Skip to main content
Advertisement
  • Neurology.org
  • Journals
    • Neurology
    • Clinical Practice
    • Education
    • Genetics
    • Neuroimmunology & Neuroinflammation
  • Online Sections
    • Neurology Video Journal Club
    • Inclusion, Diversity, Equity, Anti-racism, & Social Justice (IDEAS)
    • Innovations in Care Delivery
    • Practice Buzz
    • Practice Current
    • Residents & Fellows
    • Without Borders
  • Collections
    • COVID-19
    • Disputes & Debates
    • Health Disparities
    • Infographics
    • Null Hypothesis
    • Patient Pages
    • Translations
    • Topics A-Z
  • Podcast
  • CME
  • About
    • About the Journals
    • Contact Us
    • Editorial Board
  • Authors
    • Submit a Manuscript
    • Author Center

Advanced Search

Main menu

  • Neurology.org
  • Journals
    • Neurology
    • Clinical Practice
    • Education
    • Genetics
    • Neuroimmunology & Neuroinflammation
  • Online Sections
    • Neurology Video Journal Club
    • Inclusion, Diversity, Equity, Anti-racism, & Social Justice (IDEAS)
    • Innovations in Care Delivery
    • Practice Buzz
    • Practice Current
    • Residents & Fellows
    • Without Borders
  • Collections
    • COVID-19
    • Disputes & Debates
    • Health Disparities
    • Infographics
    • Null Hypothesis
    • Patient Pages
    • Translations
    • Topics A-Z
  • Podcast
  • CME
  • About
    • About the Journals
    • Contact Us
    • Editorial Board
  • Authors
    • Submit a Manuscript
    • Author Center
  • Home
  • Articles
  • Issues

User menu

  • My Alerts
  • Log in

Search

  • Advanced search
Neurology Genetics
Home
A peer-reviewed clinical and translational neurology open access journal
  • My Alerts
  • Log in
Site Logo
  • Home
  • Articles
  • Issues

Share

December 2016; 2 (6) Clinical/Scientific NotesOpen Access

FHF1 (FGF12) epileptic encephalopathy

Sameer Al-Mehmadi, Miranda Splitt, For DDD Study group*, Venkateswaran Ramesh, Suzanne DeBrosse, Kimberly Dessoffy, Fan Xia, Yaping Yang, Jill A. Rosenfeld, Patrick Cossette, Jacques L. Michaud, Fadi F. Hamdan, Philippe M. Campeau, Berge A. Minassian, For CENet Study group‡
First published October 28, 2016, DOI: https://doi.org/10.1212/NXG.0000000000000115
Sameer Al-Mehmadi
From the 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.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Miranda Splitt
From the 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.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
From the 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 Ramesh
From the 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.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Suzanne DeBrosse
From the 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.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kimberly Dessoffy
From the 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.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Fan Xia
From the 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.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yaping Yang
From the 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.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jill A. Rosenfeld
From the 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.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Patrick Cossette
From the 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.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jacques L. Michaud
From the 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.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Fadi F. Hamdan
From the 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.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Philippe M. Campeau
From the 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.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Berge A. Minassian
From the 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.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
From the 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.
Full PDF
Citation
FHF1 (FGF12) epileptic encephalopathy
Sameer Al-Mehmadi, Miranda Splitt, For DDD Study group*, Venkateswaran Ramesh, Suzanne DeBrosse, Kimberly Dessoffy, Fan Xia, Yaping Yang, Jill A. Rosenfeld, Patrick Cossette, Jacques L. Michaud, Fadi F. Hamdan, Philippe M. Campeau, Berge A. Minassian, For CENet Study group‡
Neurol Genet Dec 2016, 2 (6) e115; DOI: 10.1212/NXG.0000000000000115

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Permissions

Make Comment

See Comments

Downloads
932

Share

  • Article
  • Figures & Data
  • Info & Disclosures
Loading

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).1 Fibroblast-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.2 FHF2 mutation is a rare cause of generalized epilepsy with febrile seizures plus (GEFS+).3 Recently, a de novo FHF1 mutation (p.R52H) was reported in early-onset EE in 2 siblings.4 We report 3 patients from unrelated families with the same FHF1 p.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.

