{"abstract":[{"text":"Biallelic variants in NADH (nicotinamide adenine dinucleotide (NAD) + hydrogen (H))-ubiquinone oxidoreductase 1 alpha subcomplex 13 have been linked to mitochondrial complex I deficiency, nuclear type 28, based on three affected individuals from two families. With only two families reported, the clinical and molecular spectrum of NADH-ubiquinone oxidoreductase 1 alpha subcomplex 13–related diseases remains unclear. We report 10 additional affected individuals from nine independent families, identifying four missense variants (including recurrent c.170G > A) and three ultra-rare or novel predicted loss-of-function biallelic variants. Updated clinical–radiological data from previously reported families and a literature review compiling clinical features of all reported patients with isolated complex I deficiency caused by 43 genes encoding complex I subunits and assembly factors are also provided. Our cohort (mean age 7.8 ± 5.4 years; range 2.5–18) predominantly presented a moderate-to-severe neurodevelopmental syndrome with oculomotor abnormalities (84%), spasticity/hypertonia (83%), hypotonia (69%), cerebellar ataxia (66%), movement disorders (58%) and epilepsy (46%). Neuroimaging revealed bilateral symmetric T2 hyperintense substantia nigra lesions (91.6%) and optic nerve atrophy (66.6%). Protein modeling suggests missense variants destabilize a critical junction between the hydrophilic and membrane arms of complex I. Fibroblasts from two patients showed reduced complex I activity and compensatory complex IV activity increase. This study characterizes NADH-ubiquinone oxidoreductase 1 alpha subcomplex 13–related disease in 13 individuals, highlighting genotype–phenotype correlations.","lang":"eng"}],"tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)"},"year":"2025","acknowledgement":"We thank all individuals and relatives for consent to be part of the study. Families 1–4, 7, were collected as part of the SYNaPS Study Group collaboration funded by The Wellcome Trust and strategic award (Synaptopathies) funding (WT093205 MA and WT104033AIA), and research was conducted as part of the Queen Square Genomics group at the University College London, supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. We are also grateful to Queen Square Genomics at the Institute of Neurology University College London, supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre, for the bioinformatics support. For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.\r\nThis study was funded by the Medical Research Council (MR/S01165X/1, MR/S005021/1, G0601943). The Medical Research Council (MR/S01165X/1, MR/S005021/1, MRC ICGNMD), Wellcome Trust 221951/Z/20/Z, Global Parkinson’s Genetics Program, Aligning Science Across Parkinson’s, The Michael J. Fox Foundation, The National Institute for Health Research University College London Hospitals Biomedical Research Centre, Rosetree Trust, Multiple System Atrophy Trust, Brain Research UK, Sparks Great Ormond Street Hospital Charity, Muscular Dystrophy, Muscular Dystrophy Association United States of America, and King Baudouin Foundation. H.T. was supported by the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 608473. M.S.A.-H. is funded by the Science and Technology Development Fund Academy of Science Research and Technology Egypt (Grant number: 33492, Ethical approval number: 20066). R.W.T. is funded by the Wellcome Centre for Mitochondrial Research (203105/Z/16/Z), the Mitochondrial Disease Patient Cohort (UK) (G0800674), the Medical Research Council International Centre for Genomic Medicine in Neuromuscular Disease (MR/S005021/1), the Medical Research Council (MR/W019027/1), the Lily Foundation, Mito Foundation, the Pathological Society, LifeArc, the UK National Institute for Health Research Biomedical Research Centre for Ageing and Age-related disease award to the Newcastle upon Tyne Foundation Hospitals NHS Trust and the UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children. H.H. and