{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T10:48:50Z","timestamp":1778237330119,"version":"3.51.4"},"reference-count":36,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2022,4,16]],"date-time":"2022-04-16T00:00:00Z","timestamp":1650067200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>3-Methylglutaconic aciduria type I (MGCA1) is an inborn error of the leucine degradation pathway caused by pathogenic variants in the AUH gene, which encodes 3-methylglutaconyl-coenzyme A hydratase (MGH). To date, MGCA1 has been diagnosed in 19 subjects and has been associated with a variable clinical picture, ranging from no symptoms to severe encephalopathy with basal ganglia involvement. We report the case of a 31-month-old female child referred to our center after the detection of increased 3-hydroxyisovalerylcarnitine levels at newborn screening, which were associated with increased urinary excretion of 3-methylglutaconic acid, 3-hydroxyisovaleric acid, and 3-methylglutaric acid. A next-generation sequencing (NGS) panel for 3-methylglutaconic aciduria failed to establish a definitive diagnosis. To further investigate the strong biochemical indication, we measured MGH activity, which was markedly decreased. Finally, single nucleotide polymorphism array analysis disclosed the presence of two microdeletions in compound heterozygosity encompassing the AUH gene, which confirmed the diagnosis. The patient was then supplemented with levocarnitine and protein intake was slowly decreased. At the last examination, the patient showed mild clumsiness and an expressive language disorder. This case exemplifies the importance of the biochemical phenotype in the differential diagnosis of metabolic diseases and the importance of collaboration between clinicians, biochemists, and geneticists for an accurate diagnosis.<\/jats:p>","DOI":"10.3390\/ijms23084422","type":"journal-article","created":{"date-parts":[[2022,4,18]],"date-time":"2022-04-18T04:21:28Z","timestamp":1650255688000},"page":"4422","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["3-Methylglutaconic Aciduria Type I Due to AUH Defect: The Case Report of a Diagnostic Odyssey and a Review of the Literature"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0808-2827","authenticated-orcid":false,"given":"Francesca","family":"Nardecchia","sequence":"first","affiliation":[{"name":"Department of Human Neuroscience, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Caciotti","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology of Neurometabolic Diseases, Neuroscience Department, Meyer Children\u2019s Hospital, 50139 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teresa","family":"Giovanniello","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabrina","family":"De Leo","sequence":"additional","affiliation":[{"name":"Department of Translational and Precision Medicine, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lorenzo","family":"Ferri","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology of Neurometabolic Diseases, Neuroscience Department, Meyer Children\u2019s Hospital, 50139 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Serena","family":"Galosi","sequence":"additional","affiliation":[{"name":"Department of Human Neuroscience, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Santagata","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbara","family":"Torres","sequence":"additional","affiliation":[{"name":"Medical Genetics Division, IRCCS Casa Sollievo della Sofferenza Foundation, 71013 San Giovanni Rotondo, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3554-2817","authenticated-orcid":false,"given":"Laura","family":"Bernardini","sequence":"additional","affiliation":[{"name":"Medical Genetics Division, IRCCS Casa Sollievo della Sofferenza Foundation, 71013 San Giovanni Rotondo, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia","family":"Carducci","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amelia","family":"Morrone","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology of Neurometabolic Diseases, Neuroscience Department, Meyer Children\u2019s Hospital, 50139 Florence, Italy"},{"name":"Department of Neurosciences, Psychology, Pharmacology and Child Health, University of Florence, 50134 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2314-6139","authenticated-orcid":false,"given":"Vincenzo","family":"Leuzzi","sequence":"additional","affiliation":[{"name":"Department of Human Neuroscience, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1086\/344712","article-title":"3-Methylglutaconic Aciduria Type I Is Caused by Mutations in AUH","volume":"71","author":"IJlst","year":"2002","journal-title":"Am. J. Hum. