Prenatal Diagnosis of Isovaleric Acidemia From Amniotic Fluid Using Genetic and Biochemical Approaches

Abstract

Background: Isovaleric acidemia (IVA) is an inborn error of leucine metabolism and different approaches have been applied to its prenatal diagnosis. However, systemic application of a biochemical strategy is rare. To evaluate its reliability and validity, we conducted a retrospective study of our experience with metabolite measurement together with genetic analysis in IVA prenatal diagnosis at a single center.Methods: A total of eight pregnancies whose probands were diagnosed as IVA were referred to our center for prenatal diagnosis. Prenatal data of genetic analysis and metabolite measurement using tandem mass spectrometry (MS/MS) and gas chromatography/mass spectrometry (GC/MS) in amniotic fluid (AF) samples were retrospectively reviewed.Results: Genetic and biochemical results were both available in these eight at-risk fetuses. Among them, two fetuses had higher levels of isovalerylcarnitine (C5) and C5/acetylcarnitine (C2) in AF compared with normal reference range and, thus, were determined to be affected, both of whom were found to carry compound heterogeneous mutations according to genetic analysis. The remaining six fetuses were determined to be unaffected based on a normal AF metabolite profile, except one showed slightly elevated C5 and they were found to be carriers according to genetic analysis. However, the level of isovalerylglycine (IVG) could not be detected at all in both groups.Conclusion: The biochemical analysis, as a quick and convenient method, could be an additional reliable option for the prenatal diagnosis of IVA, especially in families with inconclusive genetic results, and can achieve a more precise diagnosis in conjunction with mutation analysis.

206,977 newborn screening results reveal the ethnic differences in the spectrum of inborn errors of metabolism in Huaihua, China

“…IVA, encoded by the IVD gene, is classified into two diverse phenotypes: the acute neonatal form causes metabolic acidosis, leading to lethargy, vomiting, coma, or death, while the chronic form typically has a late onset in childhood with an asymptomatic phenotype ( Vockley and Ensenauer, 2006 ; Schlune et al, 2018 ; Ding et al, 2022 ). One Miao patient was identified with IVA with acute clinical symptoms; genetic analysis detected two variants (c.631A>G and c.856G>A).…”

Organic Acidemias: Clinical Presentation in Neonates

“…44 Another, although less accurate, way of prenatal diagnosis is to detect diagnostic compounds in amniotic fluid and enzyme activity in amniocytes or chorionic villi. 45,46 The delivery should be planned in a facility equipped to handle potential metabolic or other complications. 47 After birth, expanded newborn screening should be sent at 36-48 hours to identify OAs.…”

Isovaleric Acidemia in Jordan

“…Isovalerylcarnitine elevation may also indicate IVA. Confirmation involves biochemical analysis and assessing IVD enzyme activity [8,9]. Newborn screening allows early detection, enabling proactive intervention and reducing symptom severity, morbidity, and mortality.…”