{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T17:22:57Z","timestamp":1790875377432,"version":"4.1.0"},"reference-count":24,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T00:00:00Z","timestamp":1763510400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T00:00:00Z","timestamp":1763510400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Mol Neurosci"],"DOI":"10.1007\/s12031-025-02440-6","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T07:28:23Z","timestamp":1763537303000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Hypocitrullinemia as an Early Diagnostic Biomarker for MT-ATP6 Mitochondrial Diseases"],"prefix":"10.1007","volume":"75","author":[{"given":"Yingxue","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongjuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maobin","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoxuan","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siqi","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,19]]},"reference":[{"key":"2440_CR1","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1007\/8904_2016_559","volume":"33","author":"S Balasubramaniam","year":"2017","unstructured":"Balasubramaniam S, Lewis B, Mock DM et al (2017) Leigh-Like syndrome due to homoplasmic m.8993T\u2009>\u2009G variant with hypocitrullinemia and unusual biochemical features suggestive of multiple carboxylase deficiency (MCD). JIMD Rep 33:99\u2013107. https:\/\/doi.org\/10.1007\/8904_2016_559","journal-title":"JIMD Rep"},{"key":"2440_CR2","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.ymgme.2018.02.008","volume":"124","author":"M Boyer","year":"2018","unstructured":"Boyer M, Sowa M, Di Meo I et al (2018) Response to medical and a novel dietary treatment in newborn screen identified patients with ethylmalonic encephalopathy. Mol Genet Metab 124:57\u201363. https:\/\/doi.org\/10.1016\/j.ymgme.2018.02.008","journal-title":"Mol Genet Metab"},{"key":"2440_CR3","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1007\/s10545-015-9894-9","volume":"39","author":"R Carrozzo","year":"2016","unstructured":"Carrozzo R, Verrigni D, Rasmussen M et al (2016) Succinate-CoA ligase deficiency due to mutations in SUCLA2 and SUCLG1: phenotype and genotype correlations in 71 patients. J Inherit Metab Dis 39:243\u2013252. https:\/\/doi.org\/10.1007\/s10545-015-9894-9","journal-title":"J Inherit Metab Dis"},{"key":"2440_CR4","doi-asserted-by":"publisher","first-page":"1000","DOI":"10.1177\/0883073809351983","volume":"25","author":"F-G Debray","year":"2010","unstructured":"Debray F-G, Lambert M, Allard P, Mitchell GA (2010) Low citrulline in Leigh disease: still a biomarker of maternally inherited Leigh syndrome. J Child Neurol 25:1000\u20131002. https:\/\/doi.org\/10.1177\/0883073809351983","journal-title":"J Child Neurol"},{"key":"2440_CR5","doi-asserted-by":"publisher","first-page":"817","DOI":"10.1042\/bj1410817","volume":"141","author":"KR Elliott","year":"1974","unstructured":"Elliott KR, Tipton KF (1974) Product inhibition studies on bovine liver carbamoyl phosphate synthetase. Biochem J 141:817\u2013824. https:\/\/doi.org\/10.1042\/bj1410817","journal-title":"Biochem J"},{"key":"2440_CR6","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1002\/humu.23723","volume":"40","author":"RD Ganetzky","year":"2019","unstructured":"Ganetzky RD, Stendel C, McCormick EM et al (2019) MT-ATP6 mitochondrial disease variants: phenotypic and biochemical features analysis in 218 published cases and cohort of 14 new cases. Hum Mutat 40:499\u2013515. https:\/\/doi.org\/10.1002\/humu.23723","journal-title":"Hum Mutat"},{"key":"2440_CR7","doi-asserted-by":"publisher","first-page":"1059","DOI":"10.1177\/0883073811431015","volume":"27","author":"M Henriques","year":"2012","unstructured":"Henriques M, Diogo L, Garcia P et al (2012) Mitochondrial DNA 8993T\u2009>\u2009G mutation in a child with ornithine transcarbamylase deficiency and Leigh syndrome: an unexpected association. J Child Neurol 27:1059\u20131061. https:\/\/doi.org\/10.1177\/0883073811431015","journal-title":"J Child