Shi RM, Kobayashi T, Kikuchi A, Sato R, Uematsu M, An K, Kure S. Phenytoin-responsive epileptic encephalopathy with a tandem duplication involving FGF12. Neurol Genet. 2017 Jan 23;3(1):e133.
Nonsecreting fibroblast growth factors (FGFs), which are sodium channel–binding proteins, have recently been associated with neurodevelopmental disorders, similar to some voltage-gated sodium channel subunits. Recently, a de novo mutation in FGF12 (p.R52H) was reported in a pair of siblings with epileptic encephalopathies. The affected siblings developed severe seizures within 1 month of age, and their seizures were refractory to multiple antiepileptic drugs. This mutation has a gain-of-function effect on sodium channel gating, which might lead to increased neuronal excitability. Here, we report another case of FGF12-related epileptic encephalopathy. In contrast to the previous report, the phenotype in our patient was relatively mild. Of note, his seizures responded to phenytoin, a sodium channel blocker, similar to epileptic encephalopathy associated with SCN2A4 and SCN8A,5 encoding voltage-gated sodium channel subunits.
Siekierska A, Isrie M, Liu Y, Scheldeman C, Vanthillo N, Lagae L, de Witte PA, Van Esch H, Goldfarb M, Buyse GM. Gain-of-function FHF1 mutation causes early-onset epileptic encephalopathy with cerebellar atrophy. Neurology. 2016 Jun 7;86(23):2162-70.
Voltage-gated sodium channel (Nav)-encoding genes are among early-onset epileptic encephalopathies (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.
To identify additional genes for EOEE, we performed whole-exome sequencing in a family quintet with 2 siblings with a lethal disease characterized by EOEE and cerebellar atrophy. The pathogenic nature and functional consequences of the identified sequence alteration were determined by electrophysiologic studies in vitro and in vivo.
A de novo heterozygous missense mutation was identified in the FHF1 gene (FHF1AR114H, FHF1BR52H) in the 2 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 enhanced epileptiform discharges, demonstrating the epileptic potential of this FHF1 mutation in the affected children.
Our data demonstrate that gain-of-function FHF mutations can cause neurologic disorder, and expand the repertoire of genetic causes (FHF1) and mechanisms (altered Nav gating) underlying EOEE and cerebellar atrophy.
Al-Mehmadi S, Splitt M; For DDD Study group*., Ramesh V, DeBrosse S, Dessoffy K, Xia F, Yang Y, Rosenfeld JA, Cossette P, Michaud JL, Hamdan FF, Campeau PM, Minassian BA; For CENet Study group‡.. FHF1 (FGF12) epileptic encephalopathy. Neurol Genet. 2016 Oct 28;2(6):e115.
Voltage-gated sodium channels (Navs) are mainstays of neuronal function, and mutations in the genes encoding CNS Navs (Nav1.1 [SCN1A], Nav1.2 [SCN2A], Nav1.3 [SCN3A], and Nav1.6 [SCN8A]) are causes of some of the most common and severe genetic epilepsies and epileptic encephalopathies (EE).1 Fibroblast-growth-factor homologous factors (FHFs) compose a family of 4 proteins that interact with the C-terminal tails of Navs to modulate the channels' fast, and long-term, inactivations.2FHF2 mutation is a rare cause of generalized epilepsy with febrile seizures plus (GEFS+).3 Recently, a de novo FHF1 mutation (p.R52H) was reported in early-onset EE in 2 siblings.4 We report 3 patients from unrelated families with the same FHF1 p.R52H mutation. The 5 cases together frame the FHF1 R52H EE from infancy to adulthood. As discussed below, this gain-of-function disease may be amenable to personalized therapy.