{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T10:32:49Z","timestamp":1791973969435,"version":"4.4.0"},"reference-count":26,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,11,9]],"date-time":"2020-11-09T00:00:00Z","timestamp":1604880000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["20ek0109468s0101"],"award-info":[{"award-number":["20ek0109468s0101"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["Practical Research Project (18ek0109273, 18ek0109177)"],"award-info":[{"award-number":["Practical Research Project (18ek0109273, 18ek0109177)"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"publisher","award":["Strategic Research Center in Private Universities from MEXT"],"award-info":[{"award-number":["Strategic Research Center in Private Universities from MEXT"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Leigh syndrome (LS) is most frequently characterized by the presence of focal, bilateral, and symmetric brain lesions Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a rare condition, characterized by progressive pyramidal, cerebellar, and dorsal column dysfunction. We describe a case with infantile-onset neurodegeneration, psychomotor retardation, irritability, hypotonia, and nystagmus. Brain MRI demonstrated signal abnormalities in the deep cerebral white matter, corticospinal and dorsal column tracts, and pyramids, which resemble the MRI pattern of a severe form of LBSL, and involvement of basal ganglia and thalamus that resemble the radiological features of LS. We identified biallelic loss-of-function mutations, one novel (c.756delC, p.Thr253Glnfs*44) and another reported (c.1156C &gt; T, p.Arg386Cys), in NDUFV1 (NADH:Ubiquinone Oxidoreductase Core Subunit V1) by exome sequencing. Biochemical and functional analyses revealed lactic acidosis, complex I (CI) assembly and enzyme deficiency, and a loss of NDUFV1 protein. Complementation assays restored the NDUFV1 protein, CI assembly, and CI enzyme levels. The clinical and radiological features of this case are compatible with the phenotype of LS and LBSL associated with NDUFV1 mutations.<\/jats:p>","DOI":"10.3390\/genes11111325","type":"journal-article","created":{"date-parts":[[2020,11,9]],"date-time":"2020-11-09T19:08:29Z","timestamp":1604948909000},"page":"1325","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Leigh Syndrome Due to NDUFV1 Mutations Initially Presenting as LBSL"],"prefix":"10.3390","volume":"11","author":[{"given":"Nurun Nahar","family":"Borna","sequence":"first","affiliation":[{"name":"Diagnostics and Therapeutics of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Bunkyo-ku, Tokyo 113-8421, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihito","family":"Kishita","sequence":"additional","affiliation":[{"name":"Diagnostics and Therapeutics of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Bunkyo-ku, Tokyo 113-8421, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norio","family":"Sakai","sequence":"additional","affiliation":[{"name":"Child Healthcare and Genetic Science Laboratory, Division of Health Sciences, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Hamada","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Toyonaka Municipal Hospital, Toyonaka, Osaka 560-8565, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5028-218X","authenticated-orcid":false,"given":"Koji","family":"Kamagata","sequence":"additional","affiliation":[{"name":"Department of Radiology, Graduate School of Medicine, Juntendo University, Bunkyo-ku, Tokyo 113-8421, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masakazu","family":"Kohda","sequence":"additional","affiliation":[{"name":"Diagnostics and Therapeutics of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Bunkyo-ku, Tokyo 113-8421, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Ohtake","sequence":"additional","affiliation":[{"name":"Department of Pediatrics &amp; Clinical Genomics, Faculty of Medicine, Saitama Medical University, Moroyama, Saitama 350-0495, Japan"},{"name":"Center for Intractable Diseases, Saitama Medical University Hospital, Moroyama, Saitama 350-0495, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kei","family":"Murayama","sequence":"additional","affiliation":[{"name":"Department of Metabolism, Chiba Children\u2019s Hospital, Midori-ku, Chiba 266-0007, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasushi","family":"Okazaki","sequence":"additional","affiliation":[{"name":"Diagnostics and Therapeutics of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Bunkyo-ku, Tokyo 113-8421, Japan"},{"name":"Laboratory for Comprehensive Genomic Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.ymgme.2011.11.188","article-title":"Mitochondrial complex I deficiency of nuclear origin I. Structural genes","volume":"105","author":"Loublier","year":"2012","journal-title":"Mol. Genet. Metab."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1016\/j.mito.2013.03.010","article-title":"A novel familial case of diffuse leukodystrophy related to NDUFV1 compound heterozygous mutations","volume":"13","author":"Fonseca","year":"2013","journal-title":"Mitochondrion"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1111\/j.1399-0004.2011.01743.x","article-title":"A novel NDUFV1 gene mutation in complex I deficiency in consanguineous siblings with brainstem lesions and Leigh syndrome","volume":"82","author":"Vilain","year":"2012","journal-title":"Clin. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.gene.2012.12.024","article-title":"Leigh syndrome associated with mitochondrial complex I deficiency due to novel mutations in NDUFV1 and NDUFS2","volume":"516","author":"Marin","year":"2013","journal-title":"Gene"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.pediatrneurol.2006.08.007","article-title":"Early-onset ophthalmoplegia in Leigh-like syndrome due to NDUFV1 mutations","volume":"36","author":"Laugel","year":"2007","journal-title":"Pediatr. