[{"article_processing_charge":"No","oa_version":"Submitted Version","month":"11","day":"10","citation":{"apa":"Kaiyrzhanov, R., Rad, A., Lin, S.-J., Bertoli-Avella, A., Kallemeijn, W. W., Godwin, A., … Maroofian, R. (2023). Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders. <i>Brain</i>. Oxford University Press. <a href=\"https://doi.org/10.1093/brain/awad380\">https://doi.org/10.1093/brain/awad380</a>","ieee":"R. Kaiyrzhanov <i>et al.</i>, “Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders,” <i>Brain</i>. Oxford University Press, 2023.","ama":"Kaiyrzhanov R, Rad A, Lin S-J, et al. Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders. <i>Brain</i>. 2023. doi:<a href=\"https://doi.org/10.1093/brain/awad380\">10.1093/brain/awad380</a>","ista":"Kaiyrzhanov R, Rad A, Lin S-J, Bertoli-Avella A, Kallemeijn WW, Godwin A, Zaki MS, Huang K, Lau T, Petree C, Efthymiou S, Ghayoor Karimiani E, Hempel M, Normand EA, Rudnik-Schöneborn S, Schatz UA, Baggelaar MP, Ilyas M, Sultan T, Alvi JR, Ganieva M, Fowler B, Aanicai R, Akay Tayfun G, Al Saman A, Alswaid A, Amiri N, Asilova N, Shotelersuk V, Yeetong P, Azam M, Babaei M, Bahrami Monajemi G, Mohammadi P, Samie S, Banu SH, Basto JP, Kortüm F, Bauer M, Bauer P, Beetz C, Garshasbi M, Hameed Issa A, Eyaid W, Ahmed H, Hashemi N, Hassanpour K, Herman I, Ibrohimov S, Abdul-Majeed BA, Imdad M, Isrofilov M, Kaiyal Q, Khan S, Kirmse B, Koster J, Lourenço CM, Mitani T, Moldovan O, Murphy D, Najafi M, Pehlivan D, Rocha ME, Salpietro V, Schmidts M, Shalata A, Mahroum M, Talbeya JK, Taylor RW, Vazquez D, Vetro A, Waterham HR, Zaman M, Schrader TA, Chung WK, Guerrini R, Lupski JR, Gleeson J, Suri M, Jamshidi Y, Bhatia KP, Vona B, Schrader M, Severino M, Guille M, Tate EW, Varshney GK, Houlden H, Maroofian R. 2023. Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders. Brain., awad380.","short":"R. Kaiyrzhanov, A. Rad, S.-J. Lin, A. Bertoli-Avella, W.W. Kallemeijn, A. Godwin, M.S. Zaki, K. Huang, T. Lau, C. Petree, S. Efthymiou, E. Ghayoor Karimiani, M. Hempel, E.A. Normand, S. Rudnik-Schöneborn, U.A. Schatz, M.P. Baggelaar, M. Ilyas, T. Sultan, J.R. Alvi, M. Ganieva, B. Fowler, R. Aanicai, G. Akay Tayfun, A. Al Saman, A. Alswaid, N. Amiri, N. Asilova, V. Shotelersuk, P. Yeetong, M. Azam, M. Babaei, G. Bahrami Monajemi, P. Mohammadi, S. Samie, S.H. Banu, J.P. Basto, F. Kortüm, M. Bauer, P. Bauer, C. Beetz, M. Garshasbi, A. Hameed Issa, W. Eyaid, H. Ahmed, N. Hashemi, K. Hassanpour, I. Herman, S. Ibrohimov, B.A. Abdul-Majeed, M. Imdad, M. Isrofilov, Q. Kaiyal, S. Khan, B. Kirmse, J. Koster, C.M. Lourenço, T. Mitani, O. Moldovan, D. Murphy, M. Najafi, D. Pehlivan, M.E. Rocha, V. Salpietro, M. Schmidts, A. Shalata, M. Mahroum, J.K. Talbeya, R.W. Taylor, D. Vazquez, A. Vetro, H.R. Waterham, M. Zaman, T.A. Schrader, W.K. Chung, R. Guerrini, J.R. Lupski, J. Gleeson, M. Suri, Y. Jamshidi, K.P. Bhatia, B. Vona, M. Schrader, M. Severino, M. Guille, E.W. Tate, G.K. Varshney, H. Houlden, R. Maroofian, Brain (2023).","chicago":"Kaiyrzhanov, Rauan, Aboulfazl Rad, Sheng-Jia Lin, Aida Bertoli-Avella, Wouter W Kallemeijn, Annie Godwin, Maha S Zaki, et al. “Bi-Allelic ACBD6 Variants Lead to a Neurodevelopmental Syndrome with Progressive and Complex Movement Disorders.” <i>Brain</i>. Oxford University Press, 2023. <a href=\"https://doi.org/10.1093/brain/awad380\">https://doi.org/10.1093/brain/awad380</a>.","mla":"Kaiyrzhanov, Rauan, et al. “Bi-Allelic ACBD6 Variants Lead to a Neurodevelopmental Syndrome with Progressive and Complex Movement Disorders.” <i>Brain</i>, awad380, Oxford University Press, 2023, doi:<a href=\"https://doi.org/10.1093/brain/awad380\">10.1093/brain/awad380</a>."