Abstracts

Rationale: Early-onset epileptic encephalopathies (EOEEs) are often caused by mutations enhancing excitatory or suppressing inhibitory neuronal activity in the brain. Voltage-gated sodium channel (Nav)-encoding genes are among EOEE targets, suggesting that other genes encoding Nav–binding proteins, such as fibroblast growth factor homologous factors (FHFs), may also play roles in these disorders.Methods: To identify additional genes for EOEEs we performed whole-exome sequencing in a family quintet with two siblings affected by a lethal neurodegenerative disease characterized by EOEE and cerebellar atrophy. The pathogenic nature and functional consequences of the identified sequence alteration were determined by electrophysiological studies.Results: A de novo heterozygous missense mutation was identified in the FHF1 gene (FHF1AR114H, FHF1BR52H) in the two affected siblings. The mutant FHF1 proteins had a strong gain-of-function phenotype in transfected Neuro2A cells, enhancing the depolarizing shifts in Nav1.6 voltage-dependent fast inactivation, predicting increased neuronal excitability. Surprisingly, the gain-of-function effect is predicted to result from weaker interaction of mutant FHF1 with the Nav cytoplasmic tail. Transgenic overexpression of mutant FHF1B in zebrafish larvae induced epileptiform discharges.Conclusions: Our data provide the first demonstration of a neurological disorder caused by gain-of-function FHF mutation, and expand the repertoire of genetic causes (FHF1) and mechanisms (Nav fast inactivation gating) underlying EOEE and cerebellar atrophy.