Defining the phenotype of FHF1 developmental and epileptic encephalopathy - Aix-Marseille Université Access content directly
Journal Articles Epilepsia Year : 2020

Defining the phenotype of FHF1 developmental and epileptic encephalopathy

Gaetan Lesca


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.
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Dates and versions

hal-03149027 , version 1 (24-02-2021)



Marina Trivisano, Alessandro Ferretti, Elizabeth Bebin, Linda Huh, Gaetan Lesca, et al.. Defining the phenotype of FHF1 developmental and epileptic encephalopathy. Epilepsia, 2020, 61 (7), ⟨10.1111/epi.16582⟩. ⟨hal-03149027⟩
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