{"year":"2022","acknowledged_ssus":[{"_id":"EM-Fac"},{"_id":"LifeSc"}],"intvolume":"       145","volume":145,"project":[{"call_identifier":"H2020","grant_number":"754411","name":"ISTplus - Postdoctoral Fellowships","_id":"260C2330-B435-11E9-9278-68D0E5697425"}],"acknowledgement":"We thank all patients and family members for their participation in this study. We thank Melanie Pieraks and Eva Reinthaler (Neurolentech, Austria) for generating the human iPSC lines and\r\nfor performing quality checks. We thank Vanessa Zheden and Daniel Gütl for their excellent technical support in the specimen preparation for transmission electron microscopy and Flavia Leite for preparing the lentiviruses. The support from Electron Microscopy Facility and Molecular Biology Services at IST Austria is greatly acknowledged. We would like to thank Doctors Jane Hurst and Richard Scott for their help in retrieving the detailed clinical information of Patient 17. The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network. See Supplementary Material for Undiagnosed Disease Network consortium details. Genetic information on Patient 23 was made available through access to the data and findings generated by the 100 000 Genomes\r\nProject; www.genomicsengland.co.uk (to K.L.). \r\nThis 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\r\nDECODE-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\r\nare 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. ","isi":1,"keyword":["Neurology (clinical)"],"external_id":{"isi":["000807770000001"]},"publication_identifier":{"eissn":["1460-2156"],"issn":["0006-8950"]},"doi":"10.1093/brain/awac145","page":"2687-2703","author":[{"full_name":"Guerrini, Renzo","last_name":"Guerrini","first_name":"Renzo"},{"last_name":"Mei","first_name":"Davide","full_name":"Mei, Davide"},{"full_name":"Szigeti, Margit Katalin","id":"44F4BDC0-F248-11E8-B48F-1D18A9856A87","first_name":"Margit Katalin","last_name":"Szigeti","orcid":"0000-0001-9500-8758"},{"full_name":"Pepe, Sara","first_name":"Sara","last_name":"Pepe"},{"full_name":"Koenig, Mary Kay","first_name":"Mary Kay","last_name":"Koenig"},{"last_name":"Von Allmen","first_name":"Gretchen","full_name":"Von Allmen, Gretchen"},{"full_name":"Cho, Megan T","last_name":"Cho","first_name":"Megan T"},{"full_name":"McDonald, Kimberly","first_name":"Kimberly","last_name":"McDonald"},{"full_name":"Baker, Janice","first_name":"Janice","last_name":"Baker"},{"full_name":"Bhambhani, Vikas","last_name":"Bhambhani","first_name":"Vikas"},{"full_name":"Powis, Zöe","first_name":"Zöe","last_name":"Powis"},{"first_name":"Lance","last_name":"Rodan","full_name":"Rodan, Lance"},{"first_name":"Rima","last_name":"Nabbout","full_name":"Nabbout, Rima"},{"full_name":"Barcia, Giulia","first_name":"Giulia","last_name":"Barcia"},{"full_name":"Rosenfeld, Jill A","first_name":"Jill A","last_name":"Rosenfeld"},{"first_name":"Carlos A","last_name":"Bacino","full_name":"Bacino, Carlos A"},{"full_name":"Mignot, Cyril","last_name":"Mignot","first_name":"Cyril"},{"first_name":"Lillian H","last_name":"Power","full_name":"Power, Lillian H"},{"full_name":"Harris, Catharine J","last_name":"Harris","first_name":"Catharine