ATP1A3-Related Disorders: An Ever-Expanding Clinical Spectrum.

Philippe A Salles,Ignacio F Mata,Tobias Brünger,Dennis Lal,Hubert H Fernandez

doi:10.3389/fneur.2021.637890

Abstract

The Na+/K+ ATPases are Sodium-Potassium exchanging pumps, with a heteromeric α-β-γ protein complex. The α3 isoform is required as a rescue pump, after repeated action potentials, with a distribution predominantly in neurons of the central nervous system. This isoform is encoded by the ATP1A3 gene. Pathogenic variants in this gene have been implicated in several phenotypes in the last decades. Carriers of pathogenic variants in this gene manifest neurological and non-neurological features in many combinations, usually with an acute onset and paroxysmal episodes triggered by fever or other factors. The first three syndromes described were: (1) rapid-onset dystonia parkinsonism; (2) alternating hemiplegia of childhood; and, (3) cerebellar ataxia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS syndrome). Since their original description, an expanding number of cases presenting with atypical and overlapping features have been reported. Because of this, ATP1A3-disorders are now beginning to be viewed as a phenotypic continuum representing discrete expressions along a broadly heterogeneous clinical spectrum.

Highlights

Considered rare, ATP1A3-related disorders have been capturing our attention in the last decade by virtue of cumulative cases reporting an expanding range of clinical and genetic variability
The three classic phenotypes related to ATP1A3 pathogenic variants—rapid-onset dystonia parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS)—diverge in several clinical features with different pathogenic variants associated with each syndrome
Marzin et al reported three children with de novo p.Asp742Tyr, p.Cys346Arg, and p.Asp609Tyr variants in ATP1A3, respectively, manifesting features close to those cases reported by Paciorkowski et al with early-onset encephalopathy, seizures and non-epileptic attacks of movement disorders, mainly observed during infancy

Summary

Introduction

Considered rare, ATP1A3-related disorders have been capturing our attention in the last decade by virtue of cumulative cases reporting an expanding range of clinical and genetic variability. The three classic phenotypes related to ATP1A3 pathogenic variants—rapid-onset dystonia parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS)—diverge in several clinical features with different pathogenic variants associated with each syndrome.

Results

Conclusion