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 70th or 420th 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).


This image shows the reaction catalyzed by alpha-L-iduronidase.
This image shows the reaction catalyzed by alpha-L-iduronidase.  Sources: images on the left from Google Images.  Enzyme structure from Bie et al. 2013 .  Structures and arrangement are my own.
Diagram of common symptoms of Hurler Syndrome
Diagram of common symptoms of Hurler Syndrome.  Source:

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




8 Replies to “Hurler Syndrome”

  1. Very well written, easy to understand with 0 science background. All of the words I did not know there was a definition for. I would be surprised if someone can’t understand the article.
    Good job Zachary

  2. Overall, very understandable for the lay person. I would say that the 2nd paragraph might need further clarification for someone without a science background. The catalytic reaction and the role of its substrates was a little unclear to me, but did not keep me from understanding the article as a whole.

    1. Lorri – Thank you for the insightful comment. I added a sentence and a few additional phrases to clarify that second paragraph. Additionally, I replaced one of the images on the page with a new one that I created. I hope that the new image clears up where the GAGs are in the body and what is happening at the level of the molecule. Let me know what you think / if there is anything I can do to make it clearer!

  3. This article was very easy to read and understand. Although there were terms that I was unfamiliar with, they were always linked and explained clearly. Overall, very informative! Thank you!

  4. Thanks for teaching us about Hurler Syndrome! This was great, really enjoyed hearing the details about the genetic basis for the disease. Glad you went through 3 potential therapeutic options as well. Which do you think is most promising today?

    One question I went on to look up was the purpose of the iduronidase reaction in the first place. It appears it’s really a first step in GAG catabolism? You explained that the deficiency causes a buildup, so that makes sense 🙂

  5. John – Thanks for reading! I think of the therapy options, the bone marrow transplant is the most promising. Enzyme replacement therapy works well enough too; the real issue is early diagnosis in order for treatment to work. Based on how rare the disease is, I don’t think much resource is going into Hurler-specific cures. I imagine that if gene therapy is shown to be very successful in the context of a more “high profile” disease, it will probably be adapted for Hurler Syndrome later. In regards to your second comment, I am linking you here to a KEGG pathway illustrate how early on the IDUA reaction is. It’s enzyme number is 3.21.76, and it’s highlighted in red for the heparan sulfate pathway (it also appears dermatan sulfate pathway).

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