Causes for Mucopolysaccharidosis

General: Mucopolysaccharidosis (MPS) is a group of diseases that are also classified as lysosomal storage diseases. Lysosomes are compartments in the cell that contain various enzymes that degrade (break down) molecules. In MPS, glycosaminoglycans or mucopolysaccharides are not degraded.

Glycosaminoglycans are polysaccharides, or long-chain sugars, that normally help the growth of bone, skin, tendons, connective tissues, and eyes. Glycosaminoglycans are also typically found in the fluid that surrounds joints. When they are not broken down, glycosaminoglycans may cause progressive cellular damage.

Normally, a gene (specific region of DNA) provides the body with instructions on how to make an enzyme. There are 11 enzymes involved in the breakdown of glycosaminoglycans. A deficiency or absence of any one of the enzymes may cause MPS, but only seven have been found to occur in humans. The type of MPS is classified by the enzyme that is deficient. The most likely pattern of inheritance is autosomal recessive although some types of MPS may be inherited as an X-linked dominant trait.

MPS I: MPS I is caused by a deficiency of the enzyme alpha-L-iduronidase.

MPS II: MPS II is caused by a deficiency of the enzyme iduronate sulfatase. This is the only form of MPS that is X-linked dominant.

MPS III: MPS III is caused by a deficiency of an enzyme that breaks down heparan sulfate. There are four subtypes of MPS III, and they are types A, B, C, and D. Type A affects the enzyme heparan N-sulfatase, B affects alpha-N-acetylglucosaminidase, C affects acetyl-CoA alpha-glucosaminide acetyltransferase, and D affects N-acetylglucosamine 6-sulfatase.

MPS IV: MPS IV is caused by a deficiency of an enzyme that breaks down keratin sulfate. There are two subtypes of MPS IV. Type A affects the enzyme N-acetylgalactosamine 6-sulfatase and type B affects beta-galactosidase.

MPS VI: MPS VI is caused by a deficiency of the enzyme N-acetylgalactosamine 4-sulfatase.

MPS VII: MPS VII is caused by a deficiency of the enzyme beta-glucuronidase.

MPS IX: MPS IX is caused by a deficiency of the enzyme hyaluronidase.

Autosomal recessive inheritance: Most types of mucopolysaccharidosis (MPS) are autosomal recessive disorders that are inherited at birth. MPS II or Hunter syndrome is the only form of MPS that is X-linked dominant. In a recessive genetic disorder, a person must inherit two copies of the genetic mutation (one copy from each parent) to develop MPS. People who inherit a mutation from only one parent are called "carriers," and they may pass the mutation to their children.

If only one parent has one copy of the mutated gene, then each child will have a 50% chance of inheriting one mutated gene and also being a carrier. If both parents are carriers, each child has a 25% chance of inheriting two mutated genes, a 50% chance of inheriting only one mutation, and a 25% chance of inheriting neither of the mutations.

If one parent has MPS and the other parent does not carry the trait, then all of the children will be carriers. If one parent has MPS and the other parent is a carrier, then each child has a 50% chance of having MPS or of being a carrier. If both parents have MPS, then all of their children will also have MPS.

X-linked dominant inheritance: MPS II or Hunter syndrome is an X-linked dominant inherited genetic condition. Normal individuals have two copies of most genes (one inherited from the father and one from the mother). In a dominant genetic disorder, only one copy of a certain gene needs to be defective for the condition to manifest. It has been shown that a deficiency or mutation in the enzyme iduronate sulfatase, which is located on the X chromosome, may cause MPS II.

Females have two copies of the X chromosome, but males have one X chromosome and one Y chromosome. Males inherit an X chromosome from the mother and a Y chromosome from the father, so a male can only inherit MPS II from the mother. A female needs to inherit two mutant copies to develop MPS II (one from each parent), whereas a male only needs to inherit one mutant copy to develop the condition. MPS II is more common in males that females. Females who inherit only one mutant copy are called "carriers." Females who are carriers may exhibit some mild symptoms.

Random occurrence: It is unknown whether MPS can occur as the result of a spontaneous genetic mutation with no family history of the disease.

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