},"status":"public","publication_status":"epub_ahead","publication_identifier":{"issn":["0006-8950"],"eissn":["1460-2156"]},"doi":"10.1093/brain/awad380","abstract":[{"lang":"eng","text":"The acyl-CoA-binding domain-containing protein 6 (ACBD6) is ubiquitously expressed, plays a role in the acylation of lipids and proteins, and regulates the N-myristoylation of proteins via N-myristoyltransferase enzymes (NMTs). However, its precise function in cells is still unclear, as is the consequence of ACBD6 defects on human pathophysiology. Utilizing exome sequencing and extensive international data sharing efforts, we identified 45 affected individuals from 28 unrelated families (consanguinity 93%) with bi-allelic pathogenic, predominantly loss-of-function (18/20) variants in ACBD6. We generated zebrafish and Xenopus tropicalis acbd6 knockouts by CRISPR/Cas9 and characterized the role of ACBD6 on protein N-myristoylation with YnMyr chemical proteomics in the model organisms and human cells, with the latter also being subjected further to ACBD6 peroxisomal localization studies. The affected individuals (23 males and 22 females), with ages ranging from 1 to 50 years old, typically present with a complex and progressive disease involving moderate-to-severe global developmental delay/intellectual disability (100%) with significant expressive language impairment (98%), movement disorders (97%), facial dysmorphism (95%), and mild cerebellar ataxia (85%) associated with gait impairment (94%), limb spasticity/hypertonia (76%), oculomotor (71%) and behavioural abnormalities (65%), overweight (59%), microcephaly (39%) and epilepsy (33%). The most conspicuous and common movement disorder was dystonia (94%), frequently leading to early-onset progressive postural deformities (97%), limb dystonia (55%), and cervical dystonia (31%). A jerky tremor in the upper limbs (63%), a mild head tremor (59%), parkinsonism/hypokinesia developing with advancing age (32%), and simple motor and vocal tics were among other frequent movement disorders. Midline brain malformations including corpus callosum abnormalities (70%), hypoplasia/agenesis of the anterior commissure (66%), short midbrain and small inferior cerebellar vermis (38% each), as well as hypertrophy of the clava (24%) were common neuroimaging findings. acbd6-deficient zebrafish and Xenopus models effectively recapitulated many clinical phenotypes reported in patients including movement disorders, progressive neuromotor impairment, seizures, microcephaly, craniofacial dysmorphism, and midbrain defects accompanied by developmental delay with increased mortality over time. Unlike ACBD5, ACBD6 did not show a peroxisomal localisation and ACBD6-deficiency was not associated with altered peroxisomal parameters in patient fibroblasts. Significant differences in YnMyr-labelling were observed for 68 co- and 18 post-translationally N-myristoylated proteins in patient-derived fibroblasts. N-Myristoylation was similarly affected in acbd6-deficient zebrafish and Xenopus tropicalis models, including Fus, Marcks, and Chchd-related proteins implicated in neurological diseases. The present study provides evidence that bi-allelic pathogenic variants in ACBD6 lead to a distinct neurodevelopmental syndrome accompanied by complex and progressive cognitive and movement disorders."