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1038\/6772","article-title":"Mutant NDUFV1 subunit of mitochondrial complex I causes leukodystrophy and myoclonic epilepsy","volume":"21","author":"Schuelke","year":"1999","journal-title":"Nat. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"P02.172","DOI":"10.1212\/WNL.78.1_MeetingAbstracts.P02.172","article-title":"Episodic Leukoencephalopathy Due to Novel Mitochondrial Complex I NDUFV1 Gene Mutations (P02.172)","volume":"78","author":"Sekul","year":"2012","journal-title":"Neurology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1002\/ana.10456","article-title":"A new leukoencephalopathy with brainstem and spinal cord involvement and high lactate","volume":"53","author":"Barkhof","year":"2003","journal-title":"Ann. Neurol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1007\/s00062-017-0647-z","article-title":"Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and not Always Lactate Elevation","volume":"28","author":"Werner","year":"2018","journal-title":"Clin. Neuroradiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1093\/brain\/awu026","article-title":"Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation: Clinical and genetic characterization and target for therapy","volume":"137","author":"Hamilton","year":"2014","journal-title":"Brain"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1007\/s11011-017-0181-3","article-title":"Neonatal mitochondrial leukoencephalopathy with brain and spinal involvement and high lactate: Expanding the phenotype of ISCA2 gene mutations","volume":"33","author":"Toldo","year":"2018","journal-title":"Metab. Brain Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1007\/s10048-018-0561-9","article-title":"Mitochondrial ribosomal protein PTCD3 mutations cause oxidative phosphorylation defects with Leigh syndrome","volume":"20","author":"Borna","year":"2019","journal-title":"Neurogenetics"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1055\/s-0032-1329395","article-title":"Early-onset LBSL: How severe does it get?","volume":"43","author":"Steenweg","year":"2012","journal-title":"Neuropediatrics"},{"key":"ref_14","first-page":"1119","article-title":"Mitochondrial disorders: Analysis of their clinical and imaging characteristics","volume":"14","author":"Barkovich","year":"1993","journal-title":"AJNR Am. J. Neuroradiol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Rahman, S., Blok, R.B., Dahl, H.H., Danks, D.M., Kirby, D.M., Chow, C.W., Christodoulou, J., and Thorburn, D.R. (1996). Leigh syndrome: Clinical features and biochemical and DNA abnormalities. Ann. Neurol., 39.","DOI":"10.1002\/ana.410390311"},{"key":"ref_16","first-page":"1502","article-title":"Leigh Syndrome: Serial MR Imaging and Clinical Follow-up","volume":"21","author":"Arii","year":"2000","journal-title":"Am. J. Neuroradiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1007\/s00247-015-3523-5","article-title":"The neuroimaging of Leigh syndrome: Case series and review of the literature","volume":"46","author":"Bonfante","year":"2016","journal-title":"Pediatr. Radiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1590\/S0004-282X2007000300028","article-title":"Leukoencephalopathy with brainstem and spinal cord involvement and high brain lactate: Report of three Brazilian patients","volume":"65","author":"Tavora","year":"2007","journal-title":"Arq. Neuropsiquiatr."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"724","DOI":"10.3389\/fneur.2018.00724","article-title":"Overlapping Leigh Syndrome\/Myoclonic Epilepsy With Ragged Red Fibres in an Adolescent Patient With a Mitochondrial DNA A8344G Mutation","volume":"9","author":"Shen","year":"2018","journal-title":"Front. Neurol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1042\/BJ20121564","article-title":"Pathogenic mutations causing LBSL affect mitochondrial aspartyl-tRNA synthetase in diverse ways","volume":"450","author":"Kevenaar","year":"2013","journal-title":"Biochem. J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1186\/s12883-018-1180-7","article-title":"Intra-familial phenotypic heterogeneity in a Sudanese family with DARS2-related leukoencephalopathy, brainstem and spinal cord involvement and lactate elevation: A case report","volume":"18","author":"Yahia","year":"2018","journal-title":"BMC Neurol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1111\/j.1399-0004.2011.01644.x","article-title":"A novel homozygous mutation of DARS2 may cause a severe LBSL variant","volume":"80","author":"Miyake","year":"2011","journal-title":"Clin. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1007\/s12098-018-2721-1","article-title":"Cystic Leucoencephalopathy in NDUFV1 Mutation","volume":"85","author":"Wadhwa","year":"2018","journal-title":"Indian J. Pediatr."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Huntsman, R.J., Sinclair, D.B., Bhargava, R., and Chan, A. (2005). Atypical presentations of leigh syndrome: A case series and review. Pediatr. Neurol., 32.","DOI":"10.1016\/j.pediatrneurol.2004.12.009"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1177\/0883073812464273","article-title":"Early spinal cord and brainstem involvement in infantile Leigh syndrome possibly caused by a novel variant","volume":"28","author":"Tenney","year":"2013","journal-title":"J. Child. Neurol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1016\/j.braindev.2018.02.007","article-title":"Leigh syndrome with spinal cord involvement due to a hemizygous NDUFA1 mutation","volume":"40","author":"Miyauchi","year":"2018","journal-title":"Brain Dev."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/11\/11\/1325\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:31:14Z","timestamp":1760178674000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/11\/11\/1325"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,9]]},"references-count":26,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["genes11111325"],"URL":"https:\/\/doi.org\/10.3390\/genes11111325","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,9]]}}}