Last Updated: January 10, 2025
Introduction to Dentatorubral-Pallidoluysian Atrophy
Dentatorubral-pallidoluysian atrophy (DRPLA) is a progressive neurodegenerative disease resulting from the expansion of a CAG trinucleotide repeat in the gene (ATN1) encoding the protein identified as atrophin-1. 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. Prevalence of DRPLA is highest in individuals of Japanese ancestry.
Molecular Biology of DRPLA
The ATN1 gene is located on chromosome 12p13.31 and is composed of 12 exons that generate seven alternatively spliced mRNAs that collectively encode two protein isoforms. The predominant protein (isoform 1), encoded by five of the seven mRNAs, consists of 1190 amino acids. The CAG repeat begins at amino acid 483. The isoform 2 protein is composed of 1189 amino acids.
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.
Clinical Features of DRPLA
DRPLA exhibits a wide range of age of onset from infancy to adulthood. The mean age of onset is around 30 years of age. When the disease manifest before the age of 20 patients are found to have from 63 to 79 CAG repeats. When the disease manifest in patients over 40 years of age the repeat size is found to be 48 to 67. A severe infantile form of DRPLA has been identified to be associated with 90 to 93 CAG repeats.
Symptom severity and type allows for designation of a juvenile onset (prior to 20 years of age) form and an adult onset (after age 20) form. Patients affected by DRPLA have an average life-span of 8 years from definitive diagnosis.
The cardinal 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), as well as psychiatric manifestations. 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.