Phenotypic and genetic spectrum of ATP6V1A encephalopathy: a disorder of lysosomal homeostasis
Open accessAbstract
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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Neurological symptoms are most common, impacting two-thirds of affected individuals.
“Neurological symptoms, however, are most common, impacting two-thirds of affected individuals.66”
From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [66]
The Phenotypic spectrum section describes neurological features as prominent in this 26-patient cohort, but does not report that neurological symptoms affected two-thirds of patients. It identifies early hypotonia as the most common first clinical manifestation, occurring in 18 of 24 patients with available information (75%); that is a specific symptom and a different proportion. (LLM, conf=0.84)
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Cited by
Sorted by citations
Lane-Donovan, C., Paredes, M., & Kao, A. W. (2025) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2025.102854 · Cited by 3 · see citing works
- Authors
- Guerrini, R., Mei, D., Kerti-Szigeti, K., Pepe, S., Koenig, M. K., Von Allmen, G., Cho, M. T., McDonald, K., Baker, J., Bhambhani, V., Powis, Z., Rodan, L., Nabbout, R., Barcia, G., Rosenfeld, J. A., Bacino, C. A., Mignot, C., Power, L. H., Harris, C. J., Marjanovic, D., Møller, R. S., Hammer, T. B., Study, T. D., Keski Filppula, R., Vieira, P., Hildebrandt, C., Sacharow, S., Undiagnosed Diseases Network, Maragliano, L., Benfenati, F., Lachlan, K., Benneche, A., Petit, F., de Sainte Agathe, J. M., Hallinan, B., Si, Y., Wentzensen, I. M., Zou, F., Narayanan, V., Matsumoto, N., Boncristiano, A., la Marca, G., Kato, M., Anderson, K., Barba, C., Sturiale, L., Garozzo, D., Bei, R., collaborators, A., Masuelli, L., Conti, V., Novarino, G., & Fassio, A.
- Affiliations
- Meyer Children's Hospital (IT)
- Institute of Science and Technology Austria (ISTA) , Klosterneuburg , Austria
- Italian Institute of Technology (IT)
- Department of Pediatrics, Division of Child and Adolescent Neurology, The University of Texas McGovern Medical School , Houston, TX , USA
- GeneDx , Gaithersburg, MD 20877 , USA
- University of Mississippi Medical Center (US)
- Children's Minnesota (US)
- Ambry Genetics (United States) (US)
- Boston Children's Hospital (US)
- Hôpital Necker-Enfants Malades (FR)
- Baylor College of Medicine (US)
- Centre National de la Recherche Scientifique (FR)
- University of Iowa Stead Family Children’s Hospital (US)
- University of Missouri Health System (US)
- Danish Epilepsy Centre Filadelfia, Adult Neurology , Dianalund , Denmark
- University of Southern Denmark (DK)
- Filadelfia (DK)
- Oulu University Hospital (FI)
- Department of Clinical Genetics, Oulu University Hospital, Medical Research Center Oulu and PEDEGO Research Unit, University of Oulu , Oulu , Finland
- Marche Polytechnic University (IT)
- Haukeland University Hospital (NO)
- University Hospital Southampton NHS Foundation Trust (GB)
- Cincinnati Children's Hospital Medical Center (US)
- Laboratoire de Biologie Médicale Multi Sites SeqOIA, Laboratoire de Médecine Génomique, APHP. Sorbonne Université , Paris , France
- Translational Genomics Research Institute (US)
- Yokohama City University (JP)
- SHOWA Medical University (JP)
- Newborn Screening, Clinical Chemistry and Pharmacology Laboratory, Meyer Children’s University Hospital , Florence , Italy
- Institute of Polymers, Composites and Biomaterials (IT)
- University of Rome Tor Vergata (IT)
- Institute of Science and Technology Austria (AT)
- Ospedale Policlinico San Martino (IT)
- Corresponding author
- Guerrini, Renzo
- ORCID
- Guerrini, Renzo
- Mei, Davide
- Pepe, Sara
- Koenig, Mary Kay
- Cho, Megan T
- Powis, Zöe
- Nabbout, Rima
- Barcia, Giulia
- Rosenfeld, Jill A
- Bacino, Carlos A
- Mignot, Cyril
- Power, Lillian H
- Harris, Catharine J
- Møller, Rikke S
- Hammer, Trine B
- Vieira, Päivi
- Hildebrandt, Clara
- Sacharow, Stephanie
- Maragliano, Luca
- Benfenati, Fabio
- Lachlan, Katherine
- Petit, Florence
- Hallinan, Barbara
- Si, Yue
- Wentzensen, Ingrid M
- Narayanan, Vinodh
- Matsumoto, Naomichi
- Boncristiano, Alessandra
- Kato, Mitsuhiro
- Barba, Carmen
- Sturiale, Luisa
- Garozzo, Domenico
- Bei, Roberto
- Masuelli, Laura
- Conti, Valerio
- Novarino, Gaia
- Fassio, Anna
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2022-06-09
- Volume
- 145
- Issue
- 8
- Pages
- 2687-2703
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC10893886
- OpenAlex
- W4226371602
- Cited by
- 34
- References
- 0
- Citations by year
- 2026: 2 · 2025: 12 · 2024: 12 · 2023: 7 · 2022: 1
- FWCI
- 2.61
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Brain (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (publishedVersion)
- Digital Commons-TMC (Texas Medical Center) (submittedVersion)
- HAL (submittedVersion)
- Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion)
- Florence Research (University of Florence) (submittedVersion)
- CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Università Politecnica delle Marche (Università Politecnica delle Marche) (submittedVersion, other-oa)
- CNR ExploRA (submittedVersion)
- Institute of Science and Technology Austria (submittedVersion, other-oa)
- Funders
- EU 7th Framework Programme (N602531)
- Regione Toscana (DECODE-EE)
- Fondazione Cassa di Risparmio di Firenze
- IRCCS Ospedale Policlinico San Martino
- Ricerca Corrente
- Health Innovation Challenge Fund (HICF-1009-003)
- Wellcome
- Department of Health
- Wellcome Sanger Institute (WT098051)
- UK Research Ethics Committee
- Cambridge South REC (10/H0305/83)
- Republic of Ireland REC (GEN/284/12)
- DECIPHER
- ISTplus fellowship
- NIH
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › ATP Synthase and ATPases Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- ATP6V1A, V-ATPase, lysosomal homeostasis, developmental and epileptic encephalopathy, infantile spasms, intellectual disability, microcephaly, amelogenesis imperfecta, brain atrophy, LAMP1, lysosomal pH, missense mutations, iPSC-derived neurons
- MeSH terms
- Adenosine Triphosphate, Atrophy, Brain Diseases, Child, Epilepsy, Homeostasis, Humans, Infant, Lysosomes, Intellectual Disability, Phenotype, Spasms, Infantile, Vacuolar Proton-Translocating ATPases
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