Types
Sanfilippo Syndrome has four subtypes caused by a mutation in a different gene. While the specific gene and enzyme involved differ, they are generally marked by shared disease characteristics. Each type is named after a missing or defective enzyme:
Sanfilippo type A (MPS IIIA)
The most common and considered the most severe, caused by mutations in the SGSH gene on chromosome 17. The mutations may result in either a decreased or total loss of heparan N-sulfatase enzyme activity. The body needs heparan N-sulfatase to help break down heparan sulfate. When the body cannot properly break down the enzyme, it leads to toxic buildup in cells, especially in the brain. Without the enzyme, damage happens quickly, often beginning in early childhood.
The rapid progression may result in irreversible damage to the child’s body. Most children diagnosed with Type A Sanfilippo Syndrome lose skills rapidly and do not survive beyond their teenage years. Some children do not survive their teenage years, as this condition currently lacks an effective treatment.
Sanfilippo type B (MPS IIIB)
The second most common Sanfilippo type is caused by mutations in the NAGLU gene, also on chromosome 17. Children diagnosed with type B have a deficiency or total loss of N-acetylglucosaminidase, which removes a sugar called N-acetylglucosamine from the end of heparan sulfate. Without the N-acetylglucosaminidase enzyme, heparan sulfate accumulates inside the cells, which will eventually damage them.
Type B tends to progress more slowly than type A. However, the outcome is still life-limiting, as most children do not live past adolescence.
Sanfilippo type C (MPS IIIC)
The mutations in the HGSNAT gene on chromosome 8 can lead to Sanfilippo type C. The HGSNAT is needed by cells to create an enzyme called heparan-alpha-glucosaminide N-acetyltransferase. The enzyme adds an acetyl group to the end of heparan sulfate, which is critical for breaking down. The heparan sulfate only partly breaks down (limited degradation) when the enzyme dysfunctions in the child’s body. They can accumulate inside cells, causing damage.
Children who are diagnosed with Sanfilippo type C may live into early adulthood. Since the typical symptoms we see in severe cases haven’t happened yet, there are instances where kids may have a very late diagnosis. This type usually progresses more slowly, but still causes progressive cognitive and physical decline.
Sanfilippo type D (MPS IIID)
Very few cases of Type D have been documented worldwide. With four case studies, this makes Type D of Sanfilippo Syndrome the rarest subtype. It is caused by mutations in the GNS gene on chromosome 12, which affects the enzyme N-acetylglucosamine-6-sulfatase. The gene is critical as it encodes for the N-acetylglucosamine-6-sulfatase enzyme. When found at the end of heparan sulfate, the N-acetylglucosamine-6-sulfatase enzyme helps eliminate a sulfate group.
Like other types of Sanfilippo, the mutations may affect the enzyme. If it does not work properly, a toxic accumulation of heparan sulfate in cells may happen, leading to severe neurological damage.
Regardless of the subtype, children diagnosed with Sanfilippo Syndrome will experience a decline in abilities over time. This includes coarse facial features, intellectual disability, autism spectrum disorder, sleeping problems, hyperactivity, language delay, seizures, and profound neurological decline. As the disease progresses, the symptoms become increasingly severe. In the future, it may guide treatment options.
How Is the Subtype Diagnosed?
Knowing the exact Sanfilippo Syndrome subtype helps families understand the expected disease progression of the diagnosed child.
A Sanfilippo syndrome diagnosis begins with analyzing the symptoms. The physician will require a urine test, which is critical to check for elevated levels of heparan sulfate. If suspected, the physician will request genetic testing to confirm the diagnosis and identify the affected gene.
