A mouse model for mucopolysaccharidosis type III A (Sanfilippo syndrome)

Mucopolysaccharidosis type III A (MPS III A, Sanfilippo syndrome) is a Fare , autosomal recessive, lysosomal storage disease characterized by accumulat ion of heparan sulfate secondary to defective function of the lysosomal enz yme heparan N-sulfatase (sulfamidase), Here we describe a spontaneous mouse mutant that replicates many of the features found in MPS III A in children . Brain sections revealed neurons with distended lysosomes filled with memb ranous and floccular materials with some having a classical zebra body morp hology. Storage materials were also present in lysosomes of cells of many o ther tissues, and these often stained positively with periodic-acid Schiff reagent. Affected mice usually died at 7-10 months of age exhibiting a dist ended bladder and hepatosplenomegaly. Heparan sulfate isolated from urine a nd brain had nonreducing end glucosamine-N-sulfate residues that were diges ted with recombinant human sulfamidase, Enzyme assays of liver and brain ex tracts revealed a dramatic reduction in sulfamidase activity. Other lysosom al hydrolases that degrade heparan sulfate or other glycans and glycosamino glycans were either normal, or mere somewhat increased in specific activity . The MPS III A mouse provides an excellent model for evaluating pathogenic mechanisms of disease and for testing treatment strategies, including enzy me or cell replacement and gene therapy.