Isovaleric acidemia: an integrated approach toward predictive laboratory medicine

Isovaleric acidemia (IVA) is an autosomal recessive disorder caused by isovaleryl-CoA dehydrogenase (IVD) deficiency (E.C.1.2.99.10) and patients present with a heterogeneous phenotype, ranging from metabolically mild and/or intermittent to metabolically severe. A cohort of ten IVA patients with a mutual homozygous mutation, c.367G>A (p.G123R), was identified. The IVA patient group however presented with a broad clinical phenotype despite the genetic homogeneity. The homozygous group as well as twelve obligate heterozygotes and relevant control subjects were available for an integrated investigation. This thesis, entitled "Isovaleric acidemia: an integrated approach toward predictive laboratory medicine" presents the outcome of the well-established clinical, biochemical and genetic approach which is followed to characterize an inborn error of metabolism as well as the application of contemporary metabolomics technology consisting of semi-targeted GC-MS analysis as well as bioinformatics applications e.g. PCA, PLS-DA and CONCA, for the disclosure of the metabolic profiles prevailing in the IVA cohort. Furthermore, secondary hyperammonemia observed in IVA was expensively investigated and included the study of N-acetylglutamate synthase (NAGS) and the inhibition of this initial step in the urea cycle by isovaleryl-CoA and other short-chain- and short/branched acyl-CoAs. In additional, the study also resulted in the development of novel IVD and NAGS enzyme assays applicable in the diagnostics of IEMs. The integrated outcomes of these approaches opened the possibility to propose a model on future predictive laboratory medicine in the investigations of inherited metabolic diseases.