}],"_id":"14543","author":[{"last_name":"Kaiyrzhanov","full_name":"Kaiyrzhanov, Rauan","first_name":"Rauan"},{"full_name":"Rad, Aboulfazl","last_name":"Rad","first_name":"Aboulfazl"},{"last_name":"Lin","full_name":"Lin, Sheng-Jia","first_name":"Sheng-Jia"},{"first_name":"Aida","last_name":"Bertoli-Avella","full_name":"Bertoli-Avella, Aida"},{"last_name":"Kallemeijn","full_name":"Kallemeijn, Wouter W","first_name":"Wouter W"},{"first_name":"Annie","full_name":"Godwin, Annie","last_name":"Godwin"},{"first_name":"Maha S","last_name":"Zaki","full_name":"Zaki, Maha S"},{"orcid":"0000-0002-2512-7812","full_name":"Huang, Kevin","last_name":"Huang","id":"3b3d2888-1ff6-11ee-9fa6-8f209ca91fe3","first_name":"Kevin"},{"first_name":"Tracy","full_name":"Lau, Tracy","last_name":"Lau"},{"first_name":"Cassidy","full_name":"Petree, Cassidy","last_name":"Petree"},{"first_name":"Stephanie","last_name":"Efthymiou","full_name":"Efthymiou, Stephanie"},{"full_name":"Ghayoor Karimiani, Ehsan","last_name":"Ghayoor Karimiani","first_name":"Ehsan"},{"first_name":"Maja","last_name":"Hempel","full_name":"Hempel, Maja"},{"first_name":"Elizabeth A","full_name":"Normand, Elizabeth A","last_name":"Normand"},{"last_name":"Rudnik-Schöneborn","full_name":"Rudnik-Schöneborn, Sabine","first_name":"Sabine"},{"first_name":"Ulrich A","last_name":"Schatz","full_name":"Schatz, Ulrich A"},{"full_name":"Baggelaar, Marc P","last_name":"Baggelaar","first_name":"Marc P"},{"first_name":"Muhammad","last_name":"Ilyas","full_name":"Ilyas, Muhammad"},{"full_name":"Sultan, Tipu","last_name":"Sultan","first_name":"Tipu"},{"first_name":"Javeria Raza","full_name":"Alvi, Javeria Raza","last_name":"Alvi"},{"first_name":"Manizha","full_name":"Ganieva, Manizha","last_name":"Ganieva"},{"last_name":"Fowler","full_name":"Fowler, Ben","first_name":"Ben"},{"last_name":"Aanicai","full_name":"Aanicai, Ruxandra","first_name":"Ruxandra"},{"first_name":"Gulsen","last_name":"Akay Tayfun","full_name":"Akay Tayfun, Gulsen"},{"last_name":"Al Saman","full_name":"Al Saman, Abdulaziz","first_name":"Abdulaziz"},{"last_name":"Alswaid","full_name":"Alswaid, Abdulrahman","first_name":"Abdulrahman"},{"first_name":"Nafise","full_name":"Amiri, Nafise","last_name":"Amiri"},{"first_name":"Nilufar","last_name":"Asilova","full_name":"Asilova, Nilufar"},{"first_name":"Vorasuk","last_name":"Shotelersuk","full_name":"Shotelersuk, Vorasuk"},{"full_name":"Yeetong, Patra","last_name":"Yeetong","first_name":"Patra"},{"first_name":"Matloob","last_name":"Azam","full_name":"Azam, Matloob"},{"first_name":"Meisam","full_name":"Babaei, Meisam","last_name":"Babaei"},{"first_name":"Gholamreza","full_name":"Bahrami Monajemi, Gholamreza","last_name":"Bahrami Monajemi"},{"first_name":"Pouria","last_name":"Mohammadi","full_name":"Mohammadi, Pouria"},{"first_name":"Saeed","full_name":"Samie, Saeed","last_name":"Samie"},{"first_name":"Selina Husna","last_name":"Banu","full_name":"Banu, Selina Husna"},{"first_name":"Jorge Pinto","last_name":"Basto","full_name":"Basto, Jorge