PIGN encephalopathy: Characterizing the epileptology

Allan Bayat^{1

2}, Guillem de Valles-Ibáñez³, Manuela Pendziwiat^{4

5}, Alexej Knaus⁶, Kerstin Alt⁷, Elisa Biamino⁸, Annette Bley^{9

10}, Sophie Calvert¹¹, Patrick Carney¹², Alfonso Caro-Llopis¹³, Berten Ceulemans¹⁴, Janice Cousin¹⁵, Suzanne Davis³, Vincent des Portes¹⁶, Patrick Edery¹⁷, Eleina England¹⁸, Carlos Ferreira¹⁹, Jeremy Freeman^{20

21}, Blanca Gener²², Magali Gorce²³, Delphine Heron²⁴, Michael S Hildebrand^{25

26}, Aleksandra Jezela-Stanek²⁷, Pierre-Simon Jouk²⁸, Boris Keren²⁴, Katja Kloth²⁹, Gerhard Kluger⁷, Marius Kuhn⁷, Johannes R Lemke^{30

31}, Hong Li³², Francisco Martinez¹³, Caroline Maxton³³, Heather C Mefford³⁴, Giuseppe Merla⁸, Hanna Mierzewska³⁵, Alison Muir³⁴, Sandra Monfort³⁶, Joost Nicolai³⁶, Jennifer Norman³⁷, Gina O'Grady³⁸, Barbara Oleksy³⁹, Carmen Orellana³⁶, Laura Elena Orec⁴⁰, Charlotte Peinhardt³², Ewa Pronicka⁴¹, Monica Rosello³⁶, Fernando Santos-Simarro⁴², Eva Maria Christina Schwaibold⁴³, Alexander P A Stegmann⁴⁴, Constance T Stumpel⁴⁵, Elzbieta Szczepanik³⁹, Iwona Terczyńska⁴⁶, Julien Thevenon⁴⁷, Andreas Tzschach⁴⁸, Patrick Van Bogaert²³, Roberta Vittorini⁸, Sonja Walsh⁴⁸, Sarah Weckhuysen^{49

50}, Barbara Weissman⁴⁰, Lynne Wolfe¹⁹, Alexandre Reymond⁵¹, Pasquelena De Nittis⁵¹, Annapurna Poduri⁵², Heather Olson⁵², Pasquale Striano⁵¹, Gaetan Lesca¹⁷, Ingrid E Scheffer^{25

