Alternating Hemiplegia of Childhood: Understanding the Genotype-Phenotype Relationship of ATP1A3 Variations

Abstract

Alternating hemiplegia of childhood (AHC) is a rare neurological disorder affecting children with an onset before 18 months. Diagnostic clues include transient episodes of hemiplegia alternating in the laterality or quadriparesis, nystagmus and other paroxysmal attacks as tonic and dystonic spells. Epilepsy is also a common feature. In the past, a great effort has been done to understand the genetic basis of the disease leading to the discovery of mutations in the ATP1A3 gene encoding for the alpha3 subunit of Na⁺/K⁺ATPase, a protein already related to another disease named Rapid Onset Dystonia Parkinsonism (RDP). ATP1A3 mutations account for more than 70% of cases of AHC. In particular, three hotspot mutations account for about 60% of all cases, and these data have been confirmed in large population studies. Specifically, the p.Asp801Asn variant has been found to cause 30-43% of all cases, p.Glu815Lys is responsible for 16-35% of cases and p.Gly947Arg accounts for 8-15%. These three mutations are associated with different clinical phenotype in terms of symptoms, severity and prognosis. In vitro and in vivo models reveal that a crucial role of Na⁺/K⁺ATPase pump activity emerges in maintaining a correct membrane potential, survival and homeostasis of neurons. Herein, we attempt to summarize all clinical, genetic and molecular aspects of AHC considering ATP1A3 as its primary disease-causing determinant.

Keywords: AHC; ATP1A3; Na+/K+ATPase; animal models; genetics.

Figure 1

Distribution of AHC-causing variants along the ATP1A3 gene and mRNA. Note: Columns show the number of AHC-causing variants (light grey bars) and the total number of pathogenic ATP1A3 variants (dark grey bars) reported in each exon. Abbreviations: AHC, alternating hemiplegia of childhood; Nt, Nucleotides; bp, basepairs.

Figure 2

Location of AHC-causing variants in the ATP1A3 protein. Notes: White dots show AHC-causing variants, black dots indicate variants causing EIEE with the presence of hemiplegic attacks, blue-and-white dots show variants causing both RDP and AHC. According to functional domains localization, variants are divided into ion binding site variants (black), membrane variants (blue), stalk variants (green), P domain variants (purple) and extracellular variants (red). The three-different cytosolic domains of the ATP1A3 protein are indicated in red (A domain), green (N domain) and blue (P domain). Abbreviations: AHC, alternating hemiplegia of childhood; EIEE, early infantile epileptic encephalopathy; RDP, rapid-onset dystonia-parkinsonism.

Figure 3

Frequency of AHC-causing variants in different cohorts. Notes: The graph shows the relative frequency of variants affecting each specific ATP1A3 residue in a North American (blue line, N= 151), European (red line, N= 130) and a Chinese (black line, N= 45) cohort. The peaks are expressed as the percentage of the total number of AHC patients in each cohort. The three hotspots for AHC-causing variants (Asp801, Glu915 and Gly947) are indicated above the corresponding peak. Abbreviation: AHC, alternating hemiplegia of childhood.