TWO NOVEL MUTATIONS IN THE AMINO TERMINUS OF ATP1A2 ASSOCIATED TO A MILD PHENOTYPE OF HEMIPLEGIC MIGRAINE

Familial hemiplegic migraine (FHM) is a rare autosomal dominant subtype of of themigraine characterized by motor symptoms as part of the aura. The gene calcium channel a1-subunit (CACNA1A) on chromosome 19p13, the Na+/K+ ATPase gene (ATP1A2) on chromosome 1q23 and more recently the gene for the voltage gated sodium channel (SCN1A) located in 2q24 region have been identified as causative genes for FHM. The pathogenesis of FHM is still unclear, although a mechanism of facilitation of cortical spreading depression (CSD) induced by ion dysfunction has been hypothesized. We report two families (HM-1 and HM-2) in which we found two novel mutations p.Tyr9Asn and p.Arg65Trp, in ATP1A2 gene. Except for an overall milder phenotype and a variable age of onset, the patients of HM-1 and -2 families are similar to the FHM2 families reported in the literature showing a stereotypic pattern of migraine associated to hemisensory and hemiparetic attacks with an overall benign course. However, the limited size of the family HM2 and the availability of few members for a direct clinical evaluation prevent us from definitely determine the familial or sporadic occurrence of the disease in this family. The mutations detected in our patients are located in the extreme amino-terminus of the ATP1A2 protein, known to be part of the A domain and representing an uncommon target for mutations. Changes in the length and composition of the N-terminus tail were demonstrated to affect cation specificity and pump conformational equilibrium. Few mutations have been described so far in the amino terminal portion of the protein and it could be hypothesized that a destabilizing effect of the two mutations found may explain the mild phenotype and the late age of onset observed such as the susceptibility to common forms of migraine. However to demonstrate this hypothesis more mutations have to be identified in the N-terminus of ATP1A2.