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Alternating hemiplegia of childhood 2 (AHC2) is a rare neurodevelopmental disorder characterized by recurrent episodes of hemiplegia, developmental delay, and seizures. It is defined by de novo heterozygous mutations in ATP1A3, encoding the neuron-specific Na+/K+-ATPase α3 subunit, manifesting typically before 18 months of age. Patients often present with episodic hemiplegias that alternate sides, tonic and dystonic spells, and variable cognitive impairment. The continuum of ATP1A3-related disorders includes rapid-onset dystonia-parkinsonism and CAPOS syndrome, illustrating phenotypic overlap within the gene. Diagnosis of AHC2 is clinical but can be confirmed by ATP1A3 sequencing. Early molecular diagnosis informs management and genetic counseling.
Inheritance of AHC2 is autosomal dominant with most cases arising from de novo missense variants in ATP1A3. No multigenerational transmissions have been documented, consistent with a recurrence risk driven by de novo events. Over 180 unrelated probands have been reported with AHC or overlapping phenotypes (PMID:24523486). The variant spectrum is dominated by missense changes clustering in transmembrane and functional domains, notably p.Asp801Asn (PMID:24996492), p.Glu815Lys, and p.Gly947Arg. Splice-site and truncating variants are rare. Recurrent de novo hotspots suggest critical residues for pump function.
Functional assessments consistently demonstrate loss-of-function and dominant-negative effects of AHC2 variants. Knock-in murine models harboring p.Asp801Asn recapitulate key AHC features including hemiplegia and seizure susceptibility (PMID:25523819). iPSC-derived neurons from patients with p.Gly947Arg exhibit impaired pump currents, depolarized resting potentials, and reduced firing frequency (PMID:29567111). Xenopus oocyte assays reveal selective deficits in proton transport and forward cycling for severe variants (PMID:25681536). These models validate ATP1A3 haploinsufficiency and defective ionic homeostasis as core mechanisms.
Pathogenicity is attributed to haploinsufficiency and dominant-negative interference, leading to neuronal hyperexcitability and altered excitatory–inhibitory balance. Mutations in key cation-binding sites, such as Asp801 and Gly947, disrupt Na+ affinity and pump conformational transitions. Structural modeling supports perturbation of ion coordination and allosteric regulation. Variants distal to binding sites can alter proton translocation and exacerbate severity. Rescue experiments in Drosophila and transgenic mice highlight the therapeutic potential of restoring wild-type ATPase activity.
No robust conflicting evidence disputing ATP1A3 as the causative gene in AHC2 has emerged. Reports of atypical phenotypes, such as hemidystonia with polymicrogyria, expand the spectrum but do not refute the core association. Penetrance of AHC2 variants is complete for paroxysmal events, though severity can vary. Alternative genetic etiologies have been ruled out by comprehensive gene panels and genomic sequencing. The consistency across studies over two decades substantiates the gene–disease link.
In summary, ATP1A3 mutations are definitively implicated in AHC2, supported by extensive genetic and functional evidence. Molecular diagnosis enables early intervention, anticipatory guidance, and eligibility for emerging targeted therapies. While further studies may refine genotype–phenotype correlations, current data justify inclusion of ATP1A3 in diagnostic panels for early-onset hemiplegia. Key take-home: Sequencing ATP1A3 is essential for diagnosis and management of alternating hemiplegia of childhood 2.
Gene–Disease AssociationDefinitiveOver 180 probands across multiple cohorts with replication over >10 years and concordant functional data Genetic EvidenceStrong
Functional EvidenceStrongMultiple in vivo and in vitro models (mouse, iPSC, oocyte) demonstrate loss‐of‐function and dominant‐negative effects Functional evidence modelingModerateStructural modeling supports disruption of cation-binding and allosteric regulation |