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Hurler syndrome

Mucopolysaccharidosis type I, MPS I, Hurler's disease, Gargoylism

Overview

Hurler syndrome (mucopolysaccharidosis type I, MPS I, Hurler's disease, gargoylism), is a genetic disorder that results in the buildup of glycosaminoglycans (formerly known as mucopolysaccharides) due to a deficiency of alpha-L iduronidase, an enzyme responsible for the degradation of mucopolysaccharides in lysosomes. Without this enzyme, a buildup of heparan sulfate and dermatan sulfate occurs in the body. 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 α-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 syndrome is often classified as a lysosomal storage disease, and is clinically related to Hunter Syndrome. Hunter syndrome is X-linked while Hurler syndrome is autosomal recessive.

It is named for Gertrud Hurler (1889–1965), a German pediatrician

Symptoms - Hurler syndrome

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Causes - Hurler syndrome

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 non-working copies of the IDUA gene. If someone is born with one normal and one defective copy of the gene (s)he is called a carrier and will produce less α-L-iduronidase than an individual with two normal copies of the gene. The slightly reduced production of the enzyme in carriers, however, remains sufficient for normal function and the person should not show any symptoms of the disease.

Prevention - Hurler syndrome

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Diagnosis - Hurler syndrome

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 - Hurler syndrome

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Treatment - Hurler syndrome

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

Bone marrow transplantation (BMT) and umbilical cord blood transplantation (UCBT) can be used as treatments for MPS. 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. There is no cure for MPS I.

Gene therapy

There is currently a great deal of interest in treating MPS I with gene therapy. This approach has been taken with retroviral, lentiviral, AAV, and even nonviral vectors to deliver the iduronidase gene. Successful treatment of the mouse, dog, and cat models of MPS I has occurred and may pave the way for future human trials.

Resources - Hurler syndrome

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