2. Academic Validation
  3. Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy

Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy

  • Brain. 2021 Oct 22;144(9):2659-2669. doi: 10.1093/brain/awab124.
Edgard Verdura 1 2,  Agustí Rodríguez-Palmero 1 3,  Valentina Vélez-Santamaria 1 4,  Laura Planas-Serra 1 2,  Irene de la Calle 1,  Miquel Raspall-Chaure 5 6,  Agathe Roubertie 7 8,  Mehdi Benkirane 9,  Francesco Saettini 10,  Lisa Pavinato 11,  Giorgia Mandrile 12,  Melanie O'Leary 13,  Emily O'Heir 13,  Estibaliz Barredo 14,  Almudena Chacón 14,  Vincent Michaud 15 16,  Cyril Goizet 16 17,  Montserrat Ruiz 1 2,  Agatha Schlüter 1 2,  Isabelle Rouvet 18,  Julia Sala-Coromina 5 6,  Chiara Fossati 19,  Maria Iascone 20,  Francesco Canonico 21,  Anna Marcé-Grau 5,  Precilla de Souza 22,  David R Adams 22 23,  Carlos Casasnovas 1 2 4,  Heidi L Rehm 13,  Heather C Mefford 24,  Luis González Gutierrez-Solana 2 25,  Alfredo Brusco 11 26,  Michel Koenig 9,  Alfons Macaya 5 6,  Aurora Pujol 1 2 27
Affiliations

Affiliations

  • 1 Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08908, Barcelona, Catalonia, Spain.
  • 2 Centre for Biomedical Research in Network on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029, Madrid, Spain.
  • 3 Pediatric Neurology Unit, Department of Pediatrics, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Catalonia, Spain.
  • 4 Neuromuscular Unit, Neurology Department, Hospital Universitari de Bellvitge, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.
  • 5 Neurology Research Group, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain.
  • 6 Department of Paediatric Neurology, Vall d'Hebron University Hospital, Barcelona, Spain.
  • 7 Département de Neuropédiatrie, Hôpital Gui de Chauliac Pôle Neurosciences Tête et Cou, Montpellier, France.
  • 8 INSERM U1051, Institut des Neurosciences de Montpellier, Montpellier, France.
  • 9 Laboratoire de Génétique de Maladies Rares EA7402, Institut Universitaire de Recherche Clinique, Université de Montpellier, CHU Montpellier, CEDEX 5, 34295 Montpellier, France.
  • 10 Paediatric Hematology Department, Fondazione MBBM, University of Milano Bicocca, Monza, Italy.
  • 11 Department of Medical Sciences, University of Torino, 10126 Torino, Italy.
  • 12 Thalassemia Centre and Medical Genetics Unit, San Luigi Gonzaga University Hospital, Orbassano, Italy.
  • 13 Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 14 Neuropediatric Department, Hospital Universitario Gregorio Marañón, Madrid, Spain.
  • 15 Molecular Genetics Laboratory, Bordeaux University Hospital, Bordeaux, Aquitaine, France.
  • 16 INSERM U1211, Rare Diseases Laboratory: Genetics and Metabolism, University of Bordeaux, Talence, Aquitaine, France.
  • 17 Reference Center for Rare Neurogenetic Diseases, Department of Medical Genetics, University Hospital Centre Bordeaux Pellegrin Hospital Group, Bordeaux, Aquitaine, France.
  • 18 Cellular Biotechnology Department and Biobank, Hospices Civils de Lyon, CHU de Lyon, Lyon, France.
  • 19 Department of Paediatrics, Fondazione MBBM, Monza, Italy.
  • 20 Molecular Genetics Laboratory, USSD LGM, Papa Giovanni XXIII Hospital, Bergamo, Italy.
  • 21 Department of Neuroradiology, University of Milan-Bicocca, San Gerardo Hospital, ASST di Monza, Monza, Italy.
  • 22 Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD, USA.
  • 23 Undiagnosed Diseases Program, The Common Fund, NIH, Bethesda, MD, USA.
  • 24 Division of Genetic Medicine, Department of Paediatrics, University of Washington, Seattle, WA 98195, USA.
  • 25 Pediatric Neurology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.
  • 26 Medical Genetics Unit, Città della Salute e della Scienza, University Hospital, 10126 Turin, Italy.
  • 27 Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Catalonia, Spain.
PMID: 34415322 DOI: 10.1093/brain/awab124
Abstract

Phosphoinositides are lipids that play a critical role in processes such as cellular signalling, ion channel activity and membrane trafficking. When mutated, several genes that encode proteins that participate in the metabolism of these lipids give rise to neurological or developmental phenotypes. PI4KA is a phosphoinositide kinase that is highly expressed in the brain and is essential for life. Here we used whole exome or genome sequencing to identify 10 unrelated patients harbouring biallelic variants in PI4KA that caused a spectrum of conditions ranging from severe global neurodevelopmental delay with hypomyelination and developmental brain abnormalities to pure spastic paraplegia. Some patients presented immunological deficits or genito-urinary abnormalities. Functional analyses by western blotting and immunofluorescence showed decreased PI4KA levels in the patients' fibroblasts. Immunofluorescence and targeted lipidomics indicated that PI4KA activity was diminished in fibroblasts and peripheral blood mononuclear cells. In conclusion, we report a novel severe metabolic disorder caused by PI4KA malfunction, highlighting the importance of phosphoinositide signalling in human brain development and the myelin sheath.

Keywords

PI4KA; hypomyelinating leukodystrophy; inborn errors of metabolism; phosphoinositol; spastic paraplegia.

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