Hurler Syndrome

Hurler Syndrome (also known as mucopolysaccharidosis I, MPS I, or gargoylism) is an inherited lysosomal storage disorder. The disease is caused by a genetic mutation that leads to a deficiency in the enzyme α-L-iduronidase (IDUA). There are three forms of the disease; Hurler, Hurler-Scheie, and Scheie Syndromes. This website focuses on Hurler Syndrome, the most severe form of the disease.

The inherited genetic mutation that causes Hurler Syndrome is located on the IDUA gene on chromosome 4. Over 50 mutations of the IDUA gene have been shown to cause the disease, but the most common mutations affect the 70^th or 420^th amino acid of α-L-iduronidase. IDUA catalyzes a reaction that produces l-iduronic acid. Its substrates (starting materials) are the glycosaminoglycans (GAGs) heparan sulfate and dermatan sulfate. In the disease state, the protein displays limited functionality which results in the buildup of GAGs in the lysosome (the compartment in the cell where the reaction takes place).  In other words, because the enzyme does not function, the starting materials accumulate in the body’s cells. This buildup leads to symptoms across many body symptoms, including (but not limited to) stiff joints, coarse facial features, hepatosplenomegaly, and mental retardation. Left untreated, Hurler Syndrome is usually fatal by the age of 10 (Matte et al, 2003).

Currently, there are three prevalent forms of treatment. One strategy involves hematopoietic stem cell transplantation. Donor stem cells that are able to make healthy α-L-iduronidase are introduced into the Hurler Syndrome patient, where they are able to multiply and provide the patient with functioning enzyme. When successful, stem cell transplantation can extend life for decades. Unfortunately, due to the high variations in disease-causing mutations, the success of transplantation is highly variable (Aldenhoven et al, 2008).

Another treatment is enzyme replacement therapy (ERT), in which non-mutant enzyme is pumped into the body intravenously. Historically, ERT has been thought to be limited by the blood brain barrier blocking protein from accessing the central nervous system. Recently, researchers have shown in a mouse model that repeated high doses of enzyme can be successful in improving the metabolic health of the spleen, liver, and central nervous system (Ou et al, 2014).

A final treatment option is gene therapy, wherein non-mutated copies of the IDUA gene are introduced into Hurler Syndrome patients. This treatment is still in experimental stages, but researches hypothesize that intrathecal gene therapy can correct the defects of the central nervous system and offer a safer, less invasive option than enzyme replacement therapy. Most recently, successful trials of intrathecal gene therapy were carried out in feline models, where Hurler Syndrome manifestations in the central nervous system were corrected. The authors indicated that their results could lead to human trials of the therapy (Hinderer et al, 2014).

| History and Metabolic Context | Molecular Basis of the Disease State | Treatments and Disease Management | Conclusions and Proposals for Future Work | Annotated Bibliography |

• Aldenhoven, M., Boelens, J., de Koning, T.J., 2008. The Clinical Outcome of Hurler Syndrome after Stem Cell Transplantation. Biology of Blood and Marrow Transplant 14, 485–498. doi:10.1016/j.bbmt.2008.01.009
• Hinderer, C., Bell, P., Gurda, B.L., Wang, Q., Louboutin, J.-P., Zhu, Y., Bagel, J., O’Donnell, P., Sikora, T., Ruane, T., Wang, P., Haskins, M.E., Wilson, J.M., 2014. Intrathecal Gene Therapy Corrects CNS Pathology in a Feline Model of Mucopolysaccharidosis I. Molecular Therapy 22, 2018–2027. doi:10.1038/mt.2014.135
• Matte, U., Yogalingam, G., Brooks, D., Leistner, S., Schwartz, I., Lima, L., Norato, D.Y., Brum, J.M., Beesley, C., Winchester, B., Giugliani, R., Hopwood, J.J., 2003. Identification and characterization of 13 new mutations in mucopolysaccharidosis type I patients. Molecular Genetics and Metabolism 78, 37–43. doi:10.1016/S1096-7192(02)00200-7
• Ou, L., Herzog, T., Koniar, B.L., Gunther, R., Whitley, C.B., 2014. High-dose enzyme replacement therapy in murine Hurler syndrome. Molecular Genetics and Metabolism 111, 116–122. doi:10.1016/j.ymgme.2013.09.008