Abstract
BackgroundPropionic acidemia (PA) is a serious metabolic disorder, and different approaches have been applied to its prenatal diagnosis. To evaluate the reliability and validity of a biochemical strategy in the prenatal diagnosis of PA, we conducted a retrospective study of our 11-year experiences at a single center.MethodsWe accumulated data from 78 pregnancies from 58 families referred to our center and provided prenatal diagnosis by directed genetic analysis and/or metabolite measurement using tandem mass spectrometry (MS/MS) and gas chromatography/mass spectrometry (GC/MS) of amniotic fluid (AF) samples.ResultsSixty-five unaffected fetuses (83.33%) and 13 affected fetuses (16.67%) were confirmed in our study. The characteristic metabolites including propionylcarnitine (C3) level, C3/acetylcarnitine (C2) ratio and 2-methylcitric acid (2MCA) level in unaffected and affected groups showed significant differences (P < 0.0001), while the level of 3-hydroxypropionic acid (3HPA) showed no significant difference between the two groups (P > 0.05).Of the 78 pregnancies, 24 fetuses were found to have either one causative pathogenic variant or were without genetic information in the proband. Three of these fetuses had elevated AF levels of C3, C3/C2 ratio, and 2MCA and, thus, were determined to be affected, while the remaining fetuses were determined to be unaffected based on a normal AF metabolite profile. Our genetic and biochemical results were highly consistent with postnatal follow-up results on all unaffected fetuses.ConclusionsWe conclude that a biochemical approach can serve as a fast and convenient prenatal diagnostic method for pregnancies at an increased risk for PA, which could be used in conjunction with genetic testing for precise prenatal diagnosis of this disorder. In our analysis, the characteristic metabolites C3 level, C3/C2 ratio, and 2MCA level in AF supernatant were dependable biochemical markers for diagnosis, of which the C3/C2 ratio appears to be the most reliable biochemical marker for the prenatal diagnosis of PA.
Highlights
Propionic acidemia (PA, OMIM #606054) is an organic acidemia attributed to the deficiency of propionyl-CoA carboxylase (PCC, EC6.4.1.3)
Propionyl-CoA carboxylase (PCC), which catalyzes the carboxylation of propionyl-CoA to D-methylmalonyl-CoA [1, 2], is a 750 kDa heterododecamer composed of 6 propionyl-CoA carboxylase alpha (PCCA) and 6 propionyl-CoA carboxylase beta subunits (PCCB) [3, 4]
Different approaches have been applied to prenatal diagnosis of PA including direct propionyl-CoA carboxylase activity assay in chorionic villi (CV) [9, 10], quantification of the characteristic metabolites including acylcarnitines, propionic acids and methylcitric acids in cell-free amniotic fluid (AF) [11,12,13,14]; and direct pathogenic variant analysis of PCCA or PCCB genes in amniocytes
Summary
Propionic acidemia (PA, OMIM #606054) is an organic acidemia attributed to the deficiency of propionyl-CoA carboxylase (PCC, EC6.4.1.3). Propionyl-CoA has a broad influence on metabolism, including impacts on the urea cycle, the citric acid cycle, and the glycine cleavage system [5]. Reliable methods for prenatal diagnosis are essential for neonatal management of PA. Different approaches have been applied to prenatal diagnosis of PA including direct propionyl-CoA carboxylase activity assay in chorionic villi (CV) [9, 10], quantification of the characteristic metabolites including acylcarnitines, propionic acids and methylcitric acids in cell-free amniotic fluid (AF) [11,12,13,14]; and direct pathogenic variant analysis of PCCA or PCCB genes in amniocytes. Propionic acidemia (PA) is a serious metabolic disorder, and different approaches have been applied to its prenatal diagnosis. To evaluate the reliability and validity of a biochemical strategy in the prenatal diagnosis of PA, we conducted a retrospective study of our 11-year experiences at a single center
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