Objective: To determine characteristics that distinguish individuals with presentation suggestive of RDP in ATP1A3 mutation carriers compared with non-carriers.

Background: Mutations in the ATP1A3 gene are causative both for RDP and alternating hemiplegia of childhood. The phenotype continues to expand to include intermediate forms, and likely the phenotype is broader, suggesting that clinicians may cast wider nets to identify cases.

Methods: In order to further define characterizing features of RDP and aid in selection of cases for ATP1A3 screening, we report clinical features from subjects for whom referring clinicians noted features suggestive of RDP. Participants were screened for mutations in all ATP1A3 exons, and clinical features were compared using Fisher’s exact or rank sum statistics.

Results: 7 individuals from 6 families had mutations in ATP1A3 and 25 did not demonstrate mutations. Average age at exam was not different in the mutation group compared with the non-mutation group (median 30 yrs IQR 27-44 vs 39 yrs IQR 21-53). Symptoms were abrupt (<24 hour in onset) in 57.1% of mutation carriers compared with 8% of non-carriers (p=0.01). There was a known trigger for 57.1% of mutation positive cases (28.6% had emotional trigger, 28.6% exercise and 28.6% head trauma, with one person having all three), whereas only 8% of mutation negative cases had triggers (both exercise) (p=0.01). 100% of RDP cases had bulbar features on exam, whereas only 44% of mutation negative cases did (p=0.01). None of the cases with adequate trial of l-dopa or agonists (only 2) had response, whereas 22% (4/18) of mutation negative cases exhibited response.

Conclusions: Our data strongly support that while over half of mutation positive cases have rapid onset of symptoms, almost half do not. Thus while ATP1A3 carriers more likely have very rapid onset of disease, non-sudden onset should not be an exclusion criteria. Triggers for RDP are more commonly described in mutation positive cases, but it is unclear if this is related to the trigger per se or recall of onset. Similar to prior reports, cranial disease was present in all cases, therefore it is likely that this is a defining feature of RDP, although we cannot exclude clinician bias in not referring cases for screening where cranial features were not present. It is likely that with broader screening the phenotype will further expand.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-distinguishing-clinical-features-of-rapid-onset-parkinson-dystonia-rdp-syndrome-due-to-atp1a3-mutations/