PhD thesis, Birgit van Dooijeweert
Research in this thesis was conducted to contribute to the phenotypic characterization of hereditary anemias, in particular of Diamond-Blackfan anemia (DBA).
Phenotyping is at the root of recognizing and understanding disorders by forming the contextual framework whereupon research and care can be commenced.
The clinical phenotype that patients endure is the ultimate culmination of the genetic background and pathophysiological processes they evoke, and recognizing the phenotypic spectrum in these rare disorders is crucial for both the diagnostic evaluation as well as long term clinical treatment.
In the first and third part of this thesis we focus on DBA, a rare bone marrow failure disorder with a broad range of underlying molecular defects and clinical phenotypes. Since registries have historically proven to be crucial in increasing disease understanding, we established the Dutch DBA Registry (DBAN) and created a comprehensive overview of 43 patients. Further on, we used DBAN to address iron overload, an important and understudied complication in DBA, and show that iron overload occurs often, even in patients wild only mildly elevated ferritin levels.
In the second part of this thesis we explored the fairly uncharted omics layer of ‘metabolomics’ in the field of rare hereditary anemias. In the studies that are presented in this part of the thesis, we employed untargeted metabolomics to define disease specific metabolic signatures for the hereditary anemias pyruvate kinase deficiency, DBA and hereditary spherocytosis and show this could serve both future diagnostic potential as well as generate novel insights into the pathophysiology of these disorders.