Attenuated Mucopolysaccharidosis Type I

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Classifications

Lysosomal Storage

ICIMD (Inherited Metabolic Disorders)

ISDS Skeletal Nosology

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Mappings

MONDO

MONDO:0011759 Hurler-Scheie syndrome Not Yet Curated

Hurler-Scheie syndrome is the intermediate attenuated MPS I phenotype and is one of the two MONDO concepts this entry covers. narrowMatch rather than exactMatch because this entry deliberately spans both attenuated concepts; the Hurler-Scheie subtype is curated in has_subtypes.

MONDO:0011760 Scheie syndrome Not Yet Curated

Scheie syndrome is the mildest attenuated MPS I phenotype and is the second MONDO concept this entry covers. narrowMatch for the same reason; the Scheie subtype is curated in has_subtypes.

MONDO:0001586 mucopolysaccharidosis type 1 Not Yet Curated

MPS type 1 is the parent concept spanning the whole IDUA-deficiency spectrum. It is broader than this entry because it also subsumes Hurler syndrome, which dismech curates separately; recorded as broadMatch so it is not retired from the curation queue by this entry alone.

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Inheritance

1

Autosomal recessive inheritance HP:0000007

Biallelic pathogenic IDUA variants cause disease. When both parents are confirmed carriers, each pregnancy has a 25% recurrence risk. Carrier enzyme testing is unreliable; familial molecular testing supports reproductive counseling.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:20301341 SUPPORT REVIEW SYNTHESIS Human Clinical

"MPS I is inherited in an autosomal recessive manner."

Inheritance mode summarized in GeneReviews.

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Subtypes

2

Hurler-Scheie syndrome (MPS I H/S) MONDO:0011759

IDUA hgnc:5391

Historical intermediate phenotype with progressive somatic disease and variable neurologic involvement. It overlaps with Scheie syndrome and is usually grouped with it as attenuated MPS I for clinical management.

Show evidence (1 reference)

PMID:32764324 SUPPORT REVIEW SYNTHESIS Human Clinical

"Three MPS I subtypes have been classified that differ in the severity of disease, ranging from mild (Scheie syndrome) to moderate (Hurler–Scheie) to severe (Hurler syndrome or MPS-IH)"

Historical clinical categories within one disease spectrum.

Scheie syndrome (MPS I S, formerly MPS V) MONDO:0011760

IDUA hgnc:5391

Historical mildest phenotype, sometimes recognized only in adulthood. Significant progressive joint, ocular and cardiac disease may occur despite relatively preserved cognition. The label does not specify an individual prognosis.

Show evidence (1 reference)

PMID:32764324 SUPPORT REVIEW SYNTHESIS Human Clinical

"Three MPS I subtypes have been classified that differ in the severity of disease, ranging from mild (Scheie syndrome) to moderate (Hurler–Scheie) to severe (Hurler syndrome or MPS-IH)"

Historical clinical categories within one disease spectrum.

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Discussions and Knowledge Gaps

4

What predicts cognitive involvement and treatment responsiveness within attenuated MPS I?

INTERPRETATION OPEN cognitive_and_treatment_heterogeneity

Attenuated disease is not synonymous with absence of CNS involvement. In the French cohort, 21 of 25 had normal cognition, but four had pre-ERT impairment. The small intrathecal laronidase trial found no treatment-associated cognitive improvement; it does not establish that intrathecal delivery can never work. Eight participants, short controlled follow-up, stable controls and lack of a human brain-uptake assay limit interpretation.

Show evidence (2 references)

PMID:41353341 SUPPORT PRIMARY RESULT Human Clinical

"Before ERT, 4 (16%) patients had cognitive impairment since the median age of 7.3 years."

Attenuated subset of an uncontrolled treated cohort, not population prevalence.

PMID:31839529 SUPPORT PRIMARY RESULT Human Clinical

"Nor was there a significant difference between treatment and control groups in any of the neuropsychological tests. Subjects in the control group did not experience any significant decline over the 12 month untreated period in any neuropsychological test except the Brief Visuospatial Memory..."

Eight-person randomized open-label pilot with ongoing intravenous ERT; no demonstrated cognitive benefit in this design.

What can untreated echocardiographic registry findings establish about myocardial disease and treatment effects?

INTERPRETATION OPEN cardiac_natural_history_and_source_limitations

The cardiac registry uses echocardiograms obtained before ERT or HSCT. It therefore does not demonstrate treatment-related stabilization. Valve findings are ever-observed during irregular follow-up, not graded incident events. Among attenuated patients, posterior-wall hypertrophy occurred in 27 of 87 with measurements, septal hypertrophy in 14 of 86 and low shortening fraction in seven of 104. Normal group averages and stable modeled trajectories do not exclude individual myocardial involvement; histology, cardiac MRI, strain and diastolic measurements were unavailable.

Show evidence (3 references)

PMID:37850463 SUPPORT PRIMARY RESULT Human Clinical

"All available echocardiography assessments completed prior to treatment initiation were used."

Treatment censoring defines the natural-history period.

PMID:37850463 SUPPORT PRIMARY RESULT Human Clinical

"Left ventricular hypertrophy of the posterior wall was the most common finding in both phenotypes (47.7 and 31% in severe and attenuated, respectively)."

Primary echo finding; wall thickening is not histologic proof of infiltration.

PMID:37850463 SUPPORT PRIMARY RESULT Human Clinical

"Cardiac data elements did not include other components of more recent interest such as aortic dimensions, aortic root dilation, strain, and diastolic function."

Missing cardiac domains limit mechanistic and prognostic inference.

How well do residual-activity assays and genotype predict individual outcomes?