Patient 1 (P1, table) is a 3-year-old boy. Convulsive seizures began on day 2 of his life and remain intractable, with frequent status epilepticus (SE) manifesting as generalized or right-sided facial seizures. His EEGs show slow backgrounds and multifocal epileptiform discharges (figure e-1 at Neurology.org/ng). Multiple antiepileptic drug (AED) regimens failed, but he is currently at his best on a combination of the ketogenic diet and medications indicated in the table. He has severe global developmental delay, is nonverbal, has poor visual and social interaction, just started rolling slightly and sitting with support, and is tube-fed. He has generalized hypotonia with head lag and does not track. He suffers from chronic constipation. MRI at onset was normal, and at 2 years revealed widened ventricles and pericerebral CSF spaces (figure e-2A).

View this table:
  • View inline
  • View popup
  • Download powerpoint
Table

Phenotypic features of 5 patients with FHF1 R52H epileptic encephalopathy

Patient 2 (P2) is a 16-year-old girl with intractable seizures since age 6 weeks and frequent SE. Seizures included generalized tonic-clonic (GTC) and partial seizures with left-sided facial twitching and lip-smacking (figure e-3). Phenytoin has been part of her AEDs, and relatively efficacious, since age 6 years. Since age 7, she develops 24 hours of severe ataxia after every GTC, which then gradually improves. Vagal nerve stimulation substantially improved seizure, and ataxia, intensities, and frequencies. MRI at 16 months was unremarkable but at 8 years showed cerebellar atrophy (figure e-2B). She suffers from chronic constipation. She has severe cognitive impairment with single words, has normal motor development, and ambulates. She needs help with all activities of daily living.

Patient 3 (P3) is an 18-year-old girl with intractable epilepsy since day 2 of her life with frequent SE. Seizures include leftward head deviation followed by generalized convulsion. EEGs were slow with multifocal spikes in infancy and Lennox-Gastaut–like in early childhood. She suffers from chronic constipation, hypohydrosis, and reduced lacrimation, suggesting autonomic dysfunction. She has moderate intellectual disability and can read simple books. She ambulates with a spastic circumductive gait and has substantial heel cord tightness. Current therapies (table) include vagal nerve stimulation. MRI at present shows bilateral mesial temporal sclerosis and mild prominence of cerebellar folia, findings not present in MRIs from early childhood (figure e-2C).

All 3 patients had the same de novo FHF1 NM_004113.5:c.155G>A, p.R52H mutation detected by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing, and no other relevant de novo change. The table summarizes their clinical features and those of the recently published4 original sib-pair. Salient features of the latter pair include neonatal-onset intractable epilepsy, profound intellectual disability, severe feeding difficulties, MRI initially unremarkable and subsequently exhibiting cerebellar atrophy, ataxia, and death in SE.4

Based on 5 patients, the core FHF1 R52H disease comprises neonatal-onset persistent intractable epilepsy and moderate-to-severe intellectual disability. Radiologically, neurodegeneration, especially cerebellar, is present, which, beyond a mutational consequence appears to be aggravated by the severity and frequency of SE. It may also be exacerbated by treatment of SE. All 4 patients with cerebellar atrophy, including the original 2, were on phenytoin (table), repeatedly loaded and subsequently chronically maintained because of relative success in SE management and prevention. It may be cautious to use alternative medications, where possible, until this putative phenytoin cerebellar iatrogenicity is clarified.

Siekierska et al.4 demonstrated in vitro and in vivo that R52H is a toxic gain-of-function mutation. To date, thousands of patients with EE have undergone exome sequencing. Our rare finding of an FHF1 mutation suggests that FHF1 R52H might be a mutation-specific disease. It is possible that future FHF1 mutations with similar effects will be identified, but these would be expected to act through similar gain-of-function mechanisms. As such, methods to downregulate the R52H and related alleles, e.g., with allele-specific antisense oligonucleotides, could prove therapeutic in this catastrophic encephalopathy.

