Hurler syndrome

For patient information click here Template:DiseaseDisorder infobox Template:Search infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Synonyms: Hurler-Pfaundler syndrome, Hurler-Hunter syndrome, Hunter’s syndrome, Johnie McL disease, Pfaundler-Hurler disease, Pfaundler-Hurler syndrome, Sheldon-Ellis syndrome, Thompson’s syndrome, Hurler's disease, Hurler's syndrome

Overview

Hurler syndrome, also known as mucopolysaccharidosis type I (MPS I), Hurler's disease and gargoylism, is a genetic disorder that results in the deficiency of alpha-L iduronidase, which is an enzyme that breaks down mucopolysaccharides. Without this enzyme, the buildup of heparan sulfate and dermatan sulfate occurs in the body (the heart, liver, brain etc.). Symptoms appear during childhood and early death can occur due to organ damage.

MPS I is divided into three subtypes based on severity of symptoms. All three types result from an absence of, or insufficient levels of, the enzyme alpha-L-iduronidase. MPS I H or Hurler syndrome is the most severe of the MPS I subtypes. The other two types are MPS I S or Scheie syndrome and MPS I H-S or Hurler-Scheie syndrome.

Hurler's Syndrome is often classified as a lysosomal storage disease and is mechanistically related to Hunter's Syndrome (X-linked recessive).

Genetic Profile

Children born to an MPS I parent carry a defective IDUA gene, which has been mapped to the 4p16.3 site on chromosome 4. The gene is named IDUA because of its iduronidase enzyme protein product. As of 2001, 52 different mutations in the IDUA gene have been shown to cause Hurler syndrome.

Because Hurler syndrome is an autosomal recessive disorder, affected persons have two bad copies of the IDUA gene. If someone is born with one normal and one defective copy of the gene he is called a carrier and will produce less alpha-L-iduronidase than an individual with two normal copies of the gene. The reduced production of the enzyme, however, is sufficient for normal function and the person should not show any symptoms of the disease.

Features

The condition is marked by progressive deterioration, hepatosplenomegaly, dwarfism and gargoyle-like faces. There is a progressive mental retardation, with death frequently occurring by the age of 10 years.

Developmental delay is evident by the end of the first year, and patients usually stop developing between ages 2 and 4. This is followed by progressive mental decline and loss of physical skills. Language may be limited due to hearing loss and an enlarged tongue. In time, the clear layers of the cornea become clouded and retinas may begin to degenerate. Carpal tunnel syndrome (or similar compression of nerves elsewhere in the body) and restricted joint movement are common.

Affected children may be quite large at birth and appear normal but may have inguinal (in the groin) or umbilical (where the umbilical cord passes through the abdomen) hernias. Growth in height may be initially faster than normal, then begins to slow before the end of the first year and often ends around age 3. Many children develop a short body trunk and a maximum stature of less than 4 feet. Distinct facial features (including flat face, depressed nasal bridge, and bulging forehead) become more evident in the second year. By age 2, the ribs have widened and are oar-shaped. The liver, spleen and heart are often enlarged. Children may experience noisy breathing and recurring upper respiratory tract and ear infections. Feeding may be difficult for some children, and many experience periodic bowel problems. Children with Hurler syndrome often die before age 10 from obstructive airway disease, respiratory infections, or cardiac complications.

There is some clinical similarity with Hunter syndrome.

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.

Treatment

Enzyme replacement therapies are currently in use, BioMarin Pharmaceutical provides therapeutics for mucopolysaccaradosis type I (MPS I), by manufacturing Aldurazyme® (commercialized by Genzyme Corporation). Enzyme replacement therapy has proven useful in reducing non-neurological symptoms and pain.

Bone marrow transplantation (BMT) and umbilical cord blood transplantation (UCBT) can successfully treat the mucopolysaccharidoses. Abnormal physical characteristics, except for those affecting the skeleton and eyes, can be improved, and neurologic degeneration can often be halted. BMT and UCBT are high-risk procedures with high rates of morbidity and mortality. However, they are the only treatments that have the potential to cure the disease.

Epidemiology

Hurler syndrome has an overall frequency of ca. 1 per 115,000 population.

References

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