Electrospray Tandem Mass Spectrometry for Analysis of Acylcarnitines in Dried Postmortem Blood Specimens Collected at Autopsy from Infants with Unexplained Cause of Death

Abstract

Background: Deaths from inherited metabolic disorders may remain undiagnosed after postmortem examination and may be classified as sudden infant death syndrome. Tandem mass spectrometry (MS/MS) may reveal disorders of fatty acid oxidation in deaths of previously unknown cause. Methods: We obtained filter-paper blood from 7058 infants from United States and Canadian Medical Examiners. Acylcarnitine and amino acid profiles were obtained by MS/MS. Specialized interpretation was used to evaluate profiles for disorders of fatty acid, organic acid, and amino acid metabolism. The analyses of postmortem blood specimens were compared with the analyses of bile specimens, newborn blood specimens, and specimens obtained from older infants at risk for metabolic disorders. Results: Results on 66 specimens suggested diagnoses of metabolic disorders. The most frequently detected disorders were medium-chain and very-long-chain acyl-CoA dehydrogenase deficiencies (23 and 9 cases, respectively), glutaric acidemia type I and II deficiencies (3 and 8 cases, respectively), carnitine palmitoyl transferase type II/translocase deficiencies (6 cases), severe carnitine deficiency (4 cases), isovaleric acidemia/2-methylbutyryl-CoA dehydrogenase deficiencies (4 cases), and long-chain hydroxyacyl-CoA dehydrogenase/trifunctional protein deficiencies (4 cases). Conclusions: Postmortem metabolic screening can explain deaths in infants and children and provide estimates of the number of infant deaths attributable to inborn errors of metabolism. MS/MS is cost-effective for analysis of postmortem specimens and should be considered for routine use by Medical Examiners and pathologists in unexpected/unknown infant and child death.

Newborn screening with tandem mass spectrometry: Examining its cost-effectiveness in the Wisconsin Newborn Screening Panel

“…15 The largest study of infants with unexplained cause of death to date found a very small proportion of such cases to be due to MCAD, constituting 0.25:100,000 live births. 16 Because it is unclear how to combine this rate with the estimated rate of clinical MCAD diagnoses derived from English data, in the base case analysis, we conservatively assume that all undi-agnosed MCAD cases in the absence of screening are asymptomatic.…”

“…In the model, these infants represent 63% of all cases observed with screening. If it is assumed that the infant mortality rate of 0.25:100,000 16 can be directly combined with base case data, in the absence of screening, one would expect 25% of MCAD cases to not be diagnosed with the disorder despite the presence of symptoms. We incorporate this figure into our best estimate result.…”

The effect of oral L-carnitine supplementation on the lipid profiles of hyperlipidaemic children

“…These samples were stored at +4 C until analysed. Free carnitine and acylcarnitine were measured from dried filter paper blood and urine spots using electrospray tandem mass spectrometry (Micromass, Manchester, UK) as previously described [24,25].…”

Minor plasma lipids modulate clotting factor activities and may affect thrombosis risk

“…Total long-chain ACs (acyl chains >10 carbons) circulate in plasma, with reported concentrations ranging between 1 and 4 μmol/L, 33,[80][81][82] and their levels can reach to 10-30 μmol/L under certain metabolic conditions. [83][84][85][86] Long-chain ACs are lipid metabolites with a hydrophobic side chain and a free amine like sphingosine (Figure 4), but they belong to the long-chain AC family which plays an important role in energy metabolism through mitochondrial β-oxidation of fatty acids. 87 The acylcarnitines and Co-A are produced by the reaction in which acyl moieties are transferred to carnitine from acyl-CoA by carnitine palmitoyl transferase-I (Figure 3, Figure S1, Table S2).…”