Evaluation of 3‐methylcrotonyl‐CoA carboxylase deficiency detected by tandem mass spectrometry newborn screening

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Abstract
Summary: Since the addition of tandem mass spectrometry (MS/MS) to the North Carolina Newborn Screening Program, 20 infants with two consecutive elevated 3‐hydroxyisovalerylcarnitine (C5OH) levels have been evaluated for evidence of inborn errors of metabolism associated with this metabolite. Ten of these 20 infants had significant concentrations of both 3‐hydroxyisovaleric acid and 3‐methylcrotonylglycine in their urine, suggestive of 3‐methylcrotonyl‐CoA carboxylase (3‐MCC) deficiency. Four of these 10 were infants whose abnormal metabolites were found to be of maternal origin. Of 8 patients with probable 3‐MCC deficiency, 7 have been tested and found to have the enzyme deficiency confirmed in lymphoblasts or cultured fibroblasts; one of these 7 infants had only marginally decreased 3‐MCC activity in lymphocytes but deficient 3‐MCC in fibroblasts. We estimate the incidence of 3‐MCC deficiency at 1:64000 live births in North Carolina. We conclude that MS/MS newborn screening will detect additional inborn errors of metabolism, such as 3‐MCC deficiency, not traditionally associated with newborn screening. The evaluation of newborns with two abnormally elevated C5OH levels on MS/MS newborn screening should include, at least, urine organic acid analysis by capillary GC‐MS and a plasma acylcarnitine profile by MS/MS. Long‐term follow‐up is needed to determine the outcome of presymptomatically diagnosed patients with 3‐MCC deficiency by MS/MS newborn screening.

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