FHF1 (FGF12) epileptic encephalopathy.
Voltage-gated sodium channels (Navs) are mainstays of neuronal function, and mutations in the genes encoding CNS Navs (Nav1.1 [SCN1A], Nav1.2 [SCN2A], Nav1.3 [SCN3A], and Nav1.6 [SCN8A]) are causes of some of the most common and severe genetic epilepsies and epileptic encephalopathies (EE).1Fibroblast-growth-factor homologous factors (FHFs) compose a family of 4 proteins that interact with the C-terminal tails of Navs to modulate the channels' fast, and long-term, inactivations.2FHF2mutation is a rare cause of generalized epilepsy with febrile seizures plus (GEFS+).3Recently, a de novoFHF1mutation (p.R52H) was reported in early-onset EE in 2 siblings.4We report 3 patients from unrelated families with the sameFHF1p.R52H mutation. The 5 cases together frame the FHF1 R52H EE from infancy to adulthood. As discussed below, this gain-of-function disease may be amenable to personalized therapy.
Program in Genetics and Genome Biology and Division of Neurology (S.A.-M., B.A.M.), Department of Paediatrics, The Hospital for Sick Children, and University of Toronto, Ontario, Canada; Institute of Genetic Medicine (M.S.), International Centre for Life, Pediatric Neurology (V.R.), Newcastle General Hospital, UK; Center for Human Genetics (S.D., K.D.), UH Case Medical Center, Cleveland, OH; Department of Molecular and Human Genetics (F.X., Y.Y., J.A.R.), Baylor College of Medicine, Houston, TX; Baylor Miraca Genetics Laboratories (F.X., Y.Y.), Houston, TX; The Deciphering Developmental Disorders (DDD) Study, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK; Division of Neurology (P.C.), CHUM Notre-Dame, Hospital University of Montreal, Quebec, Canada; Department of Pediatrics (J.L.M., P.M.C.), Department of Neurosciences (J.L.M., P.M.C.), Université de Montréal, Québec, Canada; and CHU Sainte-Justine Research Center (J.L.M., F.A.H., P.M.C.), Montreal, Quebec, Canada.
Sameer
S
Al-Mehmadi
Program in Genetics and Genome Biology and Division of Neurology (S.A.-M., B.A.M.), Department of Paediatrics, The Hospital for Sick Children, and University of Toronto, Ontario, Canada; Institute of Genetic Medicine (M.S.), International Centre for Life, Pediatric Neurology (V.R.), Newcastle General Hospital, UK; Center for Human Genetics (S.D., K.D.), UH Case Medical Center, Cleveland, OH; Department of Molecular and Human Genetics (F.X., Y.Y., J.A.R.), Baylor College of Medicine, Houston, TX; Baylor Miraca Genetics Laboratories (F.X., Y.Y.), Houston, TX; The Deciphering Developmental Disorders (DDD) Study, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK; Division of Neurology (P.C.), CHUM Notre-Dame, Hospital University of Montreal, Quebec, Canada; Department of Pediatrics (J.L.M., P.M.C.), Department of Neurosciences (J.L.M., P.M.C.), Université de Montréal, Québec, Canada; and CHU Sainte-Justine Research Center (J.L.M., F.A.H., P.M.C.), Montreal, Quebec, Canada.
Miranda
M
Splitt
Program in Genetics and Genome Biology and Division of Neurology (S.A.-M., B.A.M.), Department of Paediatrics, The Hospital for Sick Children, and University of Toronto, Ontario, Canada; Institute of Genetic Medicine (M.S.), International Centre for Life, Pediatric Neurology (V.R.), Newcastle General Hospital, UK; Center for Human Genetics (S.D., K.D.), UH Case Medical Center, Cleveland, OH; Department of Molecular and Human Genetics (F.X., Y.Y., J.A.R.), Baylor College of Medicine, Houston, TX; Baylor Miraca Genetics Laboratories (F.X., Y.Y.), Houston, TX; The Deciphering Developmental Disorders (DDD) Study, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK; Division of Neurology (P.C.), CHUM Notre-Dame, Hospital University of Montreal, Quebec, Canada; Department of Pediatrics (J.L.M., P.M.C.), Department of Neurosciences (J.L.M., P.M.C.), Université de Montréal, Québec, Canada; and CHU Sainte-Justine Research Center (J.L.M., F.A.H., P.M.C.), Montreal, Quebec, Canada.
