Metakromatik lökodistrofi hastalığının alt tiplerinin tanımlanması, patojenik mutasyonların belirlenmesi, patogenezde inflamasyonun incelenmesi

Abstract

Pekgul, F., Identification of subtypes of metachromatic leukodystrophy, determination of pathogenic mutations, investigation of inflammation in pathogenesis, Hacettepe University Faculty of Medicine, Thesis in Medical Biochemistry, Ankara, 2018. Metachromatic leukodystrophy (MLD) is a lysosomal storage disease characterized by sulfatide accumulation in various tissues. It is inherited autosomal recessively. MLD is divided into three types according to the age of clinical onset of the patients. These are late infantile, juvenile and adult types. MLD occurs in the deficiency of a lysosomal enzyme, arylsulfatase A (ASA) or the saposin B (Sap-B) protein, the activator protein of this enzyme. Sulfatides that cannot be hydrolysed due to the failure of the ASA, which is responsible for the breakdown of sulfatides, accumulate in many tissues, especially in the nervous system cells and cause neural damage. In the laboratories, the diagnosis of MLD is made by the arylsulfatase A (ASA) enzyme assay. Although this test is necessary for the diagnosis of MLD, it is insufficient to make an accurate diagnosis. In this study, we aimed to establish all the necessary analyzes for the diagnosis of MLD in our country and to reveal the molecular mechanism of the disease. For this purpose, 12 lysosomal enzyme analysis by spectrophotometric and fluorometric methods, enzyme protein and activator protein determination by Western blot analysis, sulfatide analysis by thin layer chromatography, and pseudo-deficiency mutation by PCR-restriction enzyme analysis were performed. In addition, anti-sulfatide and anti-MOG analyzes were performed to investigate the role of inflammation in the phenotypic variation in MLD. In conclusion, patients presenting with the suspicion of MLD were evaluated with the necessary analyzes to identify all MLD types. The mutations caused by the disease and the effect of the mutations on the protein were detected. The role of the inflammation in the severity of the clinical symptoms has been evaluated through antibody formations.