Frequency analysis of autosomal dominant cerebellar ataxias in Taiwanese patients and clinical and molecular characterization of spinocerebellar ataxia type 6.

Background Spinocerebellar ataxia (SCA) is a heterogeneous group of neurodegenerative disorders. The mutational basis for most of these disorders is an expanded CAG repeat sequence within the coding regions of the genes involved. The prevalence of SCA in the ethnic Chinese on Taiwan remains unclear. Moreover, there has been no report of SCA type 6 (SCA6) among Chinese people. Objectives To characterize the prevalence of SCA in the ethnic Chinese on Taiwan, and to specifically characterize Chinese patients with SCA6 in terms of clinical and molecular features. Patients and Methods Using a molecular approach, we investigated SCA in 74 Taiwanese families with dominantly inherited ataxias and in 49 Taiwanese patients with sporadic ataxias. Clinical and molecular features of SCA6 were further characterized in 12 patients from 8 families and in 2 sporadic cases. Furthermore, the intragenic polymorphic marker D19S1150 was amplified by polymerase chain reaction to analyze for linkage disequilibrium. Results Machado-Joseph disease–SCA3 was the most common type of autosomal dominant SCA in the Taiwanese cohort, accounting for 35 cases (47.3%), followed by SCA6 (8 [10.8%]), SCA2 (8 [10.8%]), SCA1 (4 [5.4%]), SCA7 (2 [2.7%]), dentatorubropallidoluysian atrophy (1 [1.4%]), and SCA8 (0%). The genes responsible for 16 (21.6%) of Taiwanese dominantly inherited SCA cases remain to be determined. Among the 49 patients with sporadic ataxias in the present series, 2 (4.1%) were found to harbor SCA6 mutations. In the families with SCA6, we found significant anticipation in the absence of genetic instability on transmission, indicating that some other mechanism might account for the anticipation. The same frequent allele of the intragenic DNA marker ( D19S1150 ) was shared by 7 of 10 Taiwanese families with SCA6. Conclusions Although SCA6 has, so far, not been reported in mainland Chinese, we found a geographic cluster of families with SCA6 on Taiwan. Genotyping studies suggest a founder effect in the Taiwanese patients with SCA6.

[1]  I. Kanazawa,et al.  DNA analysis in hereditary dentatorubral-pallidoluysian atrophy , 1995, Neurology.

[2]  Í. Lopes-Cendes,et al.  Correlation between CAG repeat length and clinical features in Machado-Joseph disease. , 1995, American journal of human genetics.

[3]  Yves Agid,et al.  Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats , 1996, Nature Genetics.

[4]  Georg Auburger,et al.  Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2 , 1996, Nature Genetics.

[5]  Y. Agid,et al.  Clinical and molecular features of spinocerebellar ataxia type 6 , 1997, Neurology.

[6]  M. Dichgans,et al.  Spinocerebellar ataxia type 6: Evidence for a strong founder effect among German families , 1999, Neurology.

[7]  R. Krüger,et al.  Spinocerebellar ataxia type 6: genotype and phenotype in German kindreds , 1998, Journal of neurology, neurosurgery, and psychiatry.

[8]  T. Bird,et al.  An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8) , 1999, Nature Genetics.

[9]  O. Onodera,et al.  Unstable expansion of CAG repeat in hereditary dentatorubral–pallidoluysian atrophy (DRPLA) , 1994, Nature Genetics.

[10]  A. Harding.  The clinical features and classification of the late onset autosomal dominant cerebellar ataxias. A study of 11 families, including descendants of the 'the Drew family of Walworth'. , 1982, Brain : a journal of neurology.

[11]  H. Zoghbi,et al.  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. , 1998, American journal of human genetics.

[12]  H. Lange,et al.  Mitotic stability and meiotic variability of the (CAG)n repeat in the Huntington disease gene. , 1993, Human molecular genetics.

[13]  Alexandra Durr,et al.  Spinocerebellar ataxia 3 and machado‐joseph disease: Clinical, molecular, and neuropathological features , 1996, Annals of neurology.

