(1) University of Florida, Gainesville, FL, USA
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Sanfilippo Syndrome or Mucopolysaccharidosis III (MPS III) is a group of lysosomal storage diseases resulting from a deficiency of one of four lysosomal enzymes: Type A - heparan N-sulfatase (SGSH), Type B - α-N-acetylglucosaminidase (NAGLU), Type C - acetyl CoA α-glucosaminide acetyltransferase (HGSNAT) and Type D - N-acetylglucosamine-6-sulfatase (GNS). Each of these enzymes is necessary for degradation of heparan sulphate. Deficiency of any of these enzymes manifests as a neurodegenerative disorder with accompanying somatic manifestations. Currently treatment is limited to supportive care. MPS IIIA and IIIB are the most common subtypes of MPS III and will be further discussed in this review. The integral genes underlying both these diseases have been cloned and characterized. Through genetic analysis of the cDNA from MPS IIIA and B, researchers have begun to link many genetic mutations to their resultant phenotypes, and discern geographic differences in mutational variation. Here, we highlight many of the known MPS IIIA and B mutations and present them in the context of ethnic and geographic differences in an attempt to discern genotype-phenotype correlations and patterns of inheritance.
Most mutation sites have variable severity. A few sites have predictably more or less acute disease courses but all described mutations still result in progressive neurodegeneration and premature death.
Mucopolysaccharidoses are a group of eleven inherited lysosomal storage diseases (LSDs) resulting from a
particular enzyme deficiency. Sanfilippo Syndrome, commonly referred to as Mucopolysaccharidosis III (MPS III),
results from a deficiency in one of four lysosomal
enzymes needed to break down heparan sulfate (HS). Heparan sulphate functions biologically as a proteoglycan which occurs as cell-surface and extracellular matrix macromolecules. These proteoglycans play crucial roles in regulating key developmental
signalling pathways by binding to specific protein
ligands and in maintaining cellular homeostasis. MPS III is inherited in an autosomal recessive manner and each of the four
enzyme deficiencies defines a particular type of MPS III. Namely, Type A - heparan N-sulphatase (SGSH, OMIM # 252900), Type B - α-N-acetylglucosaminidase (NAGLU, OMIM # 2529520), Type C - acetyl CoA α-glucosaminide acetyltransferase (HGSNAT, OMIM #
252930) and Type D - N-acetylglucosamine-6-sulfatase (GNS, OMIM # 252940). Deficiency of any of these enzymes manifests as a neurodegenerative
disorder with accompanying somatic manifestations. Of the mucopolysaccharidoses, MPS III is the most frequent, with an
estimated incidence of 0.28 - 4.1 per 100,000 persons
The cDNA sequences for SGSH