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.

Keywords: ATN1; DRPLA; ataxia; dementia; epilepsy; myoclonus; polyglutamine; trinucleotide.

Figure 1. Flow Diagram Summarizing the Steps Involved in the Literature Search.

Figure 2. Schematic Representation of the Differences in Clinical Symptomatology with Variation in Age at Onset. This is a schematic representation of the variation in more clinical phenotypic presentation between those with juvenile symptom onset (<20 years), and those with adult-onset disease (>20 years).

Figure 3. Example of Magnetic Resonance Imaging Findings in Dentatorubral-pallidoluysian Atrophy. (A) Sagittal T1-weighted image demonstrating global cerebral atrophy, with more marked cerebellar atrophy. (B) Axial T1-weighted image demonstrating bilateral periventricular white-matter lesions.