Clinical Guidance

There is a close correlation of genotype to phenotype in MPS I based on data from 538 individuals within the international MPS I registry . Complete loss of IDUA enzyme activity, often due to homozygosity or compound heterozygosity of the common or pathogenic variants, is associated with severe MPS I. Any combination of two "severe" variants leads to severe MPS I. In individuals with severe MPS I, 68% (257/380) had two variants that would be predicted to severely disrupt gene transcription or translation, 76 of the remaining 123 individuals (20%, 76/380) had recurrent variants, and 47 (12.4%, 47/380) had at least one unique variant. Attenuated MPS I is usually associated with at least one missense variant; registry data showed that 95.

Source: GeneReviews — "Mucopolysaccharidosis Type I"

Diagnostic Criteria

Suggestive Findings

Scenario 1 – Abnormal Newborn Screening (NBS) Result

Note: The approach to NBS for mucopolysaccharidosis type I (MPS I) is currently in evolution. Although single-tier -L-iduronidase (IDUA) enzyme activity measurement was the original and remains the most common approach taken in the United States, the potential adoption of a second tier involving measurement of dried blood spot glycosaminoglycans is currently under way by some centers. The addition of the second tier greatly increases the positive predictive value of NBS for MPS I .

Source: GeneReviews — "Mucopolysaccharidosis Type I"

Differential Diagnosis

Lysosomal storage disease. Findings in individuals with mucopolysaccharidosis type I (MPS I) overlap those of other lysosomal diseases, particularly other mucopolysaccharide disorders, including those summarized in . Clinical findings and biochemical testing can distinguish them. Table 3. Mucopolysaccharidosis Type I: Differential Diagnosis

Management Guidelines

Guidelines for the management of mucopolysaccharidosis type I (MPS I) have been developed . Evaluations Following Initial Diagnosis To establish the extent of disease and determination of phenotype (i.e., severe or attenuated) in an individual diagnosed with MPS I, the evaluations summarized in and (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 4. Mucopolysaccharidosis Type I: Recommended Evaluations Following Initial Diagnosis in a Newborn Evaluation | Comment Consultation w/metabolic physician / biochemical geneticist specialist metabolic dietitian1 | Referral to specialist center w/experience in mgmt of inherited metabolic/genetic diseases is strongly recommended. Molecular genetic testing for IDUA variants | Genotype of affected person is an important component of determining phenotype. Developmental assessment | • Consultation w/PT, OT, speech therapist • Consider referral to developmental pediatrician. Experience with the nuances of developmental assessment of children with MPS or other multisystem disorders is critical. Consultation w/social worker | To ensure understanding of the diagnosis assess parental / affected person's coping skills resources Genetic counseling by genetics professionals2 | To obtain a pedigree inform affected persons families re nature, MOI, implications of MPS I to facilitate medical personal decision making MOI = mode of inheritance; OT = occupational therapist; PT = physical therapist 1. After a new diagnosis of MPS I in a child, the closest hospital and local pediatrician should also be informed. 2. Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) Table 5. Mucopolysaccharidosis Type I: Recommended Evaluations in All Individuals

Source: GeneReviews — "Mucopolysaccharidosis Type I"

Therapies Under Investigation

With the success of ERT for MPS I demonstrated by clinical trials, an increased effort is under way to improve responsiveness to ERT and to develop other forms of therapy directed at areas/organs that may not be responsive to ERT, such as skeletal and neurologic involvement. Combined ERT and HSCT. There have been limited observational data on the outcome of individuals with severe MPS I treated with long-term combined ERT and HSCT. report on ten individuals who received long-term ERT post HSCT; growth may have been improved in the younger individuals. Delivery of enzyme to the CNS. Intravenous infusion of recombinant proteins does not lead to transfer of proteins across the blood-brain barrier. Various means to provide enzyme to the CNS are currently being researched.

Source: GeneReviews — "Mucopolysaccharidosis Type I"

Surveillance Guidelines

The recommended minimal schedule of assessments is highlighted in . Persons with MPS I, regardless of disease severity and mode of treatment, should be actively followed at a center that is experienced with the care of individuals with MPS disease. Table 7. Mucopolysaccharidosis Type I: Recommended Surveillance

Source: GeneReviews — "Mucopolysaccharidosis Type I"