J"},{"full_name":"Marjanovic, Dragan","last_name":"Marjanovic","first_name":"Dragan"},{"full_name":"Møller, Rikke S","last_name":"Møller","first_name":"Rikke S"},{"full_name":"Hammer, Trine B","last_name":"Hammer","first_name":"Trine B"},{"full_name":"Keski Filppula, Riikka","first_name":"Riikka","last_name":"Keski Filppula"},{"first_name":"Päivi","last_name":"Vieira","full_name":"Vieira, Päivi"},{"last_name":"Hildebrandt","first_name":"Clara","full_name":"Hildebrandt, Clara"},{"full_name":"Sacharow, Stephanie","last_name":"Sacharow","first_name":"Stephanie"},{"full_name":"Maragliano, Luca","last_name":"Maragliano","first_name":"Luca"},{"last_name":"Benfenati","first_name":"Fabio","full_name":"Benfenati, Fabio"},{"full_name":"Lachlan, Katherine","first_name":"Katherine","last_name":"Lachlan"},{"first_name":"Andreas","last_name":"Benneche","full_name":"Benneche, Andreas"},{"last_name":"Petit","first_name":"Florence","full_name":"Petit, Florence"},{"first_name":"Jean Madeleine","last_name":"de Sainte Agathe","full_name":"de Sainte Agathe, Jean Madeleine"},{"last_name":"Hallinan","first_name":"Barbara","full_name":"Hallinan, Barbara"},{"full_name":"Si, Yue","last_name":"Si","first_name":"Yue"},{"full_name":"Wentzensen, Ingrid M","last_name":"Wentzensen","first_name":"Ingrid M"},{"full_name":"Zou, Fanggeng","last_name":"Zou","first_name":"Fanggeng"},{"full_name":"Narayanan, Vinodh","last_name":"Narayanan","first_name":"Vinodh"},{"last_name":"Matsumoto","first_name":"Naomichi","full_name":"Matsumoto, Naomichi"},{"full_name":"Boncristiano, Alessandra","last_name":"Boncristiano","first_name":"Alessandra"},{"full_name":"la Marca, Giancarlo","first_name":"Giancarlo","last_name":"la Marca"},{"first_name":"Mitsuhiro","last_name":"Kato","full_name":"Kato, Mitsuhiro"},{"last_name":"Anderson","first_name":"Kristin","full_name":"Anderson, Kristin"},{"full_name":"Barba, Carmen","first_name":"Carmen","last_name":"Barba"},{"full_name":"Sturiale, Luisa","last_name":"Sturiale","first_name":"Luisa"},{"first_name":"Domenico","last_name":"Garozzo","full_name":"Garozzo, Domenico"},{"first_name":"Roberto","last_name":"Bei","full_name":"Bei, Roberto"},{"first_name":"Laura","last_name":"Masuelli","full_name":"Masuelli, Laura"},{"last_name":"Conti","first_name":"Valerio","full_name":"Conti, Valerio"},{"orcid":"0000-0002-7673-7178","first_name":"Gaia","last_name":"Novarino","id":"3E57A680-F248-11E8-B48F-1D18A9856A87","full_name":"Novarino, Gaia"},{"first_name":"Anna","last_name":"Fassio","full_name":"Fassio, Anna"}],"publication":"Brain","language":[{"iso":"eng"}],"_id":"12174","ec_funded":1,"article_type":"original","citation":{"short":"R. Guerrini, D. Mei, M.K. Szigeti, S. Pepe, M.K. Koenig, G. Von Allmen, M.T. Cho, K. McDonald, J. Baker, V. Bhambhani, Z. Powis, L. Rodan, R. Nabbout, G. Barcia, J.A. Rosenfeld, C.A. Bacino, C. Mignot, L.H. Power, C.J. Harris, D. Marjanovic, R.S. Møller, T.B. Hammer, R. Keski Filppula, P. Vieira, C. Hildebrandt, S. Sacharow, L. Maragliano, F. Benfenati, K. Lachlan, A. Benneche, F. Petit, J.M. de Sainte Agathe, B. Hallinan, Y. Si, I.M. Wentzensen, F. Zou, V. Narayanan, N. Matsumoto, A. Boncristiano, G. la Marca, M. Kato, K. Anderson, C. Barba, L. Sturiale, D. Garozzo, R. Bei, L. Masuelli, V. Conti, G. Novarino, A. Fassio, Brain 145 (2022) 2687–2703.","ama":"Guerrini R, Mei D, Szigeti MK, et al. Phenotypic and genetic spectrum of ATP6V1A encephalopathy: A disorder of lysosomal homeostasis. <i>Brain</i>. 