{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T04:20:16Z","timestamp":1793420416269,"version":"4.5.0"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T00:00:00Z","timestamp":1763424000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T00:00:00Z","timestamp":1763424000000},"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":["Orphanet J Rare Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Glutaric acidemia type II (GA2), also known as multiple acyl-CoA dehydrogenase deficiency (MADD), is a rare inherited error of amino acid and fatty acid metabolism. Its clinical manifestations can vary from severe events that threaten the life of a newborn to milder and late manifestations. Here, we examined an Iranian couple for pre-pregnancy counseling who had a history of the death of two children suspected of metabolic disorder.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Whole exome sequencing (WES) was performed to determine possible pathogenic genes in the parents of two deceased neonates. Sanger sequencing was then used to confirm the variant found. Subsequently, the possible impact of the identified variant on the ETFA protein was evaluated using bioinformatics tools.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      WES identified a novel heterozygous in-frame variant c.485_493del: p.E162_T164del in exon 6 of the\n                      <jats:italic>ETFA<\/jats:italic>\n                      gene, which co-segregated with the autosomal recessive GA2 disorder in the family studied. Sanger sequencing confirmed the variant found in the parents and their healthy family members and in silico approaches showed disease-causing nature of the identified mutation. Following the confirmation of the identified variant in the fetus, a legal abortion permit was issued, and the fetus was terminated with the parents\u2019 consent.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      This is the first reported case of GA2 caused by a variant in the\n                      <jats:italic>ETFA<\/jats:italic>\n                      gene in Iran and shows the importance of genetic diagnosis and management of rare clinical manifestations and conditions that can help predict prognosis and provide more accurate diagnostic information for patients and families with GA2.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13023-025-04107-2","type":"journal-article","created":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T11:48:57Z","timestamp":1763466537000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["First report of neonatal-onset glutaric aciduria type II in the Iranian population caused by a novel deleterious ETFA variant"],"prefix":"10.1186","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8136-3254","authenticated-orcid":false,"given":"Farshid","family":"Parvini","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mobarakeh","family":"Ajam-Hosseini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marziyeh","family":"Shadpour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,18]]},"reference":[{"key":"4107_CR1","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1177\/039463200501800425","volume":"18","author":"S Domizio","year":"2005","unstructured":"Domizio S, Romanelli A, Brindisino P, Puglielli C, Conte E, Domizio R, et al. Glutaric aciduria type II: a case report. Int J Immunopathol Pharmacol. 2005;18:805\u20138.","journal-title":"Int J Immunopathol Pharmacol"},{"key":"4107_CR2","doi-asserted-by":"publisher","first-page":"1101","DOI":"10.1002\/ccr3.3663","volume":"9","author":"L Carmant","year":"2021","unstructured":"Carmant L, Karalis A, Rypens F, Oligny L, Wavrant S, Lapeyraque AL, et al. Prenatal presentation of glutaric aciduria type II: A case report with radiologic, clinical, biochemical, molecular, and pathological phenotyping. Clin Case Rep. 2021;9:1101\u20133.","journal-title":"Clin Case Rep"},{"key":"4107_CR3","doi-asserted-by":"crossref","unstructured":"Mereis M, Wanders RJA, Schoonen M, Dercksen M, Smuts I, van der Westhuizen FH. Disorders of flavin adenine dinucleotide metabolism: MADD and related deficiencies. Int J Biochem Cell Biol. Elsevier Ltd. 2021.","DOI":"10.1016\/j.biocel.2020.105899"},{"key":"4107_CR4","doi-asserted-by":"crossref","unstructured":"Rose L, Hall K, Tang S, Hasadsri L, Kimonis V. Homozygous B4GALNT1 mutation and biochemical glutaric acidemia type II: A case report. Clin Neurol Neurosurg. 2020;189.","DOI":"10.1016\/j.clineuro.2019.105553"},{"key":"4107_CR5","doi-asserted-by":"crossref","unstructured":"Chautard R, Laroche-Raynaud C, Lia AS, Chazelas P, Derouault P, Sturtz F, et al. A case report of a mild form of multiple acyl-CoA dehydrogenase deficiency due to compound heterozygous mutations in the ETFA gene. BMC Med Genomics. 2020;13.","DOI":"10.1186\/s12920-020-0665-6"},{"key":"4107_CR6","doi-asserted-by":"crossref","unstructured":"Henriques BJ, Katrine Jentoft Olsen R, Gomes CM, Bross P. Electron transfer Flavoprotein and its role in mitochondrial energy metabolism in health and disease. 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Cofactors and metabolites as protein folding helpers in metabolic diseases. Curr Top Med Chem. 2013;999:29\u201335.","journal-title":"Curr Top Med Chem"},{"key":"4107_CR10","doi-asserted-by":"crossref","unstructured":"Li L, Huang Z, Huang Y, Li Y, Ma X, Li P, et al. Pomalidomide sensitizes lung cancer cells to TRAIL\/CDDP-induced apoptosis via directly targeting electron transfer Flavoprotein alpha subunit. Bioorg Chem. 2024;153.","DOI":"10.1016\/j.bioorg.2024.107815"},{"key":"4107_CR11","doi-asserted-by":"crossref","unstructured":"Ou M, Zhu L, Zhang Y, Zhang Y, Zhou J, Zhang Y, et al. A novel electron transfer flavoprotein dehydrogenase (ETFDH) gene mutation identified in a newborn with glutaric acidemia type II: a case report of a Chinese family. BMC Med Genet. 2020;21.","DOI":"10.1186\/s12881-020-00995-2"},{"key":"4107_CR12","doi-asserted-by":"crossref","unstructured":"Rayat S, Morovvati S. 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Riboflavin-responsive multiple Acyl-CoA dehydrogenation deficiency in 13 cases, and a literature review in Mainland Chinese patients. J Hum Genet. 2014;59:256\u201361.","journal-title":"J Hum Genet"},{"key":"4107_CR28","doi-asserted-by":"crossref","unstructured":"Nyhan WL, Hoffmann GF. Atlas of inherited metabolic diseases. CRC; 2020.","DOI":"10.1201\/9781315114033"},{"key":"4107_CR29","doi-asserted-by":"crossref","unstructured":"Zhang X, Zhang YL, Qui G, Pian L, Guo L, Cao H, et al. Hepatic neddylation targets and stabilizes electron transfer flavoproteins to facilitate fatty acid \u03b2-oxidation. Proc. Natl. Acad. Sci. 2020;117(5):2473\u201383.","DOI":"10.1073\/pnas.1910765117"},{"key":"4107_CR30","doi-asserted-by":"crossref","unstructured":"Li Q, Yang C, Feng L, Zhao Y, Su Y, Liu H, et al. Glutaric Acidemia, pathogenesis and nutritional therapy. Front Nutr. 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Written informed consent was obtained from parents and their son and relatives to participate in this study and for possible publication.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All methods were carried out in accordance with relevant guidelines and regulations. The informed consent was obtained from all subjects and\/or their legal guardians.","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":"590"}}