Spinocerebellar ataxia type 3

Anelyssa D'Abreu MD (Dr. D'Abreu of Rhode Island Hospital/Alpert Medical School of Brown University received consultation fees from UCB.)
Joseph H Friedman MD (Dr. Friedman of the Alpert Medical School of Brown University and University of Rhode Island, and Director of the Movement Disorders Program of Butler Hospital, received research grants from Avid and NIH as a site investigator.)
Joseph Jankovic MD, editor. (Dr. Jankovic, Director of the Parkinson's Disease Center and Movement Disorders Clinic at Baylor College of Medicine, received research funding from Allergan, Allon, Ceregene, Chelsea, EMD Serono, Impax, Ipsen, Lundbeck, Medtronic, Merz, and Teva, and compensation for his services as a consultant or an advisory committee member by Allergan, Auspex, EMD Serono, Lundbeck, Merz, Neurocrine Biosciences, and Teva.)
Originally released July 22, 1996; last updated October 27, 2016; expires October 27, 2019

This article includes discussion of spinocerebellar ataxia type 3, Azorean disease, Joseph-Machado disease, Machado-Thomas-Joseph disease, Machado-Joseph disease, MJD, MJD/SCA3, SCA3, and spinocerebellar atrophy type 3. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Spinocerebellar ataxia type 3 (also called Machado-Joseph disease, MJD/SCA3) is 1 of the 2 most common inherited ataxic syndromes in the world. This autosomal dominant disorder includes a fairly wide range of phenotypes that may precede or accompany the ataxia. With more widespread genetic testing, an increasing range of phenotypes has been recognized. Advances in molecular biology are helping to form a better picture of the underlying pathophysiology, and this better understanding has contributed to the development of multiple experimental strategies for symptomatic improvement and to slowing the progression of the disease.

Key points

 

• MJD/SCA3 is 1 of the 2 most prevalent inherited ataxias.

 

• It is an autosomal dominant, triplet nucleotide repeat, polyglutamine disorder with onset related to the number of triplet repeats.

 

• It causes a wide spectrum of disorders in addition to gait ataxia, including sensory or motor neuropathies, extraocular movement disorders, dystonia, parkinsonism, sleep disorders, autonomic dysfunction, and others.

 

• On occasion the non-ataxic signs may precede the ataxia.

 

• Individuals in the same family may have different phenotypes.

 

•There is no known treatment.

Historical note and terminology

This autosomal dominantly inherited disorder has had at least 6 names since its initial description. First described in 1972 in 2 separate reports and in 2 distinct Massachusetts families of Azorean descent, it was called "Machado disease," after the family described in the report by Nakano and colleagues (Nakano et al 1972; Woods and Schaumburg 1972). In 1976, the Joseph family, also of Azorean descent but living in California, was reported with a phenotypically different spinocerebellar disorder (Rosenberg et al 1976). 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 (Coutinho and Andrade 1978). Over the years, the terms "Machado," "Joseph," "Machado-Joseph," "Joseph-Machado," "Machado-Thomas-Joseph," and "Azorean" disease have all been used interchangeably.

In 1994, the gene defect on the long arm of chromosome 14 was identified as a CAG nonsense repeat (Kawaguchi et al 1994). Genetic testing then established the presence of this genetic abnormality in spinocerebellar ataxia in families without Portuguese ancestry. It has since become evident that the genetic abnormality causing spinocerebellar ataxia type 3 (SCA3) is the same as the genetic abnormality causing Machado-Joseph disease (MJD), despite a significant variability in phenotype. This indicates that Machado-Joseph disease and spinocerebellar ataxia type 3 are the same disease (Matilla et al 1995). It appears that this is the single most common cause of inherited ataxia in the world and is clearly not limited to those of Portuguese descent.

It is of interest that in the Azores, where the disease could be traced back into the 19th century, it had been considered a venereal disease brought back by navigators and whalers from America (Boutte 1987).

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