Hurler Syndrome – History and Metabolic Context

Hurler Syndrome (also known as Mucopolysaccharidosis I, MPS I, or Hurler’s disease) is an autosomal recessive lysosomal storage disorder. People with the disease have a dysfunctional version of the lysosomal enzyme α-L-Iduronidase (IDUA). IDUA catalyzes a hydrolysis reaction that separates L-iduronic acid (IdoA) from long, unbranched chains of the glycosaminoglycans (GAGs, also known as mucopolysaccharides) heparan sulfate and dermatan sulfate. IDUA is one of several enzymes in the GAG catabolic pathway; with a dysfunctional enzyme, the GAGs accumulate in the lysosomes across the body. As a result, cells swell and become more rigid. These swelling effects ultimately translate to the tissue and organ levels across several body systems (Herati et al. 2008).

A number of mutations in the IDUA gene (which codes for the 653 amino acid protein and is found on chromosome 4p16.3) have been found to cause Hurler syndrome, and more are being reported every year.   There is no single trend in mutation worldwide; the numbers vary from country to country and demographic groups. One of the first mutations published was the W402X (where X is a stop codon), found in 31% of patients in Australia (Scott et al. 1992). In another study, this was also found to be the most common mutation in northern Europe (35%), while only 2.1% of Caucasians had a R89Q mutation. The R89Q mutation, however, is prevalent in 25% of Japanese patients. In Italy, the most common mutation is Q70X (13%), followed by W402X and P533R (11% each), which differs from the northern European trends (Gatti et al. 1997). The Q70X mutation is also the most common mutation found in the Former Soviet Union (Voskoboeva et al. 1998). In Brazil, the most common mutations are W402X and P533R (Matte et al. 2003).

Hurler Syndrome is characterized as the most severe of the mucopolysaccharidosis diseases. The least severe form is Scheie Syndrome. Forms of the disease that are intermediate between these two extremes are classified as Hurler-Scheie syndrome. With so many different mutations (papers still routinely report tens of novel mutations found at a time), the disease is largely diagnosed and classified based on clinical presentation. Patients with certain mutations (W402X and Q70X) have been shown to have no detectable enzyme present (Matte et al. 2003). Clinical diagnosis is based on age of onset, rate of progression, and organs involved (Aldenhoven et al. 2008). Based on the above data that accounts for mutations across multiple countries and ethnic groups, the most significant mutations worldwide include W402X, Q70X, R89Q, and P533R.

 

Table of sample mutations that lead to Hurler Syndrome.  The manifold nature of the mutations that can cause the disease make genotype based diagnosis difficult, so diagnosis typically happens around 9 months of age after clinical presentation.  Source: Terlato et al. 2003.
Table of sample mutations that lead to Hurler Syndrome. The manifold nature of the mutations that can cause the disease make genotype based diagnosis difficult, so diagnosis typically happens around 9 months of age after clinical presentation. Source: Terlato et al. 2003.

As a lysosomal storage disorder, the disease state manifests broadly across many body systems. Symptoms include mental retardation, enlarged/deformed skull and facial features, hepatosplenomegaly, hernias, and shortened joints. The disease typically presents at the age of 6 months and is lethal by age 10 due to multisystem problems including respiratory complications, cardiomyopathies, or myelopathies (Aldenhoven et al. 2008). The incidence of Hurler Syndrome is 1 in 100,000 births. While categorization is often done on the clinical level, formal diagnosis can be confirmed by genetic testing (in utero), blood enzyme activity assay, or by monitoring levels of GAGs in the urine. The broad class of disease symptoms is largely based on the ubiquity of GAGs across the body. Specifically, dermatan sulfate and heparan sulfate are found in the extracellular matrix and in proteoglycans. (Campos et al. 2012). Structurally, GAGs are polymers made up of repeating dimer units. Each dimer is made up of an amino sugar (GlcNAc or GalNAc) and the uronic sugar iduronic acid. Heparan sulfate is broken down in 9 enzymatic steps that each remove a sugar unit; dermatan sulfate in 4.

Symptoms of Hurler Syndrome.  The variety of symptoms across multiple body systems makes early diagnosis challenging.  Source: https://www.lsdregistry.net/mpsiregistry/hcp/understd/mreg_hc_u_aboutmps-1.gif
Symptoms of Hurler Syndrome. The variety of symptoms across multiple body systems makes early diagnosis challenging. Source: https://www.lsdregistry.net/mpsiregistry/hcp/understd/mreg_hc_u_aboutmps-1.gif

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

6 Replies to “Hurler Syndrome – History and Metabolic Context”

  1. What is the global incidence of Hurler Syndrome, and does it vary within certain regions?

    1. Greg – Thanks for reading! The global incidence is consistent with that of the U.S.A., about 1 in 100,000. Depending on the country, I’ve seen numbers from 80-120,000. These variances, however, didn’t correlate to any geographical trend.

  2. Hey Zach, great analysis on an interesting disease. Are there specific markers or presentations that differentiate Scheie from Hurler? I know you mention severity, but is there an objective measure? In addition, do you mean to say that all presentation of Hurler are lethal by age 10, or is that only of they go unmanaged, and furthermore is Scheie lethal as well? Lastly, you said the disease can be diagnosed in utero, and in the Treatments page you note that the mannose-6-phosphate receptor is down-regulated in expression after 2 weeks of life. To your knowledge, there anything that can be done in utero after these two weeks? Are any of the treatment options you outline viable in a fetus?
    Thanks!

    1. Besher – Thanks for commenting! Since I avoided literature that went into too much detail on Scheie, I don’t have a great deal of insight into it. A lot of the symptoms overlap (corneal clouding and stiff joints, for example), but once more severe neurological symptoms present, patients are largely diagnosed as Hurler’s. The fatality at 10 is with treatment as well. Your question about treatment in-utero is a good one; I didn’t see anything in the literature. Because the symptoms present so variably, I think it would be difficult to treat an unborn baby. Enzyme replacement therapy and gene therapy could potentially work before birth, but you can imagine that there are not many trials going on that involve fetus treatments.

  3. Hi Zach! Excellent work, of course. Like Besher, I was wondering about the diagnosis of Hurler’s. You mentioned that it is usually diagnosed based off of clinical presentation. You also mentioned several mutations that are found worldwide that are indicative of Hurler’s. If Hurler’s is the most severe presentation of mucopolysaccharidosis disease, then what technically separates Hurler’s from Scheie syndrome? Are those mutations that you listed only associated with Hurler’s, or are they also associated with the intermediate Hurler-Scheie syndrome?

    In addition, you mention that patients with the W402X and Q70X have no detectable IDUA present. Are these mutations therefore particularly more lethal, and carry a lower life-expectancy? Do these children live to the usual 9-month mark at which a diagnosis can be made?

    Thanks!

    1. Gabbie – I so appreciate your saying “of course”. Just to clarify, the diagnosis begins with the clinical symptoms, but there are biomarkers, like IDUA activity and glucosaminoglycan concentrations in the urine. As I wrote to Bescher, mental retardation is a huge dividing line between Hurler and the less severe forms. A lot of the symptoms can be seen in all forms (or not), and they can also differ in severities (or not). The mutations I focused on here are associated with the most severe form (Hurler’s). The 402 and 70 mutation almost certainly lead to Hurler’s, but the 10 year life expectancy still applies. In lysosomal storage disorders, remember that the issue comes from substrate accumulation; there needs to be time for it all to buildup and cause dysfunction. The issues that are ultimately fatal are usually the manifestations in the heart and lungs.

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