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.
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.