Pinto"},{"first_name":"Fanny","full_name":"Kortüm, Fanny","last_name":"Kortüm"},{"last_name":"Bauer","full_name":"Bauer, Mislen","first_name":"Mislen"},{"first_name":"Peter","full_name":"Bauer, Peter","last_name":"Bauer"},{"full_name":"Beetz, Christian","last_name":"Beetz","first_name":"Christian"},{"first_name":"Masoud","last_name":"Garshasbi","full_name":"Garshasbi, Masoud"},{"first_name":"Awatif","last_name":"Hameed Issa","full_name":"Hameed Issa, Awatif"},{"last_name":"Eyaid","full_name":"Eyaid, Wafaa","first_name":"Wafaa"},{"first_name":"Hind","full_name":"Ahmed, Hind","last_name":"Ahmed"},{"first_name":"Narges","full_name":"Hashemi, Narges","last_name":"Hashemi"},{"first_name":"Kazem","last_name":"Hassanpour","full_name":"Hassanpour, Kazem"},{"first_name":"Isabella","last_name":"Herman","full_name":"Herman, Isabella"},{"first_name":"Sherozjon","full_name":"Ibrohimov, Sherozjon","last_name":"Ibrohimov"},{"full_name":"Abdul-Majeed, Ban A","last_name":"Abdul-Majeed","first_name":"Ban A"},{"first_name":"Maria","full_name":"Imdad, Maria","last_name":"Imdad"},{"full_name":"Isrofilov, Maksudjon","last_name":"Isrofilov","first_name":"Maksudjon"},{"full_name":"Kaiyal, Qassem","last_name":"Kaiyal","first_name":"Qassem"},{"full_name":"Khan, Suliman","last_name":"Khan","first_name":"Suliman"},{"first_name":"Brian","full_name":"Kirmse, Brian","last_name":"Kirmse"},{"last_name":"Koster","full_name":"Koster, Janet","first_name":"Janet"},{"last_name":"Lourenço","full_name":"Lourenço, Charles Marques","first_name":"Charles Marques"},{"first_name":"Tadahiro","full_name":"Mitani, Tadahiro","last_name":"Mitani"},{"first_name":"Oana","full_name":"Moldovan, Oana","last_name":"Moldovan"},{"full_name":"Murphy, David","last_name":"Murphy","first_name":"David"},{"last_name":"Najafi","full_name":"Najafi, Maryam","first_name":"Maryam"},{"last_name":"Pehlivan","full_name":"Pehlivan, Davut","first_name":"Davut"},{"first_name":"Maria Eugenia","last_name":"Rocha","full_name":"Rocha, Maria Eugenia"},{"first_name":"Vincenzo","last_name":"Salpietro","full_name":"Salpietro, Vincenzo"},{"first_name":"Miriam","last_name":"Schmidts","full_name":"Schmidts, Miriam"},{"first_name":"Adel","last_name":"Shalata","full_name":"Shalata, Adel"},{"last_name":"Mahroum","full_name":"Mahroum, Mohammad","first_name":"Mohammad"},{"last_name":"Talbeya","full_name":"Talbeya, Jawabreh Kassem","first_name":"Jawabreh Kassem"},{"full_name":"Taylor, Robert W","last_name":"Taylor","first_name":"Robert W"},{"first_name":"Dayana","full_name":"Vazquez, Dayana","last_name":"Vazquez"},{"full_name":"Vetro, Annalisa","last_name":"Vetro","first_name":"Annalisa"},{"last_name":"Waterham","full_name":"Waterham, Hans R","first_name":"Hans R"},{"first_name":"Mashaya","full_name":"Zaman, Mashaya","last_name":"Zaman"},{"last_name":"Schrader","full_name":"Schrader, Tina A","first_name":"Tina A"},{"last_name":"Chung","full_name":"Chung, Wendy K","first_name":"Wendy K"},{"full_name":"Guerrini, Renzo","last_name":"Guerrini","first_name":"Renzo"},{"full_name":"Lupski, James R","last_name":"Lupski","first_name":"James R"},{"first_name":"Joseph","last_name":"Gleeson","full_name":"Gleeson, Joseph"},{"first_name":"Mohnish","full_name":"Suri, Mohnish","last_name":"Suri"},{"first_name":"Yalda","last_name":"Jamshidi","full_name":"Jamshidi, Yalda"},{"first_name":"Kailash P","full_name":"Bhatia, Kailash P","last_name":"Bhatia"},{"last_name":"Vona","full_name":"Vona, Barbara","first_name":"Barbara"},{"full_name":"Schrader, Michael","last_name":"Schrader","first_name":"Michael"},{"full_name":"Severino, Mariasavina","last_name":"Severino","first_name":"Mariasavina"},{"first_name":"Matthew","full_name":"Guille, Matthew","last_name":"Guille"},{"last_name":"Tate","full_name":"Tate, Edward