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.