Hurler syndrome, also designated MPS I H, is the most severe form of mucopolysaccharidosis type 1 (MPS I), a lysosomal storage disorder caused by deficient activity of the enzyme alpha-L-iduronidase. The disorder belongs to the broader group of mucopolysaccharidoses, in which incompletely degraded glycosaminoglycans accumulate progressively in tissues and organs throughout the body. According to GeneReviews, MPS I is seen across all populations; the severe Hurler form occurs at a frequency of approximately 1 per 100,000 individuals, while the Orphanet prevalence estimate for the broader MPS I spectrum falls in the range of fewer than ten per million. Hurler syndrome follows an autosomal recessive inheritance pattern, meaning an affected individual carries pathogenic variants in both copies of the IDUA gene, located on chromosome 4. Onset typically occurs during infancy or early childhood, and the condition follows a progressive, multisystem course affecting the skeleton, nervous system, cardiovascular system, respiratory tract, and multiple other organ systems.

Hurler syndrome produces a broad range of clinical findings that evolve during the first years of life. Among the features consistently documented across affected individuals are coarse facial features, dermatan sulfate excretion in urine, and diminished tissue alpha-L-iduronidase activity. Additional characteristic features include hypertelorism (wide-set eyes), thick vermilion border, skeletal dysplasia, cognitive impairment, cardiac disease, and enlargement of the liver and spleen. According to GeneReviews, the clinical description for MPS I encompasses a wide continuum of findings spanning from the severe Hurler presentation to attenuated forms of the disorder. Major organ systems involved include the skeletal system, respiratory tract, and auditory system, consistent with the multisystem nature of the condition. Progressive neurological deterioration is a defining feature of the severe Hurler phenotype and distinguishes it from the milder MPS I subtypes. Cardiac involvement, including hypertrophic and valvular changes, is documented as part of the long-term disease course.

Hurler syndrome results from biallelic pathogenic variants in the IDUA gene, located on chromosome 4. Loss of IDUA enzyme activity prevents normal catabolism of the glycosaminoglycans dermatan sulfate and heparan sulfate, leading to their progressive accumulation within lysosomes of cells across multiple organ systems. According to GeneReviews genotype-phenotype data derived from 538 individuals in the international MPS I registry, complete loss of IDUA enzyme activity is closely associated with the severe Hurler phenotype. This complete loss most often arises from homozygosity or compound heterozygosity involving pathogenic variants that severely disrupt gene transcription or translation. Among individuals with severe MPS I in the registry, approximately 68 percent carried two variants of this type; the remaining individuals carried at least one recurrent or unique variant. Because both copies of IDUA must harbor pathogenic changes for the disease to manifest, parents of an affected child each typically carry one pathogenic variant without being clinically affected. The severity of MPS I is closely linked to the degree of residual enzyme activity determined by the individual's specific genetic variant combination.

Diagnosis of Hurler syndrome involves documentation of deficient alpha-L-iduronidase enzyme activity and molecular confirmation of biallelic IDUA pathogenic variants. According to GeneReviews, newborn screening programs in the United States have used single-tier measurement of alpha-L-iduronidase enzyme activity as the primary approach, with some centers adopting a second-tier measurement of glycosaminoglycans in dried blood spots to improve specificity. Confirmatory evaluation includes molecular analysis of the IDUA gene. Clinical presentation with characteristic features—coarse facial features, hepatosplenomegaly, skeletal findings, and elevated urinary dermatan sulfate—also provides a diagnostic pathway when newborn screening has not been performed. The clinical picture of MPS I overlaps with those of other lysosomal storage disorders, and biochemical and genetic testing are required to distinguish these conditions. GeneReviews notes that the age at which treatment is initiated significantly influences long-term outcomes, making early disease detection clinically significant.

According to GeneReviews, there is no cure for MPS I. Management centers on two main targeted therapeutic approaches: hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT). HSCT is described as the only therapeutic approach demonstrated to alter the natural history of central nervous system manifestations in severe MPS I. GeneReviews guidelines indicate that HSCT performed before age 2 years maximizes benefit; documented outcomes of successful HSCT include improved survival, reduction in hepatosplenomegaly, improvement in hearing, and initial stabilization of myocardial function. ERT is documented as a component of management particularly relevant to individuals with attenuated MPS I, with early initiation associated with improved long-term outcomes. GeneReviews notes that ERT demonstrates more limited efficacy in skeletal and neurological manifestations compared with its effects in other organ systems. No specific drugs are recorded as FDA-approved in this packet's approved_treatments field. Published management guidelines for MPS I describe multisystem monitoring as part of established clinical care following initial diagnosis. Research is under way to improve ERT responsiveness and develop therapies directed at organ systems less responsive to current approaches.

The prognosis for Hurler syndrome is serious. The condition is progressive and, without treatment, is associated with significantly reduced life expectancy due to multisystem organ involvement. According to GeneReviews, symptoms and disease complications are difficult or impossible to reverse once established. HSCT, when performed before age 2, has been associated with improved survival and stabilization or improvement across several organ systems, including cardiac and hepatic involvement. However, GeneReviews notes that long-term follow-up demonstrates continued progression of valvular heart disease even in HSCT-treated individuals, and that HSCT has more limited impact on skeletal manifestations. The degree of neurological involvement at the time of transplantation is a key determinant of central nervous system outcomes following HSCT. Long-term multisystem surveillance is an established element of published clinical care frameworks for this condition. Overall outcomes in severe MPS I have improved with advances in treatment, though significant morbidity persists across multiple organ systems.

Hurler syndrome has a substantial body of active clinical research. Several trials are currently under way, encompassing gene therapy approaches, optimization of stem cell transplantation protocols, and strategies to address organ systems where current treatments show limited efficacy. Among actively recruiting studies is a trial investigating Sleeping Beauty transposon-engineered B cells as a gene-based approach for MPS I, and a study of gene therapy using modified autologous hematopoietic stem cells. Registry-based studies tracking long-term outcomes across lysosomal storage diseases are also active. The dominant publication type in the research landscape for this disease is Gene Therapy and Novel Therapeutics, and the literature includes publications covering biomarkers, gene therapy, and clinical trial outcomes. Key trial sponsors include organizations working on cell and gene therapy platforms. According to GeneReviews, the demonstrated success of ERT for MPS I has spurred substantial effort to improve ERT responsiveness and develop forms of therapy—particularly for skeletal and neurological involvement—in areas where current treatments remain insufficient.