TY - JOUR
T1 - Defining the phenotype of FHF1 developmental and epileptic encephalopathy
AU - Trivisano, Marina
AU - Ferretti, Alessandro
AU - Bebin, Elizabeth
AU - Huh, Linda
AU - Lesca, Gaetan
AU - Siekierska, Aleksandra
AU - Takeguchi, Ryo
AU - Carneiro, Maryline
AU - De Palma, Luca
AU - Guella, Ilaria
AU - Haginoya, Kazuhiro
AU - Shi, Ruo Ming
AU - Kikuchi, Atsuo
AU - Kobayashi, Tomoko
AU - Jung, Julien
AU - Lagae, Lieven
AU - Milh, Mathieu
AU - Mathieu, Marie L.
AU - Minassian, Berge A.
AU - Novelli, Antonio
AU - Pietrafusa, Nicola
AU - Takeshita, Eri
AU - Tartaglia, Marco
AU - Terracciano, Alessandra
AU - Thompson, Michelle L.
AU - Cooper, Gregory M.
AU - Vigevano, Federico
AU - Villard, Laurent
AU - Villeneuve, Nathalie
AU - Buyse, Gunnar M.
AU - Demos, Michelle
AU - Scheffer, Ingrid E.
AU - Specchio, Nicola
N1 - Publisher Copyright:
© 2020 International League Against Epilepsy
PY - 2020/7/1
Y1 - 2020/7/1
N2 - Fibroblast growth-factor homologous factor (FHF1) gene variants have recently been associated with developmental and epileptic encephalopathy (DEE). FHF1 encodes a cytosolic protein that modulates neuronal sodium channel gating. We aim to refine the electroclinical phenotypic spectrum of patients with pathogenic FHF1 variants. We retrospectively collected clinical, genetic, neurophysiologic, and neuroimaging data of 17 patients with FHF1-DEE. Sixteen patients had recurrent heterozygous FHF1 missense variants: 14 had the recurrent p.Arg114His variant and two had a novel likely pathogenic variant p.Gly112Ser. The p.Arg114His variant is associated with an earlier onset and more severe phenotype. One patient carried a chromosomal microduplication involving FHF1. Twelve patients carried a de novo variant, five (29.5%) inherited from parents with gonadic or somatic mosaicism. Seizure onset was between 1 day and 41 months; in 76.5% it was within 30 days. Tonic seizures were the most frequent seizure type. Twelve patients (70.6%) had drug-resistant epilepsy, 14 (82.3%) intellectual disability, and 11 (64.7%) behavioral disturbances. Brain magnetic resonance imaging (MRI) showed mild cerebral and/or cerebellar atrophy in nine patients (52.9%). Overall, our findings expand and refine the clinical, EEG, and imaging phenotype of patients with FHF1-DEE, which is characterized by early onset epilepsy with tonic seizures, associated with moderate to severe ID and psychiatric features.
AB - Fibroblast growth-factor homologous factor (FHF1) gene variants have recently been associated with developmental and epileptic encephalopathy (DEE). FHF1 encodes a cytosolic protein that modulates neuronal sodium channel gating. We aim to refine the electroclinical phenotypic spectrum of patients with pathogenic FHF1 variants. We retrospectively collected clinical, genetic, neurophysiologic, and neuroimaging data of 17 patients with FHF1-DEE. Sixteen patients had recurrent heterozygous FHF1 missense variants: 14 had the recurrent p.Arg114His variant and two had a novel likely pathogenic variant p.Gly112Ser. The p.Arg114His variant is associated with an earlier onset and more severe phenotype. One patient carried a chromosomal microduplication involving FHF1. Twelve patients carried a de novo variant, five (29.5%) inherited from parents with gonadic or somatic mosaicism. Seizure onset was between 1 day and 41 months; in 76.5% it was within 30 days. Tonic seizures were the most frequent seizure type. Twelve patients (70.6%) had drug-resistant epilepsy, 14 (82.3%) intellectual disability, and 11 (64.7%) behavioral disturbances. Brain magnetic resonance imaging (MRI) showed mild cerebral and/or cerebellar atrophy in nine patients (52.9%). Overall, our findings expand and refine the clinical, EEG, and imaging phenotype of patients with FHF1-DEE, which is characterized by early onset epilepsy with tonic seizures, associated with moderate to severe ID and psychiatric features.
KW - FGF12
KW - FHF1
KW - developmental and epileptic encephalopathy
KW - epilepsy
KW - genetic
KW - neonatal onset
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U2 - 10.1111/epi.16582
DO - 10.1111/epi.16582
M3 - Article
C2 - 32645220
AN - SCOPUS:85087740564
SN - 0013-9580
VL - 61
SP - e71-e78
JO - Epilepsia
JF - Epilepsia
IS - 7
ER -