Mucopolysaccharidosis Type I (MPS 1) is a rare, inherited metabolic disorder classified as a lysosomal storage disorder. This condition affects the body’s ability to break down complex sugar molecules. The disorder involves the progressive accumulation of these large sugar molecules, called glycosaminoglycans (GAGs). This buildup of GAGs inside the body’s cells leads to widespread damage across multiple tissues and organs, causing a variety of physical and developmental problems.
The Specific Genetic Cause
The underlying cause of MPS 1 is a mutation in the IDUA gene, located on chromosome 4. This gene provides instructions for producing the enzyme alpha-L-iduronidase. The primary function of this enzyme is to break down the GAGs dermatan sulfate and heparan sulfate within the cell’s lysosomes.
When the IDUA gene is mutated, the resulting enzyme is either non-functional or produced in severely reduced amounts. This deficiency prevents the proper degradation of GAGs, causing them to accumulate and swell the lysosomes. This progressive storage disrupts normal cell function and leads to the damage observed in tissues throughout the body.
MPS 1 is inherited in an autosomal recessive pattern. A child must inherit a non-working copy of the IDUA gene from both parents to be affected. Individuals with only one mutated copy are carriers and typically do not exhibit symptoms. When both parents are carriers, there is a 25% chance with each pregnancy that their child will develop MPS 1.
Recognizing the Different Forms
MPS 1 is categorized into three clinical forms based on enzyme activity and disease progression: Hurler syndrome, Hurler-Scheie syndrome, and Scheie syndrome.
Hurler Syndrome
Hurler syndrome is the most severe presentation, typically manifesting within the first year or two of life and involving rapid deterioration. Children often experience significant neurological decline, marked developmental delay, and severe skeletal abnormalities. Common physical signs include coarse facial features, corneal clouding, heart valve damage, and an enlarged liver and spleen. Without intervention, life expectancy is often limited to late childhood.
Scheie Syndrome
Scheie syndrome is the mildest form, sometimes referred to as the attenuated form. Symptoms typically have a much later onset, sometimes appearing in early adulthood, and patients generally maintain normal cognitive function. Although lacking severe neurological involvement, Scheie syndrome can still cause significant somatic issues, such as stiff joints, carpal tunnel syndrome, and corneal clouding.
Hurler-Scheie Syndrome
Hurler-Scheie syndrome represents the intermediate form. Individuals usually maintain normal or near-normal intellect but experience more pronounced physical problems than those with Scheie syndrome. Physical symptoms, such as heart disease and skeletal issues, progress more slowly than in Hurler syndrome, allowing these individuals to typically live into adulthood.
How MPS 1 is Diagnosed
Diagnosis of MPS 1 often begins with newborn screening programs that measure the activity of the alpha-L-iduronidase enzyme in a blood spot. Low enzyme activity indicates the need for further testing, but does not confirm the disease. Early detection is important because starting treatment before symptoms appear can significantly improve long-term outcomes.
A traditional diagnostic step involves a urine test to measure GAG levels, specifically dermatan sulfate and heparan sulfate. While high GAG levels support the diagnosis, this test is not definitive. The most definitive step is a quantitative enzyme assay, which measures alpha-L-iduronidase activity in blood cells or cultured skin fibroblasts to confirm the enzyme deficiency.
Final confirmation is achieved through genetic testing, which involves sequencing the IDUA gene to identify two pathogenic mutations. This analysis helps predict disease severity and guides treatment decisions. A clinical assessment by a specialist, including a physical examination and imaging studies, evaluates the extent of organ and skeletal involvement.
Current Management and Therapies
Management of MPS 1 focuses on slowing disease progression and alleviating symptoms. Primary intervention strategies depend heavily on disease severity, particularly the extent of central nervous system (CNS) involvement. Two major therapeutic approaches treat the underlying enzyme deficiency.
Enzyme Replacement Therapy (ERT)
ERT involves weekly intravenous infusions of a synthetic enzyme called laronidase (Aldurazyme). ERT effectively treats non-neurological symptoms, such as improving walking capacity, pulmonary function, and reducing liver size. However, laronidase cannot effectively cross the blood-brain barrier (BBB), meaning it cannot treat the cognitive decline and neurological issues associated with severe Hurler syndrome.
Hematopoietic Stem Cell Transplantation (HSCT)
HSCT is the standard treatment for severe Hurler syndrome, especially when performed in children under two years old. This procedure replaces the patient’s immune system with donor stem cells that produce the missing alpha-L-iduronidase enzyme. Successful HSCT stabilizes cognitive function and reduces mortality by protecting the brain, heart, and lungs from progressive damage.
HSCT is a high-risk procedure requiring intensive chemotherapy and carrying risks like graft-versus-host disease. For severe cases, a combination approach is often used, where a patient receives short-term ERT to stabilize their condition before undergoing HSCT. Supportive care remains a necessary complement for all forms of MPS 1, including:
- Physical therapy
- Pain management
- Surgical procedures for skeletal issues
- Surgical procedures for cardiac issues