Venkateswaran
V
Ramesh
Program in Genetics and Genome Biology and Division of Neurology (S.A.-M., B.A.M.), Department of Paediatrics, The Hospital for Sick Children, and University of Toronto, Ontario, Canada; Institute of Genetic Medicine (M.S.), International Centre for Life, Pediatric Neurology (V.R.), Newcastle General Hospital, UK; Center for Human Genetics (S.D., K.D.), UH Case Medical Center, Cleveland, OH; Department of Molecular and Human Genetics (F.X., Y.Y., J.A.R.), Baylor College of Medicine, Houston, TX; Baylor Miraca Genetics Laboratories (F.X., Y.Y.), Houston, TX; The Deciphering Developmental Disorders (DDD) Study, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK; Division of Neurology (P.C.), CHUM Notre-Dame, Hospital University of Montreal, Quebec, Canada; Department of Pediatrics (J.L.M., P.M.C.), Department of Neurosciences (J.L.M., P.M.C.), Université de Montréal, Québec, Canada; and CHU Sainte-Justine Research Center (J.L.M., F.A.H., P.M.C.), Montreal, Quebec, Canada.
Suzanne
S
DeBrosse
Program in Genetics and Genome Biology and Division of Neurology (S.A.-M., B.A.M.), Department of Paediatrics, The Hospital for Sick Children, and University of Toronto, Ontario, Canada; Institute of Genetic Medicine (M.S.), International Centre for Life, Pediatric Neurology (V.R.), Newcastle General Hospital, UK; Center for Human Genetics (S.D., K.D.), UH Case Medical Center, Cleveland, OH; Department of Molecular and Human Genetics (F.X., Y.Y., J.A.R.), Baylor College of Medicine, Houston, TX; Baylor Miraca Genetics Laboratories (F.X., Y.Y.), Houston, TX; The Deciphering Developmental Disorders (DDD) Study, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK; Division of Neurology (P.C.), CHUM Notre-Dame, Hospital University of Montreal, Quebec, Canada; Department of Pediatrics (J.L.M., P.M.C.), Department of Neurosciences (J.L.M., P.M.C.), Université de Montréal, Québec, Canada; and CHU Sainte-Justine Research Center (J.L.M., F.A.H., P.M.C.), Montreal, Quebec, Canada.
Kimberly
K
Dessoffy
Program in Genetics and Genome Biology and Division of Neurology (S.A.-M., B.A.M.), Department of Paediatrics, The Hospital for Sick Children, and University of Toronto, Ontario, Canada; Institute of Genetic Medicine (M.S.), International Centre for Life, Pediatric Neurology (V.R.), Newcastle General Hospital, UK; Center for Human Genetics (S.D., K.D.), UH Case Medical Center, Cleveland, OH; Department of Molecular and Human Genetics (F.X., Y.Y., J.A.R.), Baylor College of Medicine, Houston, TX; Baylor Miraca Genetics Laboratories (F.X., Y.Y.), Houston, TX; The Deciphering Developmental Disorders (DDD) Study, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK; Division of Neurology (P.C.), CHUM Notre-Dame, Hospital University of Montreal, Quebec, Canada; Department of Pediatrics (J.L.M., P.M.C.), Department of Neurosciences (J.L.M., P.M.C.), Université de Montréal, Québec, Canada; and CHU Sainte-Justine Research Center (J.L.M., F.A.H., P.M.C.), Montreal, Quebec, Canada.
