article published yes Rauan Kaiyrzhanov author Kyle Thompson author Stephanie Efthymiou author Askhat Mukushev author Akbota Zharylkassyn author Chitra Prasad author Ehsan Ghayoor Karimiani author Javeria Raza Alvi author Dmitriy Niyazov author Ahmad Alahmad author Meisam Babaei author Homa Tajsharghi author Buthaina Albash author Ahmad Alaqeel author Majida Charif author Narges Hashemi author Morteza Heidari author Seyed Mehdi Kalantar author Guy Lenaers author Mohammad Yahya Vahidi Mehrjardi author Varunvenkat M. Srinivasan author Vykuntaraju K. Gowda author Seyed Hamidreza Mirabutalebi author Deanna Alexis Carere author Mojtaba Movahedinia author David Murphy author Robert Mcfarland author Mohamed S. Abdel-Hamid author Rasha M. Elhossini author Shahryar Alavi author Melanie Napier author Amaya Belanger-Quintana author Asuri N. Prasad author Jessica Jakobczyk author Agathe Roubertie author Tony Rupar author Tipu Sultan author Mehran Beiraghi Toosi author Leonid A Sazanov author 338D39FE-F248-11E8-B48F-1D18A9856A870000-0002-0977-7989 Mariasavina Severino author Henry Houlden author Robert W. Taylor author Reza Maroofian author LeSa department 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. https://research-explorer.ista.ac.at/download/18987/20126/2025_BrainComm_Kaiyrzhanov.pdf application/pdfno Oxford University Press2025 eng 2632-1297 3996328810.1093/braincomms/fcae453 71 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). 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>. 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. 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> 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. 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> 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>. 189872025-02-02T23:01:55Z2025-08-05T11:55:15Z