INTERPRETATION OPEN residual_activity_genotype_and_evidence_boundaries

The enzyme-activity study uses a small number of cultured-cell lines and overlapping residual ranges, while the genotype registry uses clinician-assigned severity and incomplete phase information. Neither establishes a universal enzyme threshold that protects the human brain. The French treatment cohort has inconsistent mortality-by-treatment-age statements between narrative and Table 2; no claim that all attenuated deaths followed adult treatment initiation is adopted. Its growth, antibody and organ outcomes are uncontrolled observations, and follow-up denominators vary by measurement.

Show evidence (2 references)

PMID:23786846 SUPPORT PRIMARY RESULT In Vitro

"Mean residual IDUA activity was 0.18% (range 0-0.6) of the control value in MPS IH fibroblasts (n=5); against 0.27% (range 0.2-0.3) in MPS IH/S cells (n=3); and 0.79% (range 0.3-1.8) in MPS IS fibroblasts (n=5)."

Small cultured-fibroblast study using an artificial substrate; activity ranges overlap and do not measure brain activity.

PMID:31194252 SUPPORT PRIMARY RESULT Human Clinical

"A total of 24 patients were homozygous for P533R; seven classified as severe and 17 classified as attenuated."

The same homozygous genotype occurred in both clinical categories.

Does anti-inflammatory treatment benefit attenuated MPS I beyond existing care?

INTERPRETATION OPEN inflammatory_therapy_evidence_is_not_attenuated_specific

A small adalimumab crossover pilot in the tissue review enrolled one post-transplant Hurler patient and one patient with attenuated MPS II. It did not demonstrate treatment efficacy in attenuated MPS I. Parent-reported pain and some range-of-motion findings favored active treatment, but another pain measure, walking distance and handgrip did not improve, one family was effectively unblinded and safety follow-up was short. This supports further research rather than routine anti-TNF care or a proven human TLR4-to-TNF causal cascade.

Show evidence (2 references)

PMID:28119823 SUPPORT PRIMARY RESULT Human Clinical

"We found comparable changes of 13° and 28° in the participant with MPS type IH (Subject # 1), who had been previously treated with hematopoietic stem cell transplantation, over just 16 weeks of treatment with adalimumab."

The MPS I participant had severe Hurler disease, not attenuated MPS I.

PMID:28119823 SUPPORT PRIMARY RESULT Human Clinical

"However, additional clinical trials are needed before this therapy should be recommended as part of clinical care."

The exploratory study does not establish routine-care efficacy.

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Pathophysiology

14

Biallelic IDUA Pathogenic Variants

Pathogenic variants in both IDUA alleles underlie the attenuated clinical spectrum. Allele-specific residual function varies, and clinical severity is not determined by a single enzyme-activity cutoff.

IDUA hgnc:5391

Downstream

Reduced Alpha-L-Iduronidase Activity Pathogenic variants reduce the amount or catalytic function of IDUA through allele-dependent effects.

Variant-Dependent IDUA Functional Instability The E276K-associated experimental finding illustrates one possible allele-dependent contribution.

Learning disability Learning difficulties occur in attenuated MPS I, but no validated residual-enzyme threshold or specific neuronal intermediate explains individual risk.

Cognitive impairment Some attenuated patients have cognitive impairment. The observed phenotype does not establish a uniform storage-to-neurodegeneration route or a protective residual-activity threshold.

Show evidence (2 references)

PMID:32764324 SUPPORT REVIEW SYNTHESIS Human Clinical

"Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive inherited disease, caused by deficiency of the enzyme α-L-iduronidase, resulting in accumulation of the glycosaminoglycans (GAGs) dermatan and heparan sulfate in organs and tissues"

Established MPS I enzyme and storage mechanism; not a subtype-specific activity threshold.

PMID:31194252 SUPPORT PRIMARY RESULT Human Clinical

"A total of 24 patients were homozygous for P533R; seven classified as severe and 17 classified as attenuated."

The same homozygous genotype occurred in both clinical categories.

Reduced Alpha-L-Iduronidase Activity

IDUA hydrolytic activity is markedly reduced. Specialized fibroblast assays may detect residual activity, but routine diagnostic assays can show little or no activity in both severe and attenuated disease.

IDUA hgnc:5391

L-iduronidase activity GO:0003940

Experimental models

Patient fibroblast residual-IDUA and thermal-stability assays PRIMARY CELL CULTURE Residual activity was markedly reduced, with overlapping clinical-subtype ranges.

Downstream

Impaired Dermatan and Heparan Sulfate Degradation Insufficient iduronidase activity limits the required hydrolytic step.

Show evidence (2 references)

PMID:32764324 SUPPORT REVIEW SYNTHESIS Human Clinical

"Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive inherited disease, caused by deficiency of the enzyme α-L-iduronidase, resulting in accumulation of the glycosaminoglycans (GAGs) dermatan and heparan sulfate in organs and tissues"

Established MPS I enzyme and storage mechanism; not a subtype-specific activity threshold.

PMID:23786846 SUPPORT PRIMARY RESULT In Vitro

"Mean residual IDUA activity was 0.18% (range 0-0.6) of the control value in MPS IH fibroblasts (n=5); against 0.27% (range 0.2-0.3) in MPS IH/S cells (n=3); and 0.79% (range 0.3-1.8) in MPS IS fibroblasts (n=5)."

Small cultured-fibroblast study using an artificial substrate; activity ranges overlap and do not measure brain activity.

Variant-Dependent IDUA Functional Instability

For the E276K allele, enzyme activity rapidly decays during incubation of fibroblast homogenates at 37 degrees Celsius and is more stable at lower temperature. This is an allele-specific experimental route to loss of activity, not evidence of accelerated intracellular protein degradation for all patients.

Experimental models

Patient fibroblast residual-IDUA and thermal-stability assays PRIMARY CELL CULTURE E276K-associated activity decayed faster at 37 degrees Celsius than at 23 degrees Celsius.

