Mucopolysaccharidosis type I

Synonyms

4

Overview

Mucopolysaccharidosis I (MPS I) is a condition that affects many parts of the body. It is a progressively debilitating disorder; however, the rate of progression varies among affected individuals. MPS I is caused by mutations in the IDUA gene. These mutations lead to reduced levels or the complete lack of the IDUA enzyme. Without the proper amount of this enzyme, large sugar molecules called glycosaminoglycans (GAGs) accumulate within cells called lysosomes. This causes the lysosomes to increase in size, causing many different organs and tissues of the body to become enlarged. This leads to the medical problems seen in the condition.

MPS I was once divided into three separate syndromes: Hurler syndrome, Hurler-Scheie syndrome, and Scheie syndrome, listed from most to least severe. Because no biochemical differences have been identified and the clinical findings overlap, the condition is now divided into two subtypes,: severe MPS I and attenuated MPS I. People with severe MPS I typically have an earlier onset of symptoms, a decline in intellectual function, and a shorter lifespan. Although there is no cure for MPS I, bone marrow transplant and enzyme replacement therapy are treatment options that may help manage the symptoms of this condition.

Symptoms

Causes

Mutations in the IDUA gene cause mucopolysaccharidosis I (MPS I). The IDUA gene provides instructions for producing an enzyme (alpha-L-iduronidase) that is involved in the breakdown of large sugar molecules called glycosaminoglycans (GAGs). Mutations in the IDUA gene reduce or completely eliminate the function of alpha-L-iduronidase. This leads to the accumulation of GAGs within cells, specifically inside the lysosomes. Lysosomes are compartments in the cell that digest and recycle different types of molecules. Conditions that cause molecules to build up inside the lysosomes, including MPS I, are called lysosomal storage disorders. The accumulation of GAGs increases the size of the lysosomes, which is why many tissues and organs are enlarged in this disorder.

Prevention

Mucopolysaccharidosis I (MPS I) is inherited in an autosomal recessive manner. This means that to be affected, a person must have a mutation in both copies of the responsible gene in each cell. Affected people inherit one mutated copy of the gene from each parent, who is referred to as a carrier. Carriers of an autosomal recessive condition typically do not have any signs or symptoms (they are unaffected). When 2 carriers of an autosomal recessive condition have children, each child has a:

• 25% (1 in 4) chance to be affected
• 50% (1 in 2) chance to be an unaffected carrier like each parent
• 25% chance to be unaffected and not be a carrier

If you are concerned about your risks to be a carrier of MPS I, we would recommend you consult with a genetics specialist.

Diagnosis

Diagnosis often can be made through clinical examination and urine tests (excess mucopolysaccharides are excreted in the urine). Enzyme assays (testing a variety of cells or body fluids in culture for enzyme deficiency) are also used to provide definitive diagnosis of one of the mucopolysaccharidoses. Prenatal diagnosis using amniocentesis and chorionic villus sampling can verify if a fetus either carries a copy of the defective gene or is affected with the disorder. Genetic counseling can help parents who have a family history of the mucopolysaccharidoses determine if they are carrying the mutated gene that causes the disorders.

Prognosis

Infants with severe MPS I appear normal at birth. Coarsening of the facial features becomes apparent within the first two years. Progressive skeletal dysplasia (dysostosis multiplex) involving all bones occurs in all individuals with severe MPS I. By age three years, linear growth ceases. Hearing loss is common. All develop progressive and profound mental retardation. Death, caused by cardiorespiratory failure, usually occurs within the first ten years of life.

The greatest variability is observed in individuals with the attenuated MPS I phenotype. Onset is usually between ages three and ten years. Although pyschomotor development may be normal in early childhood, individuals with attenuated MPS I may have learning disabilities.

The rate of disease progression and severity can range from serious life-threatening complications leading to death in the second to third decades to a normal life span with significant disability and discomfort from progressive severe restriction in range of motion of all joints. Hearing loss and cardiac valvular disease are common.

Treatment

Management of mucopolysaccharidosis I (MPS I) requires a multidisciplinary team given the wide range of symptoms. This team may include: primary care; cardiology; pulmonology; gastroenterology; neurology; ear, nose, and throat specialists; audiology; ophthalmology; orthopedics; physical therapy; dental; and developmental specialists. The two main treatment options for MPS I include hematopoietic stem cell transplant (HSCT) and enzyme replacement therapy (ERT). Both of these treatments work by replacing the missing IDUA enzyme (alpha-L-iduronidase).

HSCT is considered standard of care for individuals with severe MPS I; however, its success is dependent on timing of treatment. It is typically recommended that HSCT occur early in the disease process, prior to two years of age. Studies have shown that when successful, HSCT can improve facial, auditory, and cardiac manifestations. The effect on intellectual development is unclear with some studies suggesting an improvement, while others report a slowing of cognitive decline.
 
laronidase (Aldurazyme) - FDA-approved indication: Treatment for patients with Hurler and Hurler-Scheie forms of Mucopolysaccharidosis I (MPS I) and for patients with the Scheie form who have moderate to severe symptoms.

Resources

Refer to Research Publications.