ATP1A2 – Alternating Hemiplegia of Childhood 1

ATP1A2 encodes the α2 isoform of the Na+/K+-ATPase, critical for neuronal ion homeostasis. Monallelic pathogenic variants in ATP1A2 cause familial hemiplegic migraine type 2 and on rare occasions alternating hemiplegia of childhood 1 (AHC1). Two unrelated children with alternating hemiplegia, seizures, and mild developmental delay were found to harbor de novo heterozygous ATP1A2 missense variants c.889G>A (p.Ala297Thr) and c.970G>A (p.Gly324Ser), each absent from population databases and predicted deleterious (PMID:33794876). No additional affected relatives were reported. While functional studies in familial hemiplegic migraine contexts have shown that missense ATP1A2 mutations can impair pump kinetics, ion affinity, membrane targeting, and overall pump activity (PMID:15308625), analogous assays are lacking for AHC1-associated variants. Biallelic loss-of-function ATP1A2 mutations result in perinatal lethal hydrops fetalis syndromes with microcephaly and arthrogryposis, illustrating dosage sensitivity of α2-ATPase (PMID:30690204). Collectively, genetic evidence for ATP1A2 in AHC1 is currently limited to 2 de novo cases and requires further functional validation. Key Take-home: Heterozygous de novo ATP1A2 variants are emerging as a clinically relevant but limited cause of AHC1.

References

• BMC medical genomics • 2021 • De novo ATP1A2 variants in two Chinese children with alternating hemiplegia of childhood upgraded the gene-disease relationship and variant classification: a case report. PMID:33794876
• Progress in neurobiology • 2022 • Recurrent de novo single point variant on the gene encoding Na+/K+ pump results in epilepsy. PMID:35724808
• The Journal of biological chemistry • 2004 • Kinetic alterations due to a missense mutation in the Na,K-ATPase alpha2 subunit cause familial hemiplegic migraine type 2. PMID:15308625
• European journal of medical genetics • 2020 • Biallelic loss of function variants in ATP1A2 cause hydrops fetalis, microcephaly, arthrogryposis and extensive cortical malformations. PMID:30690204

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