Biallelic <i>NDUFA9</i> variants cause a progressive neurodevelopmental disorder with prominent dystonia and mitochondrial complex I deficiency

Biallelic <i>NDUFA9</i> variants have hitherto been associated with disease in four individuals. Hence, clinicogenetic features of <i>NDUFA9</i>-related disorder remain largely unexplored. To delineate the pheno-genotypic spectrum of <i>NDUFA9</i>-related disorder, we screened genetic databases worldwide and collected phenotypic data on individuals with biallelic <i>NDUFA9</i> variants, which were functionally investigated when possible. Eight new and four reported cases were identified. Neurodevelopmental delay followed by motor deterioration and seizures were the most common presenting features. Neurodevelopmental disorder was observed in 90% of cases surviving beyond the age of 4 months. Neurological deterioration always started in the first decade. Among ten affected surviving beyond early infancy, major clinical features included dystonia (100%), feeding difficulties/dysphagia/failure to thrive and pyramidal signs (80%), seizures and muscle weakness/atrophy (70%), and moderate-to-severe intellectual disability (60%). All showed basal ganglia MRI signal alterations, with atrophy (50%) and swelling (25%). Four individuals died by the age of 13 years. In addition to four known variants, we identified five new <i>NDUFA9</i> variants and pinpointed Arg360 (NP_004993.1) as a mutational hotspot. Protein modelling suggested that variants cause NADH:ubiquinone oxidoreductase subunit A9 (NDUFA9) misfolding and/or disruption of binding interfaces. Loss of fully assembled complex I with decreased steady-state NDUFA9 levels and/or complex I activity was documented in fibroblasts from three affected individuals. Our study strengthens the evidence that biallelic <i>NDUFA9</i> variants cause mitochondrial complex I deficiency presenting with a broad spectrum of progressive neurodevelopmental disorder, often accompanied by prominent dystonia, and a characteristic Leigh syndrome MRI pattern.

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Journal
Brain Communications
Published
2025-09-23
DOI
https://doi.org/10.1093/braincomms/fcaf369
Primary Topic
Mitochondrial Function and Pathology
Type
article
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0.00

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article

Biallelic NDUFA9 variants cause a progressive neurodevelopmental disorder with prominent dystonia and mitochondrial complex I deficiency

Varunvenkat M Srinivasan, Sahar Sedighzadeh, Lucie S Taylor, Ali Khajeh et al.
Brain Communications
Mitochondrial Function and Pathology
article

Biallelic NDUFA9 variants cause a progressive neurodevelopmental disorder with prominent dystonia and mitochondrial complex I deficiency

Varunvenkat M Srinivasan, Sahar Sedighzadeh, Lucie S Taylor, Ali Khajeh, Vykuntaraju K. Gowda, Natalia Dominik, Karine Lascelles, Mériem Tazir, Jamileh Rezazadeh Varaghchi, Mohsen Javadzadeh, Saeedeh Yaghoubi, Mariasavina Severino, Sahand Tehrani Fateh, Charlotte L. Alston, Ali Reza Tavasoli, Dalila Moualek, Daniel N. Grba, Mohammad Miryounesi, Henry Houlden, Lamia Ali Pacha, Reza Maroofian, Michael Champion, Meisam Babaei, Francesca Magrinelli, Ehsan Ghayoor Karimiani, Kailash P. Bhatia, Robert W. Taylor, Mohammad Kordi-Tamandani
article en

Abstract

Biallelic <i>NDUFA9</i> variants have hitherto been associated with disease in four individuals. Hence, clinicogenetic features of <i>NDUFA9</i>-related disorder remain largely unexplored. To delineate the pheno-genotypic spectrum of <i>NDUFA9</i>-related disorder, we screened genetic databases worldwide and collected phenotypic data on individuals with biallelic <i>NDUFA9</i> variants, which were functionally investigated when possible. Eight new and four reported cases were identified. Neurodevelopmental delay followed by motor deterioration and seizures were the most common presenting features. Neurodevelopmental disorder was observed in 90% of cases surviving beyond the age of 4 months. Neurological deterioration always started in the first decade. Among ten affected surviving beyond early infancy, major clinical features included dystonia (100%), feeding difficulties/dysphagia/failure to thrive and pyramidal signs (80%), seizures and muscle weakness/atrophy (70%), and moderate-to-severe intellectual disability (60%). All showed basal ganglia MRI signal alterations, with atrophy (50%) and swelling (25%). Four individuals died by the age of 13 years. In addition to four known variants, we identified five new <i>NDUFA9</i> variants and pinpointed Arg360 (NP_004993.1) as a mutational hotspot. Protein modelling suggested that variants cause NADH:ubiquinone oxidoreductase subunit A9 (NDUFA9) misfolding and/or disruption of binding interfaces. Loss of fully assembled complex I with decreased steady-state NDUFA9 levels and/or complex I activity was documented in fibroblasts from three affected individuals. Our study strengthens the evidence that biallelic <i>NDUFA9</i> variants cause mitochondrial complex I deficiency presenting with a broad spectrum of progressive neurodevelopmental disorder, often accompanied by prominent dystonia, and a characteristic Leigh syndrome MRI pattern.

Brain CommunicationsVol. 7(5)
Shahed University (IR), Barrow Neurological Institute (US), Queen Mary University of London (GB), University of Shahrood (IR), University of Sistan and Baluchestan (IR), University of Algiers Benyoucef Benkhedda (DZ), Shahid Chamran University of Ahvaz (IR), Guy's and St Thomas' NHS Foundation Trust (GB), University of Cambridge (GB), Istituto Giannina Gaslini (IT), Newcastle upon Tyne Hospitals NHS Foundation Trust (GB), Counseling Center (US), Children's Medical Center (IR), Zahedan University of Medical Sciences (IR), Wellcome Centre for Mitochondrial Research (GB), Evelina London Children's Healthcare (GB), National Hospital for Neurology and Neurosurgery (GB), Hôpital Mustapha Pacha (DZ), Indira Gandhi Institute of Child Health (IN), North Khorasan University of Medical Sciences (IR), University College London (GB), Shahid Beheshti University of Medical Sciences (IR), Tehran University of Medical Sciences (IR), MRC Mitochondrial Biology Unit (GB), Newcastle University (GB), Medical Research Council (GB), University of Birjand (IR)
Michael J. Fox Foundation for Parkinson's Research, Friedreich's Ataxia Research Alliance, Teva Pharmaceutical Industries, American Parkinson Disease Association, Wellcome Trust, LifeArc, Parkinson's Foundation, National Institute for Health and Care Research, Department of Health and Social Care, Parkinson's UK, Guarantors of Brain, University of Cambridge, University College London, University of Oxford, Rosetrees Trust, University College London Hospitals NHS Foundation Trust, European Academy of Neurology, Sun Pharma, Ipsen, Cerebral Palsy Alliance, National Institutes of Health, Allergan, University of California, San Francisco, Medical Research Council, National Institute of Allergy and Infectious Diseases
Openalex Percentile: Top 77%
Mitochondrial Function and Pathology
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