Mucopolysaccharidosis Type I

Mucopolysaccharidosis Type I results from mutations in the IDUA gene encoding alpha-L-iduronidase, leading to inability to break down heparan sulfate and dermatan sulfate. These glycosaminoglycans accumulate in lysosomes throughout the body, causing progressive cellular dysfunction. The three clinical phenotypes reflect the degree of enzyme deficiency: severe Hurler form has minimal enzyme activity, Hurler-Scheie has intermediate activity, and Scheie has near-normal enzyme activity with limited tissue involvement. Disease manifestations reflect GAG accumulation in different tissues: skeletal tissue causes bone dysostosis, brain accumulation causes cognitive decline, connective tissue accumulation causes joint stiffness, and cardiac valve involvement can lead to heart disease. Hurler syndrome, the most severe form, presents in early childhood with progressive coarse facial features, growth failure, developmental delay or regression, organomegaly, and progressive skeletal deformities. Cardiac involvement includes valve disease leading to heart failure. Respiratory involvement develops from upper airway narrowing and lung disease. Hearing loss is progressive. Intellectual disability becomes increasingly apparent in the second and third year of life. Without treatment, Hurler syndrome is life-limiting, with most patients dying by the second to third decade from cardiac or respiratory complications. Scheie and Hurler-Scheie forms progress more slowly and typically have normal or near-normal intelligence.