Biallelic NDUFA13 variants lead to a neurodevelopmental phenotype with gradual neurological impairment Kaiyrzhanov, Rauan Thompson, Kyle Efthymiou, Stephanie Mukushev, Askhat Zharylkassyn, Akbota Prasad, Chitra Karimiani, Ehsan Ghayoor Alvi, Javeria Raza Niyazov, Dmitriy Alahmad, Ahmad Babaei, Meisam Tajsharghi, Homa Albash, Buthaina Alaqeel, Ahmad Charif, Majida Hashemi, Narges Heidari, Morteza Kalantar, Seyed Mehdi Lenaers, Guy Mehrjardi, Mohammad Yahya Vahidi Srinivasan, Varunvenkat M. Gowda, Vykuntaraju K. Mirabutalebi, Seyed Hamidreza Carere, Deanna Alexis Movahedinia, Mojtaba Murphy, David Mcfarland, Robert Abdel-Hamid, Mohamed S. Elhossini, Rasha M. Alavi, Shahryar Napier, Melanie Belanger-Quintana, Amaya Prasad, Asuri N. Jakobczyk, Jessica Roubertie, Agathe Rupar, Tony Sultan, Tipu Toosi, Mehran Beiraghi Sazanov, Leonid A ; https://orcid.org/0000-0002-0977-7989 Severino, Mariasavina Houlden, Henry Taylor, Robert W. Maroofian, Reza ddc:570 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. Oxford University Press 2025 info:eu-repo/semantics/article doc-type:article text http://purl.org/coar/resource_type/c_2df8fbb1 https://research-explorer.ista.ac.at/record/18987 https://research-explorer.ista.ac.at/download/18987/20126 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> eng info:eu-repo/semantics/altIdentifier/doi/10.1093/braincomms/fcae453 info:eu-repo/semantics/altIdentifier/e-issn/2632-1297 info:eu-repo/semantics/altIdentifier/pmid/39963288 info:eu-repo/semantics/openAccess