Defining the phenotype of FHF1 developmental and epileptic encephalopathy

Abstract

Objective: Fibroblast-growth-factor homologous factor (FHF1) gene variants have recently been associated with developmental and epileptic encephalopathy (DEE). FHF1 gene encodes a cytosolic protein that interacts with neuronal sodium channel. Aim of this study is to report the largest series of patients with pathogenic FHF1 genetic variants in order to define electro-clinical phenotype, genotype-phenotype correlation, and information about management and prognosis. Methods: Through an international collaboration, we retrospectively collected detailed clinical, genetic, neurophysiologic and neuroimaging data of 17 patients with FHF1-related epilepsy. Results: Fourteen patients carried heterozygous missense variant c.341G>A (p.Arg114His) in FHF1 gene, two patients heterozygous missense variant c.334G>A (p.Gly112Ser) and one patient carried a chromosomal microduplication involving FHF1 gene. The majority of variants were de novo, although in 29% of cases somatic or germline parent mosaicism occurred. Patients with c.341G>A variant presented with a phenotype consisting of early onset DEE. Drug resistant epilepsy, intellectual disability, psychiatric features and status epilepticus were also common features. Tonic seizures were the most frequent seizure type. Patients who carried c.334G>A variant and FHF1 gene duplication showed a delayed epilepsy onset compared with patients carring the hotspot variant (c.341G>A). Brain MRI was normal at onset while a mild cerebral and/or cerebellar atrophy appeared during follow-up in 8 out of 17 patients (47%). Conclusion: FHF1-related DEE is characterized by an almost homogeneous clinical phenotype characterized by early-onset and drug-resistant epilepsy, intellectual disability, and psychiatric features in patients with c.334G>A variant. Few cases with a milder phenotype can occur, although a genotype-phenotype correlation had been identified. Because of the possibility of germline or somatic mosaicism, it is appropriate to offer prenatal diagnosis to couples with a child with FHF1related DEE. Recently, de novo mutations in fibroblast-growth-factor homologous factor 1 (FHF1) gene, encoding a voltage-gate sodium channel subunit (Nav1.6) binding protein, have been reported in patients with severe epilepsies [8-14], although a definite clinical phenotype has not clearly emerged. FHF1 gene is located on the long arm of chromosome 3 (3q28-q29) and c.334G>A (p.Gly112Ser) FHF1 missense variant has been demonstrated to lead to a gain-of-function of voltage-gate sodium channel (Nav1.6), predicting an increasing of neuronal excitability [12]. Aim of this study is to report the largest series of patients with pathogenic FHF1 mutations in order to delineate the electro-clinical features of FHF1-related DEE, identify genotype-phenotype correlation, improve management and define prognosis. Methods This is an international retrospective multicenter study. We collected 17 patients with FHF1-related epilepsy, followed-up in 14 epilepsy centers across the world (

Missense variants in the N-terminal domain of the A isoform of FHF2/FGF13 cause an X-linked developmental and epileptic encephalopathy

“…The epilepsy in FHF1-DEE is often intractable but responsiveness to phenytoin (a sodium channel blocker) has been noted. [47][48][49] Individuals 3 and 4 in our series gained at least transient benefit from phenytoin. The other subjects have either not been given phenytoin or their response is unknown.…”

“…FHF1-DEE is typically associated with focal epilepsy or a combined generalized and focal epilepsy. 48 Tonic seizures with autonomic signs are common in both FHF1-and FHF2-DEE. Other seizure types reported in both disorders include generalized tonic-clonic seizures, epileptic spasms, and absence and myoclonic seizures.…”

Modulating effects of FGF12 variants on NaV1.2 and NaV1.6 associated with Developmental and Epileptic Encephalopathy and Autism Spectrum Disorder

“…Previously, missense variants or copy number variants (CNVs) in FG12 have been solely identified in patients with DEE. 16 Here we describe two additional patients, one with the recurrent variant G50S/G112S and a similar epileptic phenotype as described earlier 16 , and (which was not certified by peer review) is the author/funder. All rights reserved.…”

“…In a previous study, 6 out of 17 patients carrying one of the already published FGF12 variants showed a partial response to phenytoin or lamotrigine, sodium channel blockers that enhance the channels' fast inactivation by shifting voltage-dependence towards more hyperpolarized potentials. 16 However, not all patients responded well to phenytoin, suggesting that these variants may have an additional effect which could not be identified until now. This hypothesis is supported by the FGF12 mouse variant model fgf12 R52H/+ which suffers from spontaneous seizures and dies of sudden unexplained death in epilepsy (SUDEP) at around 16 days of age.…”

“…[13][14][15] However, the detailed pathophysiological mechanism behind FGF12-associated DEE has been unclear. 16 Here we investigated the modifying effects of FGF12 on Nav1.2 and Nav1.6 in the wildtype state. Additionally, we carried out functional analyses of four FGF12 variants, including a novel variant of FGF12 causing autism spectrum disorder (ASD).…”