Structural Biochemistry/Hurler Syndrome and Treatment

Hurler Syndrome
Hurler syndrome is an inherited disease that associates with storage and urinary excretion of mucopolysaccharides dermatan sulfate and heparin sulfate. People who get Hurler syndrome cannot break down long sugar molecules called mucopolysaccharides or glycosaminoglycans – GAGs – due to alpha-L-iduronidase deficiency, a lysosomal enzyme responsible for degradation of glycosaminoglycans. GAGs can build up in the lysosomes of the brain, heart, liver, bones and other organs of the body.The accumulation of GAGs in human body results in damages to organs.

Symptoms
Child with Hurler syndrome appears normal at birth. The symptoms start to appear between 6 months and 2 years of age and most often between ages 3 and 8. Most people with Hurler syndrome can not survive beyond age 10.
 * Abnormal bones
 * Cloudy corneas
 * Deafness
 * Short stature
 * Heart diseases
 * Joint disease, including stiffness
 * Mental retardation
 * Thick, coarse facial features, i.e. Low nose bridge, flat face, large head
 * Enlarged liver and spleen
 * Diarrhea
 * Breathing difficulties and snoring

Treatment
A therapy called enzyme replacement was developed to tackle Hurler syndrome. Alpha-L-iduronidase cDNA in human and canine was used to made recombinant enzyme in Chinese hamster ovary cells. These cells secreted alpha-L-iduronidase with mannose 6-phosphate signal. Mannose 6-phosphate is a carbohydrate modification, which inhibits alpha-L-iduronidase uptake. The recombinant enzyme was tested in alpha-L-iduronidase-deficient dogs. It degraded GAGs from many organs in both short term and long term experiment. The recombinant enzyme was later tested on human and approved by FDA in 2003.

Even though having been proven to be effective, the enzyme replacement treatment has some limitations. Not all tissues are equally correctible. Mucopolysaccharides stored in central nervous system are not accessible by the enzyme due to the blood-brain barrier. Lastly, enzyme replacement treatment is very costly, about half a million dollars a year.

Another therapy for Hurler syndrome, transplantation of hematopoietic stem cells, is available. This method helps maintain the normal mental development. The therapy is only effective if it is performed early enough in life. Another limitation of this treatment is that it is risky.