{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T19:53:27Z","timestamp":1791230007297,"version":"4.1.0"},"reference-count":15,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2014,4,1]],"date-time":"2014-04-01T00:00:00Z","timestamp":1396310400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2014,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Combined D,L\u20102\u2010hydroxyglutaric aciduria (DL\u20102HGA; OMIM #615182) is a rare neurometabolic disorder clinically characterized by muscular hypotonia, severe neurodevelopmental dysfunction, and intractable seizures associated with respiratory distress. Biochemically, DL\u20102HGA patients excrete increased amounts of D\u2010 and L\u20102\u2010hydroxyglutarate (D2HG and L2HG, respectively), with predominance of D2HG, and \u03b1\u2010ketoglutarate, and show a decrease in urinary citrate. Impaired function of the mitochondrial citrate carrier (CIC) due to pathogenic mutations within the <jats:italic>SLC25A1<\/jats:italic> gene has been identified as the underlying molecular cause of the disease. CIC mediates efflux of the mitochondrial tricarboxylic acid (TCA) cycle intermediates citrate and isocitrate in exchange for cytosolic malate. Thus, depletion of cytosolic citrate as well as accumulation of citrate inside mitochondria have been considered to play a role in the pathophysiology of DL\u20102HGA. Here, we report for the first time on a patient with a genetically confirmed diagnosis of DL\u20102HGA and treatment with either malate or citrate. During malate treatment, urinary malate concentration increased, but beyond that, neither biochemical nor clinical alterations were observed. In contrast, treatment with citrate led to an increased urinary excretion of TCA cycle intermediates malate and succinate, and by trend to an increased concentration of urinary citrate. Furthermore, excretion of D2HG and L2HG was reduced during citrate treatment. Clinically, the patient showed stabilization with regard to frequency and severity of seizures. Treating DL\u20102HGA with citrate should be considered in other DL\u20102HGA patients, and its effects should be studied systematically.<\/jats:p>","DOI":"10.1007\/s10545-014-9702-y","type":"journal-article","created":{"date-parts":[[2014,3,31]],"date-time":"2014-03-31T12:22:56Z","timestamp":1396268576000},"page":"775-781","source":"Crossref","is-referenced-by-count":38,"title":["Combined D2\u2010\/L2\u2010hydroxyglutaric aciduria (<i>SLC25A1<\/i> deficiency): clinical course and effects of citrate treatment"],"prefix":"10.1002","volume":"37","author":[{"given":"Chris","family":"M\u00fchlhausen","sequence":"first","affiliation":[{"name":"Department of Pediatrics University Medical Center Hamburg\u2010Eppendorf Martinistrasse 52 Hamburg 20246 Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gajja S.","family":"Salomons","sequence":"additional","affiliation":[{"name":"Metabolic Unit, Department of Clinical Chemistry, Neuroscience Campus Amsterdam VU University Medical Center Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoltan","family":"Lukacs","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry, Metabolic Laboratory University Medical Center Hamburg\u2010Eppendorf Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduard A.","family":"Struys","sequence":"additional","affiliation":[{"name":"Metabolic Unit, Department of Clinical Chemistry, Neuroscience Campus Amsterdam VU University Medical Center Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marjo S.","family":"van der Knaap","sequence":"additional","affiliation":[{"name":"Department of Child Neurology VU University Medical Center Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kurt","family":"Ullrich","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University Medical Center Hamburg\u2010Eppendorf Martinistrasse 52 Hamburg 20246 Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren\u00e9","family":"Santer","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University Medical Center Hamburg\u2010Eppendorf Martinistrasse 52 Hamburg 20246 Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,4]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-94-009-5778-7"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2012-101485"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-008-0489-2"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/ddrr.1114"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-012-9462-5"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.232744"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M303415200"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2009-0217"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-008-0825-x"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-2000-7497"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/bies.080137"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2013.03.009"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-003-1099-7"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-005-4565-x"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1373\/clinchem.2004.033399"}],"container-title":["Journal of Inherited Metabolic Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1007\/s10545-014-9702-y","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,15]],"date-time":"2023-09-15T05:55:27Z","timestamp":1694757327000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1007\/s10545-014-9702-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,4]]},"references-count":15,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2014,9]]}},"alternative-id":["10.1007\/s10545-014-9702-y"],"URL":"https:\/\/doi.org\/10.1007\/s10545-014-9702-y","archive":["Portico"],"relation":{},"ISSN":["0141-8955","1573-2665"],"issn-type":[{"value":"0141-8955","type":"print"},{"value":"1573-2665","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,4]]}}}