University of Oulu

Renzo Guerrini, Davide Mei, Katalin Kerti-Szigeti, Sara Pepe, Mary Kay Koenig, Gretchen Von Allmen, Megan T Cho, Kimberly McDonald, Janice Baker, Vikas Bhambhani, Zöe Powis, Lance Rodan, Rima Nabbout, Giulia Barcia, Jill A Rosenfeld, Carlos A Bacino, Cyril Mignot, Lillian H Power, Catharine J Harris, Dragan Marjanovic, Rikke S Møller, Trine B Hammer, The DDD Study, Riikka Keski Filppula, Päivi Vieira, Clara Hildebrandt, Stephanie Sacharow, Undiagnosed Diseases Network, Luca Maragliano, Fabio Benfenati, Katherine Lachlan, Andreas Benneche, Florence Petit, Jean Madeleine de Sainte Agathe, Barbara Hallinan, Yue Si, Ingrid M Wentzensen, Fanggeng Zou, Vinodh Narayanan, Naomichi Matsumoto, Alessandra Boncristiano, Giancarlo la Marca, Mitsuhiro Kato, Kristin Anderson, Carmen Barba, Luisa Sturiale, Domenico Garozzo, Roberto Bei, ATP6V1A collaborators, Laura Masuelli, Valerio Conti, Gaia Novarino, Anna Fassio, Phenotypic and genetic spectrum of ATP6V1A encephalopathy: a disorder of lysosomal homeostasis, Brain, Volume 145, Issue 8, August 2022, Pages 2687–2703, https://doi.org/10.1093/brain/awac145

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

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Author: Guerrini, Renzo1; Mei, Davide1; Kerti-Szigeti, Katalin2;
Organizations: 1Neuroscience Department, Children's Hospital Meyer, University of Florence, Florence, Italy
2Institute of Science and Technology Austria (ISTA), Klosterneuburg, Austria
3Department of Experimental Medicine, University of Genoa, Italy
4Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Genova, Italy
5Department of Pediatrics, Division of Child and Adolescent Neurology, The University of Texas McGovern Medical School, Houston, TX, USA
6GeneDx, Gaithersburg, MD 20877, USA
7Pediatric Neurology, University of Mississippi Medical Center, Jackson, MS, USA
8Genetics and Genomics, Children's Minnesota, Minneapolis, MN, USA
9Ambry Genetics, Aliso Viejo, CA, USA
10Division of Genetics and Genomics and Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
11Reference Centre for Rare Epilepsies, Department of Genetics, Necker Enfants Malades Hospital, APHP, member of ERN EpiCARE, Université de Paris, Paris, France
12Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
13APHP, Sorbonne Université, Départément de Génétique, Centre de Référence Déficiences Intellectuelles de Causes Rares, Paris, France
14Institut du Cerveau (ICM), UMR S 1127, Inserm U1127, CNRS UMR 7225, Sorbonne Université, 75013 Paris, France
15Pediatric Neurology, Stead Family Department of Pediatrics, University of Iowa Stead Family Children’s Hospital, Iowa City, IA, USA
16Department of Pediatric Genetics, University of Missouri Medical Center, Columbia, MO 65212, USA
17Danish Epilepsy Centre Filadelfia, Adult Neurology, Dianalund, Denmark
18Department of Epilepsy Genetics and Personalized Treatment, Danish Epilepsy Center Filadelfia, Dianalund, Denmark
19Department of Clinical Genetics, Oulu University Hospital, Medical Research Center Oulu and PEDEGO Research Unit, University of Oulu, Oulu, Finland
20Clinic for Children and Adolescents, Oulu University Hospital, Medical Research Center Oulu and PEDEGO Research Unit, University of Oulu, Oulu, Finland
21Division of Genetics and Genomics, Metabolism Program, Boston Children's Hospital, Boston, MA, USA
22Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
23Department of Life and Environmental Sciences, Polytechnic University of Marche, Ancona, Italy
24IRCCS Ospedale Policlinico San Martino, Genova, Italy
25Wessex Clinical Genetics Service, University Hospital Southampton NHS Foundation Trust, Southampton, UK
26Human Development and Health, Faculty of Medicine University of Southampton, Southampton, UK
27Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway
28CHU Lille, Clinique de Génétique, F-59000 Lille, France
29Laboratoire de Biologie Médicale Multi Sites SeqOIA, Laboratoire de Médecine Génomique, APHP. Sorbonne Université, Paris, France
30Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
31Division of Child Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
32Neurogenomics Division, Center for Rare Childhood Disorders, Translational Genomics Research Institute (TGen), Phoenix, AZ 85012, USA
33Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
34Newborn Screening, Clinical Chemistry and Pharmacology Laboratory, Meyer Children’s University Hospital, Florence, Italy
35Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
36Department of Pediatrics, Showa University School of Medicine and Epilepsy Medical Center, Showa University Hospital, Tokyo, Japan
37Founder and Research Liaison, ‘ATP6V1A Families' Facebook group
38CNR, Institute for Polymers, Composites and Biomaterials, IPCB, 95126 Catania, Italy
39Department of Clinical Sciences and Translational Medicine, University of Rome ‘Tor Vergata', Rome, Italy
40Department of Experimental Medicine, University of Rome ‘Sapienza', Rome, Italy
Format: article
Version: accepted version
Access: open
Online Access: PDF Full Text (PDF, 17.3 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2023022728799
Language: English
Published: Oxford University Press, 2022
Publish Date: 2023-02-27
Description:

