Delayed cerebral edema and fatal coma after minor head trauma: Role of the CACNA1A calcium channel subunit gene and relationship with familial hemiplegic migraine

Abstract

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.

Genomic analysis identifies masqueraders of full‐term cerebral palsy

“…One identified gene, SPAST , was found in two cases (case 6 and 10). Among the causative variants identified in the nine patients, the variants in SPAST , GNAO1 , CACNA1A, and STXBP1 have been previously reported,27, 28, 29, 30, 31, 32 whereas the variants in the other genes ( CTNNB1 , CYP2U1 , AMPD2 , and SCN2A ) were novel. Of all the identified candidate genes, only SPAST , STXBP1 , and SPTBN2 have been previously reported in CP patients 33, 34, 35.…”

“…CACNA1A variants cause various neuropsychiatric diseases. The p.(Ser218Leu) variant has also been associated with familial hemiplegic migraines and cerebellar ataxia,30 as well as EIEE 31. If the cerebellar ataxia develops congenitally and appears stable, it may be due to ataxic CP masqueraders, as in case 9.…”

CaV2.1 voltage activated calcium channels and synaptic transmission in familial hemiplegic migraine pathogenesis

“…FHM1 is an autosomal-dominant subtype of migraine with aura, caused by a spontaneous missense mutation in the CACNA1A gene encoding the ion-conducting, pore-forming α 1A subunit of (Ophoff et al 1996), combinations of FHM1 with various degrees of cerebellar ataxia (Ducros et al 2001, Ophoff et al 1996, or fatal coma due to excessive cerebral edema (Kors et al 2001(Kors et al , 2002.…”

“…The S218L mutation causes a severe migraine phenotype combined with slowly progressive cerebellar ataxia and atrophy, epileptic seizures, coma or profound stupor, and severe, sometimes fatal, cerebral edema which can be triggered by a trivial head trauma (Chan et al 2008, Kors et al 2001 Maagdenberg et al 2010).…”

Familial Hemiplegic Migraine

“…41 While the R192Q mutation produces a pure FHM phenotype characterized by typical attacks, the S218L mutation produces a severe clinical phenotype, in which typical attacks of FHM triggered by minor head trauma are frequently followed by deep coma or profound stupor (sometimes preceded by a generalized seizure), fever, and long-lasting severe cerebral edema; other common symptoms are ataxia and cerebral and (or) cerebellar atrophy. [42][43][44] Accordingly, while the homozygous R192Q knockin mice appear healthy, the homozygous S218L mice are prone to sudden death for seemingly unknown reasons (probably due to severe seizures) and are ataxic (Arn van den Maagdenberg, personal communication). Compared with the other FHM1 mutations analyzed, S218L is one of the mutations that produces the largest shift of activation of human Ca V 2.1 channels and the largest gain-of-function especially for small depolarizations.…”