Hurler syndrome

Overview

Hurler syndrome, also known as mucopolysaccharidosis type I (MPS I H), is a rare inherited lysosomal storage disorder caused by a deficiency of the enzyme alpha-L-iduronidase. This enzyme is crucial for breaking down glycosaminoglycans (GAGs), specifically dermatan sulfate and heparan sulfate. Without functional alpha-L-iduronidase, these substances accumulate in cells, leading to progressive damage affecting multiple organs, including the skeleton, heart, eyes, and central nervous system. Hurler syndrome is the most severe form of MPS I and typically presents in infancy.

Causes

Hurler syndrome is caused by mutations in the IDUA gene, which encodes the enzyme alpha-L-iduronidase. The condition is inherited in an autosomal recessive pattern, meaning a child must inherit two copies of the mutated gene—one from each parent—to be affected. The genetic defect results in little to no enzyme activity, leading to the accumulation of glycosaminoglycans in various tissues and organs throughout the body.

Symptoms

Symptoms of Hurler syndrome typically begin in the first year of life and progressively worsen over time. Common features include:

• Coarse facial features (flat nasal bridge, thick lips, enlarged tongue)

• Developmental delay and cognitive impairment

• Enlarged liver and spleen (hepatosplenomegaly)

• Hearing loss

• Corneal clouding leading to vision problems

• Skeletal abnormalities (dysostosis multiplex)

• Joint stiffness and limited mobility

• Short stature and growth delays

• Frequent respiratory infections and obstructive airway disease

Without treatment, the condition leads to severe intellectual disability, organ failure, and early death, often by the age of 10.

Diagnosis

Early diagnosis is critical for effective intervention. Diagnostic procedures include:

• Urine tests: Elevated levels of glycosaminoglycans (dermatan sulfate and heparan sulfate)

• Enzyme assay: Measurement of alpha-L-iduronidase activity in blood or skin fibroblasts

• Genetic testing: Identification of mutations in the IDUA gene to confirm the diagnosis

• Imaging studies: X-rays to evaluate skeletal abnormalities

• Ophthalmologic and audiologic assessments: To detect vision and hearing impairments

Newborn screening programs are available in some countries and can lead to early detection before symptoms develop.

Treatment

Although there is no cure for Hurler syndrome, early treatment can significantly improve quality of life and survival. Current treatment options include:

• Hematopoietic Stem Cell Transplantation (HSCT): The only treatment that can halt neurological decline if performed early

• Enzyme Replacement Therapy (ERT): Laronidase (Aldurazyme) helps reduce non-neurological symptoms but does not cross the blood-brain barrier

• Surgical interventions: Including hernia repair, corneal transplant, and treatment of airway obstruction

• Supportive therapies: Physical therapy, special education, and respiratory support as needed

Multidisciplinary care is essential, involving geneticists, neurologists, cardiologists, orthopedists, and other specialists.

Prognosis

The prognosis for individuals with Hurler syndrome depends on the timing and type of treatment received. Without intervention, life expectancy is severely reduced, with most patients not surviving beyond the first decade of life due to cardiac or respiratory failure. However, early stem cell transplantation combined with enzyme replacement therapy can improve survival and preserve organ function, especially when administered before significant symptoms develop. Lifelong monitoring and supportive care remain crucial.