Neurol"},{"key":"2440_CR8","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1016\/0378-1119(90)90319-M","volume":"46","author":"IJ Holt","year":"1990","unstructured":"Holt IJ, Harding AE, Petty RK et al (1990) A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. Am J Hum Genet 46:428\u2013433. https:\/\/doi.org\/10.1016\/0378-1119(90)90319-M","journal-title":"Am J Hum Genet"},{"key":"2440_CR9","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.mito.2018.01.001","volume":"44","author":"AA Larson","year":"2019","unstructured":"Larson AA, Balasubramaniam S, Christodoulou J et al (2019) Biochemical signatures mimicking multiple carboxylase deficiency in children with mutations in MT-ATP6. Mitochondrion 44:58\u201364. https:\/\/doi.org\/10.1016\/j.mito.2018.01.001","journal-title":"Mitochondrion"},{"key":"2440_CR10","doi-asserted-by":"publisher","first-page":"1004","DOI":"10.1002\/ana.25110","volume":"82","author":"RR Maas","year":"2017","unstructured":"Maas RR, Iwanicka-Pronicka K, Kalkan Ucar S et al (2017) Progressive deafness-dystonia due to SERAC1 mutations: a study of 67 cases. Ann Neurol 82:1004\u20131015. https:\/\/doi.org\/10.1002\/ana.25110","journal-title":"Ann Neurol"},{"key":"2440_CR11","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1007\/8904_2014_332","volume":"17","author":"M Mori","year":"2014","unstructured":"Mori M, Mytinger JR, Martin LC et al (2014) m.8993T\u2009>\u2009G-Associated Leigh syndrome with hypocitrullinemia on newborn screening. JIMD Rep 17:47\u201351. https:\/\/doi.org\/10.1007\/8904_2014_332","journal-title":"JIMD Rep"},{"key":"2440_CR12","doi-asserted-by":"publisher","first-page":"414","DOI":"10.1111\/ane.13566","volume":"145","author":"JH Na","year":"2022","unstructured":"Na JH, Lee YM (2022) Genotype-phenotype analysis of MT-ATP6-associated Leigh syndrome. Acta Neurol Scand 145:414\u2013422. https:\/\/doi.org\/10.1111\/ane.13566","journal-title":"Acta Neurol Scand"},{"key":"2440_CR13","doi-asserted-by":"publisher","first-page":"310","DOI":"10.1002\/ana.25525","volume":"86","author":"YS Ng","year":"2019","unstructured":"Ng YS, Martikainen MH, Gorman GS et al (2019) Pathogenic variants in MT-ATP6: a united Kingdom-based mitochondrial disease cohort study. Ann Neurol 86:310\u2013315. https:\/\/doi.org\/10.1002\/ana.25525","journal-title":"Ann Neurol"},{"key":"2440_CR14","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1007\/s004310051009","volume":"158","author":"B Parfait","year":"1999","unstructured":"Parfait B, de Lonlay P, von Kleist-Retzow JC et al (1999) The neurogenic weakness, ataxia and retinitis pigmentosa (NARP) syndrome MtDNA mutation (T8993G) triggers muscle ATPase deficiency and hypocitrullinaemia. Eur J Pediatr 158:55\u201358. https:\/\/doi.org\/10.1007\/s004310051009","journal-title":"Eur J Pediatr"},{"key":"2440_CR15","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.ymgme.2021.06.007","volume":"134","author":"RH Peretz","year":"2021","unstructured":"Peretz RH, Ah Mew N, Vernon HJ, Ganetzky RD (2021) Prospective diagnosis of MT-ATP6-related mitochondrial disease by newborn screening. Mol Genet Metab 134:37\u201342. https:\/\/doi.org\/10.1016\/j.ymgme.2021.06.007","journal-title":"Mol Genet Metab"},{"key":"2440_CR16","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1023\/a:1005391300203","volume":"21","author":"D Rabier","year":"1998","unstructured":"Rabier D, Diry C, Rotig A et al (1998) Persistent hypocitrullinaemia as a marker for MtDNA NARP T 8993 G mutation? J Inherit Metab Dis 21:216\u2013219. https:\/\/doi.org\/10.1023\/a:1005391300203","journal-title":"J Inherit Metab Dis"},{"key":"2440_CR17","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1007\/bf00807268","volume":"9","author":"D Rabier","year":"1995","unstructured":"Rabier D, Kamoun P (1995) Metabolism of citrulline in man. Amino Acids 9:299\u2013316. https:\/\/doi.org\/10.1007\/bf00807268","journal-title":"Amino Acids"},{"key":"2440_CR18","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1016\/j.ajhg.2014.12.020","volume":"96","author":"C Saunders","year":"2015","unstructured":"Saunders C, Smith L, Wibrand F et al (2015) CLPB variants associated with