{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T04:48:42Z","timestamp":1785473322848,"version":"3.56.0"},"reference-count":26,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,3,4]],"date-time":"2024-03-04T00:00:00Z","timestamp":1709510400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,3,4]],"date-time":"2024-03-04T00:00:00Z","timestamp":1709510400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Neurol"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p><jats:italic>RARS2<\/jats:italic>-related mitochondrial disorder is an autosomal recessive mitochondrial encephalopathy caused by biallelic pathogenic variants in the gene encoding the <jats:italic>mitochondrial arginyl-transfer RNA synthetase 2<\/jats:italic> (<jats:italic>RARS2<\/jats:italic>, MIM *611524, NM_020320.5). RARS2 catalyzes the transfer of L-arginine to its cognate tRNA during the translation of mitochondrially-encoded proteins. The classical presentation of <jats:italic>RARS2<\/jats:italic>-related mitochondrial disorder includes pontocerebellar hypoplasia (PCH), progressive microcephaly, profound developmental delay, feeding difficulties, and hypotonia. Most patients also develop severe epilepsy by three months of age, which consists of focal or generalized seizures that frequently become pharmacoresistant and lead to developmental and epileptic encephalopathy (DEE).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Case presentation<\/jats:title>\n                <jats:p>Here, we describe a six-year-old boy with developmental delay, hypotonia, and failure to thrive who developed an early-onset DEE consistent with Lennox-Gastaut Syndrome (LGS), which has not previously been observed in this disorder. He had dysmorphic features including bilateral macrotia, overriding second toes, a depressed nasal bridge, retrognathia, and downslanting palpebral fissures, and he did not demonstrate progressive microcephaly. Whole genome sequencing identified two variants in <jats:italic>RARS2<\/jats:italic>, c.36\u2009+\u20091G\u2009&gt;\u2009T, a previously unpublished variant that is predicted to affect splicing and is, therefore, likely pathogenic and c.419\u00a0T\u2009&gt;\u2009G (p.Phe140Cys), a known pathogenic variant. He exhibited significant, progressive generalized brain atrophy and <jats:italic>ex vacuo<\/jats:italic> dilation of the supratentorial ventricular system on brain MRI and did not demonstrate PCH. Treatment with a ketogenic diet (KD) reduced seizure frequency and enabled him to make developmental progress. Plasma untargeted metabolomics analysis showed increased levels of lysophospholipid and sphingomyelin-related metabolites.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Our work expands the clinical spectrum of <jats:italic>RARS2<\/jats:italic>-related mitochondrial disorder, demonstrating that patients can present with dysmorphic features and an absence of progressive microcephaly, which can help guide the diagnosis of this condition. Our case highlights the importance of appropriate seizure phenotyping in this condition and indicates that patients can develop LGS, for which a KD may be a viable therapeutic option. Our work further suggests that analytes of phospholipid metabolism may serve as biomarkers of mitochondrial dysfunction.