Mucopolysaccharidosis Type I · MPS I

Description

Mucopolysaccharidosis type I, MPS I, is an autosomal recessive lysosomal storage disorder caused by deficiency of alpha-L-iduronidase. The enzyme is encoded by IDUA on chromosome 4p16.3. Reduced enzyme activity leaves dermatan sulfate and heparan sulfate, two glycosaminoglycans, undegraded inside lysosomes. Storage accumulates across connective tissue, bone, viscera, eye, heart, airway, and central nervous system over months to years.

Clinicians describe the condition as a continuous spectrum across three historical phenotypes. Hurler syndrome is the severe end and presents in the first year of life with coarsening facial features, hepatosplenomegaly, recurrent ear and airway infections, corneal clouding, joint stiffness, dysostosis multiplex on skeletal radiographs, cardiac valve disease, and progressive cognitive decline. Hurler-Scheie is the intermediate phenotype with later onset and slower progression. Scheie is the attenuated end with normal cognition and somatic disease that may not be recognized until later childhood or adulthood. Pooled live-birth incidence across Western newborn screening and registry data is approximately 1 in 100,000, with severe Hurler accounting for roughly half of cases.

Detection is by newborn screening on the dried blood spot. Programs measure alpha-L-iduronidase activity by tandem mass spectrometry or fluorometry, then reflex to a glycosaminoglycan or biomarker assay and IDUA gene sequencing. The condition was added to the Recommended Uniform Screening Panel in February 2016. A central diagnostic challenge is phenotype assignment in a presymptomatic infant; genotype, residual enzyme activity, and urinary glycosaminoglycan profile inform whether the child is on the severe or attenuated trajectory. The decision drives treatment choice and timing.

Treatments to date

Two disease-specific therapies are in routine use. Hematopoietic stem cell transplant from an allogeneic donor halts central nervous system disease progression in severe Hurler when performed early. Outcome data from the international consortium published by Aldenhoven and colleagues in Blood in 2015 establish that transplant before 18 to 24 months of age, ideally before 9 months, gives the best cognitive and somatic outcomes. Transplant does not reverse established skeletal disease, corneal clouding, or valvular changes, and orthopedic surgery, ophthalmologic care, and cardiology follow-up continue lifelong.

Laronidase, a recombinant human alpha-L-iduronidase, was approved by the FDA in April 2003 as enzyme replacement therapy. It is given by weekly intravenous infusion. Laronidase reduces hepatosplenomegaly, improves endurance and joint range of motion, and lowers urinary glycosaminoglycan excretion. The molecule does not cross the blood-brain barrier at standard intravenous doses, so laronidase addresses non-central-nervous-system manifestations and is the standard pharmacologic option for attenuated MPS I. In severe Hurler disease, laronidase is often used as a bridge to transplant to reduce somatic disease burden before conditioning.

Several investigational approaches target the central nervous system gap. Intrathecal laronidase has been studied in clinical trials for cognitive and spinal cord disease. Ex vivo lentiviral hematopoietic stem cell gene therapy programs have reported early data, with the goal of producing supraphysiologic enzyme from engrafted cells that cross-corrects neurons. AAV-delivered IDUA gene therapy and substrate reduction strategies are also in development. None has reached FDA approval as of May 2026.

Supportive care across the spectrum includes airway management, hearing aids, cardiac valve surveillance and surgery, hydrocephalus monitoring, cervical spine imaging, orthopedic procedures for hip dysplasia and carpal tunnel syndrome, and physical and occupational therapy. Multidisciplinary metabolic clinics coordinate this care alongside the family.