W","first_name":"Edward W"},{"full_name":"Varshney, Gaurav K","last_name":"Varshney","first_name":"Gaurav K"},{"first_name":"Henry","full_name":"Houlden, Henry","last_name":"Houlden"},{"last_name":"Maroofian","full_name":"Maroofian, Reza","first_name":"Reza"}],"title":"Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders","language":[{"iso":"eng"}],"quality_controlled":"1","type":"journal_article","main_file_link":[{"open_access":"1","url":"https://doi.org/10.1093/brain/awad380"}],"publisher":"Oxford University Press","scopus_import":"1","date_created":"2023-11-16T12:36:51Z","extern":"1","date_published":"2023-11-10T00:00:00Z","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","department":[{"_id":"GradSch"}],"article_type":"original","article_number":"awad380","date_updated":"2023-11-20T10:17:32Z","publication":"Brain","keyword":["Neurology (clinical)"],"year":"2023","oa":1},{"scopus_import":"1","acknowledged_ssus":[{"_id":"EM-Fac"},{"_id":"LifeSc"}],"date_created":"2023-01-12T12:11:45Z","date_published":"2022-08-01T00:00:00Z","external_id":{"isi":["000807770000001"]},"user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","department":[{"_id":"GaNo"}],"quality_controlled":"1","language":[{"iso":"eng"}],"type":"journal_article","isi":1,"intvolume":"       145","main_file_link":[{"url":"https://doi.org/10.1093/brain/awac145","open_access":"1"}],"publisher":"Oxford University Press","keyword":["Neurology (clinical)"],"year":"2022","oa":1,"article_type":"original","page":"2687-2703","date_updated":"2023-08-04T09:13:08Z","publication":"Brain","oa_version":"Published Version","month":"08","day":"01","citation":{"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.","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>","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.","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>","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>.","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>."},"volume":145,"article_processing_charge":"No","doi":"10.1093/brain/awac145","issue":"8","abstract":[{"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.","lang":"eng"}],"_id":"12174","author":[{"full_name":"Guerrini, Renzo","last_name":"Guerrini","first_name":"Renzo"},{"last_name":"Mei","full_name":"Mei, Davide","first_name":"Davide"},{"last_name":"Szigeti","full_name":"Szigeti, Margit Katalin","first_name":"Margit Katalin","id":"44F4BDC0-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-9500-8758"},{"first_name":"Sara","full_name":"Pepe, Sara","last_name":"Pepe"},{"first_name":"Mary Kay","last_name":"Koenig","full_name":"Koenig, Mary Kay"},{"last_name":"Von Allmen","full_name":"Von Allmen, Gretchen","first_name":"Gretchen"},{"full_name":"Cho, Megan T","last_name":"Cho","first_name":"Megan T"},{"last_name":"McDonald","full_name":"McDonald, Kimberly","first_name":"Kimberly"},{"first_name":"Janice","full_name":"Baker, Janice","last_name":"Baker"},{"full_name":"Bhambhani, Vikas","last_name":"Bhambhani","first_name":"Vikas"},{"full_name":"Powis, Zöe","last_name":"Powis","first_name":"Zöe"},{"full_name":"Rodan, Lance","last_name":"Rodan","first_name":"Lance"},{"last_name":"Nabbout","full_name":"Nabbout, Rima","first_name":"Rima"},{"full_name":"Barcia, Giulia","last_name":"Barcia","first_name":"Giulia"},{"full_name":"Rosenfeld, Jill