{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T20:24:38Z","timestamp":1785183878588,"version":"3.55.0"},"reference-count":7,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,5,11]],"date-time":"2024-05-11T00:00:00Z","timestamp":1715385600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation is an inherited disease caused by pathogenic biallelic variants in the gene DARS2, which encodes mitochondrial aspartyl-tRNA synthetase. This disease is characterized by slowly progressive spastic gait, cerebellar symptoms, and leukoencephalopathy with brainstem and spinal cord involvement. Case Presentation: Peripheral blood samples were collected from four patients from four unrelated families to extract genomic DNA. All patients underwent partial exon analysis of the DARS2 gene using Sanger sequencing, which detected the c.228-21_228-20delinsC variant in a heterozygous state. Further DNA from three patients was analyzed using a next-generation sequencing-based custom AmpliSeq\u2122 panel for 59 genes associated with leukodystrophies, and one of the patients underwent whole genome sequencing. We identified a novel pathogenic variant c.1675-1256_*115delinsGCAACATTTCGGCAACATTCCAACC in the DARS2 gene. Three patients (patients 1, 2, and 4) had slowly progressive cerebellar ataxia, and two patients (patients 1 and 2) had spasticity. In addition, two patients (patients 2 and 4) showed signs of axonal neuropathy, such as decreased tendon reflexes and loss of distal sensitivity. Three patients (patients 1, 2, and 3) also had learning difficulties. It should be noted the persistent presence of characteristic changes in brain MRI in all patients, which emphasizes its importance as the main diagnostic tool for suspicion and subsequent confirmation of LBSL. Conclusions: We found a novel indel variant in the DARS2 gene in four patients with LBSL and described their clinical and genetic characteristics. These results expand the mutational spectrum of LBSL and aim to improve the laboratory diagnosis of this form of leukodystrophy.<\/jats:p>","DOI":"10.3390\/genes15050615","type":"journal-article","created":{"date-parts":[[2024,5,14]],"date-time":"2024-05-14T08:59:37Z","timestamp":1715677177000},"page":"615","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Identification of a Novel Indel Variant in the DARS2 Gene in Russian Patients with Leukoencephalopathy with Brainstem and Spinal Cord Involvement and Lactate Elevation"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5337-1775","authenticated-orcid":false,"given":"Fatima M.","family":"Bostanova","sequence":"first","affiliation":[{"name":"Research Centre for Medical Genetics, 1 Moskvorechye St., 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3998-3609","authenticated-orcid":false,"given":"Polina G.","family":"Tsygankova","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, 1 Moskvorechye St., 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena A.","family":"Larshina","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, 1 Moskvorechye St., 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilya O.","family":"Nagornov","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, 1 Moskvorechye St., 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulia V.","family":"Evseeva","sequence":"additional","affiliation":[{"name":"Ekaterinburg Research Institute of Viral Infections, 620030 Yekaterinburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina L.","family":"Krutikhina","sequence":"additional","affiliation":[{"name":"Kirov Regional Children\u2019s Clinical Hospital, 610050 Kirov, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina E.","family":"Dzhentemirova","sequence":"additional","affiliation":[{"name":"State Budgetary Healthcare Institution \u201cMagadan Region Center for Maternal and Child Health\u201d, 685000 Magadan, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9359-6940","authenticated-orcid":false,"given":"Marina N.","family":"Kashlakova","sequence":"additional","affiliation":[{"name":"St. Petersburg State Budgetary Institution, City Polyclinic, No. 114, 197374 St. Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina S.","family":"Petukhova","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, 1 Moskvorechye St., 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inna V.","family":"Sharkova","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, 1 Moskvorechye St., 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekaterina Y.","family":"Zakharova","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, 1 Moskvorechye St., 115522 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,11]]},"reference":[{"key":"ref_1","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_2","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1038\/ng2013","article-title":"Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation","volume":"39","author":"Scheper","year":"2007","journal-title":"Nat. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2845","DOI":"10.1093\/hmg\/ddaa176","article-title":"DARS2 is indispensable for Purkinje cell survival and protects against cerebellar ataxia","volume":"29","author":"Rumyantseva","year":"2020","journal-title":"Hum. Mol. Genet."},{"key":"ref_4","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_5","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1042\/BJ20110795","article-title":"Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation is associated with cell-type-dependent splicing of mtAspRS mRNA","volume":"441","author":"Dooves","year":"2012","journal-title":"Biochem. J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.jns.2016.11.058","article-title":"Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) with a novel DARS2 mutation and isolated progressive spastic paraparesis","volume":"372","author":"Lan","year":"2017","journal-title":"J. Neurol. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/s41436-019-0686-8","article-title":"Technical standards for the interpretation and reporting of constitutional copy-number variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen)","volume":"22","author":"Riggs","year":"2020","journal-title":"Genet. Med."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/5\/615\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:40:59Z","timestamp":1760107259000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/5\/615"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,11]]},"references-count":7,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2024,5]]}},"alternative-id":["genes15050615"],"URL":"https:\/\/doi.org\/10.3390\/genes15050615","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,11]]}}}