The packet does not list a gene in its known-genes field and records no inheritance pattern in its structured inheritance field, so genetic detail here is limited to what the packet definition and GeneReviews state in text. Both describe MPS I as autosomal recessive.

GeneReviews describes a close genotype-phenotype correlation based on data from 538 individuals in the international MPS I registry. Complete loss of enzyme activity is associated with severe MPS I, and any combination of two severe variants leads to severe disease. Attenuated MPS I is usually associated with at least one missense variant, which GeneReviews postulates permits some residual enzyme activity.

GeneReviews states that the parents of an affected child are obligate heterozygotes and that heterozygotes are asymptomatic. When both parents are known to be heterozygous, each sibling of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. GeneReviews also states that affected siblings have a clinical course similar to the proband.

Newborn screening. GeneReviews describes newborn screening for MPS I as evolving. Single-tier screening based on alpha-L-iduronidase enzyme activity in dried blood spots remains the most common US approach, while some centers are adopting a second glycosaminoglycan tier that GeneReviews says greatly increases positive predictive value. Positive results are followed by biochemical confirmation of deficient enzyme activity and elevated urinary glycosaminoglycans. The packet does not contain a newborn screening field.

Symptomatic presentation. GeneReviews lists supportive but nonspecific clinical findings that include coarse facial features, early frequent upper respiratory infections including otitis media, inguinal or umbilical hernia, hepatosplenomegaly, characteristic skeletal findings (gibbus deformity, limited joint range of motion), noninflammatory arthropathy, corneal clouding, hydrocephalus, and developmental delay, and states that clinical findings alone are not diagnostic. Urine glycosaminoglycan analysis can indicate the likely presence of an MPS disorder but cannot diagnose a specific lysosomal enzyme deficiency.

Establishing the diagnosis. According to GeneReviews, the diagnosis is established in a proband with suggestive clinical and laboratory findings together with detection of deficient enzyme activity or identification of biallelic pathogenic or likely pathogenic variants on molecular genetic testing. Because of enzyme pseudodeficiency, GeneReviews states that establishing the diagnosis requires demonstration of both deficient enzyme activity and elevated urinary glycosaminoglycans.

GeneReviews states that there is no cure for MPS I and that a central component of management is initiation of treatment early in the natural history, as symptoms and complications are difficult or impossible to reverse. It describes hematopoietic stem cell transplantation (HSCT) as the only therapeutic approach demonstrated to alter the natural history of the central nervous system manifestations of severe MPS I, with the age of initiation directly influencing outcome. HSCT is described as not curative, as having more limited impact on cardiac valvular, ocular, and skeletal manifestations, and as being generally performed before age 2 years in children; GeneReviews notes that adults have not undergone HSCT.

The packet lists one FDA-approved treatment with active market status: Aldurazyme (laronidase), approved under a BLA on 2003-04-30. GeneReviews describes laronidase enzyme replacement therapy as widely licensed for non-CNS manifestations. Benefits it lists include reduced urinary glycosaminoglycans, normalization of liver and spleen volume, and stabilization but not improvement of respiratory function. GeneReviews states that laronidase does not cross the blood-brain barrier and is not expected to influence CNS disease, and does not affect corneal involvement or cardiac valvular disease progression.

Care organization. GeneReviews describes evaluation by a metabolic physician or biochemical geneticist after diagnosis and follow-up at centers experienced with MPS disease, with a surveillance table that includes at least annual skeletal, ophthalmologic, and developmental assessments.

Other designations. The packet lists orphan drug designations for several investigational products; designation is distinct from approval, and two records (ataluren and a Sigilon Therapeutics cell product) carry WITHDRAWN status.

The packet does not certify a structured natural history field. GeneReviews states that in untreated individuals with severe MPS I, death due to cardiorespiratory failure usually occurs within the first ten years of life, and that the mean age of diagnosis for severe MPS I is approximately ten months. Attenuated MPS I is described as showing the greatest variability, and GeneReviews notes that the age at which enzyme replacement therapy is started in attenuated disease influences long-term outcome. For HSCT in severe MPS I, GeneReviews states that outcome is significantly influenced by disease burden, and thus age, at diagnosis. The packet supplies no course or survival data for treated individuals beyond these statements.

The packet records 15 clinical trials for MPS I, all counted as active. Listed records include a Phase 1 study of ISP-001, Sleeping Beauty transposon-engineered B cells (NCT05682144; Immusoft of CA; recruiting), a Phase 1 gene therapy study with modified autologous hematopoietic stem cells in Hurler variant (NCT03488394; Orchard Therapeutics; active, not recruiting), a Phase 1 prenatal enzyme replacement therapy study for lysosomal storage disorders (PEARL; NCT04532047; University of California, San Francisco; recruiting), and a Phase 1 adalimumab study in MPS I, II, and VI (NCT03153319; Lundquist Institute; active, not recruiting). Registry and observational records are also listed. Registry records describe studies, not outcomes.

GeneReviews describes therapies under investigation as including combined ERT and HSCT, approaches to deliver enzyme to the CNS (including intrathecal ERT, for which it states efficacy is unclear), and stabilization of mutated enzyme with substrate analogs. The packet's research digest classifies 82 publications, with gene therapy and novel therapeutics as the dominant type. Patient organizations listed include the Canadian Society for Mucopolysaccharide and Related Diseases (which has a registry) and the MPS SuperHero Foundation.