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 journalArticle

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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.

Original languageEnglish (US)
JournalPediatrics
Volume120
Issue number5
DOIs
StatePublished - Nov 2007

Fingerprint

Diagnostic Errors
Urine
Fibroblasts
Failure to Thrive
Mutation
Acids
Missense Mutation
Down Syndrome
Gas Chromatography-Mass Spectrometry
Molecular Biology
Carbon
beta-methylcrotonylglycine
3-methylcrotonyl CoA carboxylase 1 deficiency
Newborn Infant
Messenger RNA
Enzymes
Genes

Keywords

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

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health

Cite this

Potential misdiagnosis of 3-methylcrotonyl-coenzyme A carboxylase deficiency associated with absent or trace urinary 3-methylcrotonylglycine. / Wolfe, Lynne A.; Finegold, David N.; Vockley, Jerry; Walters, Nicole; Chambaz, Celine; Suormala, Terttu; Koch, Hans Georg; Matern, Dietrich; Barshop, Bruce A.; Cropchod, Lorna J.; Baumgartner, Matthias R.; Gibson, K. Michael.

In: Pediatrics, Vol. 120, No. 5, 11.2007.

Research output: Contribution to journalArticle

Wolfe, LA, Finegold, DN, Vockley, J, Walters, N, Chambaz, C, Suormala, T, Koch, HG, Matern, D, Barshop, BA, Cropchod, LJ, Baumgartner, MR & Gibson, KM 2007, 'Potential misdiagnosis of 3-methylcrotonyl-coenzyme A carboxylase deficiency associated with absent or trace urinary 3-methylcrotonylglycine', Pediatrics, vol. 120, no. 5. https://doi.org/10.1542/peds.2007-0674
Wolfe, Lynne A. ; Finegold, David N. ; Vockley, Jerry ; Walters, Nicole ; Chambaz, Celine ; Suormala, Terttu ; Koch, Hans Georg ; Matern, Dietrich ; Barshop, Bruce A. ; Cropchod, Lorna J. ; Baumgartner, Matthias R. ; Gibson, K. Michael. / Potential misdiagnosis of 3-methylcrotonyl-coenzyme A carboxylase deficiency associated with absent or trace urinary 3-methylcrotonylglycine. In: Pediatrics. 2007 ; Vol. 120, No. 5.
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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.",
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AU - Vockley, Jerry

AU - Walters, Nicole

AU - Chambaz, Celine

AU - Suormala, Terttu

AU - Koch, Hans Georg

AU - Matern, Dietrich

AU - Barshop, Bruce A.

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AU - Gibson, K. Michael

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AB - 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.

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