Structural Biochemistry/Hurler Syndrome and Treatments

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

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

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.

Background Info

The Hurler Syndrome was first tackled by a researcher named Elizabeth F. Neufeld in the late 1960s. Initially, Neufeld linked the cause of the disease to the polymers of chondroitin sulfate B and heparitin sulfate, but due to their dissimilar chemical structures, it was very difficult to determine defects. She later hypothesized that excessive synthesis of mucopolysaccharide chains and excess of UDP-glucuronic acid, caused by defective UDP-xylose responses, were the causes. However, she was proven wrong when inhibiting the UDP-glucose dehydrogenase had no effect on the experimental cell culture she set up. Her hypothesis was again proven wrong when she used the radioactivity of (35)SO4 onto macromolecules with high solubility to measure the content of mucopolysaccharides. The mucopolysaccharide content in the cells of a Hurler patient did not decrease, whereas it did with the samples of a normal persons. As a result of these two experiments, Neufeld was later able to conclude that the Hurler syndrome was a lysosomal storage disease caused by the inability of breaking down mucopolysaccharides.

Treatments

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 correctible1. 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, half a million dollars a year1.

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.

References

Neufeld, Elizabeth F. (2011). "From Serendipity to Therapy". Annual Review of Biochemistry. 80: 1–15. doi:10.1146/annurev.biochem.031209.093756. PMID 21675915.
Kakkis, E.D.; Matynia, A.; Jonas, A.J.; Neufeld, E.F. (1994). "Overexpression of the Human Lysosomal Enzyme α-L-Iduronidase in Chinese Hamster Ovary Cells". Protein Expression and Purification. 5 (3): 225–32. doi:10.1006/prep.1994.1035. PMID 7950365.
http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002184/
Scott, H. S.; Ashton, L. J.; Eyre, H. J.; Baker, E; Brooks, D. A.; Callen, D. F.; Sutherland, G. R.; Morris, C. P.; Hopwood, J. J. (1990). "Chromosomal localization of the human alpha-L-iduronidase gene (IDUA) to 4p16.3". American journal of human genetics. 47 (5): 802–7. PMC 1683689. PMID 2220820.
Stoltzfus, L. J.; Sosa-Pineda, B; Moskowitz, S. M.; Menon, K. P.; Dlott, B; Hooper, L; Teplow, D. B.; Shull, R. M.; Neufeld, E. F. (1992). "Cloning and characterization of cDNA encoding canine alpha-L-iduronidase. MRNA deficiency in mucopolysaccharidosis I dog". The Journal of biological chemistry. 267 (10): 6570–5. PMID 1551868.
http://medschool.ucsf.edu/lysosomal/hurler/