Spinocerebellar ataxia type 6: CAG repeat expansion in α_1a voltage‐dependent calcium channel gene and clinical variations in japanese population

Abstract

Autosomal dominant spinocerebellar ataxias (SCAs) are clinically and genetically a heterogeneous group of neurodegenerative disorders. Recently, mild CAG repeat expansion in the alpha1A voltage-dependent calcium channel gene has been found to be associated with a type of autosomal dominant SCA (SCA6). We analyzed 98 Japanese families with autosomal dominant SCAs, for whom CAG repeat expansions of the SCA1, SCA2, Machado-Joseph disease/SCA3, and dentatorubral-pallidoluysian atrophy genes were excluded, and 5 apparently sporadic cases of cortical cerebellar atrophy. The diagnosis of SCA6 was confirmed in 30 families (31%) comprising 47 affected individuals and 1 sporadic case. The size of expanded CAG repeats ranged from 21 to 26 repeat units and was found to be correlated inversely with age at onset. We identified 2 SCA6 patients homozygous for expanded CAG repeats, whose ages at onset were earlier than the 95% lower confidence level, suggesting the presence of a gene dosage effect of expanded CAG repeat. Ataxia is the most common initial symptom found in 45 of the 48 patients. Patients with a prolonged disease course showed other accompanying clinical features including dystonic postures, involuntary movements, and abnormalities in tendon reflexes.

Severity and Progression Rate of Cerebellar Ataxia in 16q-linked Autosomal Dominant Cerebellar Ataxia (16q-ADCA) in the Endemic Nagano Area of Japan

“…The major concern for interpreting the data is that the ages of the patients in both groups were considerably different, even though the mean disease duration was not different between the two groups. In particular, the mean age at onset of our SCA6 patients was younger than reported previously [24][25][26][27], although the reason for this was unknown. As a result, the mean age at examination in 16q-ADCA patients (72.5 ± 8.5 years, n = 52) was about 15 years older than in SCA6 patients (57.2 ± 11.0 years, n = 25).…”

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

“…We defined unsteadiness as a sense of instability, especially while walking. Therefore, the symptom would mainly reflect gait ataxia, which was also the most frequent initial symptom according to many previous reports (Geschwind et al 1997;Gomez et al 1997;Ikeuchi et al 1997;Stevanin et al 1997). The second most frequent initial symptom was vertigo or oscillopsia.…”

“…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.…”

Clinical and genetic characterization of 16q-linked autosomal dominant spinocerebellar ataxia in South Kyushu, Japan

“…Homozygotes with triplet-repeat expansions of SCA2, SCA3 or SCA6 showed modified or severe phenotypes. [19][20][21][22][23][24] Conversely, homozygotes of SCA3, SCA6, SCA8 and SCA12 did not have severe clinical phenotypes compared with heterozygotes. 19,[25][26][27][28] On the basis of our results, there does not seem to be a strong gene dosage effect in 16q-ADCA.…”