Spinocerebellar Ataxia Type 3

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is the most common subtype of type 1 autosomal dominant cerebellar ataxia (ADCA type 1; see this term), a neurodegenerative disorder, and is characterized by ataxia, external progressive ophthalmoplegia, and other neurological manifestations.

Epidemiology

Prevalence is estimated to be 1-2 in 100,000 with significant geographical and ethnic variations: the highest prevalence has been found in the Azores (Flores Island (1/239)), intermediate prevalence rates in Portugal, Germany, the Netherlands, China and Japan, and lower prevalence in North America, Australia and India. Accurate estimates of prevalence are not available. However, SCA3 is the most common form of ADCA1 in most genetically characterized populations and accounts for up to 72 % of families with ataxia. Based on an English language literature review about 600 cases have been published.

Clinical description

SCA3 is divided into 3 forms. SCA3 type 1 (MJD Type 1, see this term) is associated with ataxia, ophthalmoparesis, pyramidal signs such as spasticity and hyperreflexia, and extrapyramidal signs including dystonia and other movement disorders presenting in adolescence. SCA3 type 2 (MJD Type 2, see this term) presents in middle adulthood with ataxia, spasticity, and dystonia. SCA3 type 3 (MJD Type 3, see this term) occurs after the age of 40 and includes ophthalmoparesis and anterior horn cell disease, i.e. fasciculations, atrophy, and weakness. Parkinsonism can also be a feature of SCA3. A likely overlooked but common feature is impairment of temperature sensation involving the entire body.

Etiology

The disease is associated with a CAG repeat expansion mutation in the ATXN3 gene (14q21) with anticipation phenomenon. The normal repeat length is 13-41 whereas repeat lengths causing SCA3 are greater than 56.

Diagnostic methods

Diagnosis is based on the clinical picture, familial history and ultimately on genetic testing.

Differential diagnosis

Differential diagnosis is broad and includes other types of SCA which may have similar features.

Antenatal diagnosis

Prenatal diagnosis and pre-manifestation diagnosis in patients with a family history of SCA can be offered.

Genetic counseling

SCA3 follows an autosomal dominant pattern of inheritance with full penetrance and anticipation phenomenon. Genetic counseling is recommended in symptomatic patients or those with a family history of the disorder due to known SCA mutation, and pre-symptomatic testing should be discussed in adults.

Management and treatment

In the absence of specific treatments to slow or stop disease progression, care is supportive. For example, parkinsonism, restless legs syndrome, spasticity, sleep disorders and depression can be treated pharmacologically. Dystonia and spasticity can be managed with local botulinum toxin injections. Occupational and physical therapy are essential. Speech therapy may also be of benefit for managing dysarthria.

Prognosis

Prognosis is poor but patients have been reported to survive for decades after onset of symptoms.