A Japanese family with spinocerebellar ataxia type 6 which includes three individuals homozygous for an expanded CAG repeat in the SCA6/CACNL1A4 gene

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Abstract

We describe a Japanese family which includes 13 patients in five generations who have dominantly inherited ataxia. Molecular testing revealed that in these patients the SCA6/CACNL1A4 gene carries the smallest known expanded CAG repeat (21 repeat units). The clinical features of these patients exhibited predominantly cerebellar ataxia with onset late in adult life and a very slowly progressive disease course. In addition, this SCA6 family showed some characteristic clinical and genetic features, including (1) apparent lack of genetic anticipation, with an intergenerationally stable CAG repeat size and (2) down-beat nystagmus and diabetes mellitus in some of the SCA6 patients. We identified three individuals homozygous for an expanded CAG repeat (21/21) in the SCA6/CACNL1A4 gene, two of whom were symptomatic. There were no apparent differences in clinical phenotype between the individuals homozygous and those heterozygous for an expanded CAG repeat in the SCA6/CACNL1A4 gene.

Introduction

Autosomal dominant spinocerebellar ataxias (ADSCAs) are a genetically heterogenous group of multisystemic, neurodegenerative disorders. CAG repeat expansions have been associated with the ADSCAs such as spinocerebellar ataxia type 1 (SCA1) [19], spinocerebellar ataxia type 2 (SCA2) 8, 21, 22, Machado-Joseph disease (MJD) [10], spinocerebellar ataxia type 7 (SCA7) [1]and dentatorubral-pallidoluysian atrophy (DRPLA) 11, 17. The number of the expanded CAG repeats associated with these diseases correlates with the age at onset of the disease, and the expanded allele displays inter-generational size instability, which is associated with the clinical phenomenon of anticipation in the diseases 1, 6, 8, 10, 11, 17, 19, 21, 22, 27. Homozygosity for expanded CAG repeats in the causative gene for MJD or DRPLA is associated with early onset of a more severe form of the disease than is heterozygosity for such expanded CAG repeats 12, 23, 25, 27. In contrast, Huntington's disease (HD) or SCA1 patients homozygous for expanded CAG repeats in the causative gene are not more severely afflicted than are heterozygotes 5, 16, 29.

Recently, Zhuchenko et al. reported that a small CAG repeat expansion in the human α1A-voltage-dependent calcium channel subunit gene (CACNL1A4) on chromosome 19p13.1-p13.2 is most likely the cause of the newly classified autosomal dominant spinocerebellar ataxia type 6 (SCA6) [30]. They identified eight unrelated SCA6 patients who carried alleles with larger CAG repeats (21–27 repeat units) in the CACNL1A4 gene than those (4–16 repeat units) in 475 non-ataxic individuals. Clinically, these SCA6 patients exhibited mild but slowly progressive cerebellar ataxia of the limbs and gait, dysarthria, nystagmus, and mild vibratory and proprioceptive sensory loss [30].

We identified a Japanese family with dominantly inherited ataxia of late adult onset. Molecular testing revealed that in these patients the SCA6/CACNL1A4 gene carries the smallest known expanded CAG repeat (21 repeat units). Here we describe the clinical and molecular features of the SCA6 in this family, which includes three individuals homozygous for an expanded CAG repeat in the SCA6/CACNL1A4 gene.

Section snippets

Clinical study

The pedigree of this family is shown in Fig. 1. The family members were thoroughly neurologically evaluated by the same neurologists (Y.T., M.N. and K.I.). Information on deceased family members was obtained from senior members of the family. Some affected family members were admitted to the Jichi Medical School Hospital. Five patients including two homozygous for an expanded CAG repeat in the SCA6/CACNL1A4 gene, and four clinically normal individuals, including an asymptomatic individual

Clinical findings

Table 1 summarizes the clinical features and the numbers of CAG repeat units in the SCA6/CACNL1A4 gene for five patients in this family.

Discussion

The SCA6/CACNL1A4 gene has some unique molecular characteristics: (1) expanded CAG repeats in the SCA6/CACNL1A4 gene are smaller (from 21 to 30 repeat units) than those in other `CAG repeat diseases' such as SCA1, SCA2, MJD, SCA7, DRPLA, HD, and spinal and bulbar muscular atrophy (SBMA) (from 36 to 130 repeat units) 1, 4, 7, 9, 14, 15, 30and (2) expanded CAG repeats in the SCA6/CACNL1A4 gene are stable in size within SCA6 families 4, 9, 14, 30with the exception of two cases that showed mild

Acknowledgements

We would like to thank the family for their willingness to participate in this study. This work was supported by a Grant-in-Aid for Scientific Research on Priority Areas and a grant (0967066) from the Ministry of Education, Science, and Culture, Japan, and a grant from the Research Committee for Ataxic Diseases and a grant for Surveys and Research on Specific Diseases from the Ministry of Health and Welfare, Japan.

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