De novo ATP1A2 variants in two Chinese children with alternating hemiplegia of childhood upgraded the gene–disease relationship and variant classification: a case report

Abstract

Background ATP1A2 gene mutation has been indicated to cause alternating hemiplegia of childhood (AHC); however, limited evidence supports this relationship so far. Case presentation We reported two Chinese patients with de novo ATP1A2 variants (c.970G>A and c.889G>A). Both patients presented with episodes of alternating hemiplegia, seizures and mild developmental delay. Brain magnetic resonance imaging revealed abnormal signals in both patients. Conclusions The new genetic evidence we reported here strengthened the gene–disease relationship, and the gene curation level between ATP1A2 and AHC became “Moderate” following the ClinGen Standard Operation Procedure. Consequently, the two variants can be reclassified as likely pathogenic.

A novel heterozygous ATP1A2 pathogenic variant in a Chinese child with MELAS‐like alternating hemiplegia

“…Huang and colleagues reported two Chinese children with AHC who both have mutations in the ATP1A2 gene: c.889G > A:p.Ala297Thr (in the third transmembrane domain) in case 1, c.970G > A:p.GLy324Ser (in the fourth transmembrane domain) in case 2. The clinical phenotype of case 2 is more serious than that of case 1, but case 1 has an earlier age of onset (D. Huang et al, 2021). However, there is no clear classification for the severity of the clinical phenotype caused by ATP1A2 mutations.…”

“…ATP1A2 gene mutation as the cause of AHC has rarely been reported. Six papers have been submitted on the topic, of which five concerned point mutations and one concerned complex heterozygous mutation (Al‐Bulushi et al, 2014; Bassi et al, 2004; Huang et al, 2021; Swoboda et al, 2004; Ueda et al, 2018; Wilbur et al, 2017; Figure 5). Most reported genetic mutation cases were heterozygotes for a single pathogenic variant (Wilbur et al, 2017).…”

“…Brain MRI in patients with AHC typically provides normal or nonspecific findings (Panagiotakaki et al, 2010; Wilbur et al, 2017). The reported brain imaging changes in patients with AHC were mainly brain atrophy (Giacanelli et al, 2017; Saito et al, 1998; Swoboda et al, 2004), corresponding unilateral cerebral hemisphere cortical edema (Huang et al, 2021; Wilbur et al, 2017), or both (Calame et al, 2021; Moya‐Mendez et al, 2021). The imaging findings of this patient were completely different from those previously reported in patients with AHC but similar to those of patients with MELAS.…”

“…This case broadens the clinical phenotypic spectrum caused by ATP1A2 mutations, while strengthening the causal relationship between ATP1A2 and AHC, and prompting our attention to the possible compound effects of multiple heterozygous variants. In 2021, Huang et al (2021) detected mutations of ATP1A2 p.Gly324Ser and p.Ala297Thr in two Chinese children by WES. This was the first time AHC patients with ATP1A2 mutation had been identified in China, expanding the clinical phenotype of AHC associated with ATP1A2 pathogenic variants in China.…”