52}, Rikke S Møller^{1

2}, Lynette G Sadleir³

Affiliations

¹ Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark.
² Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Center, Dianalund, Denmark.
³ Department of Paediatrics and Child Health, University of Otago, Wellington, New Zealand.
⁴ Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian Albrecht University, Kiel, Germany.
⁵ Institute of Clinical Molecular Biology, Christian Albrecht University of Kiel, Kiel, Germany.
⁶ Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Rhenish Friedrich Wilhelm University of Bonn, Bonn, Germany.
⁷ Center for Human Genetics, Neu-Ulm, Germany.
⁸ Department of Pediatrics, Regina Margherita Children's Hospital, Turin, Italy.
⁹ University Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁰ Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹¹ Department of Neurosciences, Queensland Children's Hospital, South Brisbane, Queensland, Australia.
¹² Department of Medicine, University of Melbourne, Parkville, Victoria, Australia.
¹³ Genomics Unit, University and Polytechnic Hospital La Fe, Valencia, Spain.
¹⁴ Department of Pediatric Neurology, Antwerp University Hospital, Edegem, Belgium.
¹⁵ Section of Human Biochemical Genetics, National Human Genome Research Institute, Bethesda, Maryland, USA.
¹⁶ Department of Neuropediatrics, Lyon University Hospital, Lyon, France.
¹⁷ Department of Medical Genetics, University Hospital of Lyon, Lyon, France.
¹⁸ Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA.
¹⁹ National Human Genome Research Institute, Bethesda, Maryland, USA.
²⁰ Royal Children's Hospital, Parkville, Victoria, Australia.
²¹ Murdoch Children's Research Institute, Parkville, Victoria, Australia.
²² Department of Genetics, Cruces University Hospital, Biocruces Bizkaia Health Research Institute, Barakaldo, Spain.
²³ Angers University Hospital, Angers, France.
²⁴ 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.
²⁵ Royal Children's Hospital, Florey institute and Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
²⁶ Epilepsy Research Centre, Department of Medicine (Austin Health), University of Melbourne, Heidelberg, Victoria, Australia.
²⁷ Department of Genetics and Clinical Immunology, National Institute of Tuberculosis and Lung Diseases, Warsaw, Poland.
²⁸ Inserm U1209, Grenoble Alpes University Hospital Center, University of Grenoble Alpes, Grenoble, France.
²⁹ Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
³⁰ Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
³¹ Center for Rare Diseases, University of Leipzig Medical Center, Leipzig, Germany.
³² Emory University School of Medicine, Atlanta, Georgia, USA.
³³ Clinic for Pediatric Neurology, Hamburg, Germany.
³⁴ Center for Pediatric Neurological Disease Research, Department of Cell and Molecular Biology, St, Jude Children's Research Hospital, Memphis, Tennessee, USA.
³⁵ Department of Child and Adolescent Neurology, Institute of Mother and Child, Warsaw, Poland.
³⁶ Department of Neurology, Maastricht University Medical Center, Maastricht, the Netherlands.
³⁷ INTEGRIS Pediatric Neurology, Oklahoma City, Oklahoma, USA.
³⁸ Starship Children's Hospital, Auckland, New Zealand.
³⁹ Center for Child and Adolescent Medicine, Pediatric Neurology, Heidelberg University Hospital, Heidelberg, Germany.
⁴⁰ Department of Medical Genetics, Children's Memorial Health Institute, Warsaw, Poland.
⁴¹ Clinical Genetics, La Paz University Hospital, Madrid, Spain.
⁴² Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
⁴³ Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands.
⁴⁴ Department of Clinical Genetics and School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands.
⁴⁵ Department of Genetics, University of Bourgogne-Franche Comté, Dijon, France.
⁴⁶ Institute of Clinical Genetics, Dresden University of Technology, Dresden, Germany.
⁴⁷ Neurology Department, University Hospital Antwerp, Antwerp, Belgium.
⁴⁸ Applied and Translational Genomics Group, Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium.
⁴⁹ Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
⁵⁰ Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA.
⁵¹ Giannina Gaslini Institute, Genoa, Italy.
⁵² Departments of Medicine and Paediatrics, University of Melbourne, Melbourne, Victoria, Australia.

PMID: 35179230
DOI: 10.1111/epi.17173

PIGN encephalopathy: Characterizing the epileptology

Allan Bayat et al. Epilepsia. 2022 Apr.

. 2022 Apr;63(4):974-991.

doi: 10.1111/epi.17173. Epub 2022 Feb 18.

