{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T01:24:52Z","timestamp":1789521892825,"version":"build-2803163510"},"reference-count":21,"publisher":"Springer Science and Business Media LLC","issue":"1","content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Orphanet J Rare Dis"],"published-print":{"date-parts":[[2012,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>Despite its first description over 40 years ago, knowledge of the clinical course of isovaleric acidemia (IVA), a disorder predisposing to severe acidotic episodes during catabolic stress, is still anecdotal. We aimed to investigate the phenotypic presentation and factors determining the neurological and neurocognitive outcomes of patients diagnosed with IVA following clinical manifestation.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>Retrospective data on 21 children and adults with symptomatic IVA diagnosed from 1976 to 1999 were analyzed for outcome determinants including age at diagnosis and number of catabolic episodes. Sixteen of 21 patients were evaluated cross-sectionally focusing on the neurological and neurocognitive status. Additionally, 155 cases of patients with IVA published in the international literature were reviewed and analyzed for outcome parameters including mortality.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>57% of study patients (12\/21) were diagnosed within the first weeks of life and 43% (9\/21) in childhood. An acute metabolic attack was the main cause of diagnostic work-up. 44% of investigated study patients (7\/16) showed mild motor dysfunction and only 19% (3\/16) had cognitive deficits. No other organ complications were found. The patients' intelligence quotient was not related to the number of catabolic episodes but was inversely related to age at diagnosis. In published cases, mortality was high (33%) if associated with neonatal diagnosis, following manifestation at an average age of 7 days.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Within the group of \"classical\" organic acidurias, IVA appears to be exceptional considering its milder neuropathologic implications. The potential to avoid neonatal mortality and to improve neurologic and cognitive outcome under early treatment reinforces IVA to be qualified for newborn screening.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1750-1172-7-9","type":"journal-article","created":{"date-parts":[[2012,1,26]],"date-time":"2012-01-26T07:23:51Z","timestamp":1327562631000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":87,"title":["Clinical and neurocognitive outcome in symptomatic isovaleric acidemia"],"prefix":"10.1186","volume":"7","author":[{"given":"Sarah C","family":"Gr\u00fcnert","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Udo","family":"Wendel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Lindner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Leichsenring","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K Otfried","family":"Schwab","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerry","family":"Vockley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Willy","family":"Lehnert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Regina","family":"Ensenauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2012,1,25]]},"reference":[{"key":"354_CR1","doi-asserted-by":"publisher","first-page":"1136","DOI":"10.1086\/426318","volume":"75","author":"R Ensenauer","year":"2004","unstructured":"Ensenauer R, Vockley J, Willard JM, Huey JC, Sass JO, Edland SD, Burton BK, Berry SA, Santer R, Gr\u00fcnert S, et al: A common mutation is associated with a mild, potentially asymptomatic phenotype in patients with isovaleric acidemia diagnosed by newborn screening. Am J Hum Genet. 2004, 75: 1136-1142. 10.1086\/426318.","journal-title":"Am J Hum Genet"},{"key":"354_CR2","doi-asserted-by":"publisher","first-page":"2290","DOI":"10.1172\/JCI111657","volume":"74","author":"CR Roe","year":"1984","unstructured":"Roe CR, Millington DS, Maltby DA, Kahler SG, Bohan TP: L-carnitine therapy in isovaleric acidemia. J Clin Invest. 1984, 74: 2290-2295. 