Spinocerebellar Ataxia Type 3Machado Joseph Disease

Pathogenesis and Pathophysiology. SCA3, or Machado-Joseph disease (MJD), is an autosomal dominant disorder. The SCA3-MJD locus on chromosome 14q was found in Japanese families with the MJD phenotype and in European ADCA families. Subsequently, the gene was isolated, and the mutation was shown to be an unstable trinucleotide CAG repeat expansion present within the coding region of the gene. y The repeat length in normals varies between 14 and 40 trinucleotides, but SCA3-MJD patients have one allele with 62 to 84 repeat units. Both the normal and mutated SCA3 genes contain uninterrupted CAG stretches. Expanded SCA3 alleles display intergenerational instability and show a tendency toward further expansion. Repeat lengths vary in different body tissues due to the mitotic instability of the expanded repeats.

In SCA3 there is an inverse correlation between the length of the CAG repeat and the age of onset, the largest alleles occurring in patients with juvenile disease onset. Because of the intergenerational instability of the expanded repeats, the age of onset varies from generation to generation with features of anticipation. In contrast to patients with SCA1, there is no paternal effect on age of onset. y , y

Neuropathologically, SCA3 is characterized by degeneration of the spinocerebellar tracts, vestibular nuclei, and dentate nucleus. The cerebellar cortex and the inferior olives are spared. In most cases, the pontine base is only moderately affected. The substantia nigra and the subthalamopallidal connections are frequently involved.y

Epidemiology and Risk Factors. The prevalence of ADCA has been reported to be 1.2 in 100,000, with large regional variations due to founder effects. y In a recent nationwide study SCA3 was found to occur in 21 percent of a population of 149 ADCA families. y SCA3 is a genetically determined disorder with no known environmental risk or precipitation factors. Children of SCA3 patients have a 50 percent risk of developing the disease.

Clinical Features and Associated Disorders. SCA3 begins at any time between early childhood and late adulthood with features of anticipation. On average, the disease starts around the age of 40 years. The clinical picture of SCA3-MJD is characterized by a wide range of clinical manifestations, the precise nature of which depends partly on the CAG repeat length. All SCA3-MJD patients suffer from a progressive syndrome marked by ataxia of gait and stance, ataxia of limb movements, and dysarthria. Vertical or horizontal gaze palsy is a frequent additional finding that occurs independently of age of onset. Saccade velocity is usually normal. Dementia, basal ganglia symptoms, pale optic discs, and bladder dysfunction are absent in most cases. In patients with a repeat length of more than 74, the disease begins early, usually before the age of 30 years, and clinical features of pyramidal tract and basal ganglia involvement are evident. Most of these patients have increased tendon reflexes, extensor plantar responses, spasticity, and dystonia. In patients with an intermediate repeat length of 71 to 74 units, the disease begins in middle age; clinical signs include mainly ataxia and gaze palsy. In patients with a repeat length of less than 71, the disease begins later, and they show signs of peripheral neuropathy with loss of tendon reflexes, amyotrophy, and decreased vibration sense. However, the boundaries between these clinical syndromes are vague, and the clinical phenotype of an individual may change as the disease progresses. Therefore, we do not advocate dividing SCA3-MJD patients into clinical subtypes. y , y , y , y , y

Differential Diagnosis and Evaluation. Diagnosis of SCA3 is made by demonstration of the CAG repeat expansion at the SCA3 locus. Clinically, SCA3 cannot be distinguished with certainty from other forms of ADCA-I. The

presence of dystonia is suggestive for SCA3. However, even in patients with SCA3, dystonia is infrequent and occurs mainly in those with an early disease onset. Absence of cerebellar atrophy on MRI is typical of SCA3 and may help to distinguish SCA3 from other mutations leading to ADCA.

Evaluation. The results of electrophysiological investigations resemble those in patients with SCA2, with evidence of peripheral axonal neuropathy and posterior column involvement; MEPs in response to transcranial magnetic stimulation and VEPs are normal in most patients. On MRI, the cerebellum and brain stem appear normal or only moderately shrunken. As in patients with SCA1 and SCA2, the cervical spinal cord is atrophic in most patients(see Fig 35-2).

Management. At present, there is no specific treatment for SCA3. Principles of symptomatic and palliative therapy are identical to those described for patients with SCA1. Patients with generalized dystonia may respond to anticholinergics.

Prognosis and Future Perspectives. SCA3 is a progressive disorder. On average, these patients become wheelchair-bound about 15 years after disease onset.

Median survival is 25 to 30 years. Progression is faster in patients with long repeats and early disease onset. The SCA3 mutation is an expanded CAG repeat that is similar to the mutations found in Huntington's disease, SCA1, and dentatorubral-pallidoluysian atrophy (DRPLA). Future studies must explore the mechanisms by which the SCA3 mutation leads to the regional specific pattern of neurodegeneration in this disorder.

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