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FHF1 (FGF12) epileptic encephalopathy.

ABSTRACT: Voltage-gated sodium channels (Na_vs) are mainstays of neuronal function, and mutations in the genes encoding CNS Na_vs (Na_v1.1 [SCN1A], Na_v1.2 [SCN2A], Na_v1.3 [SCN3A], and Na_v1.6 [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 Na_vs 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.

SUBMITTER: Al-Mehmadi S

PROVIDER: S-EPMC5087254 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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FHF1 (FGF12) epileptic encephalopathy.

Al-Mehmadi Sameer S Splitt Miranda M Ramesh Venkateswaran V DeBrosse Suzanne S Dessoffy Kimberly K Xia Fan F Yang Yaping Y Rosenfeld Jill A JA Cossette Patrick P Michaud Jacques L JL Hamdan Fadi F FF Campeau Philippe M PM Minassian Berge A BA

Neurology. Genetics 20161028 6

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 t ...[more]

PMID: 27830185

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Project description:ObjectiveFibroblast growth factor homologous factors (FHFs) are brain and cardiac sodium channel-binding proteins that modulate channel density and inactivation gating. A recurrent de novo gain-of-function missense mutation in the FHF1(FGF12) gene (p.Arg52His) is associated with early infantile epileptic encephalopathy 47 (EIEE47; Online Mendelian Inheritance in Man database 617166). To determine whether the FHF1 missense mutation is sufficient to cause EIEE and to establish an animal model for EIEE47, we sought to engineer this mutation into mice.MethodsThe Arg52His mutation was introduced into fertilized eggs by CRISPR (clustered regularly interspaced short palindromic repeats) editing to generate Fhf1R52H /F+ mice. Spontaneous epileptiform events in Fhf1R52H /+ mice were assessed by cortical electroencephalography (EEG) and video monitoring. Basal heart rhythm and seizure-induced arrhythmia were recorded by electrocardiography. Modulation of cardiac sodium channel inactivation by FHF1BR52H protein was assayed by voltage-clamp recordings of FHF-deficient mouse cardiomyocytes infected with adenoviruses expressing wild-type FHF1B or FHF1BR52H protein.ResultsAll Fhf1R52H /+ mice experienced seizure or seizurelike episodes with lethal ending between 12 and 26 days of age. EEG recordings in 19-20-day-old mice confirmed sudden unexpected death in epilepsy (SUDEP) as severe tonic seizures immediately preceding loss of brain activity and death. Within 2-53 s after lethal seizure onset, heart rate abruptly declined from 572 ± 16 bpm to 108 ± 15 bpm, suggesting a parasympathetic surge accompanying seizures that may have contributed to SUDEP. Although ectopic overexpression of FHF1BR52H in cardiomyocytes induced a 15-mV depolarizing shift in voltage of steady-state sodium channel inactivation and slowed the rate of channel inactivation, heart rhythm was normal in Fhf1R52H /+ mice prior to seizure.SignificanceThe Fhf1 missense mutation p.Arg52His induces epileptic encephalopathy with full penetrance in mice. Both Fhf1 (p.Arg52His) and Scn8a (p.Asn1768Asp) missense mutations enhance sodium channel Nav 1.6 currents and induce SUDEP with bradycardia in mice, suggesting an FHF1/Nav 1.6 functional axis underlying altered brain sodium channel gating in epileptic encephalopathy.

Dataset Information

FHF1 (FGF12) epileptic encephalopathy.

Publications

FHF1 (FGF12) epileptic encephalopathy.

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