R.K. are supported by Global Parkinson’s Genetic Program and The Michael J. Fox Foundation Grant ID: MJFF-022153.","OA_type":"gold","scopus_import":"1","_id":"18987","day":"01","article_processing_charge":"Yes","date_published":"2025-01-01T00:00:00Z","file":[{"date_updated":"2025-08-05T11:54:23Z","file_id":"20126","file_name":"2025_BrainComm_Kaiyrzhanov.pdf","file_size":1420646,"date_created":"2025-08-05T11:54:23Z","creator":"dernst","success":1,"content_type":"application/pdf","relation":"main_file","access_level":"open_access","checksum":"bdf39b64d1c1d833a20b62836751fe44"}],"citation":{"apa":"Kaiyrzhanov, R., Thompson, K., Efthymiou, S., Mukushev, A., Zharylkassyn, A., Prasad, C., … Maroofian, R. (2025). Biallelic NDUFA13 variants lead to a neurodevelopmental phenotype with gradual neurological impairment. <i>Brain Communications</i>. Oxford University Press. <a href=\"https://doi.org/10.1093/braincomms/fcae453\">https://doi.org/10.1093/braincomms/fcae453</a>","short":"R. Kaiyrzhanov, K. Thompson, S. Efthymiou, A. Mukushev, A. Zharylkassyn, C. Prasad, E.G. Karimiani, J.R. Alvi, D. Niyazov, A. Alahmad, M. Babaei, H. Tajsharghi, B. Albash, A. Alaqeel, M. Charif, N. Hashemi, M. Heidari, S.M. Kalantar, G. Lenaers, M.Y.V. Mehrjardi, V.M. Srinivasan, V.K. Gowda, S.H. Mirabutalebi, D.A. Carere, M. Movahedinia, D. Murphy, R. Mcfarland, M.S. Abdel-Hamid, R.M. Elhossini, S. Alavi, M. Napier, A. Belanger-Quintana, A.N. Prasad, J. Jakobczyk, A. Roubertie, T. Rupar, T. Sultan, M.B. Toosi, L.A. Sazanov, M. Severino, H. Houlden, R.W. Taylor, R. Maroofian, Brain Communications 7 (2025).","ama":"Kaiyrzhanov R, Thompson K, Efthymiou S, et al. Biallelic NDUFA13 variants lead to a neurodevelopmental phenotype with gradual neurological impairment. <i>Brain Communications</i>. 2025;7(1). doi:<a href=\"https://doi.org/10.1093/braincomms/fcae453\">10.1093/braincomms/fcae453</a>","ista":"Kaiyrzhanov R, Thompson K, Efthymiou S, Mukushev A, Zharylkassyn A, Prasad C, Karimiani EG, Alvi JR, Niyazov D, Alahmad A, Babaei M, Tajsharghi H, Albash B, Alaqeel A, Charif M, Hashemi N, Heidari M, Kalantar SM, Lenaers G, Mehrjardi MYV, Srinivasan VM, Gowda VK, Mirabutalebi SH, Carere DA, Movahedinia M, Murphy D, Mcfarland R, Abdel-Hamid MS, Elhossini RM, Alavi S, Napier M, Belanger-Quintana A, Prasad AN, Jakobczyk J, Roubertie A, Rupar T, Sultan T, Toosi MB, Sazanov LA, Severino M, Houlden H, Taylor RW, Maroofian R. 2025. Biallelic NDUFA13 variants lead to a neurodevelopmental phenotype with gradual neurological impairment. Brain Communications. 7(1), fcae453.","mla":"Kaiyrzhanov, Rauan, et al. “Biallelic NDUFA13 Variants Lead to a Neurodevelopmental Phenotype with Gradual Neurological Impairment.” <i>Brain Communications</i>, vol. 7, no. 1, fcae453, Oxford University Press, 2025, doi:<a href=\"https://doi.org/10.1093/braincomms/fcae453\">10.1093/braincomms/fcae453</a>.","ieee":"R. Kaiyrzhanov <i>et al.</i>, “Biallelic NDUFA13 variants lead to a neurodevelopmental phenotype with gradual neurological impairment,” <i>Brain Communications</i>, vol. 7, no. 1. Oxford University Press, 2025.","chicago":"Kaiyrzhanov, Rauan, Kyle Thompson, Stephanie Efthymiou, Askhat Mukushev, Akbota Zharylkassyn, Chitra Prasad, Ehsan Ghayoor Karimiani, et al. “Biallelic NDUFA13 Variants Lead to a Neurodevelopmental Phenotype with Gradual Neurological Impairment.” <i>Brain Communications</i>. Oxford University Press, 2025. <a href=\"https://doi.org/10.1093/braincomms/fcae453\">https://doi.org/10.1093/braincomms/fcae453</a>."