Spinocerebellar ataxia type 3 (also called Machado-Joseph disease, MJD/SCA3) is the most common spinocerebellar ataxia subtype worldwide and is an autosomal dominant triplicate nucleotide repeat expansion disorder (68; 88; 109). It has a heterogeneous presentation encompassing a wide range of motor and nonmotor symptoms. Currently, there are no disease-modifying therapies to treat spinocerebellar ataxia type 3. However, there is increasing recognition of shared pathogenic mechanisms between spinocerebellar ataxia type 3 and other neurodegenerative disorders, which raises the possibility of utilizing therapies such as antisense oligonucleotide infusions that have shown success in spinomuscular atrophy and Huntington disease trials.
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• Spinocerebellar ataxia type 3 is the most commonly inherited autosomal dominant ataxia.
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• It is mediated by an expanded triplicate nucleotide repeat that encodes for mutant ataxin-3 protein.
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• Ataxia is the most common symptom at onset, but clinical presentation is heterogeneous and includes motor and nonmotor symptoms.
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• There are no known disease modifying treatments, but RNA-based therapies show promise in spinocerebellar ataxia type 3 animal models.
Historical note and terminology
Since its initial description more than 6 names have been associated with MJD/SCA3. In 1972, 2 separate reports in 2 distinct Massachusetts families of Azorean descent were reported. The term "Machado disease" was used to describe the condition after the family described by Nakano and colleagues (81; 138). In 1976, the Joseph family, also of Azorean descent but living in California, was reported with a phenotypically different spinocerebellar disorder (97). Further investigations in the Azores, Portuguese-settled islands in the eastern Atlantic Ocean, supported the concept that Joseph disease and Machado disease reflected different phenotypic expressions of the same genetic disorder (19). Over the years, the eponyms "Machado," "Joseph," "Machado-Joseph," "Joseph-Machado," "Machado-Thomas-Joseph," and "Azorean" disease have all been used interchangeably to refer to this disorder.
The spinocerebellar ataxia nomenclature was developed in the 1990s to classify autosomal dominant progressive cerebellar syndromes following the development of diagnostic genetic tests. The affected gene loci were numbered in the order that they were discovered (68). In 1994, a cytosine-adenine-guanine (CAG) nonsense repeat on the long arm of chromosome 14 was identified as spinocerebellar ataxia type 3 (48) and was found in other spinocerebellar ataxia in families without Portuguese ancestry. Interestingly, this same genetic abnormality was also found in patients with Machado-Joseph disease, indicating that this should be considered the same disease despite significant phenotypic variability (71).