Response to anti-seizure medications in children carrying novel or previously reported HCN1 gene variants.

objectiveVariants in the HCN1 gene cause a syndrome of childhood epilepsy and developmental disability with a broad phenotypic range. Many affected children manifest with early infantile epileptic encephalopathy (EIEE) and highly drug-resistant epilepsy. There are anecdotal reports that seizures in this syndrome are exacerbated by some anti-seizure medications (ASMs), including lamotrigine and lacosamide. However, the efficacy of most ASMs in this disorder is unknown. We sought to understand which ASMs were most effective.

methodsWe compiled a registry of 10 children with HCN1 variants and refractory epilepsy via outreach to parent members of an online social affinity group, and from unsolicited parent outreach to us. Parents filled out an eight-page survey detailing their child's and parents' genetic testing results, child's developmental status, and response to ASMs. Outside medical records were provided that documented genetic testing results.

resultsFive of these variants had not been previously reported in the literature. Of these, there was phenotypic variability depending on where the variant mapped on the HCN1 ion channel structure, with variants mapping to an ion channel transmembrane domain causing more severe phenotypes. Subjects given lamotrigine or oxcarbazepine had exacerbated seizure frequency whereas those exposed to valproate or clobazam had improved seizure frequency, with two subjects becoming seizure-free. SIGNIFICANCE: We report here five novel HCN1 variants. We also provide a novel survey of ASM efficacy. These trends in ASM efficacy are similar to what has been observed in Dravet syndrome, another EIEE, raising questions about potential common pathogenic mechanisms at a cellular level. PLAIN LANGUAGE SUMMARY: We surveyed families whose children had been diagnosed with a rare epilepsy syndrome due to mutations in the HCN1 gene. In reviewing their genetic testing results, we discovered five new gene mutations (variants) that had not been previously reported. We also asked which anti-seizure medications had been most effective: they cited valproate and clobazam as most effective, while lamotrigine and oxcarbazepine made seizures worse.