Downstream

Reduced Alpha-L-Iduronidase Activity Loss of retained enzyme activity during incubation reduces measured catalytic output.

Show evidence (1 reference)

PMID:23786846 SUPPORT PRIMARY RESULT In Vitro

"IDUA(E276K) was very unstable at 37°C, but more stable at 23°C, suggesting thermal instability."

Temperature-dependent loss of enzyme activity in patient fibroblast homogenates; not protein-turnover measurement or a universal allele mechanism.

Impaired Dermatan and Heparan Sulfate Degradation

Deficient IDUA interrupts sequential lysosomal degradation of dermatan and heparan sulfate at terminal iduronic-acid residues.

glycosaminoglycan catabolic process GO:0006027 ↓ DECREASED

lysosome GO:0005764

Downstream

Lysosomal Glycosaminoglycan Accumulation Failure to complete degradation permits substrate storage.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"encodes alpha-L-iduronidase, a glycosidase that removes nonreducing terminal α-L-iduronide residues during the lysosomal degradation of heparan sulfate and dermatan sulfate, which are glycosaminoglycans in mammalian cells"

Enzymatic role of IDUA summarized in the molecular-pathogenesis section; the cached HTML entity is preserved.

PMID:32764324 SUPPORT REVIEW SYNTHESIS Human Clinical

"Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive inherited disease, caused by deficiency of the enzyme α-L-iduronidase, resulting in accumulation of the glycosaminoglycans (GAGs) dermatan and heparan sulfate in organs and tissues"

Established MPS I enzyme and storage mechanism; not a subtype-specific activity threshold.

Lysosomal Glycosaminoglycan Accumulation

Partially degraded substrates accumulate in lysosomes across tissues. The amount and consequences vary by cell type and disease stage; urine GAG excretion is not a direct measurement of every tissue pool.

lysosome GO:0005764

Downstream

Extracellular Matrix Disorganization Lysosomal storage accompanies extracellular substrate deposition and altered matrix organization; the cellular export and remodeling sequence is incompletely resolved.

Growth Plate Disorganization Storage and secondary tissue changes disturb growth-plate architecture.

Periarticular Tissue Remodeling Storage in periarticular tissues contributes to tissue remodeling and reduced compliance.

Cardiac Valve Thickening Storage-associated interstitial and matrix changes thicken valve tissue.

Upper Airway Narrowing Storage-associated soft-tissue enlargement contributes to upper airway narrowing.

Dural Thickening Storage-associated meningeal disease contributes to dural thickening; the full cellular sequence is not demonstrated here.

Hepatosplenomegaly Storage expands liver and spleen tissue; attenuated enlargement is variable.

Reduced vital capacity Storage-associated airway and thoracic skeletal disease can impair pulmonary function. Reduced vital capacity is not attributed solely to upper-airway narrowing.

Hearing impairment Storage-associated middle- and inner-ear abnormalities can impair hearing; the eustachian, ossicular and neural contributions vary.

Coarse facial features Storage in craniofacial soft tissues and bones contributes to coarse facial appearance; no growth-plate-only mechanism is asserted.

Short neck Storage-associated skeletal and soft-tissue abnormalities contribute to the short-neck appearance; their individual contributions are not resolved.

Wide mouth Craniofacial tissue storage contributes to the reported facial spectrum; the pathway to a wide mouth is inferred rather than directly assayed.

Glaucoma Storage can impair aqueous drainage through trabecular or angle abnormalities; corneal stromal disorganization is not a necessary intermediary.

Retinal degeneration Retinal storage-associated injury is distinct from the corneal stromal pathway.

Optic atrophy Several storage-associated ocular and intracranial processes can injure the optic nerve; the relative route is unresolved in attenuated disease.

Hydrocephalus Storage may interfere with cerebrospinal-fluid absorption. This proposed cranial route is distinct from the modeled cervical dural thickening.

Show evidence (1 reference)

PMID:32764324 SUPPORT REVIEW SYNTHESIS Human Clinical

"Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive inherited disease, caused by deficiency of the enzyme α-L-iduronidase, resulting in accumulation of the glycosaminoglycans (GAGs) dermatan and heparan sulfate in organs and tissues"

Established MPS I enzyme and storage mechanism; not a subtype-specific activity threshold.

Extracellular Matrix Disorganization

Accumulated GAGs and storage-laden cells alter tissue hydration and organization of structural fibers. This is not equivalent to an inherited collagen defect or proof that normal decorin biology explains every manifestation.

extracellular matrix organization GO:0030198 ↕ DYSREGULATED

Downstream

Corneal Stromal Disorganization Corneal matrix changes disturb the orderly architecture needed for transparency.

Inguinal hernia Altered abdominal-wall connective tissue is a proposed contribution to herniation; the complete tissue-failure sequence is not demonstrated.

Show evidence (1 reference)

PMID:32764324 SUPPORT REVIEW SYNTHESIS Human Clinical

"GAG deposits and GAG-laden cells also interfere with the organization of collagen and elastin fibers"

General MPS I tissue-pathology synthesis; the relative contribution to each attenuated manifestation is not quantified.

Growth Plate Disorganization

Abnormal chondrocyte morphology and growth-plate organization contribute to skeletal dysplasia and impaired longitudinal growth. Specific cathepsin-K and TLR4 routes remain proposed or model-derived and are not imposed as a proven attenuated human cascade.

Downstream

Dysostosis multiplex This tissue process contributes to the clinical finding; severity and timing vary.

Short stature This tissue process contributes to the clinical finding; severity and timing vary.

Kyphosis This tissue process contributes to the clinical finding; severity and timing vary.

Scoliosis This tissue process contributes to the clinical finding; severity and timing vary.