Abstract

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.

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.

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.

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.

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Series: Brain. A journal of neurology
ISSN: 0006-8950
ISSN-E: 1460-2156
ISSN-L: 0006-8950
Volume: 145
Issue: 8
Pages: 2687 - 2703
DOI: 10.1093/brain/awac145
OADOI: https://oadoi.org/10.1093/brain/awac145
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
3124 Neurology and psychiatry
Subjects:
Funding: This work was supported by the EU 7th Framework Programme (FP7) under the project DESIRE grant N602531 (to R.G.); the Regione Toscana under the Call for Health 2018 (grant DECODE-EE) (to R.G.); the ‘Brain Project’ by Fondazione Cassa di Risparmio di Firenze (to R.G.); IRCCS Ospedale Policlinico San Martino 5×1000 and Ricerca Corrente (to A.F. and F.B.). The European Reference Network (ERN) for rare and complex epilepsies (EpiCARE) provided financial support for meetings organization. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant number WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of Wellcome or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12 granted by the Republic of Ireland REC). This study makes use of DECIPHER (https://www.deciphergenomics.org), which is funded by Wellcome. K.K.-S. was supported by the ISTplus fellowship.
Copyright information: © The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. This is a pre-copyedited, author-produced version of an article accepted for publication in Brain following peer review. The version of record Renzo Guerrini, Davide Mei, Katalin Kerti-Szigeti, Sara Pepe, Mary Kay Koenig, Gretchen Von Allmen, Megan T Cho, Kimberly McDonald, Janice Baker, Vikas Bhambhani, Zöe Powis, Lance Rodan, Rima Nabbout, Giulia Barcia, Jill A Rosenfeld, Carlos A Bacino, Cyril Mignot, Lillian H Power, Catharine J Harris, Dragan Marjanovic, Rikke S Møller, Trine B Hammer, The DDD Study, Riikka Keski Filppula, Päivi Vieira, Clara Hildebrandt, Stephanie Sacharow, Undiagnosed Diseases Network, Luca Maragliano, Fabio Benfenati, Katherine Lachlan, Andreas Benneche, Florence Petit, Jean Madeleine de Sainte Agathe, Barbara Hallinan, Yue Si, Ingrid M Wentzensen, Fanggeng Zou, Vinodh Narayanan, Naomichi Matsumoto, Alessandra Boncristiano, Giancarlo la Marca, Mitsuhiro Kato, Kristin Anderson, Carmen Barba, Luisa Sturiale, Domenico Garozzo, Roberto Bei, ATP6V1A collaborators, Laura Masuelli, Valerio Conti, Gaia Novarino, Anna Fassio, Phenotypic and genetic spectrum of ATP6V1A encephalopathy: a disorder of lysosomal homeostasis, Brain, Volume 145, Issue 8, August 2022, Pages 2687–2703 is available online at: https://doi.org/10.1093/brain/awac145.