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12883-024-03571-w","type":"journal-article","created":{"date-parts":[[2024,3,4]],"date-time":"2024-03-04T06:02:21Z","timestamp":1709532141000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Expanded clinical phenotype and untargeted metabolomics analysis in RARS2-related mitochondrial disorder: a case report"],"prefix":"10.1186","volume":"24","author":[{"given":"Ameya S.","family":"Walimbe","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keren","family":"Machol","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen F.","family":"Kralik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth A.","family":"Mizerik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoel","family":"Gofin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mir Reza","family":"Bekheirnia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charul","family":"Gijavanekar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah H.","family":"Elsea","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa T.","family":"Emrick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Scaglia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,4]]},"reference":[{"key":"3571_CR1","doi-asserted-by":"publisher","unstructured":"Joseph JT, Innes AM, Smith AC, Vanstone MR, Schwartzentruber JA, Bulman DE, Majewski J, Daza RA, Hevner RF, Michaud J, Boycott KM; FORGE Canada Consortium. Neuropathologic features of pontocerebellar hypoplasia type 6. J Neuropathol Exp Neurol. 2014;73(11):1009\u201325. https:\/\/doi.org\/10.1097\/NEN.0000000000000123.","DOI":"10.1097\/NEN.0000000000000123"},{"key":"3571_CR2","doi-asserted-by":"publisher","unstructured":"Sevin\u00e7 S, \u0130nci A, Ezg\u00fc FS, Emino\u011flu FT. A Patient with a Novel\u00a0RARS2\u00a0Variant Exhibiting Liver Involvement as a New Clinical Feature and Review of the Literature. Mol Syndromol. 2022;13(3):226\u2013234. https:\/\/doi.org\/10.1159\/000519604.","DOI":"10.1159\/000519604"},{"key":"3571_CR3","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.pediatrneurol.2022.04.002","volume":"131","author":"Y Zhang","year":"2022","unstructured":"Zhang Y, Yu Y, Zhao X, Xu Y, Chen L, Li N, Yao R, Wang J, Yu T. Novel RARS2 Variants: Updating the Diagnosis and Pathogenesis of Pontocerebellar Hypoplasia Type 6. Pediatr Neurol. 2022;131:30\u201341. https:\/\/doi.org\/10.1016\/j.pediatrneurol.2022.04.002.","journal-title":"Pediatr Neurol"},{"issue":"3","key":"3571_CR4","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1007\/s10545-011-9413-6","volume":"35","author":"E Glamuzina","year":"2012","unstructured":"Glamuzina E, Brown R, Hogarth K, Saunders D, Russell-Eggitt I, Pitt M, de Sousa C, Rahman S, Brown G, Grunewald S. Further delineation of pontocerebellar hypoplasia type 6 due to mutations in the gene encoding mitochondrial arginyl-tRNA synthetase, RARS2. J Inherit Metab Dis. 2012;35(3):459\u201367. https:\/\/doi.org\/10.1007\/s10545-011-9413-6.","journal-title":"J Inherit Metab Dis"},{"issue":"5","key":"3571_CR5","doi-asserted-by":"publisher","first-page":"707","DOI":"10.21037\/tp-20-110.","volume":"9","author":"Y Xu","year":"2020","unstructured":"Xu Y, Wu BB, Wang HJ, Zhou SZ, Cheng GQ, Zhou YF. A term neonate with early myoclonic encephalopathy caused by RARS2 gene variants: a case report. Transl Pediatr. 2020;9(5):707\u201312. https:\/\/doi.org\/10.21037\/tp-20-110.","journal-title":"Transl Pediatr"},{"key":"3571_CR6","doi-asserted-by":"publisher","unstructured":"de Valles-Ib\u00e1\u00f1ez G, Hildebrand MS, Bahlo M, King C, Coleman M, Green TE, Goldsmith J, Davis S, Gill D, Mandelstam S, Scheffer IE, Sadleir LG. Infantile-onset myoclonic developmental and epileptic encephalopathy: A new RARS2 phenotype. Epilepsia Open. 2022;7(1):170\u2013180. https:\/\/doi.org\/10.1002\/epi4.12553.","DOI":"10.1002\/epi4.12553"},{"issue":"16","key":"3571_CR7","doi-asserted-by":"publisher","first-page":"6656","DOI":"10.1021\/ac901536h","volume":"81","author":"AM Evans","year":"2009","unstructured":"Evans AM, DeHaven CD, Barrett T, Mitchell