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Title: PIGN encephalopathy: Characterizing the epileptology.
Austin Authors: Bayat, Allan;de Valles-Ibáñez, Guillem;Pendziwiat, Manuela;Knaus, Alexej;Alt, Kerstin;Biamino, Elisa;Bley, Annette;Calvert, Sophie;Carney, Patrick W ;Caro-Llopis, Alfonso;Ceulemans, Berten;Cousin, Janice;Davis, Suzanne;des Portes, Vincent;Edery, Patrick;England, Eleina;Ferreira, Carlos;Freeman, Jeremy;Gener, Blanca;Gorce, Magali;Heron, Delphine;Hildebrand, Michael S ;Jezela-Stanek, Aleksandra;Jouk, Pierre-Simon;Keren, Boris;Kloth, Katja;Kluger, Gerhard;Kuhn, Marius;Lemke, Johannes R;Li, Hong;Martinez, Francisco;Maxton, Caroline;Mefford, Heather C;Merla, Giuseppe;Mierzewska, Hanna;Muir, Alison;Monfort, Sandra;Nicolai, Joost;Norman, Jennifer;O'Grady, Gina;Oleksy, Barbara;Orellana, Carmen;Orec, Laura Elena;Peinhardt, Charlotte;Pronicka, Ewa;Rosello, Monica;Santos-Simarro, Fernando;Schwaibold, Eva Maria Christina;Stegmann, Alexander P A;Stumpel, Constance T;Szczepanik, Elzbieta;Terczyńska, Iwona;Thevenon, Julien;Tzschach, Andreas;Van Bogaert, Patrick;Vittorini, Roberta;Walsh, Sonja;Weckhuysen, Sarah;Weissman, Barbara;Wolfe, Lynne;Reymond, Alexandre;De Nittis, Pasquelena;Poduri, Annapurna;Olson, Heather;Striano, Pasquale;Lesca, Gaetan;Scheffer, Ingrid E ;Møller, Rikke S;Sadleir, Lynette G
Affiliation: The Florey Institute of Neuroscience and Mental Health
Epilepsy Research Centre
Medicine (University of Melbourne)
Department of Neurosciences, Queensland Children's Hospital, South Brisbane, Queensland, Australia
Royal Children's Hospital, Parkville, Victoria, Australia
Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark
Department of Medicine, University of Melbourne, Parkville, Victoria, Australia
Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Center, Dianalund, Denmark
Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian Albrecht University, Kiel, Germany
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Rhenish Friedrich Wilhelm University of Bonn, Bonn, Germany
Center for Human Genetics, Neu-Ulm, Germany
University Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Genomics Unit, University and Polytechnic Hospital La Fe, Valencia, Spain
Department of Pediatric Neurology, Antwerp University Hospital, Edegem, Belgium
Section of Human Biochemical Genetics, National Human Genome Research Institute, Bethesda, Maryland, USA
Department of Neuropediatrics, Lyon University Hospital, Lyon, France
Department of Medical Genetics, University Hospital of Lyon, Lyon, France
Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA
Department of Genetics, Cruces University Hospital, Biocruces Bizkaia Health Research Institute, Barakaldo, Spain
Institute of Clinical Molecular Biology, Christian Albrecht University of Kiel, Kiel, Germany
Department of Genetics and Clinical Immunology, National Institute of Tuberculosis and Lung Diseases, Warsaw, Poland
Inserm U1209, Grenoble Alpes University Hospital Center, University of Grenoble Alpes, Grenoble, France
Department of Genetics, Intellectual Disability and Autism Clinical Research Group, Pierre and Marie Curie University, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France..
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany..
