title: Potential misdiagnosis of 3-methylcrotonyl-coenzyme A carboxylase deficiency associated with absent or trace urinary 3-methylcrotonylglycine.
abstract: We report 2 patients with isolated 3-methylcrotonyl-coenzyme A carboxylase deficiency whose urine was devoid of, or contained only trace, 3-methylcrotonylglycine, the pathognomonic marker for this disorder. The first patient, a girl with trisomy 21, was detected through newborn screening with an elevated 5 carbon hydroxycarnitine species level, and the second patient came to clinical attention at the age of 5 months because of failure to thrive and developmental delay. Investigation of urinary organic acids revealed an elevated 3-hydroxyisovaleric acid level but no demonstrable 3-methylcrotonylglycine in both patients. Enzyme studies in cultured fibroblasts confirmed isolated 3-methylcrotonyl-coenzyme A carboxylase deficiency with residual activities of 5% to 7% and 12% of the median control value, respectively. Incorporation of 14C-isovaleric acid into intact fibroblasts was essentially normal, showing that the overall pathway was at least partially functional and potentially explaining the absence of 3-methylcrotonylglycine in urine. Mutation analysis of the MCCA and MCCB genes revealed that both patients were compound heterozygous for a missense mutation, MCCB-c.1015G-->A (p.V339M), and a second mutation that leads to undetectable MCCB messenger (poly A+) RNA. Absent or trace 3-methylcrotonylglycine levels in urine raises the potential for misdiagnosis in the clinical biochemical genetics laboratory based solely on urine organic acid analysis using combined gas chromatography-mass spectrometry.
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. michael.gibson@chp.edu
authors.forename: Lynne A
authors.initials: LA
authors.lastname: Wolfe
authors.forename: David N
authors.initials: DN
authors.lastname: Finegold
authors.forename: Jerry
authors.initials: J
authors.lastname: Vockley
authors.forename: Nicole
authors.initials: N
authors.lastname: Walters
authors.forename: Celine
authors.initials: C
authors.lastname: Chambaz
authors.forename: Terttu
authors.initials: T
authors.lastname: Suormala
authors.forename: Hans Georg
authors.initials: HG
authors.lastname: Koch
authors.forename: Dietrich
authors.initials: D
authors.lastname: Matern
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Barshop
authors.forename: Lorna J
authors.initials: LJ
authors.lastname: Cropcho
authors.forename: Matthias R
authors.initials: MR
authors.lastname: Baumgartner
authors.forename: K Michael
authors.initials: KM
authors.lastname: Gibson
mesh_terms: D019735:Carbon-Carbon Ligases / Q000172:deficiency* / Q000235:genetics; D002648:Child; D003951:Diagnostic Errors / Q000379:methods; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000172:deficiency / Q000235:genetics / Q000652:urine; D006801:Humans; D007223:Infant; D008661:Metabolism, Inborn Errors / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense / Q000235:genetics
chemical_list: C002163:beta-methylcrotonylglycine; D019735:Carbon-Carbon Ligases; C021573:methylcrotonoyl-CoA carboxylase; D005998:Glycine