Sanfilippo syndrome: Clinical genetic diagnosis and therapies

This chapter aims to briefly review the natural history, pathophysiology, clinical features, and molecular genetics of Sanfilippo syndrome, together with current and emerging advances and future perspectives, particularly to achieve early diagnosis and effective therapy. Sanfilippo syndrome has a systematic name of mucopolysaccharidosis type III (MPS III). It is an autosomal-recessive lysosomal storage disorder (LSD) that affects about 1 in 70,000 live births (Meikle et al., 1999; Poorthuis et al., 1999). Sanfilippo syndrome is the most common MPS, and represents four biochemically distinct disorders, each of which results from a deficiency of one of four enzymes required for the lysosomal degradation of the glycosaminoglycan (GAG) heparan sulfate (HS): sulfamidase (MPS IIIA); α-Nacetylglucosaminidase (MPS IIIB); acetyl Co:A glucosamine N-acetyl transferase (MPS IIIC); and glucosamine-6-sulfatase (MPS IIID). Fragments of partially degraded HS accumulate in lysosomes and are elevated in the urine of all Sanfilippo patients. Genes for all but one (type C) of the four MPS III types have been characterized and used to identify mutations that lead to a deficiency of the enzyme product, storage of HS fragments, and the Sanfilippo phenotype. No currently available therapies are yet able alter the natural history of Sanfilippo syndrome. The grouping and in-depth study of the genes and enzyme systems involved in this syndrome have provided extensive insight and appreciation of cellular processes involved in the systematic turnover of HS. This insight is slowly but surely identifying options for the development of potential therapies.