M, Milgram E. Integrated, nontargeted ultrahigh performance liquid chromatography\/electrospray ionization tandem mass spectrometry platform for the identification and relative quantification of the small-molecule complement of biological systems. Anal Chem. 2009;81(16):6656\u201367. https:\/\/doi.org\/10.1021\/ac901536h.","journal-title":"Anal Chem"},{"issue":"12","key":"3571_CR8","doi-asserted-by":"publisher","first-page":"1004","DOI":"10.1136\/archdischild-2013-304308","volume":"98","author":"K Kastrissianakis","year":"2013","unstructured":"Kastrissianakis K, Anand G, Quaghebeur G, Price S, Prabhakar P, Marinova J, Brown G, McShane T. Subdural effusions and lack of early pontocerebellar hypoplasia in siblings with RARS2 mutations. Arch Dis Child. 2013;98(12):1004\u20137. https:\/\/doi.org\/10.1136\/archdischild-2013-304308.","journal-title":"Arch Dis Child"},{"key":"3571_CR9","doi-asserted-by":"publisher","unstructured":"Edvardson S, Shaag A, Kolesnikova O, Gomori JM, Tarassov I, Einbinder T, Saada A, Elpeleg O. Deleterious mutation in the mitochondrial arginyl-transfer RNA synthetase gene is associated with pontocerebellar hypoplasia. Am J Hum Genet. 2007;81(4):857\u201362. https:\/\/doi.org\/10.1086\/521227.","DOI":"10.1086\/521227"},{"key":"3571_CR10","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1007\/978-1-4614-3722-2_16","volume-title":"Mitochondrial disorders caused by nuclear genes","author":"H Tyynismaa","year":"2013","unstructured":"Tyynismaa H. Mitochondrial aminoacyl-tRNA synthetases. In: Wong LJC, editor. Mitochondrial disorders caused by nuclear genes. New York: Springer; 2013. p. 263\u201376."},{"key":"3571_CR11","doi-asserted-by":"publisher","unstructured":"Nevanlinna V, Konovalova S, Ceulemans B, Muona M, Laari A, Hilander T, Gorski K, Valanne L, Anttonen AK, Tyynismaa H, Courage C, Lehesjoki AE. A patient with pontocerebellar hypoplasia type 6: Novel RARS2 mutations, comparison to previously published patients and clinical distinction from PEHO syndrome. Eur J Med Genet. 2020;63(3):103766. https:\/\/doi.org\/10.1016\/j.ejmg.2019.103766.","DOI":"10.1016\/j.ejmg.2019.103766"},{"issue":"1","key":"3571_CR12","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1186\/s11689-019-9292-y","volume":"11","author":"AS Fine","year":"2019","unstructured":"Fine AS, Nemeth CL, Kaufman ML, Fatemi A. Mitochondrial aminoacyl-tRNA synthetase disorders: an emerging group of developmental disorders of myelination. J Neurodev Disord. 2019;11(1):29. https:\/\/doi.org\/10.1186\/s11689-019-9292-y.","journal-title":"J Neurodev Disord"},{"key":"3571_CR13","doi-asserted-by":"publisher","unstructured":"van Berge L, Hamilton EM, Linnankivi T, Uziel G, Steenweg ME, Isohanni P, Wolf NI, Kr\u00e4geloh-Mann I, Brautaset NJ, Andrews PI, de Jong BA, al Ghamdi M, van Wieringen WN, Tannous BA, Hulleman E, W\u00fcrdinger T, van Berkel CG, Polder E, Abbink TE, Struys EA, Scheper GC, van der Knaap MS; LBSL Research Group. Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation: clinical and genetic characterization and target for therapy. Brain. 2014;137(Pt 4):1019\u201329. https:\/\/doi.org\/10.1093\/brain\/awu026.","DOI":"10.1093\/brain\/awu026"},{"issue":"2","key":"3571_CR14","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1002\/ana.10456","volume":"53","author":"MS van der Knaap","year":"2003","unstructured":"van der Knaap MS, van der Voorn P, Barkhof F, Van Coster R, Kr\u00e4geloh-Mann I, Feigenbaum A, Blaser S, Vles JS, Rieckmann P, Pouwels PJ. A new leukoencephalopathy with brainstem and spinal cord involvement and high lactate. Ann Neurol. 