A Japanese family with spinocerebellar ataxia type 6 which includes three individuals homozygous 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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Cited by (37)
Gene dosage effect in spinocerebellar ataxia type 6 homozygotes: A clinical and neuropathological study
2017, Journal of the Neurological SciencesCitation Excerpt :Numerous studies have reported this pattern in typical SCA6 subjects with heterozygous expansions. However, the age-of-onset in SCA6 subjects with expansions in both alleles (homozygous mutations) remains unclear, with some reports of earlier disease onset in SCA6 homozygotes, suggestive of a gene dosage effect [6–13], but other reports finding no effect [2,14,15]. In other polyQ diseases such as MJD [16] and dentatorubral-pallidoluysian atrophy [17], homozygotes have a much earlier age-of-onset than heterozygotes, demonstrating a strong gene dosage effect.
Dominantly Inherited Spinocerebellar Syndromes
2015, Neuromuscular Disorders of Infancy, Childhood, and Adolescence: A Clinician's ApproachThe Hereditary Ataxias
2013, Emery and Rimoin's Principles and Practice of Medical GeneticsSpinocerebellar ataxia type 6
2012, Handbook of Clinical NeurologyCitation Excerpt :A recent retrospective study has shown even closer correlation of age of onset with the sum of the two allele sizes (Takahashi et al., 2004). Several individuals who are homozygous for an abnormal expansion in the CACNA1A gene have been reported (Geschwind et al., 1997; Ikeuchi et al., 1997; Matsuyama et al., 1997; Takiyama et al., 1998). In three, the onset was earlier and symptoms appeared more severe than in individuals who are heterozygous (Geschwind et al., 1997; Ikeuchi et al., 1997).
Molecular biology of Huntington's disease
2011, Handbook of Clinical Neurology16q-linked autosomal dominant cerebellar ataxia: A clinical and genetic study
2006, Journal of the Neurological Sciences