Spinocerebellar ataxia type 6

Abstract

Spinocerebellar ataxia type 6 (SCA6) is a newly classified autosomal-dominant cerebellar ataxia (ADCA) associated with CAG repeat expansion. We screened 111 patients with cerebellar ataxia for the SCA6 mutation. Of these, 35 patients were found to have expanded CAG repeats in the SCA6 gene, indicating that second to SCA3, SCA6 is the most common ADCA in Japan. Expanded alleles ranged from 21 to 29 repeats, whereas normal alleles had seven to 17 repeats. There was no change in the CAG repeat length during meiosis. The age at onset was inversely correlated with the repeat length. The main clinical feature of the 35 patients with SCA6 was slowly progressive cerebellar ataxia; multisystem involvement was not common. The 35 patients included nine cases without apparent family history of cerebellar ataxia. The sporadic cases had smaller CAG repeats (21 or 22 repeats) and a later age at onset (64.9 +/- 4.9 years) than the other cases with established family history. We also identified one patient who was homozygous for the SCA6 repeat expansion. The homozygote showed an earlier age of onset and more severe clinical manifestations than her sister, a heterozygote carrying an expanded allele with the same repeat length as the homozygote. This finding suggests that the dosage of the CAG repeat expansion plays an important role in phenotypic expression in SCA6.

A clinical and genetic study in a large cohort of patients with spinocerebellar ataxia type 6

“…This was also true for previous reports. The two homozygous patients in previous reports Matsumura et al 1997) showed earlier ages of onset than our 95% confidence interval for the expanded allele alone, but were within the 95% confidence interval for total repeat numbers. From these observations, it is possible that the total number of repeat-units in both alleles is a good parameter to predict the age of onset in SCA6.…”

“…Gene dosage effect, i.e. earlier age of onset in homozygous patients, was seen in previous reports in SCA6 Matsumura et al 1997), although in some other groups this was not evident (Matsuyama et al 1997;Takiyama et al 1998). In the present series, only one of four homozygous patients showed a significantly earlier onset compared with heterozygous patients who had the same number of CAG repeats in the expanded allele.…”

“…It is also possible that patients may confuse ataxia with vertigo, and complain of ''unsteadiness'' instead of vertigo. Various episodic features, including vertigo and episodic ataxia, were reported in previous studies of SCA6 (Geschwind et al 1997;Gomez et al 1997;Yabe et al 2003), but only a small number of our subjects had episodic symptoms as in others (Matsumura et al 1997). Episodic symptoms were frequently reported in foreign reports, and this variability might be due to the difference in modifying gene effect among ethnicities.…”

“…In Japan, SCA6 seems to be either the most common or second most common subtype of the SCAs (Matsumura et al 1997;Watanabe et al 1998;Sasaki et al 2000;Maruyama et al 2002), but its prevalence is lower in Western Europe and North America (Geschwind et al 1997;Scho¨ls et al 1997Scho¨ls et al , 1998Stevanin et al 1997). In contrast, other dominantly inherited pure cerebellar ataxias seem to be infrequent in Japan, including SCA5 (Holmberg et al 1995), SCA10 (Zu et al 1999), SCA11 (Worth et al 1999), SCA14 , SCA15 (Knight et al 2003), SCA16 (Miyoshi et al 2001), and SCA22 (Chung et al 2003).…”

“…The main clinical feature of SCA6 is slowly progressive cerebellar ataxia, but extracerebellar symptoms, such as pyramidal tract signs, abnormal involuntary movements, parkinsonism, hyporeflexia, intellectual impairment, and urinary incontinence, have also been reported (Geschwind et al 1997;Gomez et al 1997;Ikeuchi et al 1997;Matsumura et al 1997;Scho¨ls et al 1997;Stevanin et al 1997;Watanabe et al 1998;Yabe et al 1998). The induction of vertigo and oscillopsia by changes of the head position can also occur in SCA6 patients.…”