Spondylolisthesis This tissue process contributes to the clinical finding; severity and timing vary.

Show evidence (1 reference)

PMID:32764324 SUPPORT REVIEW SYNTHESIS Human Clinical

"The epiphyseal growth plates in patients affected by MPS I ... and in animal models of MPS I ... are disorganized and show large chondrocytes with large vacuolar contents"

Human and model pathology summarized together; not an attenuated-specific longitudinal experiment.

Periarticular Tissue Remodeling

GAG storage and secondary changes in ligaments and joint capsules restrict joint movement. Clinical noninflammatory arthropathy does not imply the absence of all molecular inflammatory signaling.

Downstream

Median Nerve Compression Hand connective-tissue changes can contribute to tunnel crowding, alongside bony factors; the dominant mechanism was not isolated in the surgical cohort.

Limitation of joint mobility This tissue process contributes to the clinical finding; severity and timing vary.

Joint contracture This tissue process contributes to the clinical finding; severity and timing vary.

Claw hand deformity Periarticular remodeling and stiffness contribute to hand contractures; osseous and neural contributions are not excluded.

Show evidence (1 reference)

PMID:32764324 SUPPORT REVIEW SYNTHESIS Human Clinical

"Joint symptoms, such as joint stiffness and limited range of joint mobility, stem from GAG accumulation and secondary pathogenic cascades in the ligaments and capsule around the joints"

Review synthesis linking periarticular tissue disease to joint dysfunction.

Corneal Stromal Disorganization

Keratocyte storage and altered stromal fibril spacing impair corneal transparency.

Downstream

Corneal opacity This tissue process contributes to the clinical finding; severity and timing vary.

Show evidence (1 reference)

PMID:32764324 SUPPORT REVIEW SYNTHESIS Human Clinical

"Corneal clouding is caused by aberrant GAG deposits in stromal keratocytes and disruption of normal collagen alignment in the corneal stroma ... The usually highly uniform collagen fibrils show great variations in diameter, and the fibrils are spaced further apart"

Corneal pathology synthesis across MPS I; the severe infant timing elsewhere in this review is not assigned to attenuated disease.

Cardiac Valve Thickening

Storage-laden valve interstitial cells and matrix accumulation thicken valve leaflets and restrict normal movement, particularly in the mitral and aortic valves.

Downstream

Mitral regurgitation This tissue process contributes to the clinical finding; severity and timing vary.

Mitral stenosis This tissue process contributes to the clinical finding; severity and timing vary.

Aortic regurgitation This tissue process contributes to the clinical finding; severity and timing vary.

Aortic valve stenosis This tissue process contributes to the clinical finding; severity and timing vary.

Left ventricular hypertrophy Valve dysfunction can impose ventricular loading and contribute to hypertrophy. This is one possible route and does not establish that every registry case is secondary to valve disease.

Show evidence (1 reference)

PMID:32764324 SUPPORT REVIEW SYNTHESIS Human Clinical

"The most commonly affected valves are the mitral and the aortic valves that are significantly thickened ... by progressive infiltration of GAG-laden activated valvular interstitial cells into the valvular tissues ... and excessive deposits of collagen ... Functional outcomes are poor mobility of..."

Review synthesis of valve tissue pathology and mechanical dysfunction.

Upper Airway Narrowing

Oropharyngeal soft-tissue storage and altered airway anatomy can obstruct airflow, particularly during sleep. The relative roles of obstruction and central contributions vary.

Downstream

Obstructive sleep apnea This tissue process contributes to the clinical finding; severity and timing vary.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"Storage of GAGs within the oropharynx with associated enlargement of the tonsils and adenoids can contribute to upper airway complications, along with narrowed trachea, thickened vocal cords, redundant tissue in the upper airway, and an enlarged tongue."

General MPS I airway mechanism; attenuated obstructive sleep apnea is separately documented.

Median Nerve Compression

Restricted space and altered connective tissues within the carpal tunnel compress the median nerve. The precise contributions of bony anatomy, tendons and retinaculum remain unresolved; storage-positive foam cells are not necessary in every sampled case.

Downstream

Constrictive median neuropathy This tissue process contributes to the clinical finding; severity and timing vary.

Show evidence (2 references)

PMID:41656624 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"The flexor retinaculum was thickened and synovial tissues appeared swollen in six cases."

Intraoperative observation in a mostly Hurler post-HSCT cohort; extrapolation to attenuated disease is indirect.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"Poor hand function resulting from the characteristic claw hand deformity, carpal tunnel syndrome, and interphalangeal joint stiffness is often observed."

Clinical synthesis specific to the described MPS I manifestation.

Dural Thickening

Dural thickening is one route to cervical canal compromise in attenuated MPS I. Skeletal stenosis and instability can also contribute.

Downstream

Cervical Spinal Cord Compression Thickened dura narrows the space around the spinal cord.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"Progressive compression of the spinal cord with resulting cervical myelopathy caused by thickening of the dura (hypertrophic pachymeningitis cericalis) is common in individuals with attenuated MPS I."

Attenuated-specific clinical mechanism; the source spelling is preserved in the quote.

Cervical Spinal Cord Compression

Mechanical compression of the cervical cord can cause progressive myelopathy and irreversible neurologic injury if unrecognized.

Downstream

Spinal cord compression This tissue process contributes to the clinical finding; severity and timing vary.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"Progressive compression of the spinal cord with resulting cervical myelopathy caused by thickening of the dura (hypertrophic pachymeningitis cericalis) is common in individuals with attenuated MPS I."

Attenuated-specific clinical mechanism; the source spelling is preserved in the quote.

