biostudies-literatureDemetriadou AUniverzita Karlova v PrazeCharles UniversityThe Cyprus Institute of Neurology and GeneticsMinistry of Health Czech RepublicGeneral University Hospital Praguee70029https://www.ebi.ac.uk/biostudies/studies/S-EPMC12010149biostudies-literatureUnknown48(3)3-methylglutaconic aciduria (3-MGCA) is a biochemical finding in a diverse group of inherited metabolic disorders. Conditions manifesting 3-MGCA are classified into two major categories, primary and secondary. Primary 3-MGCAs involve two inherited enzymatic deficiencies affecting leucine catabolism, whereas secondary 3-MGCAs comprise a larger heterogeneous group of conditions that have in common compromised mitochondrial energy metabolism. Here, we report 3-MGCA in two siblings presenting with sensorineural hearing loss and neurological abnormalities associated with a novel, homozygous missense variant (c.1999C>G, p.Leu667Val) in the YME1L1 gene which encodes a mitochondrial ATP-dependent metalloprotease. We show that the identified variant results in compromised YME1L1 function, as evidenJournal of inherited metabolic diseaseYME1L1 Dysfunction Associated With 3-Methylglutaconic Aciduria.PMC120101492024-21DRO-VFN64165UNCE/24/MED/022Petrou PPParamera EDionysiou MDrousiotou AMavrikiou GGrafakou OSismani CAnastasiadou VKrizova JHansikova HDemetriadou AMalekkou AIoannou IGeorgiou TBurska DPapakonstantinou ETheodosiou AfalseYME1L1 Dysfunction Associated With 3-Methylglutaconic Aciduria.3-methylglutaconic aciduria (3-MGCA) is a biochemical finding in a diverse group of inherited metabolic disorders. Conditions manifesting 3-MGCA are classified into two major categories, primary and secondary. Primary 3-MGCAs involve two inherited enzymatic deficiencies affecting leucine catabolism, whereas secondary 3-MGCAs comprise a larger heterogeneous group of conditions that have in common compromised mitochondrial energy metabolism. Here, we report 3-MGCA in two siblings presenting with sensorineural hearing loss and neurological abnormalities associated with a novel, homozygous missense variant (c.1999C>G, p.Leu667Val) in the YME1L1 gene which encodes a mitochondrial ATP-dependent metalloprotease. We show that the identified variant results in compromised YME1L1 function, as eviden2025-01-01T00:00:00Z2025 May2026-06-03T04:53:13.769Z2025-07-03T03:04:40.326ZS-EPMC120101494025504810.1002/jimd.70029