Spinocerebellar ataxia type 3

Kanae J Nagao MBBS FRACP (

Dr. Nagao of Royal Melbourne Hospital Movement Disorders Department has no relevant financial relationships to disclose.

)
Neepa Patel MD (

Dr. Patel of the Henry Ford Health System received honorariums from USWorldMed for speaking engagements and from Guidepoint and Revance as a consultant.

)
Robert Fekete MD, editor. (

Dr. Fekete of New York Medical College received consultation fees from Acadia, Acorda, Adamas, Amneal/Impax, Kyowa Kirin, Lundbeck, Neurocrine, and Teva.

)
Originally released July 22, 1996; last updated October 18, 2020; expires October 18, 2023

Overview

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 (Margolis 2002; Paulson 2012; Schőls et al 2004). 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.

Key points

 

• Spinocerebellar ataxia type 3 is the most commonly inherited autosomal dominant ataxia.

 

• It is mediated by an expanded triplicate nucleotide repeat that encodes for mutant ataxin-3 protein.

 

• Ataxia is the most common symptom at onset, but clinical presentation is heterogeneous and includes motor and nonmotor symptoms.

 

• 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 (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 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 (Margolis 2002). In 1994, a cytosine-adenine-guanine (CAG) nonsense repeat on the long arm of chromosome 14 was identified as spinocerebellar ataxia type 3 (Kawaguchi et al 1994) 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 (Matilla et al 1995).

The content you are trying to view is available only to logged in, current MedLink Neurology subscribers.

If you are a subscriber, please log in.

If you are a former subscriber or have registered before, please log in first and then click select a Service Plan or contact Subscriber Services. Site license users, click the Site License Acces link on the Homepage at an authorized computer.

If you have never registered before, click Learn More about MedLink Neurology  or view available Service Plans.

Find out how you can join MedLink Neurology