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Pathogenic variants in NDUFAF6 have been increasingly recognized as a cause of mitochondrial disease, particularly Leigh syndrome, a severe neurodegenerative disorder characterized by bilateral symmetrical lesions in the central nervous system. To date, fewer than 50 patients with NDUFAF6-related mitochondrial disease have been reported, displaying a broad phenotypic spectrum ranging from early-onset neurodevelopmental regression to milder, more chronic presentations. The molecular mechanisms underlying these phenotypes are linked to impaired complex I assembly and reduced enzymatic activity, highlighting the critical role of NDUFAF6 in mitochondrial function.<\/jats:p>\n                  <jats:p>Here we present a cohort of 27 patients (14 males and 13 females) from 18 families harbouring biallelic variants in the NDUFAF6 gene. The patient\u2019s mean age was 9.15 \u00b1 8.30 years (range: 4 weeks to 25 years); 12 patients (37%) had died by the time the data were collected for this article. The clinical presentation showed wide phenotypic variability, from mild to severe psychomotor regression (74%) most commonly before the age of 5 years, hypotonia (22%), movement disorders (30%), and hypertonia (15%). Bilateral striatal necrosis lesions were the most characteristic features on cranial MRI (67%) although white matter abnormalities were also noted (15%), occasionally accompanied by cystic formations, suggestive of early neurodevelopmental anomalies.<\/jats:p>\n                  <jats:p>Genomic sequencing was applied, leading to the identification of 19 distinct variants in the NDUFAF6 gene, including nine novel variants not previously reported and either absent or extremely rare in public population databases. Functional studies confirmed the pathogenicity of these variants, demonstrating a deleterious effect on NDUFAF6 protein expression and a consequent impairment in complex I assembly and stability.<\/jats:p>\n                  <jats:p>To date, this represents the largest reported cohort of patients with NDUFAF6-associated mitochondrial disease. Our findings provide a comprehensive overview of clinical characteristics\u2014including age of symptom onset, phenotypic variability, and patient outcomes\u2014aiming to improve prognostic information and facilitate genetic counselling in clinical practice.<\/jats:p>","DOI":"10.1093\/braincomms\/fcag095","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T06:09:18Z","timestamp":1773900558000},"source":"Crossref","is-referenced-by-count":1,"title":["Neurological manifestations and genotype\u2013phenotype correlations in\n                    <i>NDUFAF6<\/i>\n                    -associated mitochondrial disease"],"prefix":"10.1093","volume":"8","author":[{"given":"Alessandra","family":"Torraco","sequence":"first","affiliation":[{"name":"Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Ges\u00f9 Children's Hospital, IRCCS , 00146 Rome ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte L","family":"Alston","sequence":"additional","affiliation":[{"name":"Mitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University , Newcastle upon Tyne NE2 4HH ,","place":["UK"]},{"name":"NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust , Newcastle upon Tyne NE1 4LP ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Barcia","sequence":"additional","affiliation":[{"name":"Service de M\u00e9decine G\u00e9nomique des Maladies Rares\u2014APHP, H\u00f4pital Necker Enfants Malades, Imagine Institute, Universit\u00e9 Paris Cit\u00e9 , 75015 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Verrigni","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Ges\u00f9 Children's Hospital, IRCCS , 00146 Rome ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Rizza","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Ges\u00f9 Children's Hospital, IRCCS , 00146 Rome ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"Di Nottia","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Ges\u00f9 Children's Hospital, IRCCS , 00146 Rome ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasia","family":"Altobelli","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Ges\u00f9 Children's Hospital, IRCCS , 00146 Rome ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9324-2871","authenticated-orcid":false,"given":"Diego","family":"Martinelli","sequence":"additional","affiliation":[{"name":"Division of Metabolic Diseases and Hepatology, Bambino Ges\u00f9 Children's Hospital, IRCCS , 00165 Rome ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daria","family":"Diodato","sequence":"additional","affiliation":[{"name":"Neuromuscular Disorders Research Unit, Bambino Ges\u00f9 Children's Hospital, IRCCS , 00146 Rome ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4900-9877","authenticated-orcid":false,"given":"Stephanie","family":"Efthymiou","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology , Queen Square WC1N 3BG London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melis","family":"Kose","sequence":"additional","affiliation":[{"name":"Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia , Philadelphia, PA 19104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yamna","family":"Kriouile","sequence":"additional","affiliation":[{"name":"Unit of Neuropediatrics and Neurometabolism, Pediatric Department 2, Rabat Children's Hospital , BP 6527 Rabat ,","place":["Morocco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert Z","family":"Lim","sequence":"additional","affiliation":[{"name":"Mitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University , Newcastle upon Tyne NE2 4HH ,","place":["UK"]},{"name":"NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust , Newcastle upon Tyne NE1 4LP ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Morlino","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Fondazione IRCCS-Casa Sollievo della Sofferenza , 71013 San Giovanni Rotondo ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2876-4745","authenticated-orcid":false,"given":"Barbara","family":"Siri","sequence":"additional","affiliation":[{"name":"Division of Metabolic Diseases and Hepatology, Bambino Ges\u00f9 Children's Hospital, IRCCS , 00165 Rome ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7523-6833","authenticated-orcid":false,"given":"Nebal Waill","family":"Saadi","sequence":"additional","affiliation":[{"name":"Unit of Pediatric Neurology, College of Medicine\/University of Baghdad, Children Welfare Teaching Hospital , 12114 Baghdad ,","place":["Iraq"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Novelli","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Ges\u00f9 Children's Hospital, IRCCS , 00146 Rome ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2866-7777","authenticated-orcid":false,"given":"Henry","family":"Houlden","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology , Queen Square WC1N 3BG London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Dionisi-Vici","sequence":"additional","affiliation":[{"name":"Division of Metabolic Diseases and Hepatology, Bambino Ges\u00f9 Children's Hospital, IRCCS , 00165 Rome ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"McFarland","sequence":"additional","affiliation":[{"name":"Mitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University , Newcastle upon Tyne NE2 4HH ,","place":["UK"]},{"name":"NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust , Newcastle upon Tyne NE1 4LP ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0589-0703","authenticated-orcid":false,"given":"Agn\u00e8s","family":"R\u00f6tig","sequence":"additional","affiliation":[{"name":"Institut Imagine, G\u00e9n\u00e9tique des maladies mitochondriales, INSERM UMR 1163, Universit\u00e9 Paris Cit\u00e9 , 75015 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9276-4590","authenticated-orcid":false,"given":"Enrico","family":"Bertini","sequence":"additional","affiliation":[{"name":"Neuromuscular Disorders Research Unit, Bambino Ges\u00f9 Children's Hospital, IRCCS , 00146 Rome ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert W","family":"Taylor","sequence":"additional","affiliation":[{"name":"Mitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University , Newcastle upon Tyne NE2 4HH ,","place":["UK"]},{"name":"NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust , Newcastle upon Tyne NE1 4LP ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3327-4054","authenticated-orcid":false,"given":"Rosalba","family":"Carrozzo","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Ges\u00f9 Children's Hospital, IRCCS , 00146 Rome ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,3,18]]},"reference":[{"issue":"3","key":"2026041703573905300_fcag095-B1","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1016\/j.cmet.2012.07.015","article-title":"NDUFA4 is a subunit of complex IV of the mammalian electron transport chain","volume":"16","author":"Balsa","year":"2012","journal-title":"Cell Metab."},{"issue":"43","key":"2026041703573905300_fcag095-B2","doi-asserted-by":"crossref","first-page":"32724","DOI":"10.1074\/jbc.M607135200","article-title":"Bovine complex I is a complex of 45 different subunits","volume":"281","author":"Carroll","year":"2006","journal-title":"J Biol Chem"},{"issue":"3","key":"2026041703573905300_fcag095-B3","doi-asserted-by":"crossref","first-page":"107541","DOI":"10.1016\/j.celrep.2020.107541","article-title":"Dissecting the roles of mitochondrial Complex I intermediate assembly complex factors in the biogenesis of Complex I","volume":"31","author":"Formosa","year":"2020","journal-title":"Cell Rep"},{"issue":"Pt 1","key":"2026041703573905300_fcag095-B4","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1093\/brain\/awr261","article-title":"Assembly factors as a new class of disease genes for mitochondrial complex I deficiency: Cause, pathology and treatment options","volume":"135","author":"Nouws","year":"2012","journal-title":"Brain"},{"issue":"8","key":"2026041703573905300_fcag095-B5","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1002\/1873-3468.13995","article-title":"Mitochondrial disorders of the OXPHOS system","volume":"595","author":"Fernandez-Vizarra","year":"2021","journal-title":"FEBS Lett."},{"issue":"13","key":"2026041703573905300_fcag095-B6","doi-asserted-by":"crossref","first-page":"e2115566119","DOI":"10.1073\/pnas.2115566119","article-title":"Sideroflexin 4 is a complex I assembly factor that interacts with the MCIA complex and is required for the assembly of the ND2 module","volume":"119","author":"Jackson","year":"2022","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"13","key":"2026041703573905300_fcag095-B7","doi-asserted-by":"crossref","first-page":"e2100558118","DOI":"10.1073\/pnas.2100558118","article-title":"TMEM70 and TMEM242 help to assemble the rotor ring of human ATP synthase and interact with assembly factors for complex I","volume":"118","author":"Carroll","year":"2021","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"19","key":"2026041703573905300_fcag095-B8","doi-asserted-by":"crossref","first-page":"5482","DOI":"10.1038\/s44318-025-00533-x","article-title":"RTN4IP1 is required for the final stages of mitochondrial complex I assembly and CoQ biosynthesis","volume":"44","author":"Ol\u00e1hov\u00e1","year":"2025","journal-title":"EMBO J"},{"issue":"6","key":"2026041703573905300_fcag095-B9","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1212\/WNL.52.6.1255","article-title":"Respiratory chain complex I deficiency: An underdiagnosed energy generation disorder","volume":"52","author":"Kirby","year":"1999","journal-title":"Neurology"},{"key":"2026041703573905300_fcag095-B10","doi-asserted-by":"crossref","first-page":"24","DOI":"10.3389\/fgene.2020.00024","article-title":"Novel MT-ND gene variants causing adult-onset mitochondrial disease and isolated Complex I deficiency","volume":"11","author":"Ng","year":"2020","journal-title":"Front 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