Authors

Affiliations

¹ Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark.
² Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Center, Dianalund, Denmark.
³ Department of Paediatrics and Child Health, University of Otago, Wellington, New Zealand.
⁴ Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian Albrecht University, Kiel, Germany.
⁵ Institute of Clinical Molecular Biology, Christian Albrecht University of Kiel, Kiel, Germany.
⁶ Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Rhenish Friedrich Wilhelm University of Bonn, Bonn, Germany.
⁷ Center for Human Genetics, Neu-Ulm, Germany.
⁸ Department of Pediatrics, Regina Margherita Children's Hospital, Turin, Italy.
⁹ University Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁰ Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹¹ Department of Neurosciences, Queensland Children's Hospital, South Brisbane, Queensland, Australia.
¹² Department of Medicine, University of Melbourne, Parkville, Victoria, Australia.
¹³ Genomics Unit, University and Polytechnic Hospital La Fe, Valencia, Spain.
¹⁴ Department of Pediatric Neurology, Antwerp University Hospital, Edegem, Belgium.
¹⁵ Section of Human Biochemical Genetics, National Human Genome Research Institute, Bethesda, Maryland, USA.
¹⁶ Department of Neuropediatrics, Lyon University Hospital, Lyon, France.
¹⁷ Department of Medical Genetics, University Hospital of Lyon, Lyon, France.
¹⁸ Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA.
¹⁹ National Human Genome Research Institute, Bethesda, Maryland, USA.
²⁰ Royal Children's Hospital, Parkville, Victoria, Australia.
²¹ Murdoch Children's Research Institute, Parkville, Victoria, Australia.
²² Department of Genetics, Cruces University Hospital, Biocruces Bizkaia Health Research Institute, Barakaldo, Spain.
²³ Angers University Hospital, Angers, France.
²⁴ 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.
²⁵ Royal Children's Hospital, Florey institute and Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
²⁶ Epilepsy Research Centre, Department of Medicine (Austin Health), University of Melbourne, Heidelberg, Victoria, Australia.
²⁷ Department of Genetics and Clinical Immunology, National Institute of Tuberculosis and Lung Diseases, Warsaw, Poland.
²⁸ Inserm U1209, Grenoble Alpes University Hospital Center, University of Grenoble Alpes, Grenoble, France.
²⁹ Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
³⁰ Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
³¹ Center for Rare Diseases, University of Leipzig Medical Center, Leipzig, Germany.
³² Emory University School of Medicine, Atlanta, Georgia, USA.
³³ Clinic for Pediatric Neurology, Hamburg, Germany.
³⁴ Center for Pediatric Neurological Disease Research, Department of Cell and Molecular Biology, St, Jude Children's Research Hospital, Memphis, Tennessee, USA.
³⁵ Department of Child and Adolescent Neurology, Institute of Mother and Child, Warsaw, Poland.
³⁶ Department of Neurology, Maastricht University Medical Center, Maastricht, the Netherlands.
³⁷ INTEGRIS Pediatric Neurology, Oklahoma City, Oklahoma, USA.
³⁸ Starship Children's Hospital, Auckland, New Zealand.
³⁹ Center for Child and Adolescent Medicine, Pediatric Neurology, Heidelberg University Hospital, Heidelberg, Germany.
⁴⁰ Department of Medical Genetics, Children's Memorial Health Institute, Warsaw, Poland.
⁴¹ Clinical Genetics, La Paz University Hospital, Madrid, Spain.
⁴² Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
⁴³ Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands.
⁴⁴ Department of Clinical Genetics and School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands.
⁴⁵ Department of Genetics, University of Bourgogne-Franche Comté, Dijon, France.
⁴⁶ Institute of Clinical Genetics, Dresden University of Technology, Dresden, Germany.
⁴⁷ Neurology Department, University Hospital Antwerp, Antwerp, Belgium.
⁴⁸ Applied and Translational Genomics Group, Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium.
⁴⁹ Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
⁵⁰ Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA.
⁵¹ Giannina Gaslini Institute, Genoa, Italy.
⁵² Departments of Medicine and Paediatrics, University of Melbourne, Melbourne, Victoria, Australia.

PMID: 35179230
DOI: 10.1111/epi.17173

Abstract

Objective: 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.

Methods: 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.

Results: 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.

Significance: PIGN encephalopathy is a complex autosomal recessive disorder associated with a wide spectrum of epilepsy phenotypes, typically with substantial profound to severe developmental impairment.

Keywords: GPI-anchoring disorder; congenital disorder of glycosylation; developmental and epileptic encephalopathy; epilepsy; intellectual disability.

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References

REFERENCES

1. Hong Y, Maeda Y, Watanabe R, Ohishi K, Mishkind M, Riezman H, et al. Pig-n, a mammalian homologue of yeast Mcd4p, is involved in transferring phosphoethanolamine to the first mannose of the glycosylphosphatidylinositol. J Biol Chem. 1999;274:35099-106.
1. Bellai-Dussault K, Nguyen TTM, Baratang NV, Jimenez-Cruz DA, Campeau PM. Clinical variability in inherited glycosylphosphatidylinositol deficiency disorders. Clin Genet. 2019;95:112-21.
1. Fujita M, Kinoshita T. GPI-anchor remodeling: potential functions of GPI-anchors in intracellular trafficking and membrane dynamics. Biochim Biophys Acta. 2012;1821:1050-8.
1. Guerrero PA, Murakami Y, Malik A, Seeberger PH, Kinoshita T, Varon SD. Rescue of glycosylphosphatidylinositol-anchored protein biosynthesis using synthetic glycosylphosphatidylinositol oligosaccharides. ACS Chem Biol. 2021;16(11):2297-306.
1. Ihara S, Nakayama S, Murakami Y, Suzuki E, Asakawa M, Kinoshita T, et al. PIGN prevents protein aggregation in the endoplasmic reticulum independently of its function in the GPI synthesis. J Cell Sci. 2017;130:602-13.

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PIGN encephalopathy: Characterizing the epileptology

Affiliations

PIGN encephalopathy: Characterizing the epileptology

Authors

Affiliations

Abstract

References

REFERENCES

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LinkOut - more resources

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