Phenotypic and genetic spectrum of ATP6V1A encephalopathy: a disorder of lysosomal homeostasis

  • Renzo Guerrini
    Neuroscience Department, Children's Hospital Meyer, University of Florence , Florence , Italy
  • Davide Mei
    Neuroscience Department, Children's Hospital Meyer, University of Florence , Florence , Italy
  • Katalin Kerti-Szigeti
    Institute of Science and Technology Austria (ISTA) , Klosterneuburg , Austria
  • Sara Pepe
    Department of Experimental Medicine, University of Genoa , Italy
  • Mary Kay Koenig
    Department of Pediatrics, Division of Child and Adolescent Neurology, The University of Texas McGovern Medical School , Houston, TX , USA
  • Gretchen Von Allmen
    Department of Pediatrics, Division of Child and Adolescent Neurology, The University of Texas McGovern Medical School , Houston, TX , USA
  • Megan T Cho
    GeneDx , Gaithersburg, MD 20877 , USA
  • Kimberly McDonald
    Pediatric Neurology, University of Mississippi Medical Center , Jackson, MS , USA
  • Janice Baker
    Genetics and Genomics, Children's Minnesota , Minneapolis, MN , USA
  • Vikas Bhambhani
    Genetics and Genomics, Children's Minnesota , Minneapolis, MN , USA
  • Zöe Powis
    Ambry Genetics , Aliso Viejo, CA , USA
  • Lance Rodan
    Division of Genetics and Genomics and Department of Neurology, Boston Children’s Hospital, Harvard Medical School , Boston, MA , USA
  • Rima Nabbout
    Reference Centre for Rare Epilepsies, Department of Genetics, Necker Enfants Malades Hospital, APHP, member of ERN EpiCARE, Université de Paris , Paris , France
  • Giulia Barcia
    Reference Centre for Rare Epilepsies, Department of Genetics, Necker Enfants Malades Hospital, APHP, member of ERN EpiCARE, Université de Paris , Paris , France
  • Jill A Rosenfeld
    Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, Texas , USA
  • Carlos A Bacino
    Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, Texas , USA
  • Cyril Mignot
    APHP, Sorbonne Université, Départément de Génétique, Centre de Référence Déficiences Intellectuelles de Causes Rares , Paris , France
  • Lillian H Power
    Pediatric Neurology, Stead Family Department of Pediatrics, University of Iowa Stead Family Children’s Hospital , Iowa City, IA , USA
  • Catharine J Harris
    Department of Pediatric Genetics, University of Missouri Medical Center , Columbia, MO 65212 , USA
  • Dragan Marjanovic
    Danish Epilepsy Centre Filadelfia, Adult Neurology , Dianalund , Denmark
  • Rikke S Møller
    Department of Epilepsy Genetics and Personalized Treatment, Danish Epilepsy Center Filadelfia , Dianalund , Denmark
  • Trine B Hammer
    Department of Epilepsy Genetics and Personalized Treatment, Danish Epilepsy Center Filadelfia , Dianalund , Denmark
  • Riikka Keski Filppula
    Department of Clinical Genetics, Oulu University Hospital, Medical Research Center Oulu and PEDEGO Research Unit, University of Oulu , Oulu , Finland
  • Päivi Vieira
    Clinic for Children and Adolescents, Oulu University Hospital, Medical Research Center Oulu and PEDEGO Research Unit, University of Oulu , Oulu , Finland
  • Clara Hildebrandt
    Division of Genetics and Genomics, Metabolism Program, Boston Children's Hospital , Boston, MA , USA
  • Stephanie Sacharow
    Boston Children’s Hospital, Harvard Medical School , Boston, MA , USA
  • Luca Maragliano
    Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia , Genova , Italy
  • Fabio Benfenati
    Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia , Genova , Italy
  • Katherine Lachlan
    Wessex Clinical Genetics Service, University Hospital Southampton NHS Foundation Trust , Southampton , UK
  • Andreas Benneche
    Department of Medical Genetics, Haukeland University Hospital , Bergen , Norway
  • Florence Petit
    CHU Lille, Clinique de Génétique , F-59000 Lille , France
  • Jean Madeleine de Sainte Agathe
    Laboratoire de Biologie Médicale Multi Sites SeqOIA, Laboratoire de Médecine Génomique, APHP. Sorbonne Université , Paris , France
  • Barbara Hallinan
    Department of Pediatrics, University of Cincinnati College of Medicine , Cincinnati, OH , USA
  • Yue Si
    GeneDx , Gaithersburg, MD 20877 , USA
  • Ingrid M Wentzensen
    GeneDx , Gaithersburg, MD 20877 , USA
  • Fanggeng Zou
    GeneDx , Gaithersburg, MD 20877 , USA
  • Vinodh Narayanan
    Neurogenomics Division, Center for Rare Childhood Disorders, Translational Genomics Research Institute (TGen) , Phoenix, AZ 85012 , USA
  • Naomichi Matsumoto
    Department of Human Genetics, Yokohama City University Graduate School of Medicine , Yokohama , Japan
  • Alessandra Boncristiano
    Neuroscience Department, Children's Hospital Meyer, University of Florence , Florence , Italy
  • Giancarlo la Marca
    Newborn Screening, Clinical Chemistry and Pharmacology Laboratory, Meyer Children’s University Hospital , Florence , Italy
  • Mitsuhiro Kato
    Department of Pediatrics, Showa University School of Medicine and Epilepsy Medical Center, Showa University Hospital , Tokyo , Japan
  • Kristin Anderson
    Founder and Research Liaison, ‘ATP6V1A Families' Facebook group
  • Carmen Barba
    Neuroscience Department, Children's Hospital Meyer, University of Florence , Florence , Italy
  • Luisa Sturiale
    CNR, Institute for Polymers, Composites and Biomaterials, IPCB , 95126 Catania , Italy
  • Domenico Garozzo
    CNR, Institute for Polymers, Composites and Biomaterials, IPCB , 95126 Catania , Italy
  • Roberto Bei
    Department of Clinical Sciences and Translational Medicine, University of Rome ‘Tor Vergata' , Rome , Italy
  • Laura Masuelli
    Department of Experimental Medicine, University of Rome ‘Sapienza' , Rome , Italy
  • Valerio Conti
    Neuroscience Department, Children's Hospital Meyer, University of Florence , Florence , Italy
  • Gaia Novarino
    Institute of Science and Technology Austria (ISTA) , Klosterneuburg , Austria
  • Anna Fassio
    Department of Experimental Medicine, University of Genoa , Italy

