--- DOAJ_listed: '1' OA_place: publisher OA_type: gold PlanS_conform: '1' _id: '18987' abstract: - lang: eng 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. 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." article_number: fcae453 article_processing_charge: Yes article_type: original author: - first_name: Rauan full_name: Kaiyrzhanov, Rauan last_name: Kaiyrzhanov - first_name: Kyle full_name: Thompson, Kyle last_name: Thompson - first_name: Stephanie full_name: Efthymiou, Stephanie last_name: Efthymiou - first_name: Askhat full_name: Mukushev, Askhat last_name: Mukushev - first_name: Akbota full_name: Zharylkassyn, Akbota last_name: Zharylkassyn - first_name: Chitra full_name: Prasad, Chitra last_name: Prasad - first_name: Ehsan Ghayoor full_name: Karimiani, Ehsan Ghayoor last_name: Karimiani - first_name: Javeria Raza full_name: Alvi, Javeria Raza last_name: Alvi - first_name: Dmitriy full_name: Niyazov, Dmitriy last_name: Niyazov - first_name: Ahmad full_name: Alahmad, Ahmad last_name: Alahmad - first_name: Meisam full_name: Babaei, Meisam last_name: Babaei - first_name: Homa full_name: Tajsharghi, Homa last_name: Tajsharghi - first_name: Buthaina full_name: Albash, Buthaina last_name: Albash - first_name: Ahmad full_name: Alaqeel, Ahmad last_name: Alaqeel - first_name: Majida full_name: Charif, Majida last_name: Charif - first_name: Narges full_name: Hashemi, Narges last_name: Hashemi - first_name: Morteza full_name: Heidari, Morteza last_name: Heidari - first_name: Seyed Mehdi full_name: Kalantar, Seyed Mehdi last_name: Kalantar - first_name: Guy full_name: Lenaers, Guy last_name: Lenaers - first_name: Mohammad Yahya Vahidi full_name: Mehrjardi, Mohammad Yahya Vahidi last_name: Mehrjardi - first_name: Varunvenkat M. full_name: Srinivasan, Varunvenkat M. last_name: Srinivasan - first_name: Vykuntaraju K. full_name: Gowda, Vykuntaraju K. last_name: Gowda - first_name: Seyed Hamidreza full_name: Mirabutalebi, Seyed Hamidreza last_name: Mirabutalebi - first_name: Deanna Alexis full_name: Carere, Deanna Alexis last_name: Carere - first_name: Mojtaba full_name: Movahedinia, Mojtaba last_name: Movahedinia - first_name: David full_name: Murphy, David last_name: Murphy - first_name: Robert full_name: Mcfarland, Robert last_name: Mcfarland - first_name: Mohamed S. full_name: Abdel-Hamid, Mohamed S. last_name: Abdel-Hamid - first_name: Rasha M. full_name: Elhossini, Rasha M. last_name: Elhossini - first_name: Shahryar full_name: Alavi, Shahryar last_name: Alavi - first_name: Melanie full_name: Napier, Melanie last_name: Napier - first_name: Amaya full_name: Belanger-Quintana, Amaya last_name: Belanger-Quintana - first_name: Asuri N. full_name: Prasad, Asuri N. last_name: Prasad - first_name: Jessica full_name: Jakobczyk, Jessica last_name: Jakobczyk - first_name: Agathe full_name: Roubertie, Agathe last_name: Roubertie - first_name: Tony full_name: Rupar, Tony last_name: Rupar - first_name: Tipu full_name: Sultan, Tipu last_name: Sultan - first_name: Mehran Beiraghi full_name: Toosi, Mehran Beiraghi last_name: Toosi - first_name: Leonid A full_name: Sazanov, Leonid A id: 338D39FE-F248-11E8-B48F-1D18A9856A87 last_name: Sazanov orcid: 0000-0002-0977-7989 - first_name: Mariasavina full_name: Severino, Mariasavina last_name: Severino - first_name: Henry full_name: Houlden, Henry last_name: Houlden - first_name: Robert W. full_name: Taylor, Robert W. last_name: Taylor - first_name: Reza full_name: Maroofian, Reza last_name: Maroofian citation: ama: Kaiyrzhanov R, Thompson K, Efthymiou S, et al. Biallelic NDUFA13 variants lead to a neurodevelopmental phenotype with gradual neurological impairment. Brain Communications. 2025;7(1). doi:10.1093/braincomms/fcae453 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. Brain Communications. Oxford University Press. https://doi.org/10.1093/braincomms/fcae453 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.” Brain Communications. Oxford University Press, 2025. https://doi.org/10.1093/braincomms/fcae453. ieee: R. Kaiyrzhanov et al., “Biallelic NDUFA13 variants lead to a neurodevelopmental phenotype with gradual neurological impairment,” Brain Communications, vol. 7, no. 1. Oxford University Press, 2025. 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.” Brain Communications, vol. 7, no. 1, fcae453, Oxford University Press, 2025, doi:10.1093/braincomms/fcae453. 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). date_created: 2025-02-02T23:01:55Z date_published: 2025-01-01T00:00:00Z date_updated: 2025-08-05T11:55:15Z day: '01' ddc: - '570' department: - _id: LeSa doi: 10.1093/braincomms/fcae453 external_id: pmid: - '39963288' file: - access_level: open_access checksum: bdf39b64d1c1d833a20b62836751fe44 content_type: application/pdf creator: dernst date_created: 2025-08-05T11:54:23Z date_updated: 2025-08-05T11:54:23Z file_id: '20126' file_name: 2025_BrainComm_Kaiyrzhanov.pdf file_size: 1420646 relation: main_file success: 1 file_date_updated: 2025-08-05T11:54:23Z has_accepted_license: '1' intvolume: ' 7' issue: '1' language: - iso: eng month: '01' oa: 1 oa_version: Published Version pmid: 1 publication: Brain Communications publication_identifier: eissn: - 2632-1297 publication_status: published publisher: Oxford University Press quality_controlled: '1' scopus_import: '1' status: public title: Biallelic NDUFA13 variants lead to a neurodevelopmental phenotype with gradual neurological impairment tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87 volume: 7 year: '2025' ...