Classical galactosemia A cloud with a silver lining

For classical galactosemia, (CG), an autosomal recessive inborn error of galactose metabolism, a galactose-restricted diet is the only available treatment. The diet prevents death in the first weeks of life, but unfortunately does not prevent the occurrence of long-term complications in these patients. Severity of complications varies substantially between patients and methods for early prognostication are not available. There is an urgent need for insight into the pathophysiological processes underlying these complications. In this thesis, prevalence and clinical significance of long term complications (cognitive impairment, bone health problems, social problems) are studied in more detail in cross-sectional study designs and systematic reviews, pooling data in a meta-analysis. Capacities and impairments of body functions (such as motor functions and mental functions), leading to need for additional care in patients with CG, are evaluated. Effectiveness of newborn screening for CG in the Netherlands from 2007 to 2015, and the identification of individuals with previously unreported clinical and biochemical phenotypes and genotypes (variant patients), are reported. A new method for galactose metabolism profiling in cultured fibroblasts was developed, which is able to discriminate classical patients from variant patients, and may proof to be useful in early prognostication. Finally, an international and evidence-based guideline, created by many experts (from Europe and the United States) in the field, is presented. The recommendations in this guideline include diagnosis, treatment and follow-up of CG and were designed to be applicable in countries worldwide.