2003;53(2):252\u20138. https:\/\/doi.org\/10.1002\/ana.10456.","journal-title":"Ann Neurol"},{"key":"3571_CR15","doi-asserted-by":"publisher","unstructured":"Bendeck JL, Villamizar I, Prieto C, Celis LG. Mutaci\u00f3n heterocigota, autos\u00f3mica recesiva del gen RARS2 en una paciente colombiana de padres no consangu\u00edneos [Autosomal recessive heterocygote mutation of the RARS2 gene in a Colombian patient with non- consanguineous parents]. Arch Argent Pediatr. 2022;120(1): e39-e48. Spanish. https:\/\/doi.org\/10.5546\/aap.2022.e39.","DOI":"10.5546\/aap.2022.e39"},{"key":"3571_CR16","doi-asserted-by":"publisher","unstructured":"Ngoh A, Bras J, Guerreiro R, Meyer E, McTague A, Dawson E, Mankad K, Gunny R, Clayton P, Mills PB, Thornton R, Lai M, Forsyth R, Kurian MA. RARS2 mutations in a sibship with infantile spasms. Epilepsia. 2016;57(5): e97-e102. https:\/\/doi.org\/10.1111\/epi.13358.","DOI":"10.1111\/epi.13358"},{"issue":"3","key":"3571_CR17","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1016\/j.ejpn.2016.02.012","volume":"20","author":"D Nishri","year":"2016","unstructured":"Nishri D, Goldberg-Stern H, Noyman I, Blumkin L, Kivity S, Saitsu H, Nakashima M, Matsumoto N, Leshinsky-Silver E, Lerman-Sagie T, Lev D. RARS2 mutations cause early onset epileptic encephalopathy without ponto-cerebellar hypoplasia. Eur J Paediatr Neurol. 2016;20(3):412\u20137. https:\/\/doi.org\/10.1016\/j.ejpn.2016.02.012.","journal-title":"Eur J Paediatr Neurol"},{"issue":"1","key":"3571_CR18","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1111\/j.1528-1167.2006.00906.x","volume":"48","author":"HC Kang","year":"2007","unstructured":"Kang HC, Lee YM, Kim HD, Lee JS, Slama A. Safe and effective use of the ketogenic diet in children with epilepsy and mitochondrial respiratory chain complex defects. Epilepsia. 2007;48(1):82\u20138. https:\/\/doi.org\/10.1111\/j.1528-1167.2006.00906.x.","journal-title":"Epilepsia"},{"issue":"13","key":"3571_CR19","doi-asserted-by":"publisher","first-page":"175628641989781","DOI":"10.1177\/1756286419897813","volume":"6","author":"JH Na","year":"2020","unstructured":"Na JH, Kim HD, Lee YM. Effective and safe diet therapies for Lennox-Gastaut syndrome with mitochondrial dysfunction. Ther Adv Neurol Disord. 2020;6(13):1756286419897813. https:\/\/doi.org\/10.1177\/1756286419897813.","journal-title":"Ther Adv Neurol Disord"},{"issue":"1","key":"3571_CR20","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1186\/s13023-021-01927-w","volume":"16","author":"H Zweers","year":"2021","unstructured":"Zweers H, van Wegberg AMJ, Janssen MCH, Wortmann SB. Ketogenic diet for mitochondrial disease: a systematic review on efficacy and safety. Orphanet J Rare Dis. 2021;16(1):295. https:\/\/doi.org\/10.1186\/s13023-021-01927-w.","journal-title":"Orphanet J Rare Dis"},{"key":"3571_CR21","doi-asserted-by":"publisher","unstructured":"Paoli A, Bianco A, Damiani E, Bosco G. Ketogenic diet in neuromuscular and neurodegenerative diseases. Biomed Res Int. 2014;2014:474296. https:\/\/doi.org\/10.1155\/2014\/474296.","DOI":"10.1155\/2014\/474296"},{"issue":"1","key":"3571_CR22","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1055\/s-0041-1732446","volume":"53","author":"Y Murofushi","year":"2022","unstructured":"Murofushi Y, Hayakawa I, Abe Y, Ohto T, Murayama K, Suzuki H, Takenouchi T, Kosaki K, Kubota M. Ketogenic Diet for KARS-Related Mitochondrial Dysfunction and Progressive Leukodystrophy. Neuropediatrics. 