2022;145(8):2687-2703. doi:<a href=\"https://doi.org/10.1093/brain/awac145\">10.1093/brain/awac145</a>","ista":"Guerrini R, Mei D, Szigeti MK, Pepe S, Koenig MK, Von Allmen G, Cho MT, McDonald K, Baker J, Bhambhani V, Powis Z, Rodan L, Nabbout R, Barcia G, Rosenfeld JA, Bacino CA, Mignot C, Power LH, Harris CJ, Marjanovic D, Møller RS, Hammer TB, Keski Filppula R, Vieira P, Hildebrandt C, Sacharow S, Maragliano L, Benfenati F, Lachlan K, Benneche A, Petit F, de Sainte Agathe JM, Hallinan B, Si Y, Wentzensen IM, Zou F, Narayanan V, Matsumoto N, Boncristiano A, la Marca G, Kato M, Anderson K, Barba C, Sturiale L, Garozzo D, Bei R, Masuelli L, Conti V, Novarino G, Fassio A. 2022. Phenotypic and genetic spectrum of ATP6V1A encephalopathy: A disorder of lysosomal homeostasis. Brain. 145(8), 2687–2703.","chicago":"Guerrini, Renzo, Davide Mei, Margit Katalin Szigeti, Sara Pepe, Mary Kay Koenig, Gretchen Von Allmen, Megan T Cho, et al. “Phenotypic and Genetic Spectrum of ATP6V1A Encephalopathy: A Disorder of Lysosomal Homeostasis.” <i>Brain</i>. Oxford University Press, 2022. <a href=\"https://doi.org/10.1093/brain/awac145\">https://doi.org/10.1093/brain/awac145</a>.","apa":"Guerrini, R., Mei, D., Szigeti, M. K., Pepe, S., Koenig, M. K., Von Allmen, G., … Fassio, A. (2022). Phenotypic and genetic spectrum of ATP6V1A encephalopathy: A disorder of lysosomal homeostasis. <i>Brain</i>. Oxford University Press. <a href=\"https://doi.org/10.1093/brain/awac145\">https://doi.org/10.1093/brain/awac145</a>","ieee":"R. Guerrini <i>et al.</i>, “Phenotypic and genetic spectrum of ATP6V1A encephalopathy: A disorder of lysosomal homeostasis,” <i>Brain</i>, vol. 145, no. 8. Oxford University Press, pp. 2687–2703, 2022.","mla":"Guerrini, Renzo, et al. “Phenotypic and Genetic Spectrum of ATP6V1A Encephalopathy: A Disorder of Lysosomal Homeostasis.” <i>Brain</i>, vol. 145, no. 8, Oxford University Press, 2022, pp. 2687–703, doi:<a href=\"https://doi.org/10.1093/brain/awac145\">10.1093/brain/awac145</a>."},"publisher":"Oxford University Press","scopus_import":"1","oa":1,"oa_version":"Published Version","date_created":"2023-01-12T12:11:45Z","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","quality_controlled":"1","title":"Phenotypic and genetic spectrum of ATP6V1A encephalopathy: A disorder of lysosomal homeostasis","status":"public","article_processing_charge":"No","month":"08","date_updated":"2023-08-04T09:13:08Z","type":"journal_article","day":"01","department":[{"_id":"GaNo"}],"main_file_link":[{"open_access":"1","url":"https://doi.org/10.1093/brain/awac145"}],"abstract":[{"lang":"eng","text":"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.\r\nHere 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>\r\n               <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.\r\nATP6V1A-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."}],"publication_status":"published","date_published":"2022-08-01T00:00:00Z","issue":"8"}