Objective: To describe the clinical presentation of a novel likely pathogenic variant in ATP1A3.

Background: Rapid onset dystonia-parkinsonism is related to mutations in ATP1A3 gene. It is characterized by acute onset of dystonia and parkinsonism from days to weeks, but occasionally patients report a more protracted onset over months. It usually appears in adolescence or early adulthood. Dystonia begins focally and classically progresses following a rostro-caudal gradient. Bulbar involvement is usually prominent. Frequently patients recognize triggers like fever, alcohol consumption or emotional stress that may precipitate deterioration. Nevertheless symptoms often stabilize with little response to medical therapies or surgery.

Method: Clinical assessment. Next generation sequencing (NGS).

Results: A 55 year old woman presented in our clinic with a long-standing history of generalized dystonia. She was born without perinatal complications from healthy non-consanguineous parents. She has 9 healthy siblings without neurological complaints. She recalls abrupt onset of facial involuntary grimacing in adolescence. At 18 year-old, right hand dystonia acutely appeared, making writing and fine motor tasks difficult. In the following years, she describes two additional episodes of rapid deterioration, with right leg and trunk involvement. She recognizes concurrent alcohol consumption and emotional stress. Since then dystonia has remained stable. Neurological examination revealed prominent oromandibular dystonia with a tendency to sustained jaw closing with partially unintelligible speech and generalized dystonia with right limbs being more affected. Right hand showed a fixed contraction with hand closure. Rigidity was elicited in right limbs although it was difficult to assess due to dystonia. No benefit was obtained with levodopa, anticholinergic drugs or botulinum toxin. A thorough laboratory investigation was conducted to rule out acquired etiologies. Brain MRI was normal. Presynaptic nigrostriatal imaging demonstrated left presynaptic denervation. Genetic testing with a NGS gene panel focused on dystonia genes showed an heterozygous variant in ATP1A3 gene: c.2974G>A (p.Asp992Asn), which has never been reported and is classified as pathogenic by in silico prediction tools.

Conclusion: We describe a proband with rapid onset generalized dystonia with a clinical phenotype similar to DYT/PARK-ATP1A3 patients and a novel variant not previously reported.

References: 1. Haq IU., Snively BM., Swadner KJ et al. Revising rapid-onset dystonia-parkinsonism: broadening indications for ATP1A3 testing. Mov Disord 2019; 34(10):1528-1536. 2. Marras C., Lang A., van de Warrenburg BP. et al. Nomenclature of Genetic Movement Disorders: Recommendations of the International Parkinson and Movement Disorders Society Task Force. Mov. Disord 2016; 31 (4): 436-457.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-novel-variant-c-2974ga-p-asp992asp-of-dyt-park-atp1a3/