Dentatorubral-pallidoluysian atrophy (DRPLA) is a progressive neurodegenerative disease resulting from the expansion of a CAG trinucleotide repeat in the atrophin-1 gene. Normal individuals have 7–34 CAG repeats whereas affected individuals have from 49–88 repeats. The disease gets its name from the neuropathology of the disease which shows that the major areas affected by the neurodegeneration are the dentatorubral and pallidoluysian systems. Like most all of the trinucleotide repeat expansion diseases, DRPLA is inherited as an autosomal dominant condition.
The atrophin-1 gene (ATN1) is located on chromosome 12p13.31 and is composed of 11 exons that generate two alternatively spliced mRNAs. Both mRNAs encode the same 1190 amino acid protein. The CAG repeat begins at amino acid 483. Expression of atrophin-1 is highest in neuronal tissues at all developmental stages. The precise function of atrophin-1 remains unknown but the protein contains a nuclear localization signal and a nuclear export signal. In DRPLA patients an N-terminal cleavage fragment of atrophin-1 (which contains the nuclear localization signal) accumulates in the nucleus. Atrophin-1 may act as a transcriptional corepressor as evidenced from studies in Drosophila.
The clinical manifestations of DRPLA include myoclonic epilepsy (a form of epilepsy associated with involuntary muscle twitching: myoclonus), ataxia, dementia, loss of coordination and choreoathetosis (occurrence of involuntary movements in combination with chorea which itself refers to irregular, rapid, uncontrolled, and excessive movements). All of these manifesting symptoms are due to the significant reduction in tissues of the brain and spinal chord. Observations in numerous patients has revealed that the pallidoluysian degeneration is more severe than the dentatorubral degeneration in the juvenile-onset disorder and the reverse is true for the late adult-onset disorder.