ATP1A3-Related Disorders: An Ever-Expanding Clinical Spectrum

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.

Keywords: ATP1A3; CAPOS syndrome; Dyt12; alternating hemiplegia; ataxia; rapid-onset dystonia parkinsonism; sodium-potassium-exchanging ATPase.

Figure 1

Overlapping of ATP1A3-related disorders. RDP, rapid-onset dystonia-parkinsonism; AHC, alternating hemiplegia of childhood; CAPOS, cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss; CAOS, cerebellar ataxia, areflexia, optic atrophy, and sensorineural hearing loss. With permission from Salles and Fernandez, reference (1).

Figure 2

ATP1A3 missense variants mapped on a protein structure model of the α3 subunit of the Na+/K+-ATPase. The homology model was obtained from the SWISS-Model repository (template: 4RET). (A) Pathogenic missense variants. Spheres are colored by disorder type. Residues associated with multiple distinct disorders were colored in yellow. (B) Population variants in ATP1A3 were collected from the gnomAD database (81) and visualized as blue spheres on the homology model. *Asp350Lys did not match any protein isoform in Uniprot (82), could not be aligned to the canonical ATP1A3 sequence and is thus not displayed in the figure. In case of AHC and RDP, we only included the pathogenic variants reported as more frequent according to the references (8, 14), respectively. AHC, alternating hemiplegia of childhood; ASD, autistic spectrum disorder; CAPOS, cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss; COS, childhood-onset schizophrenia; CP, cerebral palsy; D-DEMO dystonia, dysmorphism, encephalopathy, MRI abnormalities, and no hemiplegia; EE, early life epilepsy; FIPWE, fever-induced paroxysmal weakness and encephalopathy; PD, paroxysmal dyskinesias; RECA, relapsing encephalopathy with cerebellar ataxia; RDP, rapid-onset dystonia-parkinsonism; ROA, rapid onset cerebellar ataxia; SPCA, slowly progressive cerebellar ataxia.

Figure 3

ATP1A3 variant associated disorder severity and variant position analysis. Patients with ATP1A3 variants were grouped by disorder severity into three groups. (A) The corresponding missense variants were visualized on the protein structure and colored according to grouping (mild disorder = cyan; moderate disorder = pink; severe disorder = red). Gray-coloring of spheres indicates residues where variants from multiple severity groups have been reported. Amino acid residue paralog conservation (B) and population constrained (C) were assessed for variants from each severity group together with a neutral comparison group, missense variants from the DiscovEHR database (see methods in Supplementary Material for details).