Phenotype variation correlates with CAG repeat length in SCA2 - A study of 28 Japanese patients1

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Abstract

Spinocerebellar ataxia-2 (SCA2) is an autosomal dominant ataxia caused by an abnormal CAG repeat expansion in a novel gene on chromosome 12q24.1. The size of the mutant allele is unstable during transmission, and correlates inversely with age at onset. We studied eight Japanese SCA2 families, including 28 patients, to assess the effect of repeat length on the phenotype features of SCA2. Frequencies of slow eye movements (SEM), reflex activity, dementia, choreiform movements, and axial tremor correlated significantly with CAG repeat size. Parkinsonism was seen in a man homozygote for SCA2 mutation. The clinical variety of SCA2 is apparently influenced by the size of the mutant allele, as is the case in other CAG repeat disorders.

Introduction

Dominantly inherited spinocerebellar ataxia (SCA) is a cluster of heterogeneous disorders. Among these disorders, SCA2 was first mapped to chromosome 12q23–q24.1, based on a linkage study of a Cuban cohort of subjects [10]. Mutation of the SCA2 gene has recently been identified, independently by three different groups, including our group 13, 31, 33: the number of CAG repeat units in mutant SCA2 alleles inversely correlates with age at onset, and is unstable during transmission regardless of gender of the affected parent; the SCA2 gene is expressed ubiquitously. A similar mutation was already found in the open reading frame of each gene causing spinal and bulbar muscular atrophy (SBMA) [20]and Huntington's disease (HD) [39], SCA1 [29], Machado–Joseph disease (MJD) [16], dentatorubral–pallidoluysian atrophy (DRPLA) 18, 26, and SCA7 [5].

Neuropathologically, SCA2 affects a multi-systemic structure throughout the nervous system. Olivopontocerebellar atrophy (OPCA) with severe nigral degeneration was the common finding in seven autopsied patients from Cuba [27]. Clinically, the majority of patients had tremor, slow eye movement (SEM) and hyporeflexia, in addition to ataxia 27, 28. After the first description of Cuban subjects, a number of SCA2 families from different ethnic background have been reported 2, 3, 6, 7, 12, 22, 30. Their clinical features are quite similar to those of Cuban subjects. On the other hand, marked phenotype variation was noted in the six families studied by Geschwind et al. [9]. Recent studies reported that the frequency of several clinical signs, such as myoclonus, dystonia and myokymia, increased with the number of CAG repeats 4, 23, 36. Our previous study on a large pedigree disclosed that clinical features varied depending on age at onset [34]. Knowledge of unstable CAG expansions in SCA2 has made it feasible to analyze the phenotypic variations of SCA2 based on size of the expanded CAG repeat of the mutant SCA2 gene. In the present work, we asked whether CAG repeat size of the mutant allele correlates with the phenotypic variation in SCA2.

Section snippets

SCA2 families and their background

Based on the linkage study, we identified two Japanese families with SCA2 (P2 and P35) in Hokkaido island [12]. Since that report, we identified six other unrelated families (Table 1). Seven of the eight families were originally found on Hokkaido island, and one other family (P65) was identified in Tokyo. Ancestors of the families in Hokkaido came from various areas of the Islands of Japan, and there was no segregation in any particular area. All families were found to be linked with the

Clinical features of SCA2 patients

In 27 patients heterozygous for SCA2 alleles, ataxia occurred first and was the dominant feature from onset. However, in one man homozygous for SCA2 mutation, symptoms were first like those for parkinsonism, and parkinsonism concomitant with ataxia and slow eye movement (SEM) was the prominent feature at the time of the present study. Neurological findings of the 28 patients are summarized in Table 2, according to the duration of illness. As shown, ataxia–SEM–hyporeflexia syndrome was the most

Discussion

Ataxia associated with SEM and hyporeflexia is commonly described in previous studies 2, 3, 6, 7, 8, 27, 28, indicating that it is the most frequent phenotype in SCA2. However, the phenotype can vary within or between families 3, 6, 9, 34. Our results indicate that such clinical variation in SCA2 is influenced by the CAG repeat length of mutant allele. Dementia, SEM, hyporeflexia, axial tremor, or choreiform movements significantly correlate with CAG repeat size or age at onset. Among them,

Acknowledgements

We thank members of the families for participation in this study. This study was supported by a Grant-in-Aid for Scientific Research on Priority Areas and a Grant-in-Aid for Scientific Research {A(2) and B(2)}, Ministry of Education, Science, Sports and Culture, Japan, and a grant from Research on Ataxic Diseases, the Ministry of Health and Welfare, Japan.

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    1

    Presented in part at the 122nd annual meeting of the American Neurological Association, San Diego, Cal, Sep–Oct, 1997.

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