Phenotypic and genetic spectrum of ATP6V1A encephalopathy: a disorder of lysosomal homeostasis
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- Renzo Guerrini
- Neuroscience Department, Children's Hospital Meyer, University of Florence , Florence , Italy
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- Davide Mei
- Neuroscience Department, Children's Hospital Meyer, University of Florence , Florence , Italy
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- Katalin Kerti-Szigeti
- Institute of Science and Technology Austria (ISTA) , Klosterneuburg , Austria
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- Sara Pepe
- Department of Experimental Medicine, University of Genoa , Italy
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- Mary Kay Koenig
- Department of Pediatrics, Division of Child and Adolescent Neurology, The University of Texas McGovern Medical School , Houston, TX , USA
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- Gretchen Von Allmen
- Department of Pediatrics, Division of Child and Adolescent Neurology, The University of Texas McGovern Medical School , Houston, TX , USA
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- Megan T Cho
- GeneDx , Gaithersburg, MD 20877 , USA
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- Kimberly McDonald
- Pediatric Neurology, University of Mississippi Medical Center , Jackson, MS , USA
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- Janice Baker
- Genetics and Genomics, Children's Minnesota , Minneapolis, MN , USA
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- Vikas Bhambhani
- Genetics and Genomics, Children's Minnesota , Minneapolis, MN , USA
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- Zöe Powis
- Ambry Genetics , Aliso Viejo, CA , USA
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- Lance Rodan
- Division of Genetics and Genomics and Department of Neurology, Boston Children’s Hospital, Harvard Medical School , Boston, MA , USA
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- Rima Nabbout
- Reference Centre for Rare Epilepsies, Department of Genetics, Necker Enfants Malades Hospital, APHP, member of ERN EpiCARE, Université de Paris , Paris , France
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- Giulia Barcia
- Reference Centre for Rare Epilepsies, Department of Genetics, Necker Enfants Malades Hospital, APHP, member of ERN EpiCARE, Université de Paris , Paris , France
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- Jill A Rosenfeld
- Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, Texas , USA
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- Carlos A Bacino
- Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, Texas , USA
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- Cyril Mignot
- APHP, Sorbonne Université, Départément de Génétique, Centre de Référence Déficiences Intellectuelles de Causes Rares , Paris , France
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- Lillian H Power
- Pediatric Neurology, Stead Family Department of Pediatrics, University of Iowa Stead Family Children’s Hospital , Iowa City, IA , USA
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- Catharine J Harris
- Department of Pediatric Genetics, University of Missouri Medical Center , Columbia, MO 65212 , USA
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- Dragan Marjanovic
- Danish Epilepsy Centre Filadelfia, Adult Neurology , Dianalund , Denmark
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- Rikke S Møller
- Department of Epilepsy Genetics and Personalized Treatment, Danish Epilepsy Center Filadelfia , Dianalund , Denmark
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- Trine B Hammer
- Department of Epilepsy Genetics and Personalized Treatment, Danish Epilepsy Center Filadelfia , Dianalund , Denmark
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- Riikka Keski Filppula
- Department of Clinical Genetics, Oulu University Hospital, Medical Research Center Oulu and PEDEGO Research Unit, University of Oulu , Oulu , Finland
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- Päivi Vieira
- Clinic for Children and Adolescents, Oulu University Hospital, Medical Research Center Oulu and PEDEGO Research Unit, University of Oulu , Oulu , Finland
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- Clara Hildebrandt
- Division of Genetics and Genomics, Metabolism Program, Boston Children's Hospital , Boston, MA , USA
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- Stephanie Sacharow
- Boston Children’s Hospital, Harvard Medical School , Boston, MA , USA
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- Luca Maragliano
- Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia , Genova , Italy
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- Fabio Benfenati
- Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia , Genova , Italy
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- Katherine Lachlan
- Wessex Clinical Genetics Service, University Hospital Southampton NHS Foundation Trust , Southampton , UK
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- Andreas Benneche
- Department of Medical Genetics, Haukeland University Hospital , Bergen , Norway
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- Florence Petit
- CHU Lille, Clinique de Génétique , F-59000 Lille , France
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- Jean Madeleine de Sainte Agathe
- Laboratoire de Biologie Médicale Multi Sites SeqOIA, Laboratoire de Médecine Génomique, APHP. Sorbonne Université , Paris , France
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- Barbara Hallinan
- Department of Pediatrics, University of Cincinnati College of Medicine , Cincinnati, OH , USA
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- Yue Si
- GeneDx , Gaithersburg, MD 20877 , USA
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- Ingrid M Wentzensen
- GeneDx , Gaithersburg, MD 20877 , USA
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- Fanggeng Zou
- GeneDx , Gaithersburg, MD 20877 , USA
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- Vinodh Narayanan
- Neurogenomics Division, Center for Rare Childhood Disorders, Translational Genomics Research Institute (TGen) , Phoenix, AZ 85012 , USA
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- Naomichi Matsumoto
- Department of Human Genetics, Yokohama City University Graduate School of Medicine , Yokohama , Japan
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- Alessandra Boncristiano
- Neuroscience Department, Children's Hospital Meyer, University of Florence , Florence , Italy
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- Giancarlo la Marca
- Newborn Screening, Clinical Chemistry and Pharmacology Laboratory, Meyer Children’s University Hospital , Florence , Italy
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- Mitsuhiro Kato
- Department of Pediatrics, Showa University School of Medicine and Epilepsy Medical Center, Showa University Hospital , Tokyo , Japan
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- Kristin Anderson
- Founder and Research Liaison, ‘ATP6V1A Families' Facebook group
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- Carmen Barba
- Neuroscience Department, Children's Hospital Meyer, University of Florence , Florence , Italy
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- Luisa Sturiale
- CNR, Institute for Polymers, Composites and Biomaterials, IPCB , 95126 Catania , Italy
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- Domenico Garozzo
- CNR, Institute for Polymers, Composites and Biomaterials, IPCB , 95126 Catania , Italy
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- Roberto Bei
- Department of Clinical Sciences and Translational Medicine, University of Rome ‘Tor Vergata' , Rome , Italy
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- Laura Masuelli
- Department of Experimental Medicine, University of Rome ‘Sapienza' , Rome , Italy
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- Valerio Conti
- Neuroscience Department, Children's Hospital Meyer, University of Florence , Florence , Italy
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- Gaia Novarino
- Institute of Science and Technology Austria (ISTA) , Klosterneuburg , Austria
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- 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
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- Brain
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Brain 145 (8), 2687-2703, 2022-06-09
Oxford University Press (OUP)
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詳細情報 詳細情報について
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- CRID
- 1360861704780844160
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- ISSN
- 14602156
- 00068950
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- データソース種別
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