Historical introduction

Spinocerebellar ataxia type 3 (SCA3) is a form of dominant ataxia which, prior to the recognition of its genotype, would have been labeled as Marie's ataxia, olivoponto-cerebellar atrophy, or autosomal dominant cerebellar ataxia type 1. The occurrence of a dominant ataxia among the Azorean immigrants to the USA was first described by Nakano et al. (1972) in the family of William Machado from Massachusetts. A second family from the Azores, descended from Anton Joseph, with a dominantly inherited neurodegenerative disease that was primarily characterized by spasticity and rigidity, was described from California by Rosenberg et al. (1976). Neuropathologic examination in this family showed loss of nigral and spinal cord neurons. Other Azorean families with a similar disorder had members with a Parkinsonian phenotype (Romanul et al., 1977). Field trips to the Azores by Portuguese and American workers found a high prevalence of this dominantly inherited neurodegenerative disorder among the residents of the Azorean islands (Coutinho and Andrade, 1978). The disease was characterized by considerable intrafamilial variation in clinical phenotype; both the ataxic and the spastic-rigid phenotypes were found within the same families, and the disease was variously named Machado–Joseph disease and Azorean disease of the nervous system (Romanul et al., 1977; Dawson, 1977). Though the disorder shared many features with dominantly inherited cerebellar ataxia in non- Portuguese populations, its unique phenotypic variability was thought to reflect a disease prevalent only among the Portuguese Azoreans. A similar clinical disorder occurring in non-Portuguese families was thought to result from the introduction of Portuguese genes into these ethnic groups (Healton et al., 1980; Sakai et al., 1983; Subramony et al., 1993).