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2012","DOI":"10.1111\/j.1742-4658.2006.05218.x","article-title":"Biochemical Characterization of Human 3-Methylglutaconyl-CoA Hydratase and Its Role in Leucine Metabolism: Human 3-Methylglutaconyl-CoA Hydratase","volume":"273","author":"Mack","year":"2006","journal-title":"FEBS J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1002\/humu.10202","article-title":"Mutations in TheAUH Gene Cause 3-Methylglutaconic Aciduria Type I","volume":"21","author":"Ly","year":"2003","journal-title":"Hum. Mutat."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Baumgartner, M.R., Saudubray, J.-M., and Walter, J.H. (2016). Inborn Metabolic Diseases: Diagnosis and Treatment, Springer. [6th ed.].","DOI":"10.1007\/978-3-662-49771-5"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1016\/S0022-3476(82)80698-7","article-title":"Inherited 3-Methylglutaconic Aciduria in Two Brothers--Another Defect of Leucine Metabolism","volume":"101","author":"Duran","year":"1982","journal-title":"J. Pediatr."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1172\/JCI112415","article-title":"Deficiency of 3-Methylglutaconyl-Coenzyme A Hydratase in Two Siblings with 3-Methylglutaconic Aciduria","volume":"77","author":"Narisawa","year":"1986","journal-title":"J. Clin. Investig."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.plipres.2010.04.001","article-title":"Functional and Structural Properties of Mammalian Acyl-Coenzyme A Thioesterases","volume":"49","author":"Kirkby","year":"2010","journal-title":"Prog. Lipid Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1016\/j.ymgme.2011.07.021","article-title":"Phenotypic Heterogeneity in Two Siblings with 3-Methylglutaconic Aciduria Type I Caused by a Novel Intragenic Deletion","volume":"104","author":"Tucker","year":"2011","journal-title":"Mol. Genet. Metab."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1016\/j.braindev.2017.04.007","article-title":"Early Infantile Presentation of 3-Methylglutaconic Aciduria Type 1 with a Novel Mutation in AUH Gene: A Case Report and Literature Review","volume":"39","author":"Tavasoli","year":"2017","journal-title":"Brain Dev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1023\/A:1005476315892","article-title":"Variable Clinical Presentation in Three Patients with 3-Methylglutaconyl-Coenzyme A Hydratase Deficiency","volume":"21","author":"Gibson","year":"1998","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1023\/A:1005670911799","article-title":"3-Methylglutaconyl-CoA Hydratase Deficiency: A New Patient with Speech Retardation as the Leading Sign","volume":"23","author":"Ensenauer","year":"2000","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1007\/BF02435977","article-title":"3-Methylglutaconyl-Coenzyme-A Hydratase Deficiency: A New Case","volume":"15","author":"Gibson","year":"1992","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0009-8981(94)90083-3","article-title":"The Detection of 3-Methylglutarylcarnitine and a New Dicarboxylic Conjugate, 3-Methylglutaconylcarnitine, in 3-Methylglutaconic Aciduria","volume":"230","author":"Jooste","year":"1994","journal-title":"Clin. Chim. Acta"},{"key":"ref_14","first-page":"e11951","article-title":"Acute Encephalopathic Presentation of 3-Methylglutaconic Aciduria Type I With a Novel Mutation in AUH Gene","volume":"12","author":"Dudipala","year":"2020","journal-title":"Cureus"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1023\/A:1005421111554","article-title":"3-Methylglutaconic Aciduria Type I: Clinical Heterogeneity as a Neurometabolic Disease","volume":"22","author":"Shoji","year":"1999","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1111\/j.1442-200x.2005.02130.x","article-title":"A Molecular Lesion in a Japanese Patient with Severe Phenotype of 3-Methylglutaconic Aciduria Type I","volume":"47","author":"Matsumori","year":"2005","journal-title":"Pediatr. Int."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.pediatrneurol.2003.09.016","article-title":"3-Methylglutaconic Aciduria Type I in a Boy with Fever-Associated Seizures","volume":"30","author":"Illsinger","year":"2004","journal-title":"Pediatr. Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1002\/nbm.1018","article-title":"NMR Spectroscopic Studies on the Late Onset Form of 3-Methylglutaconic Aciduria Type I and Other Defects in Leucine Metabolism","volume":"19","author":"Engelke","year":"2006","journal-title":"NMR Biomed."