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Pathograph

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Phenotypes

30

Cardiovascular 6

Mitral regurgitation HP:0001653

Show evidence (2 references)

PMID:32764324 SUPPORT REVIEW SYNTHESIS Human Clinical

"The most commonly affected valves are the mitral and the aortic valves that are significantly thickened ... by progressive infiltration of GAG-laden activated valvular interstitial cells into the valvular tissues ... and excessive deposits of collagen ... Functional outcomes are poor mobility of..."

Review synthesis of valve tissue pathology and mechanical dysfunction.

PMID:37850463 SUPPORT PRIMARY RESULT Human Clinical

"Mitral regurgitation was the most common and earliest finding for individuals with both severe (58.3%, median age 1.2 years) and attenuated (74.2%, median age 8.0 years) disease."

Voluntary registry; 196 of 264 attenuated patients with valve data had an ever-recorded finding before ERT or HSCT.

Aortic valve stenosis HP:0001650

Show evidence (1 reference)

PMID:32764324 SUPPORT REVIEW SYNTHESIS Human Clinical

"The most commonly affected valves are the mitral and the aortic valves that are significantly thickened ... by progressive infiltration of GAG-laden activated valvular interstitial cells into the valvular tissues ... and excessive deposits of collagen ... Functional outcomes are poor mobility of..."

Review synthesis of valve tissue pathology and mechanical dysfunction.

Aortic regurgitation HP:0001659

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"Cardiac involvement can present as progressive disease of the mitral and aortic valves with regurgitation and/or stenosis, for which valve replacement may be necessary."

Clinical synthesis specific to the described MPS I manifestation.

Mitral stenosis HP:0001718

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"Cardiac involvement can present as progressive disease of the mitral and aortic valves with regurgitation and/or stenosis, for which valve replacement may be necessary."

Clinical synthesis specific to the described MPS I manifestation.

Hepatosplenomegaly HP:0001433

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"<b>Hepatosplenomegaly</b> is variable in individuals with attenuated MPS I."

Attenuated-specific clinical synthesis; the balanced inline HTML preserves the diagnostic subject exactly.

Left ventricular hypertrophy HP:0001712

Show evidence (1 reference)

PMID:37850463 SUPPORT PRIMARY RESULT Human Clinical

"Left ventricular hypertrophy of the posterior wall was the most common finding in both phenotypes (47.7 and 31% in severe and attenuated, respectively)."

Attenuated posterior-wall abnormality was measured in 27 of 87 with available data before ERT/HSCT; no histologic infiltration assay.

Digestive 1

Inguinal hernia HP:0000023

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"Many have also had inguinal hernias during infancy, often requiring repeated surgical correction."

Clinical synthesis specific to the described MPS I manifestation.

Ear 1

Hearing impairment HP:0000365

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"Hearing impairment, most commonly in the high frequency range, is likely caused by a combination of eustachian tube dysfunction, dysostosis of the ossicles of the middle ear, and eighth nerve involvement."

Clinical synthesis specific to the described MPS I manifestation.

Eye 4

Corneal opacity HP:0007957

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"Corneal clouding, exhibited by approximately 82% of children with attenuated MPS I, was identified at a median age of 9.1 years"

Clinical synthesis specific to the described MPS I manifestation.

Glaucoma HP:0000501

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"Corneal clouding can lead to significant visual disability. Glaucoma, retinal degeneration, and optic atrophy can occur."

Clinical synthesis specific to the described MPS I manifestation.

Retinal degeneration HP:0000546

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"Corneal clouding can lead to significant visual disability. Glaucoma, retinal degeneration, and optic atrophy can occur."

Clinical synthesis specific to the described MPS I manifestation.

Optic atrophy HP:0000648

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"Corneal clouding can lead to significant visual disability. Glaucoma, retinal degeneration, and optic atrophy can occur."

Clinical synthesis specific to the described MPS I manifestation.

Head and Neck 3

Coarse facial features HP:0000280

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"Coarseness of facial features is less obvious than in individuals with severe MPS I. Findings can include a short neck, wide mouth, and square jaw."

Clinical synthesis specific to the described MPS I manifestation.

Short neck HP:0000470

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"Coarseness of facial features is less obvious than in individuals with severe MPS I. Findings can include a short neck, wide mouth, and square jaw."

Clinical synthesis specific to the described MPS I manifestation.

Wide mouth HP:0000154

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"Coarseness of facial features is less obvious than in individuals with severe MPS I. Findings can include a short neck, wide mouth, and square jaw."

Clinical synthesis specific to the described MPS I manifestation.

Limbs 1

Claw hand deformity HP:0034337

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"Poor hand function resulting from the characteristic claw hand deformity, carpal tunnel syndrome, and interphalangeal joint stiffness is often observed."

Clinical synthesis specific to the described MPS I manifestation.

Musculoskeletal 6

Limitation of joint mobility HP:0001376

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"Progressive arthropathy affecting all joints and eventually leading to loss of or severe restriction in range of motion is universal."

Clinical synthesis specific to the described MPS I manifestation.

Joint contracture HP:0034392

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"Progressive arthropathy affecting all joints and eventually leading to loss of or severe restriction in range of motion is universal."

Attenuated-specific fixed and progressive joint limitation.

Dysostosis multiplex HP:0000943

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"The MPS I Registry showed that more than 85% of persons with attenuated MPS I have dysostosis, primarily in the vertebrae and femur"

Clinical synthesis specific to the described MPS I manifestation.

Kyphosis HP:0002808

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"Kyphosis, scoliosis, and severe back pain are common. Spondylolisthesis of the lower spine leading to spinal cord compression can occur."

Clinical synthesis specific to the described MPS I manifestation.

Scoliosis HP:0002650

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"Kyphosis, scoliosis, and severe back pain are common. Spondylolisthesis of the lower spine leading to spinal cord compression can occur."

Clinical synthesis specific to the described MPS I manifestation.

