Clinical Guidance

Age of onset inversely correlates with the size of the CAG repeat expansion. Some individuals with the largest reported expansions (86 and 83 repeats) had disease onset at age five years and 11 years, respectively . Despite such observations, there is evidence that other nonspecified genetic or non-genetic factors also contribute . Phenotype. A loose correlation exists between the size of the CAG repeat expansion and the clinical phenotype [, , , , , , , , ]. In general, the longest disease-causing CAG repeats cause earlier-onset disease that is more likely to have dystonia as part of the presentation. In contrast, the shortest disease-causing CAG repeats cause later-onset disease that is more likely to have peripheral manifestations such as neuropathy and weakness.

Source: GeneReviews — "Spinocerebellar Ataxia Type 3"

Penetrance

In SCA3, penetrance approaches 100% and is age related. CAG repeat sizes associated with reduced penetrance of SCA3 are not firmly defined. Of note, an asymptomatic individual age 66 years with 68 CAGs has been reported .

Source: GeneReviews — "Spinocerebellar Ataxia Type 3"

Diagnostic Criteria

Suggestive Findings

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), should be suspected in individuals with the following clinical findings and family history . Clinical findings. Progressive cerebellar ataxia often and variably associated with:

• Pyramidal signs

• A dystonic-rigid extrapyramidal syndrome

• Significant peripheral amyotrophy and generalized areflexia

• Progressive external ophthalmoplegia

• Action-induced facial and lingual fasciculations; bulging eyes

Family history. Consistent with autosomal dominant inheritance (i.e., multiple affected family members in successive generations or a single occurrence in a family). Absence of a family history of SCA3 does not preclude this diagnosis.

Establishing the Diagnosis

The diagnosis of SCA3 is established in a pro...

Source: GeneReviews — "Spinocerebellar Ataxia Type 3"

Differential Diagnosis

Individuals with spinocerebellar ataxia type 3 (SCA3) may present with unexplained ataxia that is part of the larger differential diagnosis of hereditary and acquired ataxias (see Hereditary Ataxia Overview). Progressive ataxia, often associated with evidence of upper motor neuron dysfunction including brisk tendon reflexes and extensor plantar responses, can be seen in individuals with SCA3 as well as in many other dominantly inherited ataxias. Thus, it is difficult and often impossible to distinguish SCA3 from the other hereditary ataxias (see Hereditary Ataxia Overview). The presence of dystonia and parkinsonian features, including a beneficial response to levodopa or dopamine agonists, can cause diagnostic confusion with dopa-responsive dystonia and Parkinson disease .

Source: GeneReviews — "Spinocerebellar Ataxia Type 3"

Management Guidelines

Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 3 (SCA3), the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 3. Recommended Evaluations Following Initial Diagnosis in Individuals with Spinocerebellar Ataxia Type 3

Source: GeneReviews — "Spinocerebellar Ataxia Type 3"

Therapies Under Investigation

Currently, no medication has been proven to slow or halt the progression of SCA3. The recent promise of nucleotide-based gene silencing strategies in other neurodegenerative diseases such as spinal muscular atrophy, coupled with preclinical success of gene silencing therapy in mouse models of SCA3 , suggest that similar nucleotide-based gene silencing strategies for SCA3 may soon be tested in human clinical trials. Ataxia investigators in Europe and in the United States are currently engaged in a collaborative grant application for trial readiness for SCA3 (READISCA) that is seeking to define the natural history of SCA3 and appropriate disease biomarkers . Troriluzole, a prodrug (i.e.

Source: GeneReviews — "Spinocerebellar Ataxia Type 3"

Surveillance Guidelines

Table 5. Recommended Surveillance for Individuals with Spinocerebellar Ataxia Type 3

Source: GeneReviews — "Spinocerebellar Ataxia Type 3"