A","last_name":"Rosenfeld","first_name":"Jill A"},{"last_name":"Bacino","full_name":"Bacino, Carlos A","first_name":"Carlos A"},{"full_name":"Mignot, Cyril","last_name":"Mignot","first_name":"Cyril"},{"full_name":"Power, Lillian H","last_name":"Power","first_name":"Lillian H"},{"first_name":"Catharine J","last_name":"Harris","full_name":"Harris, Catharine J"},{"first_name":"Dragan","full_name":"Marjanovic, Dragan","last_name":"Marjanovic"},{"last_name":"Møller","full_name":"Møller, Rikke S","first_name":"Rikke S"},{"first_name":"Trine B","last_name":"Hammer","full_name":"Hammer, Trine B"},{"full_name":"Keski Filppula, Riikka","last_name":"Keski Filppula","first_name":"Riikka"},{"full_name":"Vieira, Päivi","last_name":"Vieira","first_name":"Päivi"},{"full_name":"Hildebrandt, Clara","last_name":"Hildebrandt","first_name":"Clara"},{"full_name":"Sacharow, Stephanie","last_name":"Sacharow","first_name":"Stephanie"},{"last_name":"Maragliano","full_name":"Maragliano, Luca","first_name":"Luca"},{"first_name":"Fabio","full_name":"Benfenati, Fabio","last_name":"Benfenati"},{"first_name":"Katherine","last_name":"Lachlan","full_name":"Lachlan, Katherine"},{"full_name":"Benneche, Andreas","last_name":"Benneche","first_name":"Andreas"},{"last_name":"Petit","full_name":"Petit, Florence","first_name":"Florence"},{"first_name":"Jean Madeleine","full_name":"de Sainte Agathe, Jean Madeleine","last_name":"de Sainte Agathe"},{"full_name":"Hallinan, Barbara","last_name":"Hallinan","first_name":"Barbara"},{"first_name":"Yue","last_name":"Si","full_name":"Si, Yue"},{"full_name":"Wentzensen, Ingrid M","last_name":"Wentzensen","first_name":"Ingrid M"},{"first_name":"Fanggeng","last_name":"Zou","full_name":"Zou, Fanggeng"},{"full_name":"Narayanan, Vinodh","last_name":"Narayanan","first_name":"Vinodh"},{"first_name":"Naomichi","full_name":"Matsumoto, Naomichi","last_name":"Matsumoto"},{"first_name":"Alessandra","full_name":"Boncristiano, Alessandra","last_name":"Boncristiano"},{"full_name":"la Marca, Giancarlo","last_name":"la Marca","first_name":"Giancarlo"},{"first_name":"Mitsuhiro","full_name":"Kato, Mitsuhiro","last_name":"Kato"},{"full_name":"Anderson, Kristin","last_name":"Anderson","first_name":"Kristin"},{"first_name":"Carmen","full_name":"Barba, Carmen","last_name":"Barba"},{"first_name":"Luisa","full_name":"Sturiale, Luisa","last_name":"Sturiale"},{"first_name":"Domenico","last_name":"Garozzo","full_name":"Garozzo, Domenico"},{"full_name":"Bei, Roberto","last_name":"Bei","first_name":"Roberto"},{"last_name":"Masuelli","full_name":"Masuelli, Laura","first_name":"Laura"},{"full_name":"Conti, Valerio","last_name":"Conti","first_name":"Valerio"},{"orcid":"0000-0002-7673-7178","first_name":"Gaia","id":"3E57A680-F248-11E8-B48F-1D18A9856A87","last_name":"Novarino","full_name":"Novarino, Gaia"},{"full_name":"Fassio, Anna","last_name":"Fassio","first_name":"Anna"}],"title":"Phenotypic and genetic spectrum of ATP6V1A encephalopathy: A disorder of lysosomal homeostasis","ec_funded":1,"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. ","publication_status":"published","status":"public","project":[{"_id":"260C2330-B435-11E9-9278-68D0E5697425","grant_number":"754411","call_identifier":"H2020","name":"ISTplus - Postdoctoral Fellowships"}],"publication_identifier":{"eissn":["1460-2156"],"issn":["0006-8950"]}}]