Because several FHM families could not be

Because several FHM families could not be linked to known FHM genes,57 additional genes probably exist for FHM. SLC1A3, PRRT2, and SLC4A4 have been proposed, but based on only limited evidence. 99 In one patient with migraine, alternating hemiplegia, seizures, and episodic ataxia, a heterozygous missense mutation was identified in SLC1A3, which encodes the excitatory aminoacid transporter 1 (EAAT1). 100 The mutation had a dominant-negative effect, leading to decreased EAAT1 TRAM-34 and substantially decreased glutamate reuptake, which is predicted to result in neuronal hyperexcitability. Heterozygous PRRT2 mutations have been identified in a few patients with hemiplegic migraine. 101 Most of these patients also had paroxysmal kinesigenic dyskinesia. Although PRRT2 might have a role in hemiplegic migraine through dysfunction of PRRT2-mediated and SNAP25-mediated neurotransmitter release, the evidence is scarce. 102 Other PRRT2 mutations have previously been identified in hundreds of individuals with paroxysmal kinesigenic dyskinesia or other paroxysmal disorders, but never hemiplegic migraine. 103 Possibly, PRRT2 could act as a genetic cofactor that contributes to the risk of hemiplegic migraine. 102 Finally, homozygous SLC4A4 mutations, leading to a non-functional sodium bicarbonate cotransporter NBCe1, were reported in a few patients with hemiplegic migraine and proximal renal tubular acidosis. 104 Some of these patients also had episodic ataxia and ocular abnormalities. The investigators hypothesised that NBCe1 dysfunction and deranged synaptic pH regulation in astrocytes could lead to neuronal hyperexcitability predisposing to migraine.