Machado-Joseph Disease: from first descriptions to new perspectives

Spinocerebellar ataxias (SCAs) are autosomal dominant inherited ataxias, which constitute a heterogeneous group of typically late-onset, progressive, and often fatal neurodegenerative disorders, characterized by progressive cerebellar dysfunction, variably associated with other symptoms of the central and peripheral nervous systems [1-3]. Nearly 30 subtypes of SCAs have been described, and based on the nature of the underlying causative mutations, these subtypes can be divided into three major categories: 1) "polyglutamine" ataxias, caused by CAG repeat expansions that encode a pure repeat of the amino acid glutamine in the corresponding protein; 2) non-coding repeat ataxias, caused by repeat expansions falling outside of the protein-coding region of the respective disease genes; and 3) ataxias caused by conventional mutations in specific genes (deletion, missense, nonsense, and splice site mutations) [1]. The focus of this review, Machado-Joseph disease (MJD; MIM #109150) [4], also known as spinocerebellar ataxia type 3 (SCA3) [5], belongs to the first of the above cited categories [6]. Several alternative designations have been given to this disorder, namely "Machado disease" [7], "nigro-spino-dentatal degeneration with nuclear ophthalmoplegia" [8], "autosomal dominant striatonigral degeneration" [9] and "Azorean disease of the nervous system" [10]. Presently, the most widely used designations are MJD and SCA3.Globally, SCAs are considered rare disorders, with prevalence estimates varying from 0.3 to 2.0 per 100,000 [11]. MJD is presently considered the most common form of SCA worldwide [12]. The availability of a molecular test has allowed a thorough identification of cases, changing the initial geographic distribution pattern of MJD, initially thought to be related with the Portuguese discoveries and currently known to be present in many ethnic backgrounds [12], with strong geographic variation.Among SCAs, the relative frequency of MJD is higher in countries suc