[14]  F. Hazama,et al.  Somatic mosaicism of CAG repeat in dentatorubral-pallidoluysian atrophy (DRPLA). , 1995, Human molecular genetics.

[15]  Q. Pan,et al.  Frequency of SCA1, SCA2, SCA3/MJD, SCA6, SCA7, and DRPLA CAG trinucleotide repeat expansion in patients with hereditary spinocerebellar ataxia from Chinese kindreds. , 2000, Archives of neurology.

[16]  Dennis E Bulman,et al.  Familial Hemiplegic Migraine and Episodic Ataxia Type-2 Are Caused by Mutations in the Ca2+ Channel Gene CACNL1A4 , 1996, Cell.

[17]  S. Tsuji,et al.  Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT , 1996, Nature Genetics.

[18]  Y. Agid,et al.  Polyglutamine expansion as a pathological epitope in Huntington's disease and four dominant cerebellar ataxias , 1995, Nature.

[19]  William B. Dobyns,et al.  Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the α1A-voltage-dependent calcium channel , 1997, Nature Genetics.

[20]  F. Martínez,et al.  Genetics of the SCA6 gene in a large family segregating an autosomal dominant “pure” cerebellar ataxia , 1999, Journal of medical genetics.

[21]  Shigenobu Nakamura,et al.  CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1 , 1994, Nature Genetics.

[22]  O. Hurko.  Recent advances in heritable ataxias , 1997, Annals of neurology.

[23]  Melvin G McInnis,et al.  Expansion of a novel CAG trinucleotide repeat in the 5′ region of PPP2R2B is associated with SCA12 , 1999, Nature Genetics.

[24]  T. Klockgether,et al.  SCA6 is caused by moderate CAG expansion in the alpha1A-voltage-dependent calcium channel gene. , 1997, Human molecular genetics.

[25]  R. Ophoff,et al.  Episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6) due to CAG repeat expansion in the CACNA1A gene on chromosome 19p. , 1997, Human molecular genetics.

[26]  M. Hayden,et al.  Somatic and gonadal mosaicism of the Huntington disease gene CAG repeat in brain and sperm , 1994, Nature Genetics.

[27]  H. Zoghbi.  CAG Repeats in SCA6 , 1997, Neurology.

[28]  J. Sambrook,et al.  Molecular Cloning: A Laboratory Manual , 2001 .

[29]  A. Sano,et al.  Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p , 1994, Nature Genetics.

[30]  D. Zee,et al.  Spinocerebellar ataxia type 6: Gaze‐evoked and vertical nystagmus, Purkinje cell degeneration, and variable age of onset , 1997, Annals of neurology.

[31]  G. Yvert,et al.  Variation on a trinucleotide theme , 1999, Nature Network Boston.

[32]  D. Geschwind,et al.  Spinocerebellar ataxia type 6 , 1997, Neurology.

[33]  Ren-Shyan Liu,et al.  Machado‐joseph disease: Clinical, molecular, and metabolic characterization in chinese kindreds , 1997, Annals of neurology.

[34]  G. Rouleau,et al.  Analysis of SCA1, DRPLA, MJD, SCA2, and SCA6 CAG repeats in 48 Portuguese ataxia families. , 1998, American journal of medical genetics.

[35]  K. Hsiao,et al.  DNA polymorphisms and deletion analysis of the Duchenne-Becker muscular dystrophy gene in the Chinese. , 1991, American journal of medical genetics.

[36]  松山 善次郎.  Molecular features of the CAG repeats of spinocerebellar ataxia 6 (SCA6) , 1998 .

[37]  T. Takayanagi,et al.  Spinocerebellar ataxia type 6 , 1997, Neurology.

[38]  Huda Y. Zoghbi,et al.  Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1 , 1993, Nature Genetics.

[39]  Y. Agid,et al.  Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion , 1997, Nature Genetics.

[40]  M. Polymeropoulos,et al.  Mutations in American families with spinocerebellar ataxia (SCA) type 3 , 1996, Neurology.