Introduction

Spinocerebellar ataxia type 6 (SCA6) belongs to the group of autosomal dominant cerebellar ataxias (ADCAs) as well as to that of channelopathies (Ptacek, 1997). Its highly variable phenotype defies a clear-cut classification in any of the three major types of ADCAs, as defined by Harding (1982), though sharing the type of mutation (expansion of a CAG repeat stretch) with SCA1, SCA2, SCA3, and SCA7. The expandable sequence is embedded in a calcium channel gene, CACNA1A, on chromosome 19p13, coding for the α1A subunit of voltage-gated calcium channels type P/Q, expressed predominantly in cerebellar Purkinje and granule cells. In many respects, SCA6 differs from ADCAs with the same type of mutation, and is unique among channelopathies for being due to the expansion of a repeat sequence.

Point mutations at the CACNA1A gene are known to cause episodic ataxia type 2 (EA2) and familial hemiplegic migraine (Ophoff et al., 1996). These disorders, and particularly EA2, share some features with SCA6, raising the problem of the relationship among the three allelic diseases.

Clinical features

SCA6 exhibits a highly variable clinical picture. In some studies (e.g., Zhuchenko et al., 1997 ; Geschwind et al., 1997; Filla et al., 1999) the phenotype includes a multisystem in addition to a cerebellar involvement, as observed in ADCA type I; in others (Ishikawa et al., 1997; Nagai et al., 1998; Watanabe et al., 1998; Garcia-Planells et al., 1999) the disease has been classified as a pure cerebellar ataxia (ADCA type III); and in others (Jodice et al., 1997; Jen et al., 1998; Yabe et al., 1998) it showed the features of EA2, with ataxia/vertigo episodes and interictal cerebellar deficits with variable degree of severity.