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Defining the phenotype of FHF1 developmental and epileptic encephalopathy
Author(s) -
Trivisano Marina,
Ferretti Alessandro,
Bebin Elizabeth,
Huh Linda,
Lesca Gaetan,
Siekierska Aleksandra,
Takeguchi Ryo,
Carneiro Maryline,
De Palma Luca,
Guella Ilaria,
Haginoya Kazuhiro,
Shi Ruo Ming,
Kikuchi Atsuo,
Kobayashi Tomoko,
Jung Julien,
Lagae Lieven,
Milh Mathieu,
Mathieu Marie L.,
Minassian Berge A.,
Novelli Antonio,
Pietrafusa Nicola,
Takeshita Eri,
Tartaglia Marco,
Terracciano Alessandra,
Thompson Michelle L.,
Cooper Gregory M.,
Vigevano Federico,
Villard Laurent,
Villeneuve Nathalie,
Buyse Gunnar M.,
Demos Michelle,
Scheffer Ingrid E.,
Specchio Nicola
Publication year - 2020
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.16582
Subject(s) - missense mutation , epilepsy , encephalopathy , medicine , magnetic resonance imaging , phenotype , pediatrics , neuroimaging , seizure types , intellectual disability , neuroscience , psychology , genetics , biology , psychiatry , gene , radiology
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.