Fan
F
Xia
Program in Genetics and Genome Biology and Division of Neurology (S.A.-M., B.A.M.), Department of Paediatrics, The Hospital for Sick Children, and University of Toronto, Ontario, Canada; Institute of Genetic Medicine (M.S.), International Centre for Life, Pediatric Neurology (V.R.), Newcastle General Hospital, UK; Center for Human Genetics (S.D., K.D.), UH Case Medical Center, Cleveland, OH; Department of Molecular and Human Genetics (F.X., Y.Y., J.A.R.), Baylor College of Medicine, Houston, TX; Baylor Miraca Genetics Laboratories (F.X., Y.Y.), Houston, TX; The Deciphering Developmental Disorders (DDD) Study, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK; Division of Neurology (P.C.), CHUM Notre-Dame, Hospital University of Montreal, Quebec, Canada; Department of Pediatrics (J.L.M., P.M.C.), Department of Neurosciences (J.L.M., P.M.C.), Université de Montréal, Québec, Canada; and CHU Sainte-Justine Research Center (J.L.M., F.A.H., P.M.C.), Montreal, Quebec, Canada.
Yaping
Y
Yang
Program in Genetics and Genome Biology and Division of Neurology (S.A.-M., B.A.M.), Department of Paediatrics, The Hospital for Sick Children, and University of Toronto, Ontario, Canada; Institute of Genetic Medicine (M.S.), International Centre for Life, Pediatric Neurology (V.R.), Newcastle General Hospital, UK; Center for Human Genetics (S.D., K.D.), UH Case Medical Center, Cleveland, OH; Department of Molecular and Human Genetics (F.X., Y.Y., J.A.R.), Baylor College of Medicine, Houston, TX; Baylor Miraca Genetics Laboratories (F.X., Y.Y.), Houston, TX; The Deciphering Developmental Disorders (DDD) Study, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK; Division of Neurology (P.C.), CHUM Notre-Dame, Hospital University of Montreal, Quebec, Canada; Department of Pediatrics (J.L.M., P.M.C.), Department of Neurosciences (J.L.M., P.M.C.), Université de Montréal, Québec, Canada; and CHU Sainte-Justine Research Center (J.L.M., F.A.H., P.M.C.), Montreal, Quebec, Canada.
Jill A
JA
Rosenfeld
Program in Genetics and Genome Biology and Division of Neurology (S.A.-M., B.A.M.), Department of Paediatrics, The Hospital for Sick Children, and University of Toronto, Ontario, Canada; Institute of Genetic Medicine (M.S.), International Centre for Life, Pediatric Neurology (V.R.), Newcastle General Hospital, UK; Center for Human Genetics (S.D., K.D.), UH Case Medical Center, Cleveland, OH; Department of Molecular and Human Genetics (F.X., Y.Y., J.A.R.), Baylor College of Medicine, Houston, TX; Baylor Miraca Genetics Laboratories (F.X., Y.Y.), Houston, TX; The Deciphering Developmental Disorders (DDD) Study, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK; Division of Neurology (P.C.), CHUM Notre-Dame, Hospital University of Montreal, Quebec, Canada; Department of Pediatrics (J.L.M., P.M.C.), Department of Neurosciences (J.L.M., P.M.C.), Université de Montréal, Québec, Canada; and CHU Sainte-Justine Research Center (J.L.M., F.A.H., P.M.C.), Montreal, Quebec, Canada.
Patrick
P
Cossette
Program in Genetics and Genome Biology and Division of Neurology (S.A.-M., B.A.M.), Department of Paediatrics, The Hospital for Sick Children, and University of Toronto, Ontario, Canada; Institute of Genetic Medicine (M.S.), International Centre for Life, Pediatric Neurology (V.R.), Newcastle General Hospital, UK; Center for Human Genetics (S.D., K.D.), UH Case Medical Center, Cleveland, OH; Department of Molecular and Human Genetics (F.X., Y.Y., J.A.R.), Baylor College of Medicine, Houston, TX; Baylor Miraca Genetics Laboratories (F.X., Y.Y.), Houston, TX; The Deciphering Developmental Disorders (DDD) Study, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK; Division of Neurology (P.C.), CHUM Notre-Dame, Hospital University of Montreal, Quebec, Canada; Department of Pediatrics (J.L.M., P.M.C.), Department of Neurosciences (J.L.M., P.M.C.), Université de Montréal, Québec, Canada; and CHU Sainte-Justine Research Center (J.L.M., F.A.H., P.M.C.), Montreal, Quebec, Canada.
