Mucopolysaccharidosis III (MPS III)

MPS III, also referred to as Sanfilippo syndrome, is caused by a deficiency of an enzyme that is needed to break down the mucopolysaccharide/glycosaminoglycan (GAG) heparan sulfate, which is found in many tissues, but is particularly important in the central nervous system. GAGs are long, repeating chains of complex sugar molecules. When one of several enzymes is absent, a progressive buildup of the GAG material occurs. In MPS III, this increase of GAG material occurs primarily in the brain and leads to many cognitive and behavioral problems.

Forms of the disorder

MPS III is traditionally divided into four possible forms, with each type caused by a deficiency in a different enzyme. The frequency of Sanfilippo syndrome (for all four forms combined) is estimated at 1 in 70,000 births.

MPS IIIA is the most severe form. It is caused by a deficiency of the enzyme heparan N-sulfatase.

MPS IIIB has both severe and mild forms. It is caused by a deficiency of the enzyme N-acetyl-alpha-D-glucosaminidase (NAG).

MPS IIIC is rare and presents as an intermediate form between MPS IIIA and the mild form of MPS IIIB. MPS IIIC is caused by a deficiency of the enzyme acetyl CoA: alpha-glucosaminide acetyltransferase.

MPS IIID is very rare and is caused by a deficiency of the enzyme N-acetylglucosamine-6-sulfatase.

Clinical features

The symptoms of Sanfilippo syndrome are very similar among the four forms, although there is some variability. Individuals with Sanfilippo syndrome usually begin to display symptoms between the ages of 2 and 6 years. The syndrome is often difficult to detect because there are fewer outward physical changes than in the other types of MPS disorders. However, individuals with this condition may present with mild abnormalities of the bones detected by x-ray, hernias, seizures, thickened skin, chronic nasal congestion, and hyperactivity and aggression. Developmental delay is common and can lead to the eventual loss of previously acquired skills.

Genetics of the disorder

Each form of MPS III is inherited as an autosomal recessive trait. Here's how that works: All individuals have two copies of each specific MPS III gene and usually both function normally. However, a child with MPS III has alterations in both copies of their genes so that neither gene copy works properly. A child receives one copy of the altered gene from their mother and one copy of the altered gene from their father. The parents are not affected with the condition because they have one normal copy of the gene paired with one altered copy of the gene. The normal gene produces enough of the specific enzyme to prevent the disorder. This is referred to as being a carrier for the condition. When both parents are carriers, they have a 25 % chance with each pregnancy to have an affected child. In turn, parents who are carriers have a 75% chance with each pregnancy to have an unaffected child. More here about autosomal recessive inheritance.

Treatment

Management of the disorder currently involves symptomatic treatment of specific complications that can arise. While no specific treatment for MPS III is available at this time, research is being conducted that may one day lead to an effective treatment. A primary goal is to develop an enzyme replacement product that will cross the blood-brain barrier and enter into the brain cells.