Acknowledgments

Acknowledgment: The study has UK Research Ethics Committee's approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12 granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research through the Comprehensive Clinical Research Network, the Health Innovation Challenge Fund (grant HICF-1009-003), and the Wellcome Trust Sanger Institute (grant WT098051). BAM holds the University of Toronto Michael Bahen Chair in Epilepsy Research. The authors thank the Next Generation Sequencing/bioinformatics teams at McGill University, the Genome Quebec Innovation Center, the Réseau de Médecine Génétique Appliquée, and Drs. Ledia Brunga (DNA sample management); Dipayan Mitra (MRI); Ms. Gail Charlton (EEG); and Ms. Sylvia Dobrzeniecka (sequencing) for their efforts.

Footnotes

  • ↵* Member of the DDD Study group.

  • ↵‡ Directors of CENet.

  • DDD Study coinvestigators are listed at Neurology.org/ng.

  • Supplemental data at Neurology.org/ng

  • Author contributions: Dr. Al-Mehmadi, Dr. Splitt, Dr. Ramesh, Dr. DeBrosse, Dr. Dessoffy, Dr. Xia, Dr. Yang, and Dr. Rosenfeld: acquisition of data and analysis and interpretation. Dr. Cossette and Dr. Michaud: study concept and design. Dr. Hamdan and Dr. Campeau: study concept and design, analysis and interpretation, and critical review of the manuscript for important intellectual content. Dr. Minassian: study concept and design, acquisition of data, analysis and interpretation, critical revision of the manuscript for important intellectual content, and study supervision.

  • Study funding: This work was supported by Genome Canada, Genome Quebec, the Ontario Brain Institute, and the DDD Study. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the Department of Health.

  • Disclosure: Dr. Al-Mehmadi, Dr. Splitt, and Dr. Ramesh report no disclosures. Dr. DeBrosse receives funding from NIH 2U54 NS078059-04 and NIH U54NS078059-04; receives philanthropic funding from families of individuals with pyruvate dehydrogenase complex deficiency; has received funding for a trip from the Alternating Hemiplegia of Childhood Foundation; and has received royalty payments from Decision Support in Medicine, LLC. Dr. Wallis reports no disclosures. Dr. Xia has been an employee of Baylor Genetics LLC. Dr. Yang reports no disclosures. Dr. Rosenfeld has served on the editorial boards of Prenatal Diagnosis and Molecular Syndromology; has been an employee of Signature Genomic Laboratories, PerkinElmer, Inc.; and has received research support from NIH/National Human Genome Research Institute. Dr. Cossette receives funding from UCB Pharmaceuticals, Genome Quebec, Genome Canada, CIHR, and the Savoy Foundation. Dr. Michaud receives funding from Genome Quebec and Genome Canada. Dr. Hamdan reports no disclosures. Dr. Campeau serves on the editorial boards of Scientific Reports and the Journal of Pediatric Genetics; has acted as a consultant for Alexion Pharmaceuticals and Biomarin; holds stock options in Illumina, Inc.; and receives funding from the CHU Sainte-Justine Research Center, the Canadian Institutes of Health Research, the Fonds de Recherche en Sante Quebec, the Resaeau de Sante Buccodentaire et Osseuse, and the Fondation du Grand Defi Pierre Lavoie. Dr. Minassian receives funding from Genome Canada and the Ontario Brain Institute; holds patents for diagnostic testing of the following genes: EPM2A, EPM2B, MECP2, and VMA21; and has received license fee payments and royalty payments for the aforementioned patents. Go to Neurology.org/ng for full disclosure forms. The Article Processing Charge was paid by the authors.

  • Disclaimer: The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from genetic testing offered at the Baylor Miraca Genetics Laboratories.

