Barvinska O. Selective screening optimization of inborn errors of amino acids and acylcarnitines metabolism in children

The dissertation is devoted to the study of biochemical and molecular genetic peculiarities of patients with inborn errors of amino acids and acylcarnitines metabolism (IEAA) using methods of tandem mass spectrometry, RFLP analysis and Sanger sequencing. It has been established that the biological variation of amino acids and acylcarnitines in the dry blood spots of newborns and age groups of children from 7 days to 18 years depends on the gestation term, age and gender of children, which must be taken into account when interpreting the results of selective screening of IEAA. In patients with liver failure, specific profiles of amino acids and acylcarnitines (tyrosine and metionin; C0, C2, C3, C16, C18:1, C18:2, C14, C14:1, C14:2) were found, which could be used for monitoring the state of liver in these patients. To optimize the laboratory diagnosis of IEAA, the criteria for distinguishing between primary and secondary changes in the level of tyrosine, leucine, C3 were established and new ratio (C16OH + C18OH + C18: 1OH) / (C0 + C2) <0,025 for the diagnosis of isolated deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) was proposed. In patients with isolated deficiency of LCHAD from Ukraine, the part of major mutation c.1528G> C in the HADHA gene is 94.4%. The spectrum of mutations in the GCDH gene in 5 patients with glutaric acidemia type 1 is represented by 4 described missense mutations and one new pathogenic rearrangement - p.D396G, all mutations were identified in 10, 11 and 12 exons of GCDH gene. In 4 patients with isovaleric acidemia, the spectrum of mutations in the IVD gene was represented by two described: p.R53P, p.V38Gfs*20 and two novel mutations: p.S133C and c.49dupTGTGGCG. A total of 3 mutations in the MUT gene (one of them new - p.R326G) and 2 mutations in the MMAA gene have been identified in 5 patients with isolated methylmalonic acidemia from Ukraine. As a result of the study, algorithms for laboratory diagnosis of patients with suspected IEAA have been developed, which improved the effectiveness of the examination of this group of patients.