},"DOAJ_listed":"1","publication_status":"published","status":"public","oa":1,"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","publisher":"Oxford University Press","doi":"10.1093/braincomms/fcae453","date_created":"2025-02-02T23:01:55Z","pmid":1,"intvolume":"         7","author":[{"last_name":"Kaiyrzhanov","full_name":"Kaiyrzhanov, Rauan","first_name":"Rauan"},{"first_name":"Kyle","full_name":"Thompson, Kyle","last_name":"Thompson"},{"first_name":"Stephanie","full_name":"Efthymiou, Stephanie","last_name":"Efthymiou"},{"last_name":"Mukushev","full_name":"Mukushev, Askhat","first_name":"Askhat"},{"first_name":"Akbota","last_name":"Zharylkassyn","full_name":"Zharylkassyn, Akbota"},{"last_name":"Prasad","full_name":"Prasad, Chitra","first_name":"Chitra"},{"first_name":"Ehsan Ghayoor","last_name":"Karimiani","full_name":"Karimiani, Ehsan Ghayoor"},{"first_name":"Javeria Raza","full_name":"Alvi, Javeria Raza","last_name":"Alvi"},{"first_name":"Dmitriy","full_name":"Niyazov, Dmitriy","last_name":"Niyazov"},{"full_name":"Alahmad, Ahmad","last_name":"Alahmad","first_name":"Ahmad"},{"first_name":"Meisam","last_name":"Babaei","full_name":"Babaei, Meisam"},{"last_name":"Tajsharghi","full_name":"Tajsharghi, Homa","first_name":"Homa"},{"first_name":"Buthaina","full_name":"Albash, Buthaina","last_name":"Albash"},{"last_name":"Alaqeel","full_name":"Alaqeel, Ahmad","first_name":"Ahmad"},{"first_name":"Majida","full_name":"Charif, Majida","last_name":"Charif"},{"full_name":"Hashemi, Narges","last_name":"Hashemi","first_name":"Narges"},{"first_name":"Morteza","full_name":"Heidari, Morteza","last_name":"Heidari"},{"full_name":"Kalantar, Seyed Mehdi","last_name":"Kalantar","first_name":"Seyed Mehdi"},{"full_name":"Lenaers, Guy","last_name":"Lenaers","first_name":"Guy"},{"last_name":"Mehrjardi","full_name":"Mehrjardi, Mohammad Yahya Vahidi","first_name":"Mohammad Yahya Vahidi"},{"first_name":"Varunvenkat M.","full_name":"Srinivasan, Varunvenkat M.","last_name":"Srinivasan"},{"full_name":"Gowda, Vykuntaraju K.","last_name":"Gowda","first_name":"Vykuntaraju K."},{"first_name":"Seyed Hamidreza","full_name":"Mirabutalebi, Seyed Hamidreza","last_name":"Mirabutalebi"},{"first_name":"Deanna Alexis","last_name":"Carere","full_name":"Carere, Deanna Alexis"},{"first_name":"Mojtaba","last_name":"Movahedinia","full_name":"Movahedinia, Mojtaba"},{"first_name":"David","full_name":"Murphy, David","last_name":"Murphy"},{"first_name":"Robert","last_name":"Mcfarland","full_name":"Mcfarland, Robert"},{"full_name":"Abdel-Hamid, Mohamed S.","last_name":"Abdel-Hamid","first_name":"Mohamed S."},{"first_name":"Rasha M.","full_name":"Elhossini, Rasha M.","last_name":"Elhossini"},{"first_name":"Shahryar","full_name":"Alavi, Shahryar","last_name":"Alavi"},{"full_name":"Napier, Melanie","last_name":"Napier","first_name":"Melanie"},{"last_name":"Belanger-Quintana","full_name":"Belanger-Quintana, Amaya","first_name":"Amaya"},{"full_name":"Prasad, Asuri N.","last_name":"Prasad","first_name":"Asuri N."},{"last_name":"Jakobczyk","full_name":"Jakobczyk, Jessica","first_name":"Jessica"},{"first_name":"Agathe","last_name":"Roubertie","full_name":"Roubertie, Agathe"},{"last_name":"Rupar","full_name":"Rupar, Tony","first_name":"Tony"},{"first_name":"Tipu","last_name":"Sultan","full_name":"Sultan, Tipu"},{"first_name":"Mehran Beiraghi","full_name":"Toosi, Mehran Beiraghi","last_name":"Toosi"},{"id":"338D39FE-F248-11E8-B48F-1D18A9856A87","first_name":"Leonid A","full_name":"Sazanov, Leonid A","last_name":"Sazanov","orcid":"0000-0002-0977-7989"},{"last_name":"Severino","full_name":"Severino, Mariasavina","first_name":"Mariasavina"},{"full_name":"Houlden, Henry","last_name":"Houlden","first_name":"Henry"},{"first_name":"Robert W.","full_name":"Taylor, Robert W.","last_name":"Taylor"},{"full_name":"Maroofian, Reza","last_name":"Maroofian","first_name":"Reza"}],"OA_place":"publisher","date_updated":"2025-08-05T11:55:15Z","article_type":"original","department":[{"_id":"LeSa"}],"quality_controlled":"1","issue":"1","type":"journal_article","title":"Biallelic NDUFA13 variants lead to a neurodevelopmental phenotype with gradual neurological impairment","article_number":"fcae453","external_id":{"pmid":["39963288"]},"ddc":["570"],"language":[{"iso":"eng"}],"file_date_updated":"2025-08-05T11:54:23Z","month":"01","publication":"Brain Communications","has_accepted_license":"1","volume":7,"PlanS_conform":"1","oa_version":"Published Version","publication_identifier":{"eissn":["2632-1297"]}}