Potential misdiagnosis of 3-methylcrotonyl-coenzyme A carboxylase deficiency associated with absent or trace urinary 3-methylcrotonylglycine.
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.
Wolfe
Lynne A
LA
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
Finegold
David N
DN
Vockley
Jerry
J
Walters
Nicole
N
Chambaz
Celine
C
Suormala
Terttu
T
Koch
Hans Georg
HG
Matern
Dietrich
D
Barshop
Bruce A
BA
Cropcho
Lorna J
LJ
Baumgartner
Matthias R
MR
Gibson
K Michael
KM
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
C002163:beta-methylcrotonylglycine; D019735:Carbon-Carbon Ligases; C021573:methylcrotonoyl-CoA carboxylase; D005998:Glycine