Expanding the phenotypic spectrum of CACNA1A-related developmental and epileptic encephalopathy in adults

Abstract

Deleterious variants in the CACNA1A gene, encoding the CaV2.1 P/Q-type voltage-gated calcium channel, cause a broad spectrum of neurological disorders, including familial hemiplegic migraine, episodic ataxia, and developmental and epileptic encephalopathy (DEE). Information on genotype–phenotype correlations and on the factors influencing clinical variability is still limited, hindering potential applications in precision medicine. We present three adults (aged 26, 27, and 40 years) from two families with heterozygous CACNA1A deleterious variants and DEE, highlighting striking interindividual and intrafamilial variability in adult-onset presentations. Genetic testing revealed two distinct pathogenic variants [p.(Val1392Met) and p.(Glu1263Lys)], including one instance of germinal/gonosomic mosaicism in unaffected parents. The electroclinical details demonstrated profound differences, notably: a pair of siblings with the same variant showing discordant clinical severity, and an unrelated patient whose complex phenotype, dominated by cerebellar ataxia, required prolonged video-EEG to accurately diagnose a high burden of subtle absence seizures. These cases significantly expand the phenotypic spectrum and highlight the critical role of comprehensive electroclinical characterization in adults with CACNA1A-related DEE for personalized management.