Hurler syndrome (Mucopolysaccharidosis Type I, or MPS I-H) is a rare, progressive, inherited disorder belonging to the group of lysosomal storage diseases. The condition occurs because the body lacks the specific enzyme needed to break down complex sugar molecules called glycosaminoglycans (GAGs). Without this enzyme, GAGs accumulate within the cell’s lysosomes, causing cellular dysfunction and widespread tissue damage. This buildup leads to the progressive deterioration of multiple organ systems, including the skeletal system, heart, and central nervous system, often beginning in infancy. Early diagnosis and intervention are important because the condition progresses rapidly without treatment, affecting both physical health and cognitive development.
The Genetic Basis of Hurler Syndrome
Hurler syndrome is an autosomal recessive disorder, meaning a child must inherit two non-working copies of the responsible gene, one from each parent, to be affected. The IDUA gene, located on chromosome 4, provides the instructions for making the lysosomal enzyme alpha-L-iduronidase.
A deficiency of this enzyme prevents cells from properly dismantling glycosaminoglycans (GAGs), specifically dermatan sulfate and heparan sulfate. This leads to the toxic storage of these molecules inside the cell’s lysosomes. Over 200 different mutations in the IDUA gene have been identified that cause this enzyme deficiency.
The accumulation of GAGs causes the lysosomes to swell, leading to cellular damage and death throughout the body. Parents who carry one copy of the mutated gene are typically asymptomatic. The estimated frequency of MPS I, which includes Hurler syndrome, is about 1 in 100,000 newborns.
Clinical Manifestations and Progression
While infants with Hurler syndrome may appear normal at birth, symptoms typically emerge during the first year of life and progress rapidly. Early signs often include an enlarged liver and spleen (hepatosplenomegaly) and umbilical or inguinal hernias. Developmental delays become noticeable by the age of one, and cognitive decline is a distinguishing feature of the severe Hurler form.
The progressive buildup of GAGs severely affects the skeletal system, leading to abnormalities known as dysostosis multiplex. This results in short stature, an abnormally curved spine (kyphosis or scoliosis), and joint stiffness, often causing a characteristic “claw hand” deformity. Distinctive coarse facial features also become apparent, characterized by a large head, a flattened nasal bridge, enlarged lips, and widely spaced eyes.
Systemic involvement is extensive, particularly affecting the cardiovascular and respiratory systems. GAG deposits in the heart valves lead to thickening and dysfunction, which can cause valvular regurgitation and heart failure. Airway obstruction is common due to GAG accumulation in the throat and lungs, contributing to frequent respiratory infections and sleep apnea. Accumulation in the eyes causes clouding of the cornea, which impairs vision.
Neurological problems are a major component of the severe Hurler phenotype, including the progressive loss of previously acquired motor and intellectual skills. Some children may develop hydrocephalus, a buildup of cerebrospinal fluid around the brain, which places pressure on the central nervous system. Without therapeutic intervention, the progressive organ damage and neurological decline often result in a short lifespan, with many affected individuals not surviving past the first decade of life.
Diagnostic Procedures and Screening
The early detection of Hurler syndrome is paramount for improving long-term outcomes, leading many regions to implement newborn screening for MPS I. This screening involves a blood test performed shortly after birth that looks for absent or reduced alpha-L-iduronidase enzyme activity. While this initial test indicates a risk, it requires further confirmatory testing to establish a definitive diagnosis.
Initial biochemical testing involves measuring the levels of glycosaminoglycans (GAGs) excreted in the urine. Elevated GAG levels, particularly of dermatan sulfate and heparan sulfate, suggest a mucopolysaccharidosis. However, urinary GAG analysis is considered a screening tool, as false negative results can occur, and it does not specify the exact type of MPS.
The definitive diagnosis relies on enzyme activity assays, which are the gold standard. These tests precisely measure the level of alpha-L-iduronidase activity in white blood cells (leukocytes) or cultured skin cells (fibroblasts). A significantly reduced or absent enzyme level confirms the diagnosis of MPS I. Genetic testing through sequencing of the IDUA gene can also be performed to identify specific mutations, providing molecular confirmation and aiding in carrier status determination.
Current Treatment and Management Strategies
The current therapeutic approach aims to slow disease progression, manage symptoms, and introduce the missing enzyme. Primary treatment is Enzyme Replacement Therapy (ERT), involving the weekly intravenous infusion of laronidase, a manufactured form of the alpha-L-iduronidase enzyme. ERT helps cells break down stored GAGs and improves physical symptoms, such as liver and spleen enlargement and respiratory function. However, the intravenously delivered enzyme cannot effectively cross the blood-brain barrier, making ERT ineffective in preventing the progressive cognitive decline associated with the severe Hurler form.
For severe Hurler syndrome, Hematopoietic Stem Cell Transplantation (HSCT), or bone marrow transplantation, remains the standard of care to preserve neurological function. HSCT replaces the patient’s defective blood-forming stem cells with healthy donor cells that produce the functional enzyme. When performed early, ideally before two years of age, HSCT can stabilize cognitive development and improve somatic features. This procedure requires intensive chemotherapy and carries risks, including graft-versus-host disease.
Symptomatic and supportive care addresses widespread organ damage. This includes monitoring heart valve problems, performing surgery for skeletal issues like carpal tunnel syndrome, and providing physical therapy to maintain joint mobility. Research is ongoing into alternative treatments, such as gene therapy, which aims to provide a permanent source of the correct enzyme by delivering a functional copy of the IDUA gene into the patient’s cells. Early clinical trials for gene therapy have shown promise in achieving high enzyme activity and normalizing GAG levels, potentially offering a less invasive alternative to HSCT.