Evaluation of newborn screening for medium chain acyl-CoA dehydrogenase deficiency in 275 000 babies

Abstract

Objective-To evaluate newborn screening by tandem mass spectrometry for detection of medium chain acyl-CoA dehydrogenase (MCAD) deficiency, a fatty acid oxidation disorder with significant mortality in undiagnosed patients. Design-The following were studied: (a) 13 clinically detected MCAD deficient subjects, most homozygous for the common A985G mutation, whose newborn screening sample was available; (b) 275 653 consecutive neonates undergoing routine newborn screening. Screened infants with blood octanoylcarnitine levels > 1 µmol/l were analysed for the A985G mutation, had analysis of plasma and repeat blood spot acylcarnitines and urinary organic acids, and had fibroblast fatty acid oxidation or acylcarnitine studies. Result-Twelve of the 13 patients later diagnosed clinically had newborn octanoylcarnitine levels > 2.3 µmol/l. Twenty three screened babies had initial octanoylcarnitine levels > 1 µmol/l. Eleven of 12 babies with persistent abnormalities had metabolite and/or enzyme studies indicating MCAD deficiency. Only four were homozygous for the A985G mutation, the remainder carrying one copy. Conclusions-Most patients with symptomatic MCAD deficiency could be detected by newborn screening. Infants actually detected had a lower frequency of A985G alleles than clinically diagnosed cases and may have a lower risk of becoming symptomatic. (Arch Dis Child Fetal Neonatal Ed 2001;85:F105-F109)

Use of Tandem Mass Spectrometry for Multianalyte Screening of Dried Blood Specimens from Newborns

“…Typically, homozygotes produce a C8 concentration in the range of 4 -10 mol/L, although some compound heterozygotes will also produce these concentrations. Generally, compound heterozygotes produce lower C8 concentrations, in the range 1-4 mol/L in newborn specimens (15 ). Although C8 is the metabolite of primary interest in detecting MCAD deficiency by MS/MS, it is important to note that severity of disease is not easily predicted based solely on C8 concentration (95,103 ).…”

Newborn Screening Fact Sheets

“…145 Recent molecular studies performed as follow-up to newborn screening by MS/MS technology have found a lower percentage of individuals with the common A985G mutation. 136,146 A second common mutation (T199C) has been observed in US populations identified initially by MS/MS screening. The T199C mutation is a mild mutation that produces a biochemical phenotype but has never been observed in clinically affected patients.…”

“…135 Incidence MCAD deficiency has been diagnosed almost exclusively among individuals of northwestern European origin, with frequencies ranging from 1 in 46 000 to 1 in 6400. 136,137 The heterozygote frequency is 1% to 2%. A few cases have been identified in other populations, including one Pakistani patient, one black patient, and isolated cases in individuals of Southern European and Northern African origin.…”

Relationship of Octanoylcarnitine Concentrations to Age at Sampling in Unaffected Newborns Screened for Medium-Chain Acyl-CoA Dehydrogenase Deficiency

“…Previous studies have reported that acylcarnitine profiles in premature and VLBW infants differ from profiles of babies born at term or of normal birth weight (7,12 ). Were this the case, it might pose a problem in interpreting results from screening programs (4,13 ). We have demonstrated, however, that, at the population level, C8 concentrations do not vary by prematurity or birth weight over the first 2 weeks of life.…”