Objective: To study the clinical spectrum of CACNA1A S218L mutation carriers with special attention to “early seizures and cerebral oedema after trivial head trauma (ESCEATHT)”, a combination of symptoms which resembles the “juvenile head trauma syndrome”.
Patients and methods: In two patients with ESCEATHT all exons of CACNA1A were sequenced. Both patients also had hemiplegic migraine and ataxia. Subsequently, we screened the literature for S218L mutation carriers.
Results: In both patients, a de novo S218L mutation in the CACNA1A gene was found. In addition, we identified 11 CACNA1A S218L carriers from the literature. Of these 13 S218L mutation carriers, 12 (92%) had ataxia or cerebellar symptoms and nine (69%) had hemiplegic migraine that could be triggered by trivial head trauma. Three mutation carriers had the complete ESCEATHT phenotype. Seven (54%) had seizures (four had early post-traumatic seizures) and five (38%) had oedema as detected by MRI/CT.
Conclusions: The CACNA1A S218L mutation is associated with familial hemiplegic migraine, ataxia and/or ESCEATHT. A minority of S218L mutation carriers have the complete ESCEATHT phenotype but a high percentage of patients had one or more ESCEATHT symptoms. As the S218L mutation enhances the propensity for cortical spreading depression (CSD), we postulate a role for CSD not only in hemiplegic migraine but also in early seizures and cerebral oedema after trivial head trauma. As this combination of symptoms is part of the unexplained “juvenile head trauma syndrome”, a similar molecular mechanism may underlie this disorder.
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A H Stam, G-J Luijckx and B T Poll-Thé contributed equally to this paper.
Funding This work was supported by grants of the Netherlands Organisation for Scientific Research (NWO) (903-52-291, MDF, RRF, Vici 918.56.602, MDF, and 907-00-217, GMT, 920-03-473, AHS). This study was supported by a grant from the Centre for Medical Systems Biology within the framework of the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO).
Competing interests None.
Ethics approval The study was approved by the ethics committee of Leiden University Medical Centre.
Provenance and Peer review Not commissioned; externally peer reviewed.