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ABSTRACT

  • The dominantly inherited spinocerebellar ataxias (SCAs) are a heterogeneous group of neurologic disorders characterized by variable degrees of degeneration of the cerebellum, spinocerebellar tracts, and brain stem neurons. The inter- and intrafamilial variability of clinicopathologic findings hampered the classification of this group of diseases until the 1990s, during which the discovery of the genetic bases of many of the SCAs provided a means of distinguishing among them.

  • The mutational locus has been mapped for 10 SCAs: spinocerebellar ataxia 1, 2, etc. [disease in Roman font and gene in italics] (SCA1, SCA2), Machado-Joseph disease (MJD)/SCA3 (sometimes referred to here simply as SCA3), SCA4, SCA5, SCA6, SCA7, SCA8, SCA10, and dentatorubropallidoluysian atrophy (DRPLA). The clinical features shared among these SCAs are ataxia, dysarthria, and eventual bulbar dysfunction. Variable features include ophthalmoparesis (common in SCA1, 2, 3, and 7); hyporeflexia (common in SCA2 and 4); dementia (more frequent in SCA2 and common in DRPLA); dystonia and rigidity (occasional in SCA1 and common in MJD/SCA3); choreoathetosis and myoclonus (common in DRPLA); spasticity (SCA1, 3, and DRPLA); bulging eyes and fasciculations (MJD/SCA3); neuropathy (most common in SCA4 but can be seen in SCA1, 2, and 3); seizures (common in SCA10 and DRPLA); and macular degeneration and extraneuronal involvement (unique to SCA7). Neuroimaging studies demonstrate cerebellar atrophy in SCA1, 2, 3, 6, 7, and DRPLA; cortical atrophy in SCA2, 7, and DRPLA; and brain stem atrophy in SCA1, 2, 3, 7, and DRPLA. Calcification of the basal ganglia and leukodystrophic changes occur in DRPLA. Nerve conduction abnormalities occur in SCA1, 2, and 3, and are most common in SCA4. Visual evoked potentials are abnormal in SCA7, and the EEG is abnormal in DRPLA. Purkinje cell and dentate neuron degeneration is severe in SCA1, 2, 6, 7, and DRPLA, but modest in MJD/SCA3. Degeneration of the inferior olive is common in SCA1, 2, 6, and 7. Loss of brain stem neurons is common in SCA1, 2, 3, 6, and DRPLA. Basal ganglia degeneration is pronounced in DRPLA and variable in MJD/SCA3. Macular degeneration and hypomyelination of the optic tract are unique to SCA7.

  • The mutational basis of SCA1, SCA2, MJD/SCA3, SCA6, SCA7, and DRPLA is the expansion of a translated trinucleotide (CAG) repeat that encodes for a polyglutamine tract in the relevant protein. SCA8 is caused by expansion of a CTA/CTG repeat that does not appear to be translated. Expanded disease alleles typically contain 34 to 84 CAG repeats in SCA1, 2, 3, and DRPLA. In SCA6, the pathogenic range is 21 to 33, and in SCA7 it is 35 to 306. For SCA8 the expanded range varies from 110 to 130 in kindreds with established linkage to the SCA8 locus, but has been found to exceed 575 repeats in some affected patients.

  • The gene products mutated in most of the SCAs—ataxin-1, ataxin-2, ataxin-3, ataxin-7, and atrophin-1—are novel proteins of unknown function. The gene product mutated in SCA6 is the α1A voltage-gated calcium channel (CACN1A1). The distribution of the ...

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