ATP1A3 – Alternating Hemiplegia of Childhood

ATP1A3 encodes the neuron-specific α3 subunit of the Na\/K-ATPase pump, which maintains electrochemical gradients critical for neuronal excitability. Heterozygous mutations in ATP1A3 have been firmly linked to alternating hemiplegia of childhood (AHC), a rare neurodevelopmental syndrome characterized by transient, recurrent hemiplegic episodes, dystonia, choreoathetosis, hypotonia, and oculomotor abnormalities.

The association of ATP1A3 with AHC is supported by more than 105 unrelated probands harboring de novo missense or splice-site variants identified through exome sequencing and targeted analyses, including an initial discovery in seven trios and subsequent screening in 98 additional individuals (PMID:22842232). Segregation is predominantly de novo, with rare familial occurrences and one asymptomatic parental mosaicism reported.

Inheritance is autosomal dominant with high penetrance of de novo events. Segregation analyses have identified 1 affected relative in familial cases. Case reports and series collectively describe over 130 probands, with variant spectrum dominated by recurrent missense changes in critical transmembrane and functional domains, notably p.Asp801Asn, p.Glu815Lys, p.Gly947Arg, and p.Gly755Ser.

Functional assessment demonstrates that AHC-associated ATP1A3 variants severely impair Na\/K-ATPase activity, ouabain binding, and ion transport. For example, mutants p.Ser137Tyr, p.Asp801Asn, p.Glu815Lys, and p.Gly947Arg show absent or drastically reduced ATPase activity in Sf9 cell assays (PMID:24631656). In vivo, knock-in mice bearing p.Ile810Ser or p.Asp801Asn mirror key human phenotypes—paroxysmal hemiplegia, dystonia, seizures, cognitive deficits, and spreading depression—validating the pathogenic mechanism and providing platforms for therapeutic testing (PMID:23527305).

No credible studies refute the ATP1A3–AHC link; conflicting evidence has not emerged. The pathogenic mechanism is haploinsufficiency with dominant-negative effects and defective ion transport, leading to neuronal hyperexcitability and paroxysmal events.

Collectively, robust genetic and experimental data over >10 years establish ATP1A3 mutations as the definitive cause of AHC. Genetic testing for ATP1A3 variants informs diagnosis, prognosis, and family counseling, while functional models provide avenues for targeted therapies. Key Take-home: ATP1A3 screening is essential in early-onset hemiplegia, guiding diagnosis and potential precision treatments.

References

• Nature Genetics • 2012 • De novo mutations in ATP1A3 cause alternating hemiplegia of childhood PMID:22842232
• Biochimica et Biophysica Acta • 2014 • Alternating hemiplegia of childhood mutations have a differential effect on Na(+),K(+)-ATPase activity and ouabain binding PMID:24631656
• PLoS One • 2013 • Alternating hemiplegia of childhood-related neural and behavioural phenotypes in Na+,K+-ATPase α3 missense mutant mice PMID:23527305

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