Dentatorubral-pallidoluysian Atrophy: An Update

Abstract

Background: Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare, autosomal dominantly inherited disorder characterized by myoclonus, epilepsy, ataxia, and dementia. Diagnosis is challenging due to the heterogeneous presentation and symptomatic overlap with other spinocerebellar ataxias. Symptoms vary according to age of onset, with a mean age at onset of 31 years. A CAG repeat expansion in the ATN1 gene results in neuronal intranuclear inclusions, variable neuronal loss, and astrocytosis in the globus pallidus, dentate and red nuclei. No disease-modifying or curative treatments are currently available Methods: We performed an online literature search using PubMed for all articles published in an English Language format on the topics of DRPLA or ATN1 over the last 10 years. Where these articles cited other research as support for findings, or statements, these articles were also reviewed. Contemporary articles from related research fields (e.g., Huntington's Disease) were also included to support statements.Results: Forty-seven articles were identified, 10 were unobtainable and 10 provided no relevant information. The remaining 27 articles were then used for the review template: seven case reports, seven case series, six model system articles (one review article), four population clinical and genetic studies (one review article), two general review articles, and one human gene expression study. Other cited articles or research from related fields gave a further 42 articles, producing a total of 69 articles cited: 15 case series (including eight family studies), 14 model systems (one review article), 14 population clinical and genetic studies (two review articles), 10 case reports, eight clinical trials/guidelines, four genetic methodology articles, three general review articles, and one human gene expression study.Discussion: DRPLA remains an intractable, progressive, neurodegenerative disorder without effective treatment. Early recognition of the disorder may improve patient understanding, and access to services and treatments. Large-scale studies are lacking, but are required to characterize the full allelic architecture of the disorder in all populations and the heterogeneous phenotypic spectrum, including neuroimaging findings, possible biomarkers, and responses to treatment.

Spinocerebellar ataxia clinical trials: opportunities and challenges

“…Pharmacologically addressable deficits include repleting neurotrophic factors such as brain‐derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), ameliorating ion channel dysfunction, or addressing consequences of mitochondrial damage including the generation of reactive oxygen species. 28 , 29 , 30 , 31 , 32 , 33 Lastly, a less targeted approach to therapeutic development is to repurpose or modify drugs used for other neurodegenerative disorders. For instance, an ongoing trial is testing whether an analogue of riluzole provides symptomatic benefit for patients with polyglutamine SCAs.…”

Genotype–Phenotype Correlation in Progressive Supranuclear Palsy Syndromes: Clinical and Radiological Similarities and Specificities

“…Dentatorubral–pallidoluysian atrophy (DRPLA) is an inherited autosomal dominant disease due to CAG trinucleotide expansion in the ATN1 gene. It is more common in Japanese population, and myoclonus, epilepsy, ataxia, and dementia are frequent, with disease onset during the third decade of life ( 78 ). Cases with >100 CAG repeats with PSP-OM and PSP-P phenotypes have been reported.…”

Review of Hereditary and Acquired Rare Choreas

“…Some patients can present with a clinical phenotype very similar to that of HD, with chorea as the predomin ant manifestation. DRPLA is highly prevalent among the Japanese population, but has occasionally been reported elsewhere [20]. The age of presentation depends upon the size of the CAG repeat expansion in atrophin-1 (ATN1) on chromosome 12p13-31 [21].…”