autosomal-recessive mitochondrial disorder with cataract, neutropenia, epilepsy, and methylglutaconic aciduria. Am J Hum Genet 96:258\u2013265. https:\/\/doi.org\/10.1016\/j.ajhg.2014.12.020","journal-title":"Am J Hum Genet"},{"key":"2440_CR19","doi-asserted-by":"publisher","first-page":"e393","DOI":"10.1212\/nxg.0000000000000393","volume":"6","author":"C Stendel","year":"2020","unstructured":"Stendel C, Neuhofer C, Floride E et al (2020) Delineating MT-ATP6-associated disease: from isolated neuropathy to early onset neurodegeneration. Neurol Genet 6:e393. https:\/\/doi.org\/10.1212\/nxg.0000000000000393","journal-title":"Neurol Genet"},{"key":"2440_CR20","doi-asserted-by":"publisher","first-page":"1492","DOI":"10.1002\/ajmg.a.63159","volume":"191","author":"CG Tise","year":"2023","unstructured":"Tise CG, Verscaj CP, Mendelsohn BA et al (2023) MT-ATP6 mitochondrial disease identified by newborn screening reveals a distinct biochemical phenotype. Am J Med Genet A 191:1492\u20131501. https:\/\/doi.org\/10.1002\/ajmg.a.63159","journal-title":"Am J Med Genet A"},{"key":"2440_CR21","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1016\/j.ajhg.2014.01.006","volume":"94","author":"CD van Karnebeek","year":"2014","unstructured":"van Karnebeek CD, Sly WS, Ross CJ et al (2014) Mitochondrial carbonic anhydrase VA deficiency resulting from CA5A alterations presents with hyperammonemia in early childhood. Am J Hum Genet 94:453\u2013461. https:\/\/doi.org\/10.1016\/j.ajhg.2014.01.006","journal-title":"Am J Hum Genet"},{"key":"2440_CR22","doi-asserted-by":"publisher","first-page":"605803","DOI":"10.3389\/fphar.2021.605803","volume":"12","author":"J Wang","year":"2021","unstructured":"Wang J, Liu Z, Xu M et al (2021) Cinical, metabolic, and genetic analysis and follow-up of eight patients with HIBCH mutations presenting with Leigh\/Leigh-Like syndrome. Front Pharmacol 12:605803. https:\/\/doi.org\/10.3389\/fphar.2021.605803","journal-title":"Front Pharmacol"},{"key":"2440_CR23","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1093\/clinchem\/hvad039","volume":"69","author":"P Wongkittichote","year":"2023","unstructured":"Wongkittichote P, Ganetzky RD, Demczko MM et al (2023) Low plasma citrulline guiding the diagnosis of a mitochondrial disorder. Clin Chem 69:661\u2013664. https:\/\/doi.org\/10.1093\/clinchem\/hvad039","journal-title":"Clin Chem"},{"key":"2440_CR24","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1186\/s12887-020-1947-z","volume":"20","author":"H Yang","year":"2020","unstructured":"Yang H, Yu D (2020) Clinical, biochemical and metabolic characterization of patients with short-chain enoyl-CoA hydratase(ECHS1) deficiency: two case reports and the review of the literature. BMC Pediatr 20:50. https:\/\/doi.org\/10.1186\/s12887-020-1947-z","journal-title":"BMC Pediatr"}],"container-title":["Journal of Molecular Neuroscience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12031-025-02440-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12031-025-02440-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12031-025-02440-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T08:23:29Z","timestamp":1767774209000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12031-025-02440-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,19]]},"references-count":24,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["2440"],"URL":"https:\/\/doi.org\/10.1007\/s12031-025-02440-6","relation":{},"ISSN":["1559-1166"],"issn-type":[{"value":"1559-1166","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,19]]},"assertion":[{"value":"24 May 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 October 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 November 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All human and animal studies have been approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"The authors affirm that human research participants provided informed consent for publication of the images in Tables\u00a01 and 2.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to publish"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"154"}}