A novel mutation in the ATP1A2 gene causes alternating hemiplegia of childhood

Alternating hemiplegia of childhood (AHC, MIM 104290) is a rare syndrome, characterised by early onset of episodic hemi- or quadriplegia lasting minutes to days. The majority of patients are sporadic. Only a few familial cases are reported in the literature. we describe a new familial case from a Greek island with four affected members in two generations, the mother and three out of four children. All patients share a normal karyotype. Due to the partial clinical overlap of familial hemiplegic migraine (FHM) with AHC, we screened the ATP1A2 gene coding for the α2 subunit of the Na,K pump, associated with FHM type 2. found a novel heterozygous mutation segregating with the disease and causing a threonine to asparagine replacement (T378N). This missense mutation localises to the ATPases phosphorylation site of the hydrolase domain. The affected residue is highly conserved in all the known α subunits of the Na,K and Na,H pumps from vertebrates to invertebrates. Functional data suggest that loss of function of the mutated ATP1A2 isoform is involved in generating the disease phenotype. This is the first mutation associated with AHC identified so far.