atrophy, and Friedreich's ataxia genes in spinocerebellar ataxia patients in the UK. J Med Genet. 1998; 34(12):982-5. PMC: 1051147. DOI: 10.1136/jmg.34.12.982. View

11.

Takano H, Cancel G, Ikeuchi T, Lorenzetti D, Mawad R, Stevanin G . Close associations between prevalences of dominantly inherited spinocerebellar ataxias with CAG-repeat expansions and frequencies of large normal CAG alleles in Japanese and Caucasian populations. Am J Hum Genet. 1998; 63(4):1060-6. PMC: 1377499. DOI: 10.1086/302067. View

12.

Stevanin G, Herman A, Durr A, Jodice C, Frontali M, Agid Y . Are (CTG)n expansions at the SCA8 locus rare polymorphisms?. Nat Genet. 2000; 24(3):213; author reply 215. DOI: 10.1038/73408. View

13.

Saleem Q, Choudhry S, Mukerji M, Bashyam L, Padma M, Chakravarthy A . Molecular analysis of autosomal dominant hereditary ataxias in the Indian population: high frequency of SCA2 and evidence for a common founder mutation. Hum Genet. 2000; 106(2):179-87. DOI: 10.1007/s004390051026. View

14.

Squitieri F, Andrew S, Goldberg Y, Kremer B, Spence N, Zeisler J . DNA haplotype analysis of Huntington disease reveals clues to the origins and mechanisms of CAG expansion and reasons for geographic variations of prevalence. Hum Mol Genet. 1994; 3(12):2103-14. DOI: 10.1093/hmg/3.12.2103. View

15.

Van Esch H, Dom R, Bex D, Salden I, Caeckebeke J, Wibail A . Screening for FMR-1 premutations in 122 older Flemish males presenting with ataxia. Eur J Hum Genet. 2004; 13(1):121-3. DOI: 10.1038/sj.ejhg.5201312. View

16.

Pujana M, Corral J, Gratacos M, Combarros O, Berciano J, Genis D . Spinocerebellar ataxias in Spanish patients: genetic analysis of familial and sporadic cases. The Ataxia Study Group. Hum Genet. 1999; 104(6):516-22. DOI: 10.1007/s004390050997. View

17.

Ciotti P, Di Maria E, Bellone E, Ajmar F, Mandich P . Triplet repeat primed PCR (TP PCR) in molecular diagnostic testing for Friedreich ataxia. J Mol Diagn. 2004; 6(4):285-9. PMC: 1867489. DOI: 10.1016/S1525-1578(10)60523-5. View

18.

Hadjivassiliou M, Grunewald R, Sharrack B, Sanders D, Lobo A, Williamson C . Gluten ataxia in perspective: epidemiology, genetic susceptibility and clinical characteristics. Brain. 2003; 126(Pt 3):685-91. DOI: 10.1093/brain/awg050. View

19.

Silveira I, Miranda C, Guimaraes L, Moreira M, Alonso I, Mendonca P . Trinucleotide repeats in 202 families with ataxia: a small expanded (CAG)n allele at the SCA17 locus. Arch Neurol. 2002; 59(4):623-9. DOI: 10.1001/archneur.59.4.623. View

20.

Brussino A, Gellera C, Saluto A, Mariotti C, Arduino C, Castellotti B . FMR1 gene premutation is a frequent genetic cause of late-onset sporadic cerebellar ataxia. Neurology. 2005; 64(1):145-7. DOI: 10.1212/01.WNL.0000148723.37489.3F. View