NeurometPlus

Incidence

SCA1 is an autosomal dominant disorder. Offspring of affected individuals have a 50% chance of inheriting the gene mutation. Approximately 1-2 in 100,000 will develop SCA1. SCA1 represents about 6% of patients with AD cerebellar ataxia.

Clinical Characteristics

SCA1 is characterized by progressive cerebellar ataxia, dysarthria, and eventual bulbar dysfunction.
The typical age of onset for SCA1 is in the third or fourth decade, but early onset in childhood has been documented. An increase in the severity of the phenotype in later generations, a phenomenon known as anticipation, has been observed in SCA1. The duration of illness from onset to death varies from 10-30 years, but patients with juvenile onset disease (whose symptoms appear before age 13 years) show more rapid progression, as well as more severe disease, and die before they reach 16. The majority of patients initially present with difficulties in gait; quite commonly they will also have simultaneous trouble with slurred speech. They may first notice problems of balance in going down steps or making sudden turns, and athletic patients may notice difficulties even earlier in the course of activities that require exquisite control, such as skiing or dancing. Patients may display brisk deep tendon reflexes, hypermetric saccades, and nystagmus in the early stages of disease. Mild dysphagia, indicated by coughing after eating, may also occur early in the disease. As the disease progresses, the saccadic velocity slows and an up-gaze palsy develops. Nystagmus often disappears with evolving saccadic abnormalities. Hyperreflexia may be detected, the ataxia worsens, and other cerebellar signs such as dysmetria, dysdiadochokinesia, and hypotonia become apparent. Optic nerve atrophy and variable degrees of ophthalmoparesis may be detected in some patients. Muscle atrophy, decreased or absent deep tendon reflexes, and loss of proprioception or vibration sense may occur in the middle or late stages of the disease. Mild cognitive declines in verbal and nonverbal intelligence as well as memory, and some emotional lability also occur; the degree of cognitive impairment correlates with severity of disease but does not interfere with quotidian life. Extrapyramidal signs tend to take the form of chorea and dystonia and occur in advanced disease. In the final stages, bulbar difficulties are evident (atrophy of facial and masticatory muscles, perioral fasciculations, and severe dysphagia leading to frequent aspiration). Patients eventually develop respiratory failure, which is the main cause of death. Computerized tomography (CT) scans and magnetic resonance imaging (MRI) of the brains of patients with SCA1 reveal atrophy of the brachia pontis and anterior lobe of the cerebellum and enlargement of the fourth ventricle. Genotype-Phenotype Correlations: A strong correlation exists between the number of repeats and severity of disease: the larger the repeat, the earlier the onset and more severe the disease. The correlation is very broad, however -- a difference of seven repeats might lead to disease in one patient twenty years later than in another -- and so is not clinically very useful. The largest expansions of the CAG tract are found in patients with juvenile onset SCA1, who typically experience more rapid disease progression and are the offspring of affected males. Some clinical signs are more common with larger repeat size independent of disease duration: facio-lingual atrophy, dysphagia, skeletal muscle atrophy, and possibly ophthalmoparesis. Patients with more than 52 CAG repeats tend to become significantly disabled 5 years after the onset of disease. Homozygous patients do not seem to develop disease more severe than that which can be predicted by the larger of their two alleles.

Precipitants

no

Provocation Tests

no

Diagnostic Procedures

The phenotypic manifestations of SCA1 are not specific, and thus, the diagnosis of SCA1 rests on molecular genetic testing. The diagnosis of SCA1 rests upon the results of DNA-based testing to detect an abnormal CAG trinucleotide repeat expansion of the SCA1 gene on chromosome 6p22-p23. Affected individuals have alleles with 39-81 CAG trinucleotide repeats. Such testing detects 100% of cases and is widely available. Mutation analysis by direct amplification of the SCA1 CAG repeat will identify 100% of individuals who have a disease-causing SCA1 mutation. The number of CAG repeats ranges from 6-44 in normal alleles and from 39-81 repeats in disease-causing alleles. This test is available clinically and is widely accessible. Distinguishing normal from disease alleles requires additional evaluation when the allele size is in the 36-44 repeat range. Only in the remote case of infantile onset SCA1 with a repeat range in the 100's would PCR be likely to miss the mutation; in a suspected case of infantile onset SCA1, Southern blotting should be used instead. Prenatal testing by direct DNA-testing is possible for fetuses at 50% risk.