Isovaleric aciduria identified by newborn screening: Strategies to predict disease severity and stratify treatment

Abstract

Newborn screening (NBS) allows early identification of individuals with rare disease, such as isovaleric aciduria (IVA). Reliable early prediction of disease severity of positively screened individuals with IVA is needed to guide therapeutic decision, prevent life‐threatening neonatal disease manifestation in classic IVA and over‐medicalization in attenuated IVA that may remain asymptomatic. We analyzed 84 individuals (median age at last study visit 8.5 years) with confirmed IVA identified by NBS between 1998 and 2018 who participated in the national, observational, multicenter study. Screening results, additional metabolic parameters, genotypes, and clinical phenotypic data were included. Individuals with metabolic decompensation showed a higher median isovalerylcarnitine (C5) concentration in the first NBS sample (10.6 vs. 2.7 μmol/L; p < 0.0001) and initial urinary isovalerylglycine concentration (1750 vs. 180 mmol/mol creatinine; p = 0.0003) than those who remained asymptomatic. C5 was in trend inversely correlated with full IQ (R = −0.255; slope = −0.869; p = 0.0870) and was lower for the “attenuated” variants compared to classic genotypes [median (IQR; range): 2.6 μmol/L (2.1–4.0; 0.7–6.4) versus 10.3 μmol/L (7.4–13.1; 4.3–21.7); N = 73]. In‐silico prediction scores (M‐CAP, MetaSVM, and MetaLR) correlated highly with isovalerylglycine and ratios of C5 to free carnitine and acetylcarnitine, but not sufficiently with clinical endpoints. The results of the first NBS sample and biochemical confirmatory testing are reliable early predictors of the clinical course of IVA, facilitating case definition (attenuated versus classic IVA). Prediction of attenuated IVA is supported by the genotype. On this basis, a reasonable algorithm has been established for neonates with a positive NBS result for IVA, with the aim of providing the necessary treatment immediately, but whenever possible, adjusting the treatment to the individual severity of the disease.

Retrospective Review of Positive Newborn Screening Results for Isovaleric Acidemia and Development of a Strategy to Improve the Efficacy of Newborn Screening in the UK

“…Fortunately, the initial screening result appears to correlate with disease severity and, consequently, risk; it is notable that all 17 TP cases with initial C5C concentration < 7.2 µmol/L remained asymptomatic, whilst those requiring more intensive care demonstrated initial C5C results > 7.5 µmol/L. This is broadly comparable with the finding from the German NBS programme, where a review of 84 individuals with IVA confirmed by NBS concluded that an initial C5C concentration < 5.6 µmol/L was associated with asymptomatic disease course in most cases [20].…”

Causal relationship between serum metabolites and risk of thyroid cancer: a mendelian randomization study

“…Isovalerylcarnitine (C5), a carnitine derivative, is involved in fatty acid metabolism by transporting long-chain fatty acids into mitochondria for oxidation and energy production. Its levels can be in uenced by diet and metabolic status, playing a crucial role in energy metabolism [33]. Glycerol-3phosphate (G3P) is vital for growth and physiological functions in prokaryotes, plants, animals, and humans [34].…”

Organic Acidemias: Clinical Presentation in Neonates

“…103 1D. Isovaleric Academia (IVA) [104][105][106] Isovaleric academia is an AR disorder due to the deficiency of isovaleryl-CoA dehydrogenase (IVD) required in leucine metabolism. 11 A study in Germany showed C.932C>T mutation in 47% alleles.…”