{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T22:46:06Z","timestamp":1784673966597,"version":"3.55.0"},"reference-count":18,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T00:00:00Z","timestamp":1769644800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Biallelic variants in NDUFS6, encoding an accessory subunit of mitochondrial complex I, were initially associated with lethal neonatal mitochondrial encephalopathy and Leigh syndrome. Recent studies have demonstrated that NDUFS6 variants can also cause childhood- or adolescent-onset axonal neuropathy and Charcot\u2013Marie\u2013Tooth (CMT)-like phenotypes, indicating marked clinical heterogeneity. Here, we report a patient with a novel homozygous truncating NDUFS6 variant presenting with a neuropathy-predominant phenotype accompanied by epilepsy, in the absence of neonatal metabolic decompensation. The patient presented with childhood-onset progressive gait abnormality, pes cavus deformity, distal weakness requiring Achilles tendon-release surgery, pyramidal signs, urinary incontinence, and focal epileptiform EEG findings. Brain MRI showed bilateral lenticular nucleus abnormalities. Whole-exome sequencing identified a novel homozygous NDUFS6 nonsense variant (c.130C&gt;T, p.Gln44*). While neuropathy has previously been reported primarily in association with the recurrent splice-site variant c.309+5G&gt;A, our findings demonstrate that truncating NDUFS6 mutations can also underlie a neuropathy-predominant phenotype. Together with previously published cases, our findings support a phenotypic heterogeneity ranging from lethal encephalopathy to neuropathy and reinforce the role of NDUFS6 as a disease-causing gene for inherited peripheral neuropathy. These data support inclusion of NDUFS6 among established neuropathy and Charcot\u2013Marie\u2013Tooth genes.<\/jats:p>","DOI":"10.3390\/ijms27031375","type":"journal-article","created":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T08:19:38Z","timestamp":1769761178000},"page":"1375","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Expanding the Phenotypic Spectrum of NDUFS6-Related Disease: From Neonatal Mitochondrial Encephalopathy to Childhood-Onset Axonal Neuropathy"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0139-2520","authenticated-orcid":false,"given":"Savas","family":"Baris","sequence":"first","affiliation":[{"name":"Department of Medical Genetics, Ayd\u0131n Maternity and Children\u2019s Hospital, Aydin 09020, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5636-0262","authenticated-orcid":false,"given":"Rojan","family":"Ipek","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Dicle University, Diyarbak\u0131r 21280, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saniye Tugba","family":"Baris","sequence":"additional","affiliation":[{"name":"Gelisim Medical Laboratories, Division of Genetics, Istanbul 34100, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2185-3259","authenticated-orcid":false,"given":"Ibrahim","family":"Baris","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Genetics, Koc University, Istanbul 34450, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1038\/nature19754","article-title":"Accessory subunits are integral for assembly and function of human mitochondrial complex I","volume":"538","author":"Stroud","year":"2016","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1042\/BCJ20210285","article-title":"From the \u2018black box\u2019 to \u2018domino effect\u2019 mechanism: What have we learned from the structures of respiratory complex I","volume":"480","author":"Sazanov","year":"2023","journal-title":"Biochem. J."},{"key":"ref_3","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":"ref_4","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1002\/(SICI)1098-1004(200002)15:2<123::AID-HUMU1>3.0.CO;2-P","article-title":"Isolated complex I deficiency in children: Clinical, biochemical and genetic aspects","volume":"15","author":"Loeffen","year":"2000","journal-title":"Hum. Mutat."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.bbabio.2004.09.006","article-title":"Clinical and molecular findings in children with complex I deficiency","volume":"1659","author":"Bugiani","year":"2004","journal-title":"Biochim. Biophys. Acta."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Fiorini, C., Jurkute, N., Torraco, A., La Morgia, C., Ghezzi, D., Tioli, G., Rigobello, L., Ormanbekova, D., Berghella, A., and Pietro Pasti, A. (2025). Recessive variants in mitochondrial Complex I nuclear subunits are an underrated cause of optic atrophy. Brain, awaf422.","DOI":"10.1093\/brain\/awaf422"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"485","DOI":"10.3233\/JND-230181","article-title":"A Homozygous NDUFS6 Variant Associated with Neuropathy and Optic Atrophy","volume":"11","author":"Rating","year":"2024","journal-title":"J. Neuromuscul. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1038\/nature19095","article-title":"Structure of mammalian respiratory complex I","volume":"536","author":"Zhu","year":"2016","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1172\/JCI20683","article-title":"NDUFS6 mutations are a novel cause of lethal neonatal mitochondrial complex I deficiency","volume":"114","author":"Kirby","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1038\/ejhg.2009.24","article-title":"Mutated NDUFS6 is the cause of fatal neonatal lactic acidemia in Caucasus Jews","volume":"17","author":"Spiegel","year":"2009","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1136\/jmedgenet-2011-100577","article-title":"Mutation screening of 75 candidate genes in 152 complex I deficiency cases identifies pathogenic variants in 16 genes including NDUFB9","volume":"49","author":"Haack","year":"2012","journal-title":"J. Med. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1186\/s12967-016-0930-9","article-title":"New perspective in diagnostics of mitochondrial disorders: Two years\u2019 experience with whole-exome sequencing at a national paediatric centre","volume":"14","author":"Pronicka","year":"2016","journal-title":"J. Transl. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1007\/s10545-017-0042-6","article-title":"Clinical validity of biochemical and molecular analysis in diagnosing Leigh syndrome: A study of 106 Japanese patients","volume":"40","author":"Ogawa","year":"2017","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1038\/s10038-019-0594-4","article-title":"NDUFS6 related Leigh syndrome: A case report and review of the literature","volume":"64","author":"Rouzier","year":"2019","journal-title":"J. Hum. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e29239","DOI":"10.1097\/MD.0000000000029239","article-title":"Case report: Novel mutations of NDUFS6 and NHLRC2 genes potentially cause the quick postnatal death of a Chinese Hani minority neonate with mitochondrial complex I deficiency and FINCA syndrome","volume":"101","author":"Li","year":"2022","journal-title":"Medicine"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"101117","DOI":"10.1016\/j.gim.2024.101117","article-title":"Alternative splicing expands the clinical spectrum of NDUFS6-related mitochondrial disorders","volume":"26","author":"Zonnekein","year":"2024","journal-title":"Genet. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Unsel-Bolat, G., Bolat, H., Citli, S., Ozdemir, O., and Baris, I. (2025). Novel RORA Variants Reveal Genotype-Phenotype Diversity and Variable Expressivity in Neurodevelopmental Disorders. Clin. Genet.","DOI":"10.1111\/cge.70120"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/3\/1375\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T09:01:27Z","timestamp":1770109287000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/3\/1375"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,29]]},"references-count":18,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["ijms27031375"],"URL":"https:\/\/doi.org\/10.3390\/ijms27031375","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,29]]}}}