ATP1A2 encodes the alpha-2 isoform of the Na+/K+-ATPase, which is highly expressed in brain tissues and has previously been related to familial hemiplegic migraine (MIM#602481) and alternating hemiplegia of childhood (MIM#104290).
We speculate whether alternating hemiplegia of childhood shares some common pathophysiological mechanisms with familial hemiplegic migraine that may be associated with a pathogenic variant of ATP1A2.
Mutations in ATP1A3 are involved in a large spectrum of neurological disorders, including rapid onset dystonia parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS), with recent descriptions of overlapping phenotypes.
Together with the two previously reported cases, our patients confirm that ATP1A3 mutations are associated with a phenotype combining features of early-onset encephalopathy, epilepsy and dystonic fits, as in the most severe forms of alternating hemiplegia of childhood, but in which (hemi)plegic attacks are absent or only suspected retrospectively.
We conducted a randomized, double-blind, placebo-controlled crossover study of triheptanoin, at a target dose corresponding to 30% of daily calorie intake, in ten patients with alternating hemiplegia of childhood due to ATP1A3 mutations.
Mutations in ATP1A3 have previously been linked to rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and CAPOS syndrome.
De novo mutations in ATP1A3, the gene encoding the α3-subunit of Na(+),K(+)-ATPase, are associated with the neurodevelopmental disorder Alternating Hemiplegia of Childhood (AHC).
Gene sequencing revealed an identical ATP1A3 mutation as in three typical adult-onset rapid-onset dystonia parkinsonism cases but never previously described in an alternating hemiplegia of childhood case.
Mutations in ATP1A3, the gene that encodes the α3 subunit of the Na(+)/K(+) ATPase, are the primary cause of alternating hemiplegia of childhood (AHC).
Other mutations in ATP1A3 have previously been demonstrated to cause rapid-onset dystonia-parkinsonism (also called dystonia-12) or alternating hemiplegia of childhood.