title: A single mutation in MCCC1 or MCCC2 as a potential cause of positive screening for 3-methylcrotonyl-CoA carboxylase deficiency.
abstract: Isolated 3-Methylcrotonyl-CoA carboxylase deficiency (MCC deficiency) is an organic aciduria presenting with a highly variable phenotype and has been part of newborn screening programs in various countries, in particular in the US. Here we present enzymatic and genetic characterisation of 22 individuals with increased 3-hydroxyisovalerylcarnitine and/or 3-methylcrotonylglycine suggesting MCC deficiency, but only partially reduced 3-methylcrotonyl-CoA carboxylase activity. Among these, 21 carried a single mutant allele in either MCCC1 (n=20) or MCCC2 (n=1). Our results suggest that heterozygosity for such a single deleterious mutation may lead to misdiagnosis of MCC deficiency.
authors.affiliation: Division of Metabolism and Children's Research Center, University Children's Hospital, Steinwiesstrasse 75, CH-8032 Zürich, Switzerland. raphael.morscher@pmu.ac.at
authors.forename: Raphael J
authors.initials: RJ
authors.lastname: Morscher
authors.forename: Sarah Catharina
authors.initials: SC
authors.lastname: Grünert
authors.forename: Céline
authors.initials: C
authors.lastname: Bürer
authors.forename: Patricie
authors.initials: P
authors.lastname: Burda
authors.forename: Terttu
authors.initials: T
authors.lastname: Suormala
authors.forename: Brian
authors.initials: B
authors.lastname: Fowler
authors.forename: Matthias R
authors.initials: MR
authors.lastname: Baumgartner
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism; D019735:Carbon-Carbon Ligases / Q000172:deficiency / Q000235:genetics*; D002331:Carnitine / Q000031:analogs & derivatives / Q000378:metabolism; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology; D005998:Glycine / Q000031:analogs & derivatives / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation / Q000235:genetics*; D015997:Neonatal Screening; D060888:Real-Time Polymerase Chain Reaction; D012867:Skin / Q000166:cytology / Q000201:enzymology; D056806:Urea Cycle Disorders, Inborn / Q000175:diagnosis* / Q000235:genetics*
chemical_list: C098116:3-hydroxyisovalerylcarnitine; D000214:Acyl Coenzyme A; C002163:beta-methylcrotonylglycine; C033618:tiglyl-coenzyme A; D019735:Carbon-Carbon Ligases; C021573:methylcrotonoyl-CoA carboxylase; D002331:Carnitine; D005998:Glycine