Biallelic NDUFA13 variants lead to a neurodevelopmental phenotype with gradual neurological impairment

Kaiyrzhanov R. Thompson K. Efthymiou S. Mukushev A. Zharylkassyn A. Prasad C. Karimiani E.G. Alvi J.R. Niyazov D. Alahmad A. Babaei M. Tajsharghi H. Albash B. Alaqeel A. Charif M. Hashemi N. Heidari M. Kalantar S.M. Lenaers G. Mehrjardi M.Y.V. Srinivasan V.M. Gowda V.K. Mirabutalebi S.H. Carere D.A. Movahedinia M. Murphy D. McFarland R. Abdel-Hamid M.S. Elhossini R.M. Alavi S. Napier M. Belanger-Quintana A. Prasad A.N. Jakobczyk J. Roubertie A. Rupar T. Sultan T. Toosi M.B. Sazanov L. Severino M. Houlden H. Taylor R.W. Maroofian R.
2025 Oxford University Press

Brain Communications
2025 #7 Issue 1

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.

complex I deficiency , Leigh syndrome , mitochondrial disorders , NDUFA13 , neurodevelopmental disorder

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Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, London, WC1N 3BG, United Kingdom
Department of Neurology, South Kazakhstan Medical Academy, Shymkent, 160019, Kazakhstan
Mitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, United Kingdom
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, 02215-5400, MA, United States
The Institute of Childhood Neurology, Almaty, 050000, Kazakhstan
Division of Genetics and Metabolics, Department of Pediatrics, London Health Sciences, London, N6A 5W9, ON, Canada
Molecular and Clinical Sciences Institute, St. George’s University of London, London, SW17 0RE, United Kingdom
Department of Pediatric Neurology, Children’s Hospital, Institute of Child Health, Lahore, 54000, Pakistan
Department of Pediatrics, Duke University School of Medicine, Durham, 27710, NC, United States
Molecular Genetics Laboratory, Kuwait Medical Genetics Center, Ministry of Health, Sulaibikhat, 80901, Kuwait
Department of Pediatrics, North Khorasan University of Medical Sciences, Bojnurd, 9413813965, Iran
School of Health Sciences, Division of Biomedicine, University of Skovde, Skovde, 541 28, Sweden
Kuwait Medical Genetics Centre, Al-Sabah Medical Area, Kuwait City, 80901, Kuwait
Genetics Unit, Medical Sciences Research Laboratory, Faculty of Medicine and Pharmacy, University Mohammed Premier, Oujda, 60000, Morocco
BRO Biobank, Faculty of Medicine and Pharmacy, University Mohammed Premier, Oujda, 60000, Morocco
Genetic and Immuno-Cell Therapy Team, Mohammed First University, Oujda, 60000, Morocco
Department of Pediatrics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, 91778 99191, Iran
Myelin Disorders Clinic, Department of Pediatric Neurology, Children’s Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, 14197 33151, Iran
Abortion Research Centre, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, 8916188635, Iran
Angers University, MitoLab Team, MitoVasc Unit, CNRS UMR6015, INSERM U1083, SFR ICAT, Angers, 49035, France
Department of Neurology, University Hospital of Angers, Angers, 49035, France
Diabetes Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, 8916188635, Iran
Department of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bangalore, 560 029, India
GeneDx Inc., Gaithersburg, 20877, MD, United States
Children Growth Disorder Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, 8916188635, Iran
Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, WC1N 3BG, United Kingdom
NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE1 4LP, United Kingdom
Medical Molecular Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, 12622, Egypt
Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, 12622, Egypt
Servicio de Pediatría, Enfermedades Metabólicas Hereditarias, Hospital Universitario Ramón y Cajal, Madrid, 28034, Spain
Division of Pediatric Neurology, Department of Pediatrics, Western University, London, N6A 5W9, ON, Canada
Department of Neuropaediatrics, Gui de Chauliac Hospital, Montpellier University Hospital, Institut des Neurosciences, INSERM U 1298, Montpellier, 34091, France
Department of Pediatrics, University of Western Ontario, London, N6A5W9, ON, Canada
Departments of Biochemistry, Pathology and Laboratory Medicine, University of Western Ontario, London, N6A5W9, ON, Canada
Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, 91778 99191, Iran
Institute of Science and Technology Austria, Klosterneuburg, A-3400, Austria
Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, Genoa, 16147, Italy

Department of Neuromuscular Diseases
Department of Neurology
Mitochondrial Research Group
Department of Neurology
The Institute of Childhood Neurology
Division of Genetics and Metabolics
Molecular and Clinical Sciences Institute
Department of Pediatric Neurology
Department of Pediatrics
Molecular Genetics Laboratory
Department of Pediatrics
School of Health Sciences
Kuwait Medical Genetics Centre
Genetics Unit
BRO Biobank
Genetic and Immuno-Cell Therapy Team
Department of Pediatrics
Myelin Disorders Clinic
Abortion Research Centre
Angers University
Department of Neurology
Diabetes Research Center
Department of Pediatric Neurology
GeneDx Inc.
Children Growth Disorder Research Center
Department of Clinical and Movement Neurosciences
NHS Highly Specialised Service for Rare Mitochondrial Disorders
Medical Molecular Genetics Department
Clinical Genetics Department
Servicio de Pediatría
Division of Pediatric Neurology
Department of Neuropaediatrics
Department of Pediatrics
Departments of Biochemistry
Neuroscience Research Center
Institute of Science and Technology Austria
Neuroradiology Unit

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