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This inborn error of\nmetabolism is caused by mutations in the ETFA, ETFB or ETFDH genes, which encode for the\nmitochondrial ETF and ETF:QO proteins. A considerable group of patients has been described to\nrespond positively to riboflavin oral supplementation, which constitutes the prototypic treatment for\nthe pathology.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Objectives:<\/jats:title>\n<jats:p>To report mutations in ETFA, ETFB and ETFDH genes identified in Portuguese\npatients, correlating, whenever possible, biochemical and clinical outcomes with the effects of\nmutations on the structure and stability of the affected proteins, to better understand MADD\npathogenesis at the molecular level.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Methods:<\/jats:title>\n<jats:p> MADD patients were identified based on the characteristic urinary profile of organic acids\nand\/or acylcarnitine profiles in blood spots during newborn screening. Genotypic, clinical and\nbiochemical data were collected for all patients. In silico structural analysis was employed using\nbioinformatic tools carried out in an ETF:QO molecular model for the identified missense mutations.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title> Results:<\/jats:title>\n<jats:p> A survey describing clinical and biochemical features of eight Portuguese MADD patients\nwas made. Genotype analysis identified five ETFDH mutations, including one extension\n(p.X618QextX*14), two splice mutations (c.34+5G&gt;C and c.405+3A&gt;T) and two missense\nmutations (ETF:QO-p.Arg155Gly and ETF:QO-p.Pro534Leu), and one ETFB mutation (ETF\u03b2-\np.Arg191Cys). Homozygous patients containing the ETFDH mutations p.X618QextX*14,\nc.34+5G&gt;C and ETF:QO-p.Arg155Gly, all presented severe (lethal) MADD phenotypes. However,\nwhen any of these mutations are in heterozygosity with the known ETF:QO-p.Pro534Leu mild\nvariant, the severe clinical effects are partly and temporarily attenuated. Indeed, the latter\ndestabilizes an ETF-interacting loop, with no major functional consequences. However, the position\n155 in ETF:QO is localized at the ubiquinone binding and membrane interacting domain, and is\nthus expected to perturb protein structure and membrane insertion, with severe functional effects.\nStructural analysis of molecular models is therefore demonstrated to be a valuable tool to\nrationalize the effects of mutations in the context of the clinical phenotype severity.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Conclusion:<\/jats:title>\n<jats:p>Advanced molecular diagnosis, structural analysis and clinical correlations reveal that\nMADD patients harboring a severe prognosis mutation in one allele can actually revert to a milder\nphenotype by complementation with a milder mutation in the other allele. However, such patients\nare nevertheless in a precarious metabolic balance which can revert to severe fatal outcomes\nduring catabolic stress or secondary pathology, thus requiring strict clinical follow-up.<\/jats:p>\n<\/jats:sec>","DOI":"10.2174\/1566524019666190507114748","type":"journal-article","created":{"date-parts":[[2019,5,7]],"date-time":"2019-05-07T04:25:58Z","timestamp":1557203158000},"page":"487-493","update-policy":"https:\/\/doi.org\/10.2174\/bsp_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Molecular and Clinical Investigations on Portuguese Patients with Multiple acyl-CoA Dehydrogenase Deficiency"],"prefix":"10.2174","volume":"19","author":[{"given":"B\u00e1rbara J.","family":"Henriques","sequence":"first","affiliation":[{"name":"Biosystems and Integrative Sciences Institute, Faculdade de Ciencias, Universidade de Lisboa, and Departamento de Quimica e Bioquimica, Faculdade de Ciencias, 1749-016 Lisboa, Portugal"}]},{"given":"T\u00e2nia G.","family":"Lucas","sequence":"additional","affiliation":[{"name":"Biosystems and Integrative Sciences Institute, Faculdade de Ciencias, Universidade de Lisboa, and Departamento de Quimica e Bioquimica, Faculdade de Ciencias, 1749-016 Lisboa, Portugal"}]},{"given":"Esmeralda","family":"Martins","sequence":"additional","affiliation":[{"name":"Centro de Referencia na area de Doencas Hereditarias do Metabolismo, Centro Hospitalar do Porto - CHP, Porto, Portugal"}]},{"given":"Ana","family":"Gaspar","sequence":"additional","affiliation":[{"name":"Unidade de Doencas Metabolicas, Centro Hospitalar Lisboa Norte - Hospital