Holota T. Optimizing the diagnosis of hereditary metabolic diseases in newborns and children in the first year of life.

The dissertation aims to optimize the diagnosis of hereditary metabolic diseases (HMDs) in newborns and infants during their first year of life. This will be achieved by establishing reference intervals for HMD markers, conducting clinical-laboratory and biochemical comparisons, and creating an algorithm to support medical-diagnostic procedures. HMDs belong to the group of orphan diseases. Almost a third of the cases of death of children in the first year of life in Ukraine are associated with the presence of an unrecognized HMD, including 10% of «unspecified conditions», 15% of «conditions occurring in the perinatal period», 8% of «sudden infant death syndrome». To date, there are no clear limits of the values of markers of HMDs for Ukrainian children. The dissertation is devoted to the solution of the main scientific task, which was to establish the limit levels of concentrations of marker analytes of 31 HMDs for a cohort of Ukrainian children. Current tasks included comparing the limit levels of concentrations of marker analytes 31 HNDs for full-term and premature children, comparison of the limit levels of concentrations of marker analytes 31 HMDs in the group of premature children depending on body weight, improving the technique of taking capillary blood from newborns for early neonatal screening, development and implementation of a clinical diagnostic algorithm and CHECKLIST for medical support of newborns with suspicion of HMDs. Retrospectively, 399 children who met the inclusion criteria were selected for the study. The criteria for inclusion in the study were: newborns during 2020-2022 at the SI «Institute of Pediatrics, Obstetrics and Gynecology named after Academician O. M. Lukyanova of the National Academy of Medical Sciences of Ukraine», gestational age (GA) 26-42 weeks; neonatal period; obtaining voluntary informed consent from the patient's parents/guardians to participate in the study. The research groups were formed: the first (I) group consisted of 339 practically healthy full-term children with a birth weight of >2500 g, which corresponded to 85% of the studied newborns, the second (II) group included 60 preterm babies. Depending on body weight, newborns were divided into 2 subgroups. The IIA subgroup included 39 babies with low birth weight (LBW, 1500-2499 g), and the IIB group – 21 children with very low birth weight (VLBW, ≤1499 g). During neonatal screening, blood samples were taken on test cards at 48-72 hours of life for full-term babies and at 7-11 days for premature babies. As a result of the dissertation research, the reference intervals of 77 diagnostic analytes of 31 HMDs for a cohort of Ukrainian children were established for the first time, ranging from 2.5 to 97.5 percentiles for each indicator among healthy children. It was established that the values of 39 indicators among groups of examined children depend on body weight (p<0.001). Considering the likely difference in the indicators of the reference intervals for the specified analytes (from p<0.001 to p<0.0001) in premature babies from full-term newborns, it is advisable to develop reference intervals directly for premature babies, which is the subject of further research. Thirty-eight prematurely born children (63.3%) need retested retests. In addition, in the group of premature babies with VLBW, the deviation of diagnostic analytes was noted for 26 HMD analytes (34%) against 20 HMD diagnostic analytes (26%) in children with LBW. The most frequently diagnosed analyte differences are C18:2/C16, C14:1/C16, C5/C8 IS, C18:1/C16, and C5/C3, potentially responsible for fatty acids disorders and organic acidurias. Every third sample (120 cases of capillary blood sampling on test cards) was rejected during neonatal screening at the preanalytical stage. In addition, the established regularities in premature babies were the basis for supplementing the technique of taking capillary blood on test cards during expanded neonatal screening (ENS). The developed and implemented clinical-diagnostic algorithm and CHECKLIST for medical support of newborns with suspicion of HMDs made it possible to reduce the period of diagnostic search for HMDs from 3 to 1 month if positive results were obtained.