Spondylolisthesis HP:0003302

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"Kyphosis, scoliosis, and severe back pain are common. Spondylolisthesis of the lower spine leading to spinal cord compression can occur."

Clinical synthesis specific to the described MPS I manifestation.

Nervous System 6

Constrictive median neuropathy HP:0012185

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"Carpal tunnel syndrome was present at a median age of nine years 11 months in 138 individuals with attenuated MPS I included in the MPS I Registry"

Clinical synthesis specific to the described MPS I manifestation.

Obstructive sleep apnea HP:0002870

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"Sleep apnea as a result of obstructive airway disease and possibly central nervous system involvement occurs in individuals with attenuated MPS I."

Clinical synthesis specific to the described MPS I manifestation.

Spinal cord compression HP:0002176

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"Progressive compression of the spinal cord with resulting cervical myelopathy caused by thickening of the dura (hypertrophic pachymeningitis cericalis) is common in individuals with attenuated MPS I."

Attenuated-specific clinical mechanism; the source spelling is preserved in the quote.

Hydrocephalus HP:0000238

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"The risk of communicating hydrocephalus and its complications are lower in attenuated MPS I than severe MPS I. However, hydrocephalus may occur with insidious onset."

Clinical synthesis specific to the described MPS I manifestation.

Learning disability Specific learning disability HP:0001328

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"Although development may be normal in early childhood, children and adults with attenuated MPS I may have detectable learning disabilities."

Clinical synthesis specific to the described MPS I manifestation.

Cognitive impairment HP:0100543

Show evidence (1 reference)

PMID:41353341 SUPPORT PRIMARY RESULT Human Clinical

"Before ERT, 4 (16%) patients had cognitive impairment since the median age of 7.3 years."

Attenuated subset of an uncontrolled treated cohort, not population prevalence.

Respiratory 1

Reduced vital capacity HP:0002792

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"Progressive pulmonary disease may manifest as abnormalities of forced vital capacity. Respiratory complications (and cardiac involvement) are among the leading causes of premature death."

Clinical synthesis specific to the described MPS I manifestation.

Growth 1

Short stature HP:0004322

Show evidence (1 reference)

PMID:35869927 SUPPORT PRIMARY RESULT Human Clinical

"While median height remained below CDC standards during both the natural history and ERT-treated periods for individuals with attenuated MPS I, laronidase ERT was associated with slower declines in height z-scores."

Observational attenuated growth registry; treatment and untreated periods overlap within participants.

🧬

Genetic Associations

1

IDUA pathogenic variants (Causative)

Gene: IDUA hgnc:5391 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal recessive

Show evidence (2 references)

PMID:31194252 SUPPORT PRIMARY RESULT Human Clinical

"The genotype/ phenotype relationships identified in this large series of patients shows that many MPS I patients have unique variants and that certain variants have variable phenotypic effects."

Registry association with clinician-assigned severity; no direct activity assay.

PMID:31194252 SUPPORT PRIMARY RESULT Human Clinical

"A total of 24 patients were homozygous for P533R; seven classified as severe and 17 classified as attenuated."

The same homozygous genotype occurred in both clinical categories.

💊

Medical Actions

15

Intravenous laronidase enzyme replacement

Action: Pharmacotherapy NCIT:C15986

Agent: laronidase NCIT:C83864

Platform: Protein replacement

Weekly intravenous laronidase supplies recombinant IDUA for somatic disease. The current US label covers Hurler and Hurler-Scheie forms and Scheie disease with moderate-to-severe symptoms; efficacy and safety for mildly affected Scheie patients are not established. In the pivotal 26-week trial, 44 of 45 participants had attenuated disease. FVC improved; the walking-distance result was significant in a prespecified adjusted analysis but not the unadjusted comparison. Long-term observational data suggest some somatic benefit, but skeletal, corneal, valvular and spinal disease can persist or progress. CNS effects have not been established. Earlier treatment may help, but no validated age-nine cutoff follows from the uncontrolled growth cohorts.

Mechanism Target:

RESTORES Reduced Alpha-L-Iduronidase Activity — Replacement enzyme adds lysosomal hydrolase activity; distribution and clinical correction remain incomplete.

Show evidence (1 reference)

url:https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a80ac249-cae4-41f3-88bb-344088b20e60 SUPPORT REVIEW SYNTHESIS Other

"The rationale of ALDURAZYME therapy in MPS I is to provide exogenous enzyme for uptake into lysosomes and increase the catabolism of GAG. ALDURAZYME uptake by cells into lysosomes is most likely mediated by the mannose-6-phosphate-terminated oligosaccharide chains of laronidase binding to..."

Label mechanism: lysosomal delivery of replacement enzyme; receptor contribution is qualified by the source.

Show evidence (8 references)

PMID:31211405 SUPPORT REVIEW SYNTHESIS Human Clinical

"The laronidase group achieved statistically significant improvements in per cent predicted forced vital capacity compared to placebo, MD 5.60 (95% confidence intervals 1.24 to 9.96) (low-quality evidence) and in the six-minute-walk test (mean improvement of 38.1 metres in the laronidase group; P..."

Cochrane synthesis of one 45-person, 26-week trial; walk-test significance depends on the prespecified adjusted analysis.

url:https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a80ac249-cae4-41f3-88bb-344088b20e60 SUPPORT REVIEW SYNTHESIS Other

"The safety and effectiveness of treating mildly affected patients with the Scheie form have not been established."

Current regulatory indication boundary.

url:https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a80ac249-cae4-41f3-88bb-344088b20e60 SUPPORT REVIEW SYNTHESIS Other

"The effect of ALDURAZYME on central nervous system manifestations of the disorder has not been determined."

Current regulatory CNS limitation.

