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Biallelic NDUFA13 variants lead to a neurodevelopmental phenotype with gradual neurological impairment
Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, UK ; Department of Neurology, South Kazakhstan Medical Academy, Shymkent, Kazakhstan.ORCID iD: 0000-0003-1640-4010
Mitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, UK.
Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, UK.ORCID iD: 0000-0003-4900-9877
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.ORCID iD: 0000-0002-8588-4268
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2025 (English)In: Brain Communications, E-ISSN 2632-1297, Vol. 7, no 1, article id fcae453Article in journal (Refereed) Published
Abstract [en]

Biallelic variants in NADH-ubiquinone oxidoreductase 1 alpha subcomplex 13 (NDUFA13) 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 NDUFA13-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 NDUFA13-related disease in 13 individuals, highlighting genotype-phenotype correlations.

Place, publisher, year, edition, pages
Oxford University Press, 2025. Vol. 7, no 1, article id fcae453
National Category
Medical Genetics and Genomics
Research subject
Translational Medicine TRIM
Identifiers
URN: urn:nbn:se:his:diva-24791DOI: 10.1093/braincomms/fcae453ISI: 001398071600001Scopus ID: 2-s2.0-85215682302OAI: oai:DiVA.org:his-24791DiVA, id: diva2:1922161
Funder
Wellcome trust, 221951/Z/20/ZEU, FP7, Seventh Framework Programme, 608473
Note

CC BY 4.0

Published: 17 December 2024

Correspondence to: Dr Reza Maroofian, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK. r.maroofian@ucl.ac.uk

This 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. MSAH is funded by the Science and Technology Development Fund Academy of Science Research and Technology Egypt (Grant number: 33492, Ethical approval number: 20066). RWT 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 Foundaton, 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

Available from: 2024-12-18 Created: 2024-12-18 Last updated: 2025-09-29Bibliographically approved

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