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

Abstract

Mucopolysaccharidosis type III A (MPS III A, Sanfilippo syndrome) is a rare, autosomal recessive, lysosomal storage disease characterized by accumulation of heparan sulfate secondary to defective function of the lysosomal enzyme 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 membranous and floccular materials with some having a classical zebra body morphology. Storage materials were also present in lysosomes of cells of many other tissues, and these often stained positively with periodic-acid Schiff reagent. Affected mice usually died at 7-10 months of age exhibiting a distended bladder and hepatosplenomegaly. Heparan sulfate isolated from urine and brain had nonreducing end glucosamine- N -sulfate residues that were digested with recombinant human sulfamidase. Enzyme assays of liver and brain extracts revealed a dramatic reduction in sulfamidase activity. Other lysosomal hydrolases that degrade heparan sulfate or other glycans and glycosaminoglycans were either normal, or were 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 enzyme or cell replacement and gene therapy.

Systemic inflammation and neurodegeneration in a mouse model of multiple sulfatase deficiency

“…Some of them represent spontaneous mutants, whereas others were generated as KO mice. The latter are available for five diseases due to individual sulfatase deficiencies, namely metachromatic leukodystrophy, and MPSs (i.e., MPSII, MPSIIIA, MPSIVA, and MPSVI) (11)(12)(13)(14)(15)(16). In all instances the biochemical abnormalities in the mouse models replicated those observed in the corresponding human disease.…”

“…Hind limb clasping, head tremor, and seizures were also detected starting at 1 month of age, indicating neurological involvement (data not shown). All these features are important components of the phenotype observed in patients with MSD (8) and in human patients and murine models of MPSs (5)(6)(7)(11)(12)(13)(14)(15)(16).…”

“…Joint deformities were also evident in most mice. All these features are important components of the phenotype of LSDs and are observed in patients with MSD (8) and of both human patients and murine models of MPSs (5,(12)(13)(14)(15)(16). In addition, bone histological analysis of Sumf1 Ϫ/Ϫ mice showed clear signs of defective osteogenesis (C.S., unpublished data).…”

Enzyme-Replacement Therapy from Birth Delays the Development of Behavior and Learning Problems in Mucopolysaccharidosis Type IIIA Mice

“…Enzyme distribution studies in MPS IIIA mice demonstrate the presence of rhNS in the brain of newborn mice but not in the brain of 6-wk-old mice. MPS IIIA mice have only~3% of normal control mouse sulfamidase activity (5). It has been proposed that a correction of~10% of normal sulfamidase activity is required to avoid an MPS IIIA clinical phenotype (33).…”

“…Sulfamidase-deficient mice exhibit glycosaminoglycan storage vacuoles in neuronal cells from day 1 of life, which increases with age. Between 8 and 14 wk of age, the storage vacuoles in MPS IIIA mice contain granular, lipid-like material as a result of the secondary storage of gangliosides G M2 and G M3 , which are reported to accumulate in this model (5). Cerebellum and cerebral cortex sections were assessed from mice in each of the treatment groups at ages ranging from 3 to 23 wk.…”