+ 5 more references

Individualized transplantation assessment

Action: Hematopoietic Cell Transplantation NCIT:C15431

Platform: Cell therapy

HSCT is primarily standard care for selected children with severe MPS I. For attenuated disease, decisions require specialist assessment of progression, genotype, development, age and transplant risk. Its potential benefits are not confined to cognition, but it does not reliably reverse established skeletal, corneal or valve disease. A universal preserved-cognition rationale for excluding transplantation is inappropriate.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Other

"Due to the morbidity and mortality associated with HSCT, it is currently recommended primarily for children with severe MPS I."

GeneReviews management recommendation; not a controlled outcome comparison.

PMID:19117856 SUPPORT REVIEW SYNTHESIS Other

"The patient's age (>2 years or < or =2 years), predicted phenotype, and developmental quotient help define the risk/benefit profile for hematopoietic stem cell transplantation (higher risk but can preserve central nervous system function) versus enzyme replacement therapy (low risk but cannot..."

Expert risk-benefit framework, not proof of benefit in all attenuated patients.

Physical and occupational therapy

Action: Supportive Care NCIT:C15747

Platform: Other

Early range-of-motion work and functional support may preserve mobility and hand function. Established contractures may not reverse; tailor activity and assistive support to skeletal and neurologic limitations.

Mechanism Target:

MODULATES Limitation of joint mobility — Exercises aim to preserve available movement rather than remove stored substrate.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Other

"Range of motion exercises appear to offer some benefits in preserving joint function and should be started early. Once significant joint limitation has occurred, increased range of motion may not be achieved without HSCT."

GeneReviews management recommendation; not a controlled outcome comparison.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Other

"Range of motion exercises appear to offer some benefits in preserving joint function and should be started early. Once significant joint limitation has occurred, increased range of motion may not be achieved without HSCT."

GeneReviews management recommendation; not a controlled outcome comparison.

Individualized orthopedic surgery

Action: Surgical Procedure NCIT:C15329

Platform: Surgery

Joint replacement or spinal stabilization may be appropriate for selected progressive structural problems. Decisions account for other organ disease and major anesthetic risk; surgery does not correct the underlying enzyme deficiency.

Mechanism Target:

MODULATES Limitation of joint mobility — Selected joint replacement addresses a structural contributor to disability.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Other

"Various orthopedic approaches can be undertaken, particularly in individuals with attenuated disease. Joint replacement and atlanto-occipital stabilization may be necessary. These procedures must be performed at appropriate times in the individual's clinical course and must take into account the..."

GeneReviews management recommendation; not a controlled outcome comparison.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Other

"Various orthopedic approaches can be undertaken, particularly in individuals with attenuated disease. Joint replacement and atlanto-occipital stabilization may be necessary. These procedures must be performed at appropriate times in the individual's clinical course and must take into account the..."

GeneReviews management recommendation; not a controlled outcome comparison.

Carpal tunnel decompression

Action: Surgical Procedure NCIT:C15329

Platform: Surgery

Use early nerve-conduction assessment and specialist evaluation because typical sensory symptoms may be absent. Release can improve function, but recovery varies and surveillance continues for recurrence. The 13 recurrences among 21 operated patients in the 2026 series predominantly concern transplanted Hurler disease and are not an attenuated-specific rate.

Mechanism Target:

INHIBITS Median Nerve Compression — Surgical release relieves pressure on the median nerve.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Other

"thus, nerve conduction studies should be used early in the course of disease to identify persons with carpal tunnel syndrome at a time when surgical release may be most beneficial. Surgical decompression of the median nerve results in variable restoration of motor hand activity"

GeneReviews management recommendation; not a controlled outcome comparison.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Other

"thus, nerve conduction studies should be used early in the course of disease to identify persons with carpal tunnel syndrome at a time when surgical release may be most beneficial. Surgical decompression of the median nerve results in variable restoration of motor hand activity"

GeneReviews management recommendation; not a controlled outcome comparison.

PMID:41656624 SUPPORT PRIMARY RESULT Human Clinical

"Twenty-one patients underwent carpal tunnel release and 13 patients experienced recurrence."

Mostly severe post-HSCT cohort; scope does not establish attenuated recurrence probability.

Evaluation and decompression of cervical myelopathy

Action: Surgical Procedure NCIT:C15329

Platform: Surgery

Urgently evaluate progressive activity loss, gait change or other myelopathic signs, with spinal imaging and neurosurgical assessment. Early decompression can limit further injury; established deficits may persist.

Mechanism Target:

INHIBITS Cervical Spinal Cord Compression — Decompression addresses mechanical cord compromise.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Other

"Progressive compression of the spinal cord with resulting cervical myelopathy should be aggressively and quickly evaluated in individuals with attenuated disease or those who have had HSCT. Early surgical intervention may prevent severe complications."

GeneReviews management recommendation; not a controlled outcome comparison.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Other

"Progressive compression of the spinal cord with resulting cervical myelopathy should be aggressively and quickly evaluated in individuals with attenuated disease or those who have had HSCT. Early surgical intervention may prevent severe complications."

GeneReviews management recommendation; not a controlled outcome comparison.

Corneal and visual care

Action: Supportive Care NCIT:C15747

Platform: Other

Reduce glare and assess glaucoma, retinal and optic-nerve disease. Selected corneal transplantation may improve transparency, but graft clouding can recur and noncorneal disease can limit visual benefit.

Mechanism Target:

MODULATES Corneal opacity — Symptom aids and selected transplantation address the consequences of corneal clouding.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Other

"Wearing peaked caps or eye shades can help reduce glare resulting from corneal clouding. Corneal transplantation is successful for individuals with attenuated disease, although donor grafts eventually become cloudy. Individuals with clear grafts may still experience poor vision because of..."

