Abstract

Newborn screening (NBS) for isovaleric acidemia (IVA) reduces mortality and morbidity; however, it has also resulted in the detection of individuals with an asymptomatic or mild presentation for which early detection via newborn screening has not been proven to alter neurological outcome. We reevaluated biochemical and molecular data for newborns flagged positive for IVA in aim of developing a new screening algorithm to exclude the latter from positive screening. Among 2 794 365 newborns underwent routine newborn screening in Israel, 412 flagged positive for IVA, of which, 371 were false positives on recall sample testing and 41 positive newborns were referred to the clinic. 38/41 have biochemical and molecular confirmation in keeping with IVA. Among the 38 patients, 32% (12/38) were classified as symptomatic while, 68% (26/38) were classified as asymptomatic. 69% of the latter group harbor the known variant associated with mild potentially asymptomatic phenotype, c.932C>T; p. Ala311Val. Among asymptomatic patients, only 46% (12/26) are currently treated. Two novel variants have been detected in the IVD gene: c.487G>A; p. Ala163Thr and c.985A>G; p. Met329Val. Cut-off recalculation, of referred newborns' initial biochemical results, after classifying the referred patients to two binary groups of symptomatic and asymptomatic, resulted in an improved NBS algorithm comprising of C5 >5 μM and C5/C2>0.2 and C5/C3>4 flagging only those likely to have the classic symptomatic phenotype.

למאמר המלא

Rock R, Rock O, Daas S, Biton-Regev V, Sagiv N, Salah NA, Anikster Y, Barel O, Cohen RH, Dumin E, Fattal-Valevski A, Falik-Zaccai T, Herskovitz E, Josefsberg S, Khammash H, Kneller K, Korman SH, Landau YE, Lerman-Sagie T, Mandel H, Pras E, Reznik-Wolf H, Shaag A, Lotan NS, Spiegel R, Tal G, Staretz-Chacham O, Wilnai Y, Almashanu S. Newborn screening algorithm distinguishing potential symptomatic isovaleric acidemia from asymptomatic newborns. J Inherit Metab Dis. 2025 Jan;48(1):e12800. doi: 10.1002/jimd.12800. Epub 2024 Sep 24. PMID: 39318119