松本 歩

The CACNA1H gene, which encodes the T-type calcium channel Cav3.2, is known to confer susceptibility to childhood absence epilepsy (CAE) and has been implicated in various neurological disorders. However, its pathogenic significance, especially in childhood intractable epilepsies, has not been comprehensively explored. We performed whole-exome sequencing on a 4-year-old boy diagnosed with epilepsy with myoclonic-atonic seizures (EMAtS), and identified two missense variants in CACNA1H. One was a novel variant, p.D949H, inherited from the father, while the other was a known variant, p.R788C, inherited from the mother. Because the latter was previously reported to alter Cav3.2 channel function and contribute to the pathogenesis of CAE and idiopathic generalized epilepsy, we evaluated the former's functional impact using two-electrode voltage clamp analysis in Xenopus laevis oocytes. While the current-voltage relationship of the D949H mutant channel was not significantly different from that of the wild-type channel, the time constant of recovery from inactivation was significantly prolonged in the D949H variant (671.7 ± 52.0 ms vs. 455.5 ± 28.2 ms), indicating moderately impaired properties of the mutant. Notably, neither the D949H nor the R788C variant was associated with epilepsy in either parent, suggesting that these variants were not sufficient to cause epilepsy on their own, and that the compound heterozygous state of CACNA1H contributed to the EMAtS phenotype in the proband. Our findings highlight the genetic complexity of EMAtS and underscore the importance of accumulated functional impacts of modifier variants in severe epileptic diseases, even when individual variants are not pathogenic.

We report the case of a 26-year-old woman with genetically confirmed Dravet syndrome (DS) who experienced atypical neurological deterioration in early adulthood, despite a previously stable clinical course. Her early history met the classical DS criteria, with the onset of febrile and afebrile seizures in infancy, followed by myoclonic, focal, and absence seizures, as well as developmental delay. Beginning at age 20, however, she developed new symptoms, including progressive tremor, postural instability, frequent gelastic-like seizures, and dysphagia severe enough to require temporary nasogastric feeding. Neuroimaging revealed basal ganglia and thalamic calcifications that had not been present in childhood. Mitochondrial evaluation demonstrated a mild reduction in oxygen consumption, despite normal enzyme activity. Genetic analysis, performed for the first time in adulthood, identified a previously unreported de novo missense variant in SCN1A (c.4112G>A, p.Gly1371Asp). This case highlights the potential for adult-onset phenotypic progression in SCN1A-related epilepsy and may broaden the clinical spectrum of DS, underscoring the importance of ongoing surveillance during adulthood, particularly in patients with rare or novel SCN1A missense variant (p.Gly1371Asp).