Biallelic Ndufa13 Variants Lead to a Neurodevelopmental Phenotype With Gradual Neurological Impairment

Biallelic Ndufa13 Variants Lead to a Neurodevelopmental Phenotype With Gradual Neurological Impairment Publisher

Kaiyrzhanov R^{1, 2} ; Thompson K³ ; Efthymiou S¹ ; Mukushev A⁴ ; Zharylkassyn A⁵ ; Prasad C⁶ ; Karimiani EG^{1, 7} ; Alvi JR⁸ ; Niyazov D⁹ ; Alahmad A¹⁰ ; Babaei M¹¹ ; Tajsharghi H¹² ; Albash B¹³ ; Alaqeel A¹³ Show All Authors

Kaiyrzhanov R^{1, 2}
Thompson K³
Efthymiou S¹
Mukushev A⁴
Zharylkassyn A⁵
Prasad C⁶
Karimiani EG^{1, 7}
Alvi JR⁸
Niyazov D⁹
Alahmad A¹⁰
Babaei M¹¹
Tajsharghi H¹²
Albash B¹³
Alaqeel A¹³
Charif M^{14, 15, 16}
Hashemi N¹⁷
Heidari M¹⁸
Kalantar SM¹⁹
Lenaers G^{20, 21}
Mehrjardi MYV²²
Srinivasan VM²³
Gowda VK²³
Mirabutalebi SH¹⁹
Carere DA²⁴
Movahedinia M²⁵
Murphy D²⁶
Mcfarland R^{3, 27}
Abdelhamid MS²⁸
Elhossini RM²⁹
Alavi S¹
Napier M²⁴
Belangerquintana A³⁰
Prasad AN³¹
Jakobczyk J⁶
Roubertie A³²
Rupar T^{33, 34}
Sultan T⁸
Toosi MB^{17, 35}
Sazanov L³⁶
Severino M³⁷
Houlden H¹
Taylor RW^{3, 27}
Maroofian R¹

Show Affiliations

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

Source: Brain Communications Published:2025

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. © The Author(s) 2024.

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Style	Citing Format
MLA	Kaiyrzhanov R, et al.. "Biallelic Ndufa13 Variants Lead to a Neurodevelopmental Phenotype With Gradual Neurological Impairment." Brain Communications, vol. 7, no. 1, 2025, pp. -.
APA	Kaiyrzhanov R, Thompson K, Efthymiou S, Mukushev A, Zharylkassyn A, Prasad C, Karimiani EG, Alvi JR, Niyazov D, Alahmad A, Babaei M, Tajsharghi H, Albash B, Alaqeel A, Charif M, Hashemi N, Heidari M, Kalantar SM, Lenaers G, ... Maroofian R (2025). Biallelic Ndufa13 Variants Lead to a Neurodevelopmental Phenotype With Gradual Neurological Impairment. Brain Communications, 7(1), -.
Chicago	Kaiyrzhanov R, Thompson K, Efthymiou S, Mukushev A, Zharylkassyn A, Prasad C, Karimiani EG, et al.. "Biallelic Ndufa13 Variants Lead to a Neurodevelopmental Phenotype With Gradual Neurological Impairment." Brain Communications 7, no. 1 (2025): -.
Harvard	Kaiyrzhanov R et al. (2025) 'Biallelic Ndufa13 Variants Lead to a Neurodevelopmental Phenotype With Gradual Neurological Impairment', Brain Communications, 7(1), pp. -.
Vancouver	Kaiyrzhanov R, Thompson K, Efthymiou S, Mukushev A, Zharylkassyn A, Prasad C, et al.. Biallelic Ndufa13 Variants Lead to a Neurodevelopmental Phenotype With Gradual Neurological Impairment. Brain Communications. 2025;7(1):-.
BibTex	@article{ author = {Kaiyrzhanov R and Thompson K and Efthymiou S and Mukushev A and Zharylkassyn A and Prasad C and Karimiani EG and Alvi JR and Niyazov D and Alahmad A and Babaei M and Tajsharghi H and Albash B and Alaqeel A and Charif M and Hashemi N and Heidari M and Kalantar SM and Lenaers G and Mehrjardi MYV and Srinivasan VM and Gowda VK and Mirabutalebi SH and Carere DA and Movahedinia M and Murphy D and Mcfarland R and Abdelhamid MS and Elhossini RM and Alavi S and Napier M and Belangerquintana A and Prasad AN and Jakobczyk J and Roubertie A and Rupar T and Sultan T and Toosi MB and Sazanov L and Severino M and Houlden H and Taylor RW and Maroofian R}, title = {Biallelic Ndufa13 Variants Lead to a Neurodevelopmental Phenotype With Gradual Neurological Impairment}, journal = {Brain Communications}, volume = {7}, number = {1}, pages = {-}, year = {2025} }
RIS	TY - JOUR AU - Kaiyrzhanov R AU - Thompson K AU - Efthymiou S AU - Mukushev A AU - Zharylkassyn A AU - Prasad C AU - Karimiani EG AU - Alvi JR AU - Niyazov D AU - Alahmad A AU - Babaei M AU - Tajsharghi H AU - Albash B AU - Alaqeel A AU - Charif M AU - Hashemi N AU - Heidari M AU - Kalantar SM AU - Lenaers G AU - Mehrjardi MYV AU - Srinivasan VM AU - Gowda VK AU - Mirabutalebi SH AU - Carere DA AU - Movahedinia M AU - Murphy D AU - Mcfarland R AU - Abdelhamid MS AU - Elhossini RM AU - Alavi S AU - Napier M AU - Belangerquintana A AU - Prasad AN AU - Jakobczyk J AU - Roubertie A AU - Rupar T AU - Sultan T AU - Toosi MB AU - Sazanov L AU - Severino M AU - Houlden H AU - Taylor RW AU - Maroofian R TI - Biallelic Ndufa13 Variants Lead to a Neurodevelopmental Phenotype With Gradual Neurological Impairment JO - Brain Communications VL - 7 IS - 1 SP - EP - PY - 2025 ER -

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