NeurometPlus

Incidence

Overall, the inherited ataxias are rare. SCA3 is an autosomal dominant disorder. Offspring of affected individuals have a 50% chance of inheriting the gene. About 10 to 20% of the cases in U.S. series have had the SCA3 mutation.

Clinical Characteristics

The prevalence of inherited ataxias and paraplegias has ranged from 4.8 to 20.2 per 100,000. The proportion of SCA3 among the dominantly inherited ataxias has been variable. About 10 to 20% of the cases in U.S. series have had the SCA3 mutation. SCA3 is characterized by progressive cerebellar ataxia and variable findings including a dystonic-rigid syndrome, a Parkinsonian syndrome, or a combined syndrome of dystonia and peripheral neuropathy. Neurologic findings tend to evolve as the disease progresses. Occasionally, family members with the same gene mutation may exhibit other clinical features such as a dystonic-rigid syndrome, a Parkinsonian syndrome, or a combined syndrome of dystonia and peripheral neuropathy. Patients with a later adult onset often have a disorder that combines ataxia, generalized areflexia, and muscle wasting. Based on this phenotypic variability, Portuguese workers classified MJD into several types. Type I disease (13% of the cases) is characterized by a young age of onset and prominent spasticity, rigidity, and bradykinesia, often with little ataxia. Type II phenotype is the most common (57%) and is characterized by ataxia and upper motor neuron signs. Finally, type III disease (30%) manifests at a later age with ataxia and peripheral polyneuropathy. Many patients evolve from one of these types into another.The disease progresses relentlessly and death occurs from 6 to 29 years after onset. The diagnosis of SCA3 is suggested [Lima & Coutinho 1980] in individuals with the following: Cerebellar ataxia and pyramidal signs (type II) associated in variable degree with a dystonic-rigid extrapyramidal syndrome (type I) or peripheral amyotrophy (type III). Minor (but more specific) clinical signs such as progressive external ophthalmoplegia, dystonia, action-induced facial and lingual fasciculation-like movements, and bulging eyes. These findings, however, are not specific and are shared with many other dominantly inherited ataxias; thus, diagnosis rests upon molecular genetic testing.The age of onset of SCA3 is variable but is usually in the second to the fourth decade. In a large cohort of patients reported from the Azores, the mean age of onset was 37 years. Presenting features include gait problems, speech difficulties, clumsiness, and, often, visual blurring and diplopia. Progressive ataxia, hyperreflexia, nystagmus, and dysarthria occur early in the disease. As the disease evolves, increasing problems with ambulation occur, leading to the need for assistive devices including a wheelchair in 10 to 15 years after onset. Saccadic eye movements become slow and an ophthalmoparesis evolves, resulting initially in up-gaze restriction. Disconjugate eye movements result in diplopia. At the same time, a number of other "brain stem" signs develop, including temporal and facial atrophy, characteristic action-induced perioral twitches, tongue atrophy and fasciculations, dysphagia, and poor ability to cough and clear secretions. Often, a staring appearance to the eyes is observed, but neither this nor the perioral fasciculations are specific for SCA3/MJD. Upper motor neuron signs often become prominent during the initial phases. Later, evidence of a peripheral polyneuropathy appears with loss of distal sensation, loss of the ankle reflex and sometimes other reflexes as well, and some degree of muscle wasting. Late in the disease, the patients are chairbound, have severe dysarthria, dysphagia, facial and temporal atrophy, poor cough, and often dystonic posturings, ophthalmoparesis, and occasionally blepharospasm. Severe ataxia of limbs and gait, either with hyperreflexia or areflexia, associated with muscle wasting is observed. Even sitting posture is compromised, with the patients assuming various tilted positions. Death ensues from pulmonary complications and cachexia. Brain imaging studies reveal pontocerebellar atrophy. Peripheral nerve conduction studies often reveal evidence for involvement of the sensory nerves as well as the motor neurons.

Precipitants

none

Provocation Tests

none

Diagnostic Procedures

The diagnosis of SCA3 rests upon the use of DNA-based testing to detect an abnormal CAG trinucleotide repeat expansion of the SCA3 gene on chromosome 14q21. Affected individuals have alleles with 56 to 86 CAG trinucleotide repeats. Such testing detects 100% of cases and is widely available. The diagnosis of SCA3 rests upon the detection of a CAG trinucleotide repeat expansion in the SCA3/MJD1 gene (chromosomal locus 14q21) in a patient with cerebellar ataxia. Such testing detects 100% of cases.