Center for Rare Diseases, University of Leipzig Medical Center, Leipzig, Germany
Clinic for Pediatric Neurology, Hamburg, Germany
Department of Child and Adolescent Neurology, Institute of Mother and Child, Warsaw, Poland
Center for Pediatric Neurological Disease Research, Department of Cell and Molecular Biology, St, Jude Children's Research Hospital, Memphis, Tennessee, USA
Department of Neurology, Maastricht University Medical Center, Maastricht, the Netherlands
INTEGRIS Pediatric Neurology, Oklahoma City, Oklahoma, USA
Starship Children's Hospital, Auckland, New Zealand
Emory University School of Medicine, Atlanta, Georgia, USA
Clinical Genetics, La Paz University Hospital, Madrid, Spain
Institute of Human Genetics, Heidelberg University, Heidelberg, Germany
Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands
Department of Clinical Genetics and School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands
Department of Genetics, University of Bourgogne-Franche Comté, Dijon, France
Center for Child and Adolescent Medicine, Pediatric Neurology, Heidelberg University Hospital, Heidelberg, Germany
Institute of Clinical Genetics, Dresden University of Technology, Dresden, Germany
Neurology Department, University Hospital Antwerp, Antwerp, Belgium
Angers University Hospital, Angers, France
Department of Pediatrics, Regina Margherita Children's Hospital, Turin, Italy
Applied and Translational Genomics Group, Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium
Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA..
Department of Medical Genetics, Children's Memorial Health Institute, Warsaw, Poland
National Human Genome Research Institute, Bethesda, Maryland, USA
Giannina Gaslini Institute, Genoa, Italy
Department of Paediatrics and Child Health, University of Otago, Wellington, New Zealand
Departments of Medicine and Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
Murdoch Children's Research Institute, Parkville, Victoria, Australia
Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
Issue Date: 2022
Date: 2022
Publication information: Epilepsia 2022; 63(4): 974-991
Abstract: Epilepsy is common in patients with PIGN diseases due to biallelic variants; however, limited epilepsy phenotyping data have been reported. We describe the epileptology of PIGN encephalopathy. We recruited patients with epilepsy due to biallelic PIGN variants and obtained clinical data regarding age at seizure onset/offset and semiology, development, medical history, examination, electroencephalogram, neuroimaging, and treatment. Seizure and epilepsy types were classified. Twenty six patients (13 female) from 26 families were identified, with mean age 7 years (range = 1 month to 21 years; three deceased). Abnormal development at seizure onset was present in 25 of 26. Developmental outcome was most frequently profound (14/26) or severe (11/26). Patients presented with focal motor (12/26), unknown onset motor (5/26), focal impaired awareness (1/26), absence (2/26), myoclonic (2/26), myoclonic-atonic (1/26), and generalized tonic-clonic (2/26) seizures. Twenty of 26 were classified as developmental and epileptic encephalopathy (DEE): 55% (11/20) focal DEE, 30% (6/20) generalized DEE, and 15% (3/20) combined DEE. Six had intellectual disability and epilepsy (ID+E): two generalized and four focal epilepsy. Mean age at seizure onset was 13 months (birth to 10 years), with a lower mean onset in DEE (7 months) compared with ID+E (33 months). Patients with DEE had drug-resistant epilepsy, compared to 4/6 ID+E patients, who were seizure-free. Hyperkinetic movement disorder occurred in 13 of 26 patients. Twenty-seven of 34 variants were novel. Variants were truncating (n = 7), intronic and predicted to affect splicing (n = 7), and missense or inframe indels (n = 20, of which 11 were predicted to affect splicing). Seven variants were recurrent, including p.Leu311Trp in 10 unrelated patients, nine with generalized seizures, accounting for nine of the 11 patients in this cohort with generalized seizures. PIGN encephalopathy is a complex autosomal recessive disorder associated with a wide spectrum of epilepsy phenotypes, typically with substantial profound to severe developmental impairment.
DOI: 10.1111/epi.17173
ORCID: 0000-0003-4986-8006
Journal: Epilepsia
PubMed URL: 35179230
PubMed URL:
Type: Journal Article
Subjects: GPI-anchoring disorder
congenital disorder of glycosylation
developmental and epileptic encephalopathy
intellectual disability
Appears in Collections:Journal articles

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