Potential misdiagnosis of 3-methylcrotonyl-coenzyme A carboxylase deficiency associated with absent or trace urinary 3-methylcrotonylglycine

Lynne A. Wolfe, David N. Finegold, Jerry Vockley, Nicole Walters, Celine Chambaz, Terttu Suormala, Hans Georg Koch, Dietrich Matern, Bruce A. Barshop, Lorna J. Cropchod, Matthias R. Baumgartner, K. Michael Gibson

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)e1335-e1340
Issue number5
StatePublished - Nov 2007


  • 3-HIVA
  • 3-MCC
  • 3-MCG
  • 3-hydroxyisovaleric acid
  • 3-methylcrotonyl-coenzyme A carboxylase deficiency
  • 3-methylcrotonylglycinuria
  • C5-OH carnitine
  • C5-hydroxylacylcarnitine
  • Newborn screening
  • Organic acids
  • Tandem mass spectrometry

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health


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