Machado-Joseph disease and SCA3

Neurology 1996;46:4-8

Based on initial descriptions, Machado-Joseph disease (MJD) was thought to be a distinct clinicopathologic entity. This autosomal dominant disorder was originally described in the Machado family on the Azorean island of San Miguel, ^[1] in the Thomas family, which had migrated from San Miguel to Massa-chusetts, ^[2] and in the Joseph family, which had migrated from the Azorean island of Flores to California. ^[3] These families were initially considered to have distinct phenotypes, but it was soon recognized that the diverse phenotypes occurred within each family and that all three families had the same disorder. ^[4] The disorder, initially felt to be limited to Azorean and Portuguese families, has occurred in families of diverse ethnic origins on five continents. ^[5]

The most common classification of MJD divides patients into three phenotypes. ^[5] Cerebellar ataxia and ophthalmoplegia are common to all types. Type 1 has an early symptom onset, typically around 25 years, and is additionally characterized by pyramidal signs and dystonic postures. Type 2, the most common type, occurs around middle age (mean, 40 yr) and is dominated by ataxia and ophthalmoplegia, with or without pyramidal signs. Type 3 is later in onset (mean, 47 yr) and progresses slowly with prominent amyotrophy. Other findings that may help in diagnosis include facial and lingual fasciculations and staring due to lid retractions, each seen in a minority of patients. The pathology differs some-what from that of other hereditary ataxias, with sparing of the inferior olivary nuclei and Purkinje cells but substantial involvement of the dentate nuclei and substantia nigra. ^[5]

Spinocerebellar ataxia type 3 (SCA3), in contrast, was never believed to be clinically or pathologically distinct, but was distinguished from other dominantly inherited ataxias by its linkage to chromosome 14q. Among the autosomal dominant ataxias, recent years have witnessed genetic …