Objective: To update the phenotype of RDP based on a cohort of ATP1A3 mutation+ individuals.

Background: RDP is caused by mutations of the ATP1A3 gene, which encodes the α3 subunit of the Na+/K+ ATPase. The published phenotype of RDP is typified by a rostral to caudal gradient of effect, bulbar dysfunction, and abrupt symptom onset. Our group has reexamined the RDP phenotype in a cohort of 53 mutation-positive subjects (ATP1A3+) with 12 distinct mutations.

Methods: We analyzed the cohort with respect to mean Unified Parkinson’s Disease Rating motor subscale (UPDRS3) and Burke-Fahn-Marsden Dystonia Rating Scale (BMFDRS) scores, symmetric parkinsonism, and the presence of bulbar symptoms, a rostrocaudal symptom gradient, frontal lobe dysfunction, and cerebellar dysfunction.

Results: Rapidity of onset (<30 days) was characteristic of ATP1A3+ individuals, but not universal (61%). Bulbar symptoms were present in 81% of ATP1A3+ subjects. ATP1A3+ individuals were dystonic and parkinsonian (mean±SD BMFDRS 47±33 and UPDRS of 44±23). Frontal lobe function measures (trailmaking, verbal fluency) were lower in the ATP1A3+ group than in a control cohort. Neither the presence of a rostrocaudal gradient nor symmetric parkinsonism were typical of the ATP1A3+ cohort. Only 5.8% of ATP1A3+ subjects displayed a rostrocaudal gradient and were about equally likely to have a symmetric or asymmetric parkinsonism (35% symmetric, 48% asymmetric). A subset (n=12) had formal cerebellar function scale assessments, and 17% of these showed cerebellar dysfunction.

Conclusions: ATP1A3+ with RDP subjects typically show rapidity of onset, dystonia, parkinsonism, bulbar symptoms, frontal dysfunction, and possibly cerebellar dysfunction. Neither asymmetric parkinsonism nor the lack of a rostrocaudal gradient can be used to exclude a diagnosis of ATP1A3+ RDP. Our results are affected by the nonhomogenous distribution of mutations, which ranged from 1 instance to 16. Future directions include phenotypic analysis within and between mutation types.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-phenotype-of-atp1a3-rapid-onset-dystonia-parkinsonism-rdp-is-broader-than-previously-defined/