Objective: To report clinical and molecular features of a family showing intrafamilial phenotypic diversity where a novel ATP1A3 mutation was found.

Background: Originally there have been described two neurological disorders associated with ATP1A3 mutations: rapid-onset dystonia parkinsonism (RDP) and alternating hemiplegia of childhood (AHC) considered classically allelic conditions.

Methods: We obtained detailed clinical data of affected and unaffected subjects from a family showing symptoms reminiscent of alternating hemiplegia of childhood (AHC) and rapid-onset dystonia parkinsonism (RDP). We sequenced ATP1A3 gene in the whole family.

Results: The proband was a 22 year-old male who presented an abrupt onset of parkinsonism associated with bulbar symptoms at the age of 19. At examination he had anarthria and mild dysphagia. He also showed hypotonia and severe bradykinesia in four limbs with a rostrocaudal gradient of involvement. His symptoms did not respond to L-Dopa. His family history was consistent with autosomal dominant inheritance (AD) with other 13 affected individuals showing widespread intrafamilial phenotypic variability overlapping AHC and RDP syndromes and presenting many of them with epilepsy. We identified a novel missense mutation in ATP1A3 (NM_001256214: p.L866R) only in the affected members of this family. This mutation was not previously reported in RDP or AHC.

Conclusions: The phenotypic spectrum of ATP1A3-related neurological disorders has been expanded recently through the description of an increasing number of patients with intermediate or atypical phenotypes. It was proposed that AHC and RDP represent a phenotypic continuum of ATP1A3 related disorders. We present here a family carrying a novel ATP1A3 mutation in which the proband was meeting diagnostic criteria for classical RDP, but other affected subjects in his family presented with distinct phenotypes characterized by hemiplegia, epilepsy and cognitive impairment. The description of our family supports the hypothesis that conditions associated to ATP1A3 are different manifestations along a clinical spectrum rather than allelic disorders as they were previously considered.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/expanding-the-spectrum-of-atp1a3-related-disorders-continuum-from-alternating-hemiplegia-of-childhood-to-rapid-onset-dystonia-parkinsonism/