88. Establishment and clinical validation of a cut of value for newborn screening n for isovaleric acidemia and glutaric acidemia type I

M L SUEIRO, , , , , , , ; C A CASTILLO; A CHIESA.; C ARANDA; F J TORRES; A ONETO; G GUARRERA; M HUNT; HEIROA; G MACCALLINI,

Congreso; 13th International Congress of Inborn Errors of Metabolism .; 2017

SOCIEDAD LATINOAMERICANA DE ERRORES CONGENITOS Y PESQUISA NEONATAL (SLEIMPN)

Introduction: Newborn screening is a preventive healthcareprogram whose main goal is early detection, diagnosis, andintervention of inborn errors of metabolism that may otherwiseproduce serious clinical consequences or even death. Establishinga proper cutoff is a key factor when introducing a newdisorder into the screening program. Objective: To characterize,in our population, the distribution of values of isovalerilcarnitine(C5) and glutarilcarnitine (C5DCþ C6-OH),biochemical markers of isovaleric acidemia (IVA), and glutaricacidemia type 1 (GA-1), respectively, and to establish andclinically validate a cutoff value for the screening of thesedisorders. Materials and Methods: 2740 dry blood samplesof apparently healthy breast-fed newborns, obtained between2-5 days of age, were tested for C5 and C5 DC by tandem massspectrometry on an API3200 (ABSciex) using MassChromNon-derivatized kit (ChromSystems). Mean ( x), standarddeviation (SD) and different percentile values were calculated.Results were compared to those provided by the collaborativeinternational database Region 4 Stork (R4 S) up to April 2017.Cutoff value was considered clinically validated if it fell withinthe percentile 99 (P99) of normal population and percentile5 (P5) of the confirmed positive cases (405 for IVA and 539for GA-1) and within the percentile 25 (P25) and percentile75 (P75) of the distribution of cutoff values reported for thesedisorders. Results: Distribution of Values C5 x ¼ 0.12 mM,SD ¼ 0.08 mM, P99 ¼ 0.30 mM, P99.7 ¼ 0.50, P99.8 ¼ 0.55,P99.9 ¼ 0.67 mM. C5 DC x ¼ 0,20 mM, SD ¼ 0.08 mM, P99 ¼0.44 mM, P99.7 ¼ 0.50, P99.8 ¼ 0.55, P99.9 ¼ 0.57 mM.Clinical validation: Isovaleric acidemia Selected cutoff: 0.67mM(P99.9) P99?P5 range ¼ 0.38 mM?1.13 mM P25?P75 rangefor cutoff values ¼ 0.49 mM?1.00 mM Glutaric Acidemia TypeI: Selected cutoff: 0.50 mM (P99.7). P99?P5 range ¼ 0.10mM?0.28 mM; P25?P75 range for cut off values ¼ 0.25 mM?0.43mM Conclusions: We characterized the distribution of C5 andC5 DC values in our population and successfully validated theselected cut-off for IVA, allowing its implementation in a nearfuture. We failed to achieve clinical validation of GA-1 cutoff.Despite P99 falling within the P25-P75 range for reported cutoffvalues, it is above P5 of reported true positives cases, notfully meeting the validation criteria. This may be due to the factthat true positive C5 DC values reported in the R4 S databaseseem not to be discriminated between derivatized and underivatizedmethodologies.