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

Kaiyrzhanov R 1 , Thompson K 2 , Efthymiou S 1 , Mukushev A 3 , Zharylkassyn A 4 , Prasad C 5 Show all authors , Ghayoor Karimiani E 1 , Alvi JR 6 , Niyazov D 7 , Alahmad A 8 , Babaei M 9 , Tajsharghi H 10 , Albash B 11 , Alaqeel A 11 , Charif M 12 , Hashemi N 13 , Heidari M 14 , Kalantar SM 15 , Lenaers G 16 , Vahidi Mehrjardi MY 17 , Srinivasan VM 18 , Gowda VK 18 , Mirabutalebi SH 15 , Carere DA 19 , Movahedinia M 20 , Murphy D 21 , McFarland R 2 , Abdel-Hamid MS 22 , Elhossini RM 23 , Alavi S 1 , Napier M 19 , Belanger-Quintana A 24 , Prasad AN 25 , Jakobczyk J 5 , Roubertie A 26 , Rupar T 27 , Sultan T 6 , Toosi MB 13 , Sazanov L 28 , Severino M 29 , Houlden H 1 , Taylor RW 2 , Maroofian R 1

Affiliations 

  • 1 Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK
  • 2 Mitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
  • 3 Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215-5400, USA
  • 4 The Institute of Childhood Neurology, Almaty 050000, Kazakhstan
  • 5 Division of Genetics and Metabolics, Department of Pediatrics, London Health Sciences, London, ON, Canada N6A 5W9
  • 6 Department of Pediatric Neurology, Children's Hospital and Institute of Child Health, Lahore 54000, Pakistan
  • 7 Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USA
  • 8 Molecular Genetics Laboratory, Kuwait Medical Genetics Center, Ministry of Health, Sulaibikhat 80901, Kuwait
  • 9 Department of Pediatrics, North Khorasan University of Medical Sciences, Bojnurd 9413813965, Iran
  • 10 School of Health Sciences, Division of Biomedicine, University of Skovde, Skovde 541 28, Sweden
  • 11 Kuwait Medical Genetics Centre, Al-Sabah Medical Area, Kuwait City 80901, Kuwait
  • 12 Genetics Unit, Medical Sciences Research Laboratory, Faculty of Medicine and Pharmacy, University Mohammed Premier, Oujda 60000, Morocco
  • 13 Department of Pediatrics, School of Medicine, Mashhad University of Medical Sciences, Mashhad 91778 99191, Iran
  • 14 Myelin Disorders Clinic, Department of Pediatric Neurology, Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran 14197 33151, Iran
  • 15 Abortion Research Centre, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd 8916188635, Iran
  • 16 Angers University, MitoLab Team, MitoVasc Unit, CNRS UMR6015, INSERM U1083, SFR ICAT, Angers 49035, France
  • 17 Diabetes Research Center, Shahid Sadoughi University of Medical Sciences, Yazd 8916188635, Iran
  • 18 Department of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bangalore 560 029, India
  • 19 GeneDx Inc., Gaithersburg, MD 20877, USA
  • 20 Children Growth Disorder Research Center, Shahid Sadoughi University of Medical Sciences, Yazd 8916188635, Iran
  • 21 Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK
  • 22 Medical Molecular Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo 12622, Egypt
  • 23 Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo 12622, Egypt
  • 24 Servicio de Pediatría, Enfermedades Metabólicas Hereditarias, Hospital Universitario Ramón y Cajal, Madrid 28034, Spain
  • 25 Division of Pediatric Neurology, Department of Pediatrics, Western University, London, ON, Canada N6A 5W9
  • 26 Department of Neuropaediatrics, Gui de Chauliac Hospital, Montpellier University Hospital, Institut des Neurosciences, INSERM U 1298, Montpellier 34091, France
  • 27 Department of Pediatrics, University of Western Ontario, London, ON, Canada N6A5W9
  • 28 Institute of Science and Technology Austria, Klosterneuburg A-3400, Austria
  • 29 Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, Genoa 16147, Italy
Brain Commun, 2025;7(1):fcae453.
PMID: 39963288 DOI: 10.1093/braincomms/fcae453

Abstract

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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