10.1172\/JCI111657.","journal-title":"J Clin Invest"},{"key":"354_CR3","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1016\/S0022-3476(78)80164-4","volume":"92","author":"M Yudkoff","year":"1978","unstructured":"Yudkoff M, Cohn RM, Puschak R, Rothman R, Segal S: Glycine therapy in isovaleric acidemia. J Pediatr. 1978, 92: 813-817. 10.1016\/S0022-3476(78)80164-4.","journal-title":"J Pediatr"},{"key":"354_CR4","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1007\/s10545-006-0278-z","volume":"29","author":"C Dionisi-Vici","year":"2006","unstructured":"Dionisi-Vici C, Deodato F, R\u00f6schinger W, Rhead W, Wilcken B: 'Classical' organic acidurias, propionic aciduria, methylmalonic aciduria and isovaleric aciduria: long-term outcome and effects of expanded newborn screening using tandem mass spectrometry. J Inherit Metab Dis. 2006, 29: 383-389. 10.1007\/s10545-006-0278-z.","journal-title":"J Inherit Metab Dis"},{"key":"354_CR5","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1373\/clinchem.2010.151134","volume":"57","author":"R Ensenauer","year":"2011","unstructured":"Ensenauer R, Fingerhut R, Maier EM, Polanetz R, Olgem\u00f6ller B, R\u00f6schinger W, Muntau AC: Newborn screening for isovaleric acidemia using tandem mass spectrometry: data from 1.6 million newborns. Clin Chem. 2011, 57: 623-626. 10.1373\/clinchem.2010.151134.","journal-title":"Clin Chem"},{"key":"354_CR6","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1016\/S0076-6879(00)24236-5","volume":"324","author":"J Vockley","year":"2000","unstructured":"Vockley J, Mohsen al WA, Binzak B, Willard J, Fauq A: Mammalian branched-chain acyl-CoA dehydrogenases: molecular cloning and characterization of recombinant enzymes. Methods Enzymol. 2000, 324: 241-258.","journal-title":"Methods Enzymol"},{"key":"354_CR7","doi-asserted-by":"publisher","first-page":"630","DOI":"10.1007\/s10545-009-1189-6","volume":"32","author":"F H\u00f6rster","year":"2009","unstructured":"H\u00f6rster F, Garbade SF, Zwickler T, Aydin HI, Bodamer OA, Burlina AB, Das AM, De Klerk JB, Dionisi-Vici C, Geb S, et al: Prediction of outcome in isolated methylmalonic acidurias: combined use of clinical and biochemical parameters. J Inherit Metab Dis. 2009, 32: 630-639. 10.1007\/s10545-009-1189-6.","journal-title":"J Inherit Metab Dis"},{"key":"354_CR8","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1016\/0887-8994(92)90085-D","volume":"8","author":"RA Surtees","year":"1992","unstructured":"Surtees RA, Matthews EE, Leonard JV: Neurologic outcome of propionic acidemia. Pediatr Neurol. 1992, 8: 333-337. 10.1016\/0887-8994(92)90085-D.","journal-title":"Pediatr Neurol"},{"key":"354_CR9","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1007\/s10545-009-1191-12","volume":"32","author":"E Martin-Hernandez","year":"2009","unstructured":"Martin-Hernandez E, Lee PJ, Micciche A, Gr\u00fcnewald S, Lachmann RH: Long-term needs of adult patients with organic acidaemias: outcome and prognostic factors. J Inherit Metab Dis. 2009, 32: 523-533. 10.1007\/s10545-009-1191-12.","journal-title":"J Inherit Metab Dis"},{"key":"354_CR10","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1007\/BF01953939","volume":"155","author":"SB van der Meer","year":"1996","unstructured":"van der Meer SB, Poggi F, Spada M, Bonnefont JP, Ogier H, Hubert P, Depondt E, Rapoport D, Rabier D, Charpentier C, et al: Clinical outcome and long-term management of 17 patients with propionic acidaemia. Eur J Pediatr. 1996, 155: 205-210. 10.1007\/BF01953939.","journal-title":"Eur J Pediatr"},{"key":"354_CR11","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1016\/j.jpeds.2006.11.043","volume":"150","author":"D Baumgartner","year":"2007","unstructured":"Baumgartner D, Scholl-B\u00fcrgi S, Sass JO, Sperl W, Schweigmann U, Stein JI, Karall D: Prolonged QTc intervals and decreased left ventricular contractility in patients with propionic acidemia. J Pediatr. 2007, 150: 192-197. 10.1016\/j.jpeds.2006.11.043. 197 e191","journal-title":"J Pediatr"},{"key":"354_CR12","first-page":"111","volume":"40","author":"A Tokatli","year":"1998","unstructured":"Tokatli A, Coskun T, Ozalp I: Isovaleric acidemia. Clinical presentation of 6 cases. Turk J Pediatr. 