Mucopolysaccharidosis

Abstract

Mucopolysaccharidosis (MPS) is a constellation of several genetic diseases that are due to deficiency in any of 11 enzymes that contribute to the degradation of glycosaminoglycans (GAGs). MPS I is known as Hurler syndrome and Scheie syndrome in the severe and attenuated forms, respectively, and is due to deficiency of α-l-iduronidase, an enzyme that cleaves the sugar known as iduronic acid from GAG chains. MPS II (Hunter syndrome), MPS III (Sanfilippo syndrome), MPS IV (Morquio syndrome), MPS VI (Maroteaux–Lamy syndrome), and MPS VII (Sly syndrome) are due to deficiency of other enzymes that contribute to degradation of GAGs. All of these diseases result in the accumulation of GAGs in the lysosome and eventually the extracellular space and cause multisystemic disease through mechanisms that are still being studied, but likely include the induction of inflammation and destruction of tissues such as bone, cartilage, aorta, and heart valve components. The manifestations of disease can vary with the type of MPS, but can include neurological dysfunction including mental retardation, reduced mobility due to bone and joint disease, and cardiovascular disease due to abnormal heart valves and dilated blood vessels. One current treatment is hematopoietic stem cell transplantation (HSCT), which is most effective when performed as early as possible in life and is not effective for all types of MPS; this treatment has prolonged life and improved some aspects of disease, but is not totally curative. Enzyme replacement therapy (ERT) involves intravenous injection of enzyme as often as once a week, after which enzyme can diffuse to tissues and be taken to the lysosome where it is needed. ERT is not yet available for some types of MPS due to the cost of drug development and/or the perception that enzyme cannot reach the brain very efficiently. ERT has reduced several aspects of disease, but this therapy is relatively new and it is unclear how effective it will be in the long term. Gene therapy is being investigated as a way to achieve continuous expression of enzyme in the body and has been quite effective in several animal models, but has not been used in humans with MPS.