Jacques L
JL
Michaud
Program in Genetics and Genome Biology and Division of Neurology (S.A.-M., B.A.M.), Department of Paediatrics, The Hospital for Sick Children, and University of Toronto, Ontario, Canada; Institute of Genetic Medicine (M.S.), International Centre for Life, Pediatric Neurology (V.R.), Newcastle General Hospital, UK; Center for Human Genetics (S.D., K.D.), UH Case Medical Center, Cleveland, OH; Department of Molecular and Human Genetics (F.X., Y.Y., J.A.R.), Baylor College of Medicine, Houston, TX; Baylor Miraca Genetics Laboratories (F.X., Y.Y.), Houston, TX; The Deciphering Developmental Disorders (DDD) Study, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK; Division of Neurology (P.C.), CHUM Notre-Dame, Hospital University of Montreal, Quebec, Canada; Department of Pediatrics (J.L.M., P.M.C.), Department of Neurosciences (J.L.M., P.M.C.), Université de Montréal, Québec, Canada; and CHU Sainte-Justine Research Center (J.L.M., F.A.H., P.M.C.), Montreal, Quebec, Canada.
Fadi F
FF
Hamdan
Program in Genetics and Genome Biology and Division of Neurology (S.A.-M., B.A.M.), Department of Paediatrics, The Hospital for Sick Children, and University of Toronto, Ontario, Canada; Institute of Genetic Medicine (M.S.), International Centre for Life, Pediatric Neurology (V.R.), Newcastle General Hospital, UK; Center for Human Genetics (S.D., K.D.), UH Case Medical Center, Cleveland, OH; Department of Molecular and Human Genetics (F.X., Y.Y., J.A.R.), Baylor College of Medicine, Houston, TX; Baylor Miraca Genetics Laboratories (F.X., Y.Y.), Houston, TX; The Deciphering Developmental Disorders (DDD) Study, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK; Division of Neurology (P.C.), CHUM Notre-Dame, Hospital University of Montreal, Quebec, Canada; Department of Pediatrics (J.L.M., P.M.C.), Department of Neurosciences (J.L.M., P.M.C.), Université de Montréal, Québec, Canada; and CHU Sainte-Justine Research Center (J.L.M., F.A.H., P.M.C.), Montreal, Quebec, Canada.
Philippe M
PM
Campeau
Program in Genetics and Genome Biology and Division of Neurology (S.A.-M., B.A.M.), Department of Paediatrics, The Hospital for Sick Children, and University of Toronto, Ontario, Canada; Institute of Genetic Medicine (M.S.), International Centre for Life, Pediatric Neurology (V.R.), Newcastle General Hospital, UK; Center for Human Genetics (S.D., K.D.), UH Case Medical Center, Cleveland, OH; Department of Molecular and Human Genetics (F.X., Y.Y., J.A.R.), Baylor College of Medicine, Houston, TX; Baylor Miraca Genetics Laboratories (F.X., Y.Y.), Houston, TX; The Deciphering Developmental Disorders (DDD) Study, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK; Division of Neurology (P.C.), CHUM Notre-Dame, Hospital University of Montreal, Quebec, Canada; Department of Pediatrics (J.L.M., P.M.C.), Department of Neurosciences (J.L.M., P.M.C.), Université de Montréal, Québec, Canada; and CHU Sainte-Justine Research Center (J.L.M., F.A.H., P.M.C.), Montreal, Quebec, Canada.
Berge A
BA
Minassian