Potential Misdiagnosis of 3-Methylcrotonyl-Coenzyme A Carboxylase Deficiency Associated With Absent or Trace Urinary 3-Methylcrotonylglycine

doi:10.1542/peds.2007-0674

Lynne A. Wolfe, MS, CRNP^a^,b, David N. Finegold, MD^a^,b^,c^,d, Jerry Vockley, MD, PhD^a^,b^,c, Nicole Walters, RD, LDN^a^,b, Celine Chambaz, BS^e, Terttu Suormala, PhD^f, Hans Georg Koch, MD^g, Dietrich Matern, MD^h, Bruce A. Barshop, MD, PhDⁱ, Lorna J. Cropcho^d^,j, Matthias R. Baumgartner, MD^e and K. Michael Gibson, PhD^a^,b^,c^,d^,j

^a Division of Medical Genetics, Departments of
^b Pediatrics
^c Human Genetics
^j Pathology
^d Biochemical Genetics/Nutrition Laboratory, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
^e Division of Metabolism and Molecular Pediatrics, University Children's Hospital, Zurich, Switzerland
^f Metabolic Unit, University Children's Hospital, Basel, Switzerland
^g Department of Pediatrics, Children's Hospital, Braunschweig, Germany
^h Departments of Laboratory Medicine and Pathology, Pediatric and Adolescent Medicine and Medical Genetics, Mayo Clinic College of Medicine, Rochester, Minnesota
ⁱ Biochemical Genetics Laboratory, University of California at San Diego, La Jolla, California

ABSTRACT

We report 2 patients with isolated 3-methylcrotonyl-coenzymeA carboxylase deficiency whose urine was devoid of, or containedonly trace, 3-methylcrotonylglycine, the pathognomonic markerfor this disorder. The first patient, a girl with trisomy 21,was detected through newborn screening with an elevated 5 carbonhydroxycarnitine species level, and the second patient cameto clinical attention at the age of 5 months because of failureto thrive and developmental delay. Investigation of urinaryorganic acids revealed an elevated 3-hydroxyisovaleric acidlevel but no demonstrable 3-methylcrotonylglycine in both patients.Enzyme studies in cultured fibroblasts confirmed isolated 3-methylcrotonyl-coenzymeA carboxylase deficiency with residual activities of 5% to 7%and 12% of the median control value, respectively. Incorporationof ¹⁴C-isovaleric acid into intact fibroblasts was essentiallynormal, showing that the overall pathway was at least partiallyfunctional and potentially explaining the absence of 3-methylcrotonylglycinein urine. Mutation analysis of the MCCA and MCCB genes revealedthat both patients were compound heterozygous for a missensemutation, MCCB-c.1015G $->$ A (p.V339M), and a second mutation thatleads to undetectable MCCB messenger (poly A⁺) RNA. Absent ortrace 3-methylcrotonylglycine levels in urine raises the potentialfor misdiagnosis in the clinical biochemical genetics laboratorybased solely on urine organic acid analysis using combined gaschromatography-mass spectrometry.

Key Words: 3-methylcrotonyl-coenzyme A carboxylase deficiency • 3-MCC • 3-methylcrotonylglycinuria • 3-MCG • 3-hydroxyisovaleric acid • 3-HIVA • C5-hydroxylacylcarnitine • C5-OH carnitine • newborn screening • tandem mass spectrometry • organic acids

Abbreviations: CoA, coenzyme A • 3-MCC, 3-methylcrotonyl-coenzyme A carboxylase • 3-HIVA, 3-hydroxyisovaleric acid • 3-MCG, 3-methylcrotonylglycine • MCCA (MCC ${alpha}$ /MCCC1), 3-methylcrotonyl-coenzyme A carboxylase ${alpha}$ subunit • MCCB (MCCβ/MCCC2), 3-methylcrotonyl-coenzyme A carboxylase β subunit • C5-OH carnitine, 5 carbon hydroxycarnitine species • MCD, multiple carboxylase deficiency • PCC, propionyl-coenzyme A carboxylase • PCR, polymerase chain reaction • mRNA, messenger (poly A⁺) RNA • HMG-CoA lyase, 3-hydroxy-3-methylglutaryl-coenzyme A lyase • 3-MGA, 3-methylglutaconic aciduria

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EXPERIENCE & REASON

Potential Misdiagnosis of 3-Methylcrotonyl-Coenzyme A Carboxylase Deficiency Associated With Absent or Trace Urinary 3-Methylcrotonylglycine