Blood acylcarnitine levels in normal newborns and heterozygotes for medium-chain acyl-CoA dehydrogenase deficiency: a relationship between genotype and biochemical phenotype?

Patients with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency are unable to metabolize medium-chain fatty acids. Affected patients display a characteristic acylcarnitine profile when blood spots are collected after birth and analysed by tandem mass spectrometry. To determine the potential risk of metabolic decompensation in newborns with elevations of diagnostic metabolites (octanoylcarnitine>0.3, but <1 micromol/L), we investigated the relationship between octanoylcarnitine (C8) concentration in neonatal blood spots and the 985A>G MCAD genotype. Octanoylcarnitine values from 7140 newborns' blood spots were sorted. The highest C8 was approximately 0.7 micromol/L, which is below the range in classical MCAD deficiency. Samples with C8 levels above 0.25 micromol/L (group C) represented 1.4% of the total. Values between 0.05 and 0.25 micromol/L (group B) made up 87.8% of the total; 10.8% of the samples had C8 values less than 0.05 micromol/L (group A). One hundred samples from each group were selected at random and genomic DNA was amplified by PCR and analysed for the presence of the 985A>G mutation. The analysed samples from groups A and B were all homozygous normal. The 100 samples from group C contained 26 samples that were heterozygous for the 985A>G mutation. These findings indicated that the frequency distribution of heterozygotes is not random within this population. Group C was further divided into C1, the 26 heterozygotes, and C2, the remaining 74 newborns in group C. In group C1 only 2 (8%) were in the 'high-risk' group characterized by either low birth weight or requiring admission to the neonatal intensive care unit. In contrast, 28 (38%) from C2 had low birth weight or were in the neonatal intensive care unit. In our dataset, C8/C2 and C8/C12 ratios were also significantly elevated in both groups C1 and C2 compared to controls (group B). In contrast to what others have reported, the ratio of C8/C10 did not differentiate the group B controls from heterozygotes or other patients in metabolic distress (group C2), but were lower than those seen in classic MCAD or mild MCAD deficiency.