MPS I is a rare, inherited condition belonging to the group of lysosomal storage diseases (LSDs). This progressive genetic disorder affects numerous body systems, including the skeletal, respiratory, and central nervous systems. The severe form is estimated to affect approximately one in every 100,000 newborns. MPS I is a complex, multisystem condition characterized by a wide spectrum of severity across affected individuals.
The Underlying Enzyme Deficiency
The root cause of MPS I is a genetic fault preventing the body from breaking down certain complex sugar molecules. It is inherited in an autosomal recessive pattern, meaning a child must receive a non-working copy of the responsible gene from each parent. The faulty IDUA gene provides instructions for creating the alpha-L-iduronidase enzyme.
This enzyme is crucial for lysosomes, the cell’s “recycling centers.” When the enzyme is absent or deficient, it cannot degrade large sugar molecules called glycosaminoglycans (GAGs). Specifically, dermatan sulfate and heparan sulfate accumulate. This progressive buildup of GAGs within the lysosomes causes the organelles to swell and become dysfunctional, leading to tissue expansion, organ dysfunction, and the clinical symptoms of MPS I.
Recognizing the Different Subtypes
MPS I exists along a continuous clinical spectrum, traditionally categorized into three distinct subtypes reflecting severity and progression.
Hurler Syndrome (MPS I-H)
This is the most severe form, typically manifesting symptoms early in life, often within the first year. Children experience rapid progression, displaying developmental delay, coarsened facial features, and severe skeletal abnormalities (dysostosis multiplex). Untreated, this subtype leads to significant cognitive impairment and a dramatically shortened lifespan, often less than ten years.
Scheie Syndrome (MPS I-S)
This is the mildest form, with a much later onset, often presenting after five years or in adulthood. Individuals generally maintain normal intellectual development and stature. Symptoms primarily involve joint stiffness, corneal clouding, carpal tunnel syndrome, and aortic valve disease.
Hurler–Scheie Syndrome (MPS I H-S)
This intermediate phenotype typically presents in children between three and eight years of age, often with normal or near-normal intelligence. Physical manifestations, such as joint stiffness and corneal opacities, are more pronounced than in Scheie Syndrome but less severe than in Hurler Syndrome.
Identifying the Condition
Early and accurate diagnosis of MPS I is beneficial, as timely intervention significantly improves outcomes. Diagnosis often begins with a preliminary screen for accumulated GAGs. A urine test measures the level of GAGs excreted, with elevated levels indicating a lysosomal storage disorder.
Definitive diagnosis relies on specific biochemical and genetic testing. An enzyme assay measures the activity of the alpha-L-iduronidase enzyme, typically in blood cells or cultured fibroblasts. Low or absent enzyme activity confirms the biochemical diagnosis of MPS I.
Many regions now include MPS I in newborn screening programs, testing enzyme activity from a dried blood spot shortly after birth. This proactive screening identifies affected infants before symptoms appear. Genetic testing, sequencing the IDUA gene, confirms the mutation and helps distinguish carriers from affected individuals.
Current Treatment Strategies
Management of MPS I is a complex, multi-disciplinary effort focused on providing the missing enzyme or replacing defective cells to mitigate progressive damage. Enzyme Replacement Therapy (ERT) involves the weekly intravenous infusion of laronidase, a synthetic version of the alpha-L-iduronidase enzyme. ERT is effective at clearing accumulated GAGs from many organs and tissues, improving non-neurological symptoms like heart function and respiratory issues. However, the infused enzyme does not effectively cross the blood-brain barrier, limiting its ability to prevent cognitive decline.
For patients with severe Hurler Syndrome, Hematopoietic Stem Cell Transplantation (HSCT), or bone marrow transplant, is the standard of care. If performed early (ideally before two and a half years of age), HSCT provides a permanent source of functional enzyme capable of entering the central nervous system. A successful transplant stabilizes cognitive development and prevents systemic effects.
Supportive care addresses specific symptoms, including orthopedic surgeries for skeletal deformities, physical therapy for joint mobility, and cardiac monitoring for heart valve disease. Research continues into advanced treatments, with ongoing clinical trials investigating gene therapies that aim to deliver a functional copy of the IDUA gene directly to the central nervous system.