2022;53(1):65\u20138. https:\/\/doi.org\/10.1055\/s-0041-1732446.","journal-title":"Neuropediatrics"},{"issue":"Pt 5","key":"3571_CR23","doi-asserted-by":"publisher","first-page":"1387","DOI":"10.1093\/brain\/aws070","volume":"135","author":"ME Steenweg","year":"2012","unstructured":"Steenweg ME, Ghezzi D, Haack T, Abbink TE, Martinelli D, van Berkel CG, Bley A, Diogo L, Grillo E, Te Water Naud\u00e9 J, Strom TM, Bertini E, Prokisch H, van der Knaap MS, Zeviani M. Leukoencephalopathy with thalamus and brainstem involvement and high lactate \u201cLTBL\u201d caused by EARS2 mutations. Brain. 2012;135(Pt 5):1387\u201394. https:\/\/doi.org\/10.1093\/brain\/aws070.","journal-title":"Brain"},{"issue":"1","key":"3571_CR24","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1002\/ajmg.a.62482","volume":"188","author":"J Odom","year":"2022","unstructured":"Odom J, Amin H, Gijavanekar C, Elsea SH, Kralik S, Chinen J, Lin Y, Yates AMM, Mizerik E, Potocki L, Scaglia F. A phenotypic expansion of TRNT1 associated sideroblastic anemia with immunodeficiency, fevers, and developmental delay. Am J Med Genet A. 2022;188(1):259\u201368. https:\/\/doi.org\/10.1002\/ajmg.a.62482.","journal-title":"Am J Med Genet A"},{"issue":"12","key":"3571_CR25","doi-asserted-by":"publisher","first-page":"e9091","DOI":"10.15252\/emmm.201809091.PMID:30373890;PMCID:PMC6284386","volume":"10","author":"J Buzkova","year":"2018","unstructured":"Buzkova J, Nikkanen J, Ahola S, Hakonen AH, Sevastianova K, Hovinen T, Yki-J\u00e4rvinen H, Pietil\u00e4inen KH, L\u00f6nnqvist T, Velagapudi V, Carroll CJ, Suomalainen A. Metabolomes of mitochondrial diseases and inclusion body myositis patients: treatment targets and biomarkers. EMBO Mol Med. 2018;10(12):e9091. https:\/\/doi.org\/10.15252\/emmm.201809091.PMID:30373890;PMCID:PMC6284386.","journal-title":"EMBO Mol Med"},{"issue":"8","key":"3571_CR26","doi-asserted-by":"publisher","first-page":"2079","DOI":"10.1002\/ajmg.a.33531","volume":"152","author":"J Rankin","year":"2010","unstructured":"Rankin J, Brown R, Dobyns WB, Harington J, Patel J, Quinn M, et al. Pontocerebellar hypoplasia type 6: a British case with PEHO-like features. Am J Med Genet Part A. 2010;152(8):2079\u201384.","journal-title":"Am J Med Genet Part A"}],"container-title":["BMC Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12883-024-03571-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12883-024-03571-w\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12883-024-03571-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,4]],"date-time":"2024-03-04T06:02:27Z","timestamp":1709532147000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcneurol.biomedcentral.com\/articles\/10.1186\/s12883-024-03571-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,4]]},"references-count":26,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["3571"],"URL":"https:\/\/doi.org\/10.1186\/s12883-024-03571-w","relation":{},"ISSN":["1471-2377"],"issn-type":[{"value":"1471-2377","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,4]]},"assertion":[{"value":"12 September 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 February 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 March 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"According to the Baylor College of Medicine Internal Review Board (IRB) guidelines, only studies with n\u2009\u2265\u20093 patients constitute research and require an IRB-approved protocol and consent form. The patient's mother signed a consent form authorized by Texas Children's Hospital to approve publication of her child's case.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Written informed consent was obtained from the parent of the participant for publication of identifying information\/images in an online open-access publication. A copy of the written consent is available for review by the editor of this journal.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"87"}}