In Sanfilippo syndrome, the body is unable to produce the enzymes necessary to break down a large sugar molecule called heparan sulfate. This is because of mutations in the genes that encode for these enzymes. Defective or missing enzymes leads to heparan sulfate and other compounds building up within the body, which has toxic effects.
What is the role of heparan sulfate and lysosomes?
Heparan sulfate is a type of large sugar molecule called glycosaminoglycan (GAG). It attaches to various proteins within cells and regulates their function. Proteins with heparan sulfate attached play important roles in development.
Cells break down heparan sulfate and other GAGs in a specialized compartment called the lysosome. This is like the “recycling plant” of cells. Cells can then re-use the constituent parts of complex molecules.
Proteins called enzymes govern the biochemical process of breaking down molecules within lysosomes. A lysosome normally contains dozens of different enzymes, each of which is responsible for a particular step in the biochemical process for breaking down different types of compounds.
Four lysosomal enzymes are specifically necessary for different steps of breaking down heparan sulfate. In Sanfilippo syndrome, one of these enzymes is missing or defective. As a result, cells cannot break down heparan sulfate, which builds up in the body.
How does the buildup of heparan sulfate affect the body?
The exact mechanism of how the buildup of heparan sulfate leads to the symptoms of Sanfilippo syndrome, such as neurodegeneration (nerve cell death), remains one of the most poorly understood aspects of the disease.
Research has shown that the buildup of heparan sulfate leads to a buildup of other molecules, such as a type of fat molecule called gangliosides, in lysosomes and other cellular compartments. This may be because the buildup of heparan sulfate leads to dysfunction of the lysosomes, disrupting the cell’s “recycling” processes more generally. It is also possible that heparan sulfate changes the way cells make or transport other molecules.
How is Sanfilippo inherited?
Mutations in one of the four genes — which provide instructions for the enzymes that break down heparan sulfate — can cause Sanfilippo syndrome. Mutations in each gene cause one of the four types of Sanfilippo syndrome, so mutations in the SGSH gene cause Sanfilippo type A. Mutations in NAGLU cause Sanfilippo type B. Those in HGSNAT cause type C disease, and mutations in GNS cause Sanfilippo type D.
All four types are inherited in an autosomal recessive manner. This means that both copies of the gene in question (the one coming from the mother and the one coming from the father) must carry the mutation for the disease to develop.
So, typically, children with Sanfilippo syndrome are born to two parents who are both carriers of the mutation. In other words, each parent has one faulty copy of the same gene. However, because the other copy is healthy, they do not have the disease.
If two carriers have a child together, there is a 25% chance of that child inheriting two faulty copies of the gene and having Sanfilippo syndrome. There is a 50% chance of the child inheriting one faulty copy from either parent and being a carrier like their parents. Finally, there is a 25% chance that the child will inherit a healthy copy of the gene from both parents and not have the disease or be a carrier.