Objective: To clarify the temporal progression of symptoms in the rare genetic dystonia, ATP1A3 disease

Background: The ATP1A3 gene encodes the neuronally ubiquitous α3 subunit of the Na+/K+ ATPase. Mutations cause a variety of neurological phenotypes. Rapid onset dystonia parkinsonism is one of the best characterized: a bulbar-predominant dystonia with rapid symptom onset, often after physiological stress. Although the phenotype has been refined over time, its natural history remains poorly characterized due to its rarity and variability. We aimed to define the evolution of motor and nonmotor symptoms in a cohort of subjects assessed over time.

Method: Subjects manifested first motor symptoms after 18 months of age and were symptomatic at presentation with confirmed ATP1A3 mutations (n=14). They were evaluated at two timepoints using videotaped standardized personal history questionnaires and neurological scales, inclusive of the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS).

Results: Among 14 patients with follow-up visits, missing data limited full neurological tracking. Bulbar symptoms persisted universally across visits (n=14). Dystonia, gauged by the BFMDRS (n=12), varied, improving in some while worsening in others (mean change 1.0 ± 14.2, % change +5.9 ± 37.9). No association was observed between initial BFMDRS scores or disease duration and the rate of BFMDRS change. Age of onset was 20.4 ± 8.6 years and time between initial and follow visits was 5. 5 ± 2.9 years. The cohort comprised seven separate ATP1A3 mutations: too few in each mutation group for comparison on that basis.

Conclusion: Our analysis revealed enduring bulbar symptoms alongside a variable dystonia trajectory in RDP patients. Neither the initial symptom severity nor the disease duration predicted performance at the return visit. This divergence underscores the complexity of RDP and need for continued exploration of its clinical evolution, and the need for both better biomarkers of disease and natural history characterization before treatments can be effectively assessed.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/longitudinal-assessment-of-dystonic-symptoms-in-rapid-onset-dystonia-parkinsonism-genetic-dystonia-symptoms-vary-over-time/