  • Received May 4, 2016.
  • Accepted in final form August 29, 2016.
  • © 2016 American Academy of Neurology

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

References

  1. 1.↵
    1. Steinlein OK
    . Mechanisms underlying epilepsies associated with sodium channel mutations. Prog Brain Res 2014;213:97–111.
    OpenUrlCrossRefPubMed
  2. 2.↵
    1. Goldfarb M
    . Voltage-gated sodium channel-associated proteins and alternative mechanisms of inactivation and block. Cell Mol Life Sci 2012;69:1067–1076.
    OpenUrlCrossRefPubMed
  3. 3.↵
    1. Puranam RS,
    2. He XP,
    3. Yao L, et al
    . Disruption of Fgf13 causes synaptic excitatory-inhibitory imbalance and genetic epilepsy and febrile seizures plus. J Neurosci 2015;35:8866–8881.
    OpenUrlAbstract/FREE Full Text
  4. 4.↵
    1. Siekierska A,
    2. Isrie M,
    3. Liu Y, et al
    . Gain-of-function FHF1 mutation causes early-onset epileptic encephalopathy with cerebellar atrophy. Neurology 2016;86:2162–2170.
    OpenUrl

Letters: Rapid online correspondence

No comments have been published for this article.
Comment

REQUIREMENTS

If you are uploading a letter concerning an article:
You must have updated your disclosures within six months: http://submit.neurology.org

Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.

If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.

Submission specifications:

  • Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
  • Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
  • Submit only on articles published within 6 months of issue date.
  • Do not be redundant. Read any comments already posted on the article prior to submission.
  • Submitted comments are subject to editing and editor review prior to posting.

More guidelines and information on Disputes & Debates

Compose Comment

More information about text formats

Plain text

  • No HTML tags allowed.
  • Web page addresses and e-mail addresses turn into links automatically.
  • Lines and paragraphs break automatically.
Author Information
NOTE: The first author must also be the corresponding author of the comment.
First or given name, e.g. 'Peter'.
Your last, or family, name, e.g. 'MacMoody'.
Your email address, e.g. higgs-boson@gmail.com
Your role and/or occupation, e.g. 'Orthopedic Surgeon'.
Your organization or institution (if applicable), e.g. 'Royal Free Hospital'.
Publishing Agreement
NOTE: All authors, besides the first/corresponding author, must complete a separate Publishing Agreement Form and provide via email to the editorial office before comments can be posted.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.

Vertical Tabs

You May Also be Interested in

Back to top
  • Article
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Disclosures
Advertisement

Preferences and User Experiences of Wearable Devices in Epilepsy A Systematic Review and Mixed-Methods Synthesis

Dr. Daniel Friedman and Dr. Sharon Chiang

► Watch

Topics Discussed

  • All Genetics
  • All Pediatric
  • All Epilepsy/Seizures

Alert Me

  • Alert me when eletters are published
Neurology Genetics: 9 (2)

Articles

  • Articles
  • Issues
  • Popular Articles

About

  • About the Journals
  • Ethics Policies
  • Editors & Editorial Board
  • Contact Us
  • Advertise

Submit

  • Author Center
  • Submit a Manuscript
  • Information for Reviewers
  • AAN Guidelines
  • Permissions

Subscribers

  • Subscribe
  • Sign up for eAlerts
  • RSS Feed
Site Logo
  • Visit neurology Template on Facebook
  • Follow neurology Template on Twitter
  • Visit Neurology on YouTube
  • Neurology
  • Neurology: Clinical Practice
  • Neurology: Education
  • Neurology: Genetics
  • Neurology: Neuroimmunology & Neuroinflammation
  • AAN.com
  • AANnews
  • Continuum
  • Brain & Life
  • Neurology Today

Wolters Kluwer Logo

Neurology: Genetics | Online ISSN: 2376-7839

© 2023 American Academy of Neurology

  • Privacy Policy
  • Feedback
  • Advertise