De novo mutations in HCN1 cause early infantile epileptic encephalopathy

Posted by & filed under Part 28: NEUROGENETICS.

Nava C. et al. De novo mutations in HCN1 cause early infantile epileptic encephalopathy. Nat Genet. 2014 Apr 20. doi: 10.1038/ng.2952. [Epub ahead of print]
Nava et al identify de novo heterozygous mutations in HCN1 as a new cause of  Dravet-like early infantile epileptic encephalopathy; the group used exome sequencing in parent-offspring trios with fever-sensitive, intractable infantile epilepsy, followed by screening of follow-up cohorts and functional analysis of the cationic Ih current by a patch-clamp technique.

Clinically, HCN1-associated early infantile encephalopathy in the patients described presented with intractable polymorphic febrile and afebrile seizures between 4 and 13 months, with evolution towards atypical absence and focal seizures, as well as intellectual disability with autistic traits.

Pathophysiologically, HCN1 encodes a hyperpolarisation-activated cyclic nucleotide-gated sodium and potassium channel that conducts the neuronal Ih current, contributing to the stabilisation of neural networks. Interestingly, while the missense mutations described lead to severe infantile epilepsy, haploinsufficiency of HCN1 appears to have much milder effects, suggesting a dominant-negative or gain-of-function mechanism.

The study adds HCN1 to the list of genes to consider in the context of early infantile epileptic encephalopathy, especially with fever-sensitive seizures.


Posted by Alina Levtova, MD


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