1998, 40: 111-119.","journal-title":"Turk J Pediatr"},{"key":"354_CR13","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1007\/BF00538944","volume":"131","author":"M Duran","year":"1979","unstructured":"Duran M, van Sprang FJ, Drewes JG, Bruinvis L, Ketting D, Wadman SK: Two sisters with isovaleric acidaemia, multiple attacks of ketoacidosis and normal development. Eur J Pediatr. 1979, 131: 205-211. 10.1007\/BF00538944.","journal-title":"Eur J Pediatr"},{"key":"354_CR14","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1007\/BF01805706","volume":"1","author":"ME Blaskovics","year":"1978","unstructured":"Blaskovics ME, Ng WG, Donnell GN: Prenatal diagnosis and a case report of isovaleric acidaemia. J Inherit Metab Dis. 1978, 1: 9-11. 10.1007\/BF01805706.","journal-title":"J Inherit Metab Dis"},{"key":"354_CR15","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1080\/10715760802311179","volume":"42","author":"AF Solano","year":"2008","unstructured":"Solano AF, Leipnitz G, De Bortoli GM, Seminotti B, Amaral AU, Fernandes CG, Latini AS, Dutra-Filho CS, Wajner M: Induction of oxidative stress by the metabolites accumulating in isovaleric acidemia in brain cortex of young rats. Free Radic Res. 2008, 42: 707-715. 10.1080\/10715760802311179.","journal-title":"Free Radic Res"},{"key":"354_CR16","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1007\/s10571-007-9143-3","volume":"27","author":"CA Ribeiro","year":"2007","unstructured":"Ribeiro CA, Balestro F, Grando V, Wajner M: Isovaleric acid reduces Na+, K+-ATPase activity in synaptic membranes from cerebral cortex of young rats. Cell Mol Neurobiol. 2007, 27: 529-540. 10.1007\/s10571-007-9143-3.","journal-title":"Cell Mol Neurobiol"},{"key":"354_CR17","first-page":"41","volume-title":"Atlas of Metabolic Diseases","author":"WL Nyhan","year":"1998","unstructured":"Nyhan WL, Ozand P: Isovaleric acidemia. Atlas of Metabolic Diseases 1 edition. Edited by: Nyhan WL, Ozand P. London: Chapman & Hall; 1998:41-45.","edition":"1"},{"key":"354_CR18","first-page":"477","volume":"191","author":"W Lehnert","year":"1979","unstructured":"Lehnert W, Schenck W, Niederhoff H: [Isovaleric acidemia combined with hypertrophic pylorstenosis (author's transl)]. Klin Padiatr. 1979, 191: 477-482.","journal-title":"Klin Padiatr"},{"key":"354_CR19","doi-asserted-by":"publisher","first-page":"2315","DOI":"10.1007\/s00134-008-1192-7","volume":"34","author":"A Kimmoun","year":"2008","unstructured":"Kimmoun A, Abboud G, Strazeck J, Merten M, Gueant JL, Feillet F: Acute decompensation of isovaleric acidemia induced by Graves' disease. Intensive Care Med. 2008, 34: 2315-2316. 10.1007\/s00134-008-1192-7.","journal-title":"Intensive Care Med"},{"key":"354_CR20","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1097\/01.SMJ.0000051141.03668.1D","volume":"96","author":"JA Feinstein","year":"2003","unstructured":"Feinstein JA, O'Brien K: Acute metabolic decompensation in an adult patient with isovaleric acidemia. South Med J. 2003, 96: 500-503. 10.1097\/01.SMJ.0000051141.03668.1D.","journal-title":"South Med J"},{"key":"354_CR21","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/S0022-3476(84)80367-4","volume":"105","author":"VE Shih","year":"1984","unstructured":"Shih VE, Aubry RH, DeGrande G, Gursky SF, Tanaka K: Maternal isovaleric acidemia. J Pediatr. 1984, 105: 77-78. 10.1016\/S0022-3476(84)80367-4.","journal-title":"J Pediatr"}],"container-title":["Orphanet Journal of Rare Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1750-1172-7-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T18:30:34Z","timestamp":1630521034000},"score":1,"resource":{"primary":{"URL":"https:\/\/ojrd.biomedcentral.com\/articles\/10.1186\/1750-1172-7-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,1,25]]},"references-count":21,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2012,12]]}},"alternative-id":["354"],"URL":"https:\/\/doi.org\/10.1186\/1750-1172-7-9","relation":{},"ISSN":["1750-1172"],"issn-type":[{"value":"1750-1172","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,1,25]]},"assertion":[{"value":"27 September 2011","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 January 2012","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 January 2012","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"9"}}