Abstracts

Variants in the HCN1 gene cause rare syndrome of early childhood-onset epileptic encephalopathy. Anecdotal reports suggest that anti-seizure medications (ASMs) with mechanisms of action that target Na⁺ channels are ineffective in this disorder and may even exacerbate seizures. We assembled a registry of children with HCN1 variants by contacting parents who had joined a social media affinity group for this disorder. These parents filled out a survey on the clinical characteristics of their affected children, results of genetic testing, and response to ASMs. 

We assembled a registry of 12 children with HCN1 variants by either by reaching out to parents who were members of a Facebook affinity group, “HCN1 Warriors,” or from unsolicited contacts from parents to the senior author. Parents filled out an 8-page survey detailing their child’s and parents’ genetic testing results, child’s developmental status, and response to ASMs. 

Of the 12 subjects, 4 had HCN1 variants previously reported in the literature: M153I, S272P, M305L, and I380F.  All of these were associated with medically refractory epilepsy and moderate-to-severe developmental disability (DD). We also identified 8 subjects with novel HCN1 variants. Of these, six variants were associated with epilepsy. One subject was compound heterozygous for M215V amino acid substitution (maternally inherited) plus a deletion at p.73-75 (paternally inherited). The remainder had heterozygous amino acid substitutions at M215V, M278L, A387S, F389S, and A670T. Two variants were not associated with epilepsy: Y361C and R554X (c. 1660 c- >T). Both of these variants were associated with mild DD. All subjects had associated DD ranging from mild to severe, with the exception of subject #12 (A670T) who was developmentally normal.
Subjects had been exposed to a median eight different ASMs (range 2-10). Levetiracetam (LEV) was the most frequently used drug, and of ASMs with at least three exposures, cannabidiol (CBD) the least used. The two most commonly used ASMs, LEV and lamotrigine (LTG) had an efficacy index not much different from zero. However, clobazam (CLB) and valproate (VPA) demonstrated significantly better efficacy, with VPA the most effective of all ASMs. Two subjects became seizure-free with exposure to either CLB or VPA. Two ASMs caused worsening of seizure frequency: LTG and oxcarbazepine (OXC). Other ASMs perceived as having no benefit were lacosamide (LAC), phenobarbital (PB), vigabatrin (VGB), and carbamazepine (CBZ). The one subject who was deceased due to SE was being treated at the time with LTG and topiramate (TPM).