Objective: We aim to characterize the striking clinical heterogeneity of movement, epileptic, and neuropsychiatric symptoms in a cohort of four siblings with genetically confirmed DRPLA.

Background: Dentatorubral–pallidoluysian atrophy (DRPLA) is a rare autosomal dominant disease caused by CAG repeat expansions in the ATN1 gene. The phenotype classically includes ataxia, chorea, myoclonus, cognitive decline, and epilepsy, with significant variability in presentation and age of onset, which is influenced by repeat expansion size. The clinical spectrum of early-onset DRPLA is particularly broad.

Method: We report four siblings who exhibited symptom onset before age 12. Information was collected through record review, video recordings, detailed history and physical examination, neuropsychiatric assessment, and electroencephalography (EEG). Clinical features were then compared among siblings.

Results: All four children had early predominant behavioral disturbances and severe emotional dysregulation. Two had violent outbursts leading to self-mutilation. Another had severe aggression and sensory hypersensitivity, while another had multiple accounts of property destruction. Cognitive involvement varied markedly, ranging from marked global impairment to superior academic performance and foreign language acquisition skills. Only one sibling had chorea and tremor, while two siblings had myoclonus or stereotyped movements. Three siblings had some degree of ataxia, albeit mild. All four siblings displayed some difficulty with fine motor skills. Notably, there were no reported clinical seizures among any of the siblings, which is unusual in early cases, and only one had EEG evidence of generalized sharp wave discharges.

Conclusion: Our case series showcases the marked degree of heterogeneity among siblings in childhood-onset DRPLA, emphasizing that neuropsychiatric symptoms can predominate as the earliest symptoms of disease progression, overshadowing the degree of motor involvement. Of note, hallmark features of DRPLA including seizures, chorea, and other myoclonus may be absent or subtle in affected children. Considering DRPLA when presented with neuropsychiatric and motor manifestations can aid in expediting detection and guiding treatment. With early detection through genetic counseling, ancillary testing, and careful examination can help clinicians to appropriately manage these patients.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/expanding-the-childhood-spectrum-of-dentatorubral-pallidoluysian-atrophy-neuropsychiatric-and-motor-phenotypes-in-four-siblings/