Galactosemias: Lessons from the GalNet registry, state of the art fertility insights, and exploring new treatments

Galactosemias is a group of inherited disorders characterised by an aberrant cellular galactose metabolism. Depending on the affected step in the galactose metabolism pathway, patients show a broad phenotypic spectrum and experience a high disease burden. Galactosemia type I, also known as classic galactosemia (CG), is the most well-studied type of galactosemia. The standard of care, a lifelong galactose-restricted diet, fails to prevent the occurrence of long-term complications affecting female gonads, brain and bone. Galactosemia II and III, respectively known as galactokinase (GALK1) and galactose epimerase (GALE) deficiency, are less well-delineated entities and their true phenotypic spectrum is questionable. The presented work in this dissertation aims to (1) describe the natural history of galactosemia type II and III. To (2) review the state-of-the-art insights into the hypogonadotropic hypogonadism conundrum of CG and to provide novel insights into the pathophysiology of primary ovarian insufficiency (POI) using a galt knockout (KO) zebrafish. And to (3) explore new treatment options for CG.