抄録

<jats:title>Abstract</jats:title> <jats:p>Vacuolar-type H+-ATPase (V-ATPase) is a multimeric complex present in a variety of cellular membranes that acts as an ATP-dependent proton pump and plays a key role in pH homeostasis and intracellular signalling pathways. In humans, 22 autosomal genes encode for a redundant set of subunits allowing the composition of diverse V-ATPase complexes with specific properties and expression. Sixteen subunits have been linked to human disease.</jats:p> <jats:p>Here we describe 26 patients harbouring 20 distinct pathogenic de novo missense ATP6V1A variants, mainly clustering within the ATP synthase α/β family-nucleotide-binding domain. At a mean age of 7 years (extremes: 6 weeks, youngest deceased patient to 22 years, oldest patient) clinical pictures included early lethal encephalopathies with rapidly progressive massive brain atrophy, severe developmental epileptic encephalopathies and static intellectual disability with epilepsy. The first clinical manifestation was early hypotonia, in 70%; 81% developed epilepsy, manifested as developmental epileptic encephalopathies in 58% of the cohort and with infantile spasms in 62%; 63% of developmental epileptic encephalopathies failed to achieve any developmental, communicative or motor skills. Less severe outcomes were observed in 23% of patients who, at a mean age of 10 years and 6 months, exhibited moderate intellectual disability, with independent walking and variable epilepsy. None of the patients developed communicative language. Microcephaly (38%) and amelogenesis imperfecta/enamel dysplasia (42%) were additional clinical features. Brain MRI demonstrated hypomyelination and generalized atrophy in 68%. Atrophy was progressive in all eight individuals undergoing repeated MRIs.</jats:p> <jats:p>Fibroblasts of two patients with developmental epileptic encephalopathies showed decreased LAMP1 expression, Lysotracker staining and increased organelle pH, consistent with lysosomal impairment and loss of V-ATPase function. Fibroblasts of two patients with milder disease, exhibited a different phenotype with increased Lysotracker staining, decreased organelle pH and no significant modification in LAMP1 expression. Quantification of substrates for lysosomal enzymes in cellular extracts from four patients revealed discrete accumulation. Transmission electron microscopy of fibroblasts of four patients with variable severity and of induced pluripotent stem cell-derived neurons from two patients with developmental epileptic encephalopathies showed electron-dense inclusions, lipid droplets, osmiophilic material and lamellated membrane structures resembling phospholipids. Quantitative assessment in induced pluripotent stem cell-derived neurons identified significantly smaller lysosomes.</jats:p> <jats:p>ATP6V1A-related encephalopathy represents a new paradigm among lysosomal disorders. It results from a dysfunctional endo-lysosomal membrane protein causing altered pH homeostasis. Its pathophysiology implies intracellular accumulation of substrates whose composition remains unclear, and a combination of developmental brain abnormalities and neurodegenerative changes established during prenatal and early postanal development, whose severity is variably determined by specific pathogenic variants.</jats:p>

収録刊行物

  • Brain

    Brain 145 (8), 2687-2703, 2022-06-09

    Oxford University Press (OUP)

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