MPS I: Early diagnosis, and treatment of bone disease

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disease (LSD) characterized by deficient degradation and subsequent accumulation of glycosaminoglycans (GAGs). Patients present with a spectrum of symptoms, including progressive mental retardation and bone disease. To optimize outcome, early recognition of the clinical phenotype to guide decisions on therapeutic strategies are needed. Also, treatment of MPS I bone disease is currently not effective and lack of knowledge on pathophysiological mechanisms limits the development of new therapeutics. This thesis comprises studies on early diagnosis of MPS I, and pathophysiology and treatment of MPS I bone disease. Chapter 2 provides an overview of the epidemiology, diagnostics and challenges of screening for LSDs. In Chapter 3, we describe an algorithm to predict the MPS I phenotype at a young age, which can be used to guide decisions on the proper treatment before the onset of symptoms and irreversible organ damage. In Chapter 4, a study on the secondary pathological effects of GAG accumulation is described. Chapter 5 describes alterations in growth factors and GAGs in MPS I bones, which is likely involved in the development of MPS I bone disease. Finally, in Chapter 6 and 7, adverse effects of genistein are described in MPS I cells and mice. Because genistein has been promoted as a treatment for MPS III and is available over the counter, this information discourages the use of genistein in MPS I patients outside a clinical trial. Chapter 8 comprises a general discussion and future perspectives.