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1895","DOI":"10.1212\/01.wnl.0000244467.01362.54","article-title":"3-Methylglutaconic Aciduria Type I Causes Leukoencephalopathy of Adult Onset","volume":"67","author":"Eriguchi","year":"2006","journal-title":"Neurology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1212\/WNL.0b013e3181f39a8a","article-title":"3-Methylglutaconic Aciduria Type I Redefined: A Syndrome with Late-Onset Leukoencephalopathy","volume":"75","author":"Wortmann","year":"2010","journal-title":"Neurology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"158","DOI":"10.14740\/cr359w","article-title":"3-Methylglutaconyl-Coenzyme-A Hydratase Deficiency and the Development of Dilated Cardiomyopathy","volume":"5","author":"Spergel","year":"2014","journal-title":"Cardiol. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"100691","DOI":"10.1016\/j.ymgmr.2020.100691","article-title":"Precocious Puberty in a Girl with 3-Methylglutaconic Aciduria Type 1 (3-MGA-I) Due to a Novel AUH Gene Mutation","volume":"25","author":"Bizjak","year":"2020","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2024","DOI":"10.1093\/brain\/awm096","article-title":"Molecular Mechanisms and Phenotypic Variation in RYR1-Related Congenital Myopathies","volume":"130","author":"Zhou","year":"2007","journal-title":"Brain"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1086\/508500","article-title":"Epigenetic Allele Silencing Unveils Recessive RYR1 Mutations in Core Myopathies","volume":"79","author":"Zhou","year":"2006","journal-title":"Am. J. Hum. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1007\/s10545-012-9580-0","article-title":"Inborn Errors of Metabolism with 3-Methylglutaconic Aciduria as Discriminative Feature: Proper Classification and Nomenclature","volume":"36","author":"Wortmann","year":"2013","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1007\/s10545-012-9579-6","article-title":"3-Methylglutaconic Aciduria\u2014Lessons from 50 Genes and 977 Patients","volume":"36","author":"Wortmann","year":"2013","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.biochi.2019.10.004","article-title":"Mitochondrial Dysfunction, AMPK Activation and Peroxisomal Metabolism: A Coherent Scenario for Non-Canonical 3-Methylglutaconic Acidurias","volume":"168","author":"Vamecq","year":"2020","journal-title":"Biochimie"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1007\/BF01800058","article-title":"3-Hydroxy-3-Methylglutaryl-Coenzyme A Lyase Deficiency: Report of Five New Patients","volume":"11","author":"Gibson","year":"1988","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.ymgme.2017.05.014","article-title":"3-Hydroxy-3-Methylglutaryl-Coenzyme A Lyase Deficiency: Clinical Presentation and Outcome in a Series of 37 Patients","volume":"121","author":"Schlatter","year":"2017","journal-title":"Mol. Genet. Metab."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1002\/jmd2.12058","article-title":"Iron-sulfur Cluster ISD11 Deficiency (LYRM4 Gene) Presenting as Cardiorespiratory Arrest and 3-methylglutaconic Aciduria","volume":"49","author":"Coelho","year":"2019","journal-title":"JIMD Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1016\/j.ajhg.2018.01.020","article-title":"Biallelic Mutations in ATP5F1D, Which Encodes a Subunit of ATP Synthase, Cause a Metabolic Disorder","volume":"102","author":"Yoon","year":"2018","journal-title":"Am. J. Hum. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1007\/8904_2017_48","article-title":"Mitochondrial Encephalopathy and Transient 3-Methylglutaconic Aciduria in ECHS1 Deficiency: Long-Term Follow-Up","volume":"Volume 39","author":"Morava","year":"2017","journal-title":"JIMD Reports"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"S296","DOI":"10.1542\/peds.2005-2633I","article-title":"Newborn Screening: Toward a Uniform Screening Panel and System\u2014Executive Summary","volume":"117","author":"Watson","year":"2006","journal-title":"Pediatrics"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/s41436-019-0686-8","article-title":"Technical Standards for the Interpretation and Reporting of Constitutional Copy-Number Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen)","volume":"22","author":"Riggs","year":"2020","journal-title":"Genet. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1002\/humu.22751","article-title":"Optimizing the Molecular Diagnosis of GALNS: Novel Methods to Define and Characterize Morquio-A Syndrome-Associated Mutations","volume":"36","author":"Caciotti","year":"2015","journal-title":"Hum. Mutat."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2\u2212\u0394\u0394CT Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/8\/4422\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:55:32Z","timestamp":1760136932000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/8\/4422"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,16]]},"references-count":36,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2022,4]]}},"alternative-id":["ijms23084422"],"URL":"https:\/\/doi.org\/10.3390\/ijms23084422","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,16]]}}}