Santa Maria, Lisboa, Portugal"}]},{"given":"Anabela","family":"Bandeira","sequence":"additional","affiliation":[{"name":"Centro de Referencia na area de Doencas Hereditarias do Metabolismo, Centro Hospitalar do Porto - CHP, Porto, Portugal"}]},{"given":"C\u00e9lia","family":"Nogueira","sequence":"additional","affiliation":[{"name":"Unidade de Rastreio Neonatal, Metabolismo e Genetica, Departamento de Genetica Humana \u2013 Instituto Nacional de Saude Doutor Ricardo Jorge, Porto, Portugal"}]},{"given":"Otilia","family":"Brand\u00e3o","sequence":"additional","affiliation":[{"name":"Servico de Patologia Clinica, Hospital Sao Joao, Porto, Portugal"}]},{"given":"Hugo","family":"Rocha","sequence":"additional","affiliation":[{"name":"Unidade de Rastreio Neonatal, Metabolismo e Genetica, Departamento de Genetica Humana \u2013 Instituto Nacional de Saude Doutor Ricardo Jorge, Porto, Portugal"}]},{"given":"Laura","family":"Vilarinho","sequence":"additional","affiliation":[{"name":"Unidade de Rastreio Neonatal, Metabolismo e Genetica, Departamento de Genetica Humana \u2013 Instituto Nacional de Saude Doutor Ricardo Jorge, Porto, Portugal"}]},{"given":"Cl\u00e1udio M.","family":"Gomes","sequence":"additional","affiliation":[{"name":"Biosystems and Integrative Sciences Institute, Faculdade de Ciencias, Universidade de Lisboa, and Departamento de Quimica e Bioquimica, Faculdade de Ciencias, 1749-016 Lisboa, Portugal"}]}],"member":"965","reference":[{"key":"ref=1","first-page":"2357","author":"Frerman FE","year":"2001","unstructured":"Frerman FE; Goodman SI; Scriver CR;  Defects of\nelectron transfer flavoprotein and electron transfer\nflavoprotein-ubiquinone oxidoreductase: Glutaric acidemia\ntype ii the metabolic"},{"key":"ref=2","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/s10545-010-9242-z","volume":"34","author":"Bosch A.M.","year":"2011","unstructured":"Bosch A.M.; Abeling N.G.; Ijlst L.;  Brown-Vialetto-Van Laere and Fazio Londe syndrome is associated with a riboflavin transporter defect mimicking mild MADD: A new inborn error of metabolism with potential treatment. 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Lipids Health Dis 2018,17(1),254","journal-title":"Lipids Health Dis"},{"key":"ref=5","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1203\/00006450-199003000-00024","volume":"27","author":"Loehr J.P.","year":"1990","unstructured":"Loehr J.P.; Goodman S.I.; Frerman F.E.;  Glutaric acidemia type II: heterogeneity of clinical and biochemical phenotypes. Pediatr Res 1990,27(3),311-315","journal-title":"Pediatr Res"},{"key":"ref=6","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1006\/geno.1994.1035","volume":"19","author":"Antonacci R.","year":"1994","unstructured":"Antonacci R.; Colombo I.; Archidiacono N.;  Assignment of the gene encoding the beta-subunit of the electron-transfer flavoprotein (ETFB) to human chromosome 19q13.3. 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Biochim Biophys Acta 2010,1802(11),1070-1077","journal-title":"Biochim Biophys Acta"},{"key":"ref=19","doi-asserted-by":"crossref","first-page":"16212","DOI":"10.1073\/pnas.0604567103","volume":"103","author":"Zhang J.","year":"2006","unstructured":"Zhang J.; Frerman F.E.; Kim J.J.;  Structure of electron transfer flavoprotein-ubiquinone oxidoreductase and electron transfer to the mitochondrial ubiquinone pool. Proc Natl Acad Sci USA 2006,103(44),16212-16217","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref=20","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/0263-7855(90)80070-V","volume":"8","author":"Vriend G.","year":"1990","unstructured":"Vriend G.;  WHAT IF: a molecular modeling and drug design program. J Mol Graph 1990,8(1),52-56","journal-title":"J Mol Graph"},{"key":"ref=21","doi-asserted-by":"crossref","first-page":"D266","DOI":"10.1093\/nar\/gki001","volume":"33","author":"Laskowski R.A.","year":"2005","unstructured":"Laskowski R.A.; Chistyakov V.V.; Thornton J.M.;  PDBsum more: new summaries and analyses of the known 3D structures of proteins and nucleic acids. Nucleic Acids Res 2005,33,D266-D268","journal-title":"Nucleic Acids Res"},{"key":"ref=22","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.ymgme.2008.01.002","volume":"94","author":"Yotsumoto Y.","year":"2008","unstructured":"Yotsumoto Y.; Hasegawa Y.; Fukuda S.;  Clinical and molecular investigations of Japanese cases of glutaric acidemia type 2. 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