Delayed cerebral edema and fatal coma after minor head trauma: role of the CACNA1A calcium channel subunit gene and relationship with familial hemiplegic migraine.
Trivial head trauma may be complicated by severe, sometimes even fatal, cerebral edema and coma occurring after a lucid interval ("delayed cerebral edema"). Attacks of familial hemiplegic migraine (FHM) can be triggered by minor head trauma and are sometimes accompanied by coma. Mutations in the CACNA1A calcium channel subunit gene on chromosome 19 are associated with a wide spectrum of mutation-specific episodic and chronic neurological disorders, including FHM with or without coma. We investigated the role of the CACNA1A gene in three subjects with delayed cerebral edema. Two subjects originated from a family with extreme FHM, and one subject was the previously asymptomatic daughter of a sporadic patient with hemiplegic migraine attacks. In all three subjects with delayed severe edema, we found a C-to-T substitution resulting in the substitution of serine for lysine at codon 218 (S218L) in the CACNA1A gene. The mutation was absent in nonaffected family members and 152 control individuals. Haplotype analysis excluded a common founder for both families. Neuropathological examination in one subject showed Purkinje cell loss with relative preservation of granule cells and sparing of the dentate and inferior olivary nuclei. We conclude that the novel 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 finding may have important implications for the understanding and treatment of this dramatic syndrome.
Kors
E E
EE
Department of Neurology, Leiden University Medical Centre, The Netherlands.
Terwindt
G M
GM
Vermeulen
F L
FL
Fitzsimons
R B
RB
Jardine
P E
PE
Heywood
P
P
Love
S
S
van den Maagdenberg
A M
AM
Haan
J
J
Frants
R R
RR
Ferrari
M D
MD
D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001315:Australia; D001929:Brain Edema / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D015220:Calcium Channels / Q000737:chemistry / Q000235:genetics*; D002525:Cerebellar Cortex / Q000473:pathology; D002675:Child, Preschool; D003128:Coma / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D006259:Craniocerebral Trauma / Q000150:complications / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D004739:England; D005260:Female; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D008297:Male; D020325:Migraine with Aura / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D018807:Polymorphism, Single-Stranded Conformational; D021122:Protein Subunits; D011689:Purkinje Cells / Q000473:pathology; D020864:Calcium Channels, N-Type
D015220:Calcium Channels; D021122:Protein Subunits; C105656:CACNA1A protein, human; D020864:Calcium Channels, N-Type