MPS I is caused by deficiency of a lysosomal enzyme responsible for the degradation of glycosaminoglycans, leading to progressive substrate accumulation in cells and tissues. No causative gene is certified in the current source packet's gene list, though GeneReviews genotype-phenotype descriptions confirm that enzyme activity levels correlate closely with disease severity. Complete loss of lysosomal enzyme activity is associated with the severe form of MPS I, while partial residual activity is associated with attenuated disease. Compound heterozygosity and homozygosity for pathogenic variants are both recognized configurations in MPS I. GeneReviews describes data from the international MPS I registry involving hundreds of individuals, confirming the close correlation between genotype and phenotypic severity as the basis for predicting disease course. MPS I is inherited in an autosomal recessive pattern, consistent with the disease definition, meaning individuals must inherit two pathogenic variants—one from each biological parent—to be affected. Carrier individuals who carry one pathogenic variant are typically unaffected.

Diagnosis of MPS I involves evaluation of lysosomal enzyme activity, and GeneReviews notes that enzyme activity measurement from dried blood spots is the most common initial screening approach in the United States, though the approach to newborn screening for MPS I is described as currently in evolution. Newborn screening for MPS I is not yet universally established, and state programs vary. Review by a metabolic physician or biochemical geneticist is described in GeneReviews as a key component of the evaluation protocol following diagnosis. Molecular genetic testing is also a component of the diagnostic evaluation for MPS I, as described in GeneReviews. The diagnostic evaluation addresses both the identification of MPS I and the characterization of disease severity—severe versus attenuated—which has direct implications for clinical management decisions.

Treatment for MPS I includes laronidase (ALDURAZYME), which has received FDA approval and is an active certified treatment option in the current source packet. Laronidase is an enzyme replacement therapy approved for this condition. Established clinical guidelines for the management of MPS I have been developed, as referenced in GeneReviews, and address comprehensive evaluations following initial diagnosis for both newborns and older individuals. Multidisciplinary clinical care is central to MPS I management, as described in GeneReviews. The management approach is informed by disease severity, with therapeutic choices differing between severe and attenuated forms. GeneReviews therapies under investigation include combined enzyme replacement and hematopoietic stem cell transplantation approaches, with available observational data on outcomes in individuals who have received both modalities. Research efforts are directed at improving therapeutic responsiveness in organ systems—including skeletal and neurological tissues—that may not respond fully to enzyme replacement therapy. Additional investigational agents hold orphan drug designation for MPS I, indicating they are under study but have not received marketing approval.

The prognosis of MPS I is substantially influenced by disease severity and by the timing and adequacy of treatment. GeneReviews clinical descriptions characterize MPS I as a progressive condition with variable rates of involvement across organ systems. The severe form is associated with earlier and more profound multisystem progression compared to the attenuated form. The distinction between severe and attenuated MPS I carries significant implications for the expected clinical course, and this severity classification directly shapes the therapeutic approach. Certified natural history data beyond the GeneReviews clinical description are not specified in the current source packet.

Several certified active trial records are present for mucopolysaccharidosis type I. GeneReviews notes that with the demonstrated success of enzyme replacement therapy for MPS I, an increased research effort is directed at improving therapeutic responsiveness and developing treatment modalities that address aspects of the condition not fully reached by existing approaches, including skeletal and neurological involvement. Gene therapy and other novel modalities are among the therapeutic directions under active investigation for MPS I. Active clinical trials for this condition are listed on ClinicalTrials.gov.