Delayed cerebral edema and fatal coma after minor head trauma: Role of theCACNA1A calcium channel subunit gene and relationship with familial hemiplegic migraine

Trivial head trauma may be complicated by severe, sometimes even fatal: cer ebral edema and coma occurring after a lucid interval ("delayed cerebral ed ema"). Attacks of familial. hemiplegic migraine (FHM) can be triggered by m inor head trauma and are sometimes accompanied by coma. Mutations in the CA CNA1A calcium channel subunit gene on chromosome 19 are associated with a w ide spectrum of mutation-specific episodic and chronic neurological disorde rs, including FHM with or without coma. We investigated the role of the CAC NA1A gene in three subjects with delayed cerebral edema. Two subjects origi nated from a family with extreme FHM, and one subject was the previously as ymptomatic daughter of a sporadic patient with hemiplegic migraine attacks. In all three subjects with delayed severe edema, we found a C-to-T substit ution resulting in the substitution of serine for lysine at codon 218 (S218 L) in the CACNA1A gene. The mutation was absent in nonaffected family membe rs and 152 control individuals. Haplotype analysis excluded a common founde r for both families. Neuropathological examination in one subject showed Pu rkinje cell loss with relative preservation of granule cells and sparing of the dentate and inferior olivary nuclei. We conclude that the navel S218L mutation in the CACNA1A calcium channel subunit gene is involved in FHM and delayed fatal cerebral edema and coma after minor head trauma. This findin g may have important implications for the understanding and treatment of th is dramatic syndrome.