title: Homozygous TBC1D24 mutation in two siblings with familial infantile myoclonic epilepsy (FIME) and moderate intellectual disability.
abstract: Mutations in the TBC1D24 gene were first reported in an Italian family with a unique epileptic phenotype consisting of drug-responsive, early-onset idiopathic myoclonic seizures. Patients presented with isolated bilateral or focal myoclonia, which could evolve to long-lasting attacks without loss of consciousness, with a peculiar reflex component, and were associated with generalized tonic-clonic seizures. This entity was named "familial infantile myoclonic epilepsy" (FIME). More recently, TBC1D24 mutations have been shown to cause a variable range of disorders, including epilepsy of various seizure types and severity, non-syndromic deafness, and DOORS syndrome. We report on the electro-clinical features of two brothers, born to first-cousin parents, affected with infantile-onset myoclonic epilepsy. The peculiar epileptic presentation prompted us to perform direct sequencing of the TBC1D24 gene. The patients had very early onset of focal myoclonic fits with variable topography, lasting a few minutes to several hours, without loss of consciousness, which frequently evolved to generalized myoclonus or myoclonic status. Reflex myoclonia were noticed in one patient. Neurological outcome was marked by moderate intellectual disability. Despite the high frequency of seizures, repeated EEG recordings showed normal background rhythm and rare interictal spikes and waves. We found a homozygous missense mutation, c.457G>A/p.Glu153Lys, in the two affected brothers. This observation combined with recent data from the literature, suggest that mutations in TBCD24 cause a pathological continuum, with FIME at the "benign" end and severe drug-refractory epileptic encephalopathy on the severe end. Early-onset myoclonic epilepsy with focal and generalized myoclonic seizures is a common characteristic of this continuum.
authors.affiliation: Department of Pediatric Neurology, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France; Neurophysiology and Epilepsy Unit, Neurological Hospital P. Wertheimer, Hospices Civils de Lyon, Lyon, France.
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Poulat
authors.affiliation: Department of Pediatric Neurology, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France; Neurophysiology and Epilepsy Unit, Neurological Hospital P. Wertheimer, Hospices Civils de Lyon, Lyon, France.
authors.forename: Dorothée
authors.initials: D
authors.lastname: Ville
authors.affiliation: Epilepsy, Sleep and Pediatric Neurophysiology Dpt., Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France; Neurophysiology and Epilepsy Unit, Neurological Hospital P. Wertheimer, Hospices Civils de Lyon, Lyon, France.
authors.forename: Julitta
authors.initials: J
authors.lastname: de Bellescize
authors.affiliation: Department Epilepsy, Sleep and Functional Neurological Explorations, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France; Neurophysiology and Epilepsy Unit, Neurological Hospital P. Wertheimer, Hospices Civils de Lyon, Lyon, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: André-Obadia
authors.affiliation: INSERM, GMGF UMR_S 910, 13385, Aix Marseille Université, Marseille, France; Neurophysiology and Epilepsy Unit, Neurological Hospital P. Wertheimer, Hospices Civils de Lyon, Lyon, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Cacciagli
authors.affiliation: INSERM, GMGF UMR_S 910, 13385, Aix Marseille Université, Marseille, France; Service de Neurologie Pédiatrique, Hopital de la Timone-Enfants, APHM, Marseille, France; Neurophysiology and Epilepsy Unit, Neurological Hospital P. Wertheimer, Hospices Civils de Lyon, Lyon, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Milh
authors.affiliation: INSERM, GMGF UMR_S 910, 13385, Aix Marseille Université, Marseille, France; Neurophysiology and Epilepsy Unit, Neurological Hospital P. Wertheimer, Hospices Civils de Lyon, Lyon, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Villard
authors.affiliation: Department of Medical Genetics, Hospices Civils de Lyon, Lyon, France; Université Lyon 1, Lyon, France; Neurophysiology and Epilepsy Unit, Neurological Hospital P. Wertheimer, Hospices Civils de Lyon, Lyon, France. Electronic address: gaetan.lesca@chu-lyon.fr.
authors.forename: Gaetan
authors.initials: G
authors.lastname: Lesca
mesh_terms: D001921:Brain / Q000503:physiopathology; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004351:Drug Resistance; D004569:Electroencephalography; D004831:Epilepsies, Myoclonic / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D005145:Face / Q000473:pathology; D020690:GTPase-Activating Proteins; D006225:Hand / Q000473:pathology; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008565:Membrane Proteins; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins; D010375:Pedigree; D035781:Siblings
chemical_list: D002352:Carrier Proteins; D020690:GTPase-Activating Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C552551:TBC1D24 protein, human
keywords: FIME; Infantile; Myoclonic epilepsy; Myoclonus status; TBC1D24