Abstract
BackgroundThe aim of the present study was to establish a non-invasive, fast and robust enzymatic assay to confirm fatty acid oxidation defects (FAOD) in humans following informative newborn-screening or for selective screening of patients suspected to suffer from FAOD.Material/methodsThe reliability of this method was tested in whole blood from FAOD patients with specific enzymatic defects. Whole blood samples were assayed in 30 medium chain- (MCADD, age 0 to 17 years), 6 very long chain- (VLCADD, age 0 to 4 years), 6 long chain hydroxy- (LCHAD, age 1 to 6 years), 3 short chain- (SCADD, age 10 to 13 years) acyl-CoA-dehydrogenase- and 2 primary carnitine transporter deficiencies (CTD, age 3 to 5 years). Additionally, 26 healthy children (age 0 to 17 years) served as controls. Whole blood samples were incubated with stable end-labeled palmitate; labeled acylcarnitines were analyzed by tandem mass spectrometry and compared with controls and between patient groups (Mann-Whitney Rank Sum Test). Concentrations of specific labeled acylcarnitine metabolites were compared between particular underlying MCADD- (ANOVA), VLCADD- and LCHADD- genetic variants (descriptive data analysis).Results11 different acylcarnitines were analyzed. MCADD- (C8-, C10-carnitine, C8/C10- and C8/C4-carnitine), VLCADD- (C12-, C14:1-, C14:2-carnitine, C14:1/C12- and C14:2/C12-carnitine), LCHADD (C16-OH-carnitine) as well as CTD- deficiency (sum of all acylcarnitines) samples could be clearly identified and separated from control values as well as other FAOD, whereas the sum of all acylcarnitines was not conclusive between FAOD samples. Furthermore, C4- (SCADD), C14- (VLCADD) and C14-OH-carnitines (LCHADD) were discriminating between the FAOD groups. Metabolic parameters did not differ significantly between underlying MCADD variants; similar results could be observed for VLCADD- and LCHADD- variants.ConclusionThis functional method in whole blood samples is relatively simple, non-invasive and little time consuming. It allows to identify MCADD-, VLCADD-, LCHADD- and carnitine transporter deficiencies. The genetic phenotypes of one enzyme defect did not result in differing acylcarnitine patterns in MCADD, VLCADD or LCHADD in vitro.
Highlights
The aim of the present study was to establish a non-invasive, fast and robust enzymatic assay to confirm fatty acid oxidation defects (FAOD) in humans following informative newborn-screening or for selective screening of patients suspected to suffer from FAOD.Material/methods: The reliability of this method was tested in whole blood from FAOD patients with specific enzymatic defects
Metabolic parameters did not differ significantly between underlying medium chain acyl-CoA dehydrogenases deficiency (MCADD) variants; similar results could be observed for Very long chain acyl-CoA dehydrogenase deficiency (VLCADD)- and Long chain hydroxy acyl-CoA dehydrogenase deficiency (LCHADD)- variants
The genetic phenotypes of one enzyme defect did not result in differing acylcarnitine patterns in MCADD, VLCADD or LCHADD in vitro
Summary
The aim of the present study was to establish a non-invasive, fast and robust enzymatic assay to confirm fatty acid oxidation defects (FAOD) in humans following informative newborn-screening or for selective screening of patients suspected to suffer from FAOD.Material/methods: The reliability of this method was tested in whole blood from FAOD patients with specific enzymatic defects. Disorders of mitochondrial fatty acid oxidation (FAOD) are one of the most prevalent monogenic diseases with a cumulative incidence of about 1:9300 newborns [1]. Amongst this disease entity, medium chain acyl-CoA dehydrogenases deficiency (MCADD) is the most common enzymatic defect. Since 2005, the FAO diseases MCAD-, LCHAD-/ TFP-, VLCAD- and carnitine cycle defects are target diseases of the nationwide German newborn-screening program using the tandem mass spectrometry technique. This resulted in a considerable reduction of morbidity and mortality in patients suffering from FAOD. It remains unclear whether subjects with these mild (biochemical) phenotypes and/ or novel genetic variants are at risk for the development of a clinically relevant phenotype
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