{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T10:48:47Z","timestamp":1778237327996,"version":"3.51.4"},"reference-count":44,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2025,4,21]],"date-time":"2025-04-21T00:00:00Z","timestamp":1745193600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007397","name":"Univerzita Karlova v Praze","doi-asserted-by":"publisher","award":["UNCE\/24\/MED\/022"],"award-info":[{"award-number":["UNCE\/24\/MED\/022"]}],"id":[{"id":"10.13039\/100007397","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    3\u2010methylglutaconic aciduria (3\u2010MGCA) is a biochemical finding in a diverse group of inherited metabolic disorders. Conditions manifesting 3\u2010MGCA are classified into two major categories, primary and secondary. Primary 3\u2010MGCAs involve two inherited enzymatic deficiencies affecting leucine catabolism, whereas secondary 3\u2010MGCAs comprise a larger heterogeneous group of conditions that have in common compromised mitochondrial energy metabolism. Here, we report 3\u2010MGCA in two siblings presenting with sensorineural hearing loss and neurological abnormalities associated with a novel, homozygous missense variant (c.1999C&gt;G, p.Leu667Val) in the\n                    <jats:italic>YME1L1<\/jats:italic>\n                    gene which encodes a mitochondrial ATP\u2010dependent metalloprotease. We show that the identified variant results in compromised YME1L1 function, as evidenced by abnormal proteolytic processing of substrate proteins, such as OPA1 and PRELID1. Consistent with the aberrant processing of the mitochondrial fusion protein OPA1, we demonstrate enhanced mitochondrial fission and fragmentation of the mitochondrial network in patient\u2010derived fibroblasts. Furthermore, our results indicate that YME1L1\n                    <jats:sup>L667V<\/jats:sup>\n                    is associated with attenuated activity of rate\u2010limiting Krebs cycle enzymes and reduced mitochondrial respiration, which may explain the build\u2010up of 3\u2010methylglutaconic and 3\u2010methylglutaric acid due to the diversion of acetyl\u2010CoA, not efficiently processed in the Krebs cycle, towards the formation of 3\u2010methylglutaconyl\u2010CoA, the precursor of these metabolites. In summary, our findings classify YME1L1 deficiency as a new type of secondary 3\u2010MGCA, thus expanding the genetic landscape and facilitating the diagnosis of inherited metabolic disorders featuring this biochemical phenotype.\n                  <\/jats:p>","DOI":"10.1002\/jimd.70029","type":"journal-article","created":{"date-parts":[[2025,4,21]],"date-time":"2025-04-21T03:35:31Z","timestamp":1745206531000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["<scp>YME1L1<\/scp>\n                    Dysfunction Associated With 3\u2010Methylglutaconic Aciduria"],"prefix":"10.1002","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7808-0344","authenticated-orcid":false,"given":"Anthi","family":"Demetriadou","sequence":"first","affiliation":[{"name":"Biochemical Genetics Department The Cyprus Institute of Neurology and Genetics  Nicosia Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3552-3226","authenticated-orcid":false,"given":"Olga","family":"Grafakou","sequence":"additional","affiliation":[{"name":"Department of Paediatrics Inborn Errors of Metabolism Clinic, Archbishop Makarios III Hospital, State Health Services Organisation (SHSO)  Nicosia Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Theodoros","family":"Georgiou","sequence":"additional","affiliation":[{"name":"Biochemical Genetics Department The Cyprus Institute of Neurology and Genetics  Nicosia Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6247-3848","authenticated-orcid":false,"given":"Daniela","family":"Burska","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine Charles University, General University Hospital  Prague Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5918-9213","authenticated-orcid":false,"given":"Anna","family":"Malekkou","sequence":"additional","affiliation":[{"name":"Biochemical Genetics Department The Cyprus Institute of Neurology and Genetics  Nicosia Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1841-7341","authenticated-orcid":false,"given":"Jana","family":"Krizova","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine Charles University, General University Hospital  Prague Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Efstathia","family":"Paramera","sequence":"additional","affiliation":[{"name":"Neolab SA Medical Laboratory  Athens Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6702-8225","authenticated-orcid":false,"given":"Gavriella","family":"Mavrikiou","sequence":"additional","affiliation":[{"name":"Biochemical Genetics Department The Cyprus Institute of Neurology and Genetics  Nicosia Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Dionysiou","sequence":"additional","affiliation":[{"name":"Biochemical Genetics Department The Cyprus Institute of Neurology and Genetics  Nicosia Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4363-8162","authenticated-orcid":false,"given":"Athina","family":"Theodosiou","sequence":"additional","affiliation":[{"name":"Cytogenetics and Genomics Department The Cyprus Institute of Neurology and Genetics  Nicosia Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9296-8347","authenticated-orcid":false,"given":"Carolina","family":"Sismani","sequence":"additional","affiliation":[{"name":"Cytogenetics and Genomics Department The Cyprus Institute of Neurology and Genetics  Nicosia Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5096-8704","authenticated-orcid":false,"given":"Violetta","family":"Anastasiadou","sequence":"additional","affiliation":[{"name":"Karaiskakio Foundation Nicosia Cyprus and Archbishop Makarios III Hospital, State Health Services Organisation (SHSO)  Nicosia Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ioannis","family":"Ioannou","sequence":"additional","affiliation":[{"name":"Paediatric Neurology Clinic Archbishop Makarios III Hospital, State Health Services Organisation (SHSO)  Nicosia Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evangelos","family":"Papakonstantinou","sequence":"additional","affiliation":[{"name":"Neolab SA Medical Laboratory  Athens Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2734-225X","authenticated-orcid":false,"given":"Hana","family":"Hansikova","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine Charles University, General University Hospital  Prague Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5971-7637","authenticated-orcid":false,"given":"Anthi","family":"Drousiotou","sequence":"additional","affiliation":[{"name":"Biochemical Genetics Department The Cyprus Institute of Neurology and Genetics  Nicosia Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3238-3854","authenticated-orcid":false,"given":"Petros P.","family":"Petrou","sequence":"additional","affiliation":[{"name":"Biochemical Genetics Department The Cyprus Institute of Neurology and Genetics  Nicosia 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