GeneReviews management recommendation; not a controlled outcome comparison.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Other

"Wearing peaked caps or eye shades can help reduce glare resulting from corneal clouding. Corneal transplantation is successful for individuals with attenuated disease, although donor grafts eventually become cloudy. Individuals with clear grafts may still experience poor vision because of..."

GeneReviews management recommendation; not a controlled outcome comparison.

Cardiac assessment and selected valve replacement

Action: Surgical Procedure NCIT:C15329

Platform: Surgery

Monitor valve and ventricular disease with cardiology and echocardiography. Hemodynamically important valve disease may require replacement. The untreated registry describes valve and myocardial abnormalities and cannot establish that laronidase prevents progression. Endocarditis prophylaxis should follow current indication-specific cardiology guidance rather than a blanket disease rule from older literature.

Mechanism Target:

BYPASSES Mitral regurgitation — Replacing a dysfunctional valve addresses its mechanical lesion, without correcting systemic storage.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"Cardiac involvement can present as progressive disease of the mitral and aortic valves with regurgitation and/or stenosis, for which valve replacement may be necessary."

Clinical synthesis supporting specialist consideration of valve surgery.

BYPASSES Mitral stenosis — Replacing a dysfunctional valve addresses its mechanical lesion, without correcting systemic storage.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"Cardiac involvement can present as progressive disease of the mitral and aortic valves with regurgitation and/or stenosis, for which valve replacement may be necessary."

Clinical synthesis supporting specialist consideration of valve surgery.

BYPASSES Aortic regurgitation — Replacing a dysfunctional valve addresses its mechanical lesion, without correcting systemic storage.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"Cardiac involvement can present as progressive disease of the mitral and aortic valves with regurgitation and/or stenosis, for which valve replacement may be necessary."

Clinical synthesis supporting specialist consideration of valve surgery.

BYPASSES Aortic valve stenosis — Replacing a dysfunctional valve addresses its mechanical lesion, without correcting systemic storage.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"Cardiac involvement can present as progressive disease of the mitral and aortic valves with regurgitation and/or stenosis, for which valve replacement may be necessary."

Clinical synthesis supporting specialist consideration of valve surgery.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"Cardiac involvement can present as progressive disease of the mitral and aortic valves with regurgitation and/or stenosis, for which valve replacement may be necessary."

Clinical synthesis supporting specialist consideration of valve surgery.

Audiologic and ENT support

Action: Supportive Care NCIT:C15747

Platform: Other

Identify conductive and sensorineural contributors, offer hearing aids, and consider ventilation tubes or upper-airway surgery where indicated. ENT procedures require disease-experienced anesthesia planning.

Mechanism Target:

MODULATES Hearing impairment — Hearing aids and treatment of selected conductive contributors support hearing.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Other

"Tonsillectomy and adenoidectomy correct eustachian tube dysfunction and decrease upper airway obstruction. Early placement of ventilating tubes is recommended in severely affected individuals. Hearing aids should also be considered."

GeneReviews management recommendation; not a controlled outcome comparison.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Other

"Tonsillectomy and adenoidectomy correct eustachian tube dysfunction and decrease upper airway obstruction. Early placement of ventilating tubes is recommended in severely affected individuals. Hearing aids should also be considered."

GeneReviews management recommendation; not a controlled outcome comparison.

Sleep and airway support

Action: Supportive Care NCIT:C15747

Platform: Other

Evaluate obstructive and possible central sleep-disordered breathing. Selected patients require positive airway pressure, supplementary oxygen or tracheostomy; requirements are individualized rather than inferred from a pooled MPS I frequency.

Mechanism Target:

BYPASSES Upper Airway Narrowing — Positive airway pressure supports patency, while tracheostomy can bypass an obstructed upper airway.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Other

"Sleep apnea may require tracheotomy or high-pressure continuous positive airway pressure with supplemented oxygen. Tracheostomy is often required to maintain the airway and control pulmonary hypertension and right heart failure."

GeneReviews management recommendation; not a controlled outcome comparison.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Other

"Sleep apnea may require tracheotomy or high-pressure continuous positive airway pressure with supplemented oxygen. Tracheostomy is often required to maintain the airway and control pulmonary hypertension and right heart failure."

GeneReviews management recommendation; not a controlled outcome comparison.

CSF diversion for progressive hydrocephalus

Action: Surgical Procedure NCIT:C15329

Platform: Surgery

Consider shunting when pressure and progressive ventricular enlargement support clinically important hydrocephalus. Ventriculomegaly alone is not equivalent to raised pressure; treatment is palliative and requires specialist assessment.

Mechanism Target:

MODULATES Hydrocephalus — CSF diversion treats pressure and fluid accumulation.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Other

"Cerebrospinal fluid (CSF) pressure and progressive ventricular enlargement indicate need for a shunting procedure. Ventriculoperitoneal shunting in individuals with MPS I who have moderate-to-severe hydrocephalus is generally palliative and improves quality of life."

GeneReviews management recommendation; not a controlled outcome comparison.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Other

"Cerebrospinal fluid (CSF) pressure and progressive ventricular enlargement indicate need for a shunting procedure. Ventriculoperitoneal shunting in individuals with MPS I who have moderate-to-severe hydrocephalus is generally palliative and improves quality of life."

GeneReviews management recommendation; not a controlled outcome comparison.

Anesthetic precautions

Action: Supportive Care NCIT:C15747

Platform: Other

Use centers experienced with mucopolysaccharidoses. Anticipate a difficult narrowed airway, cervical instability, slow recovery and postoperative obstruction; plan positioning and airway equipment accordingly.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Other

"Dysostosis multiplex can lead to instability of the spine, including the atlanto-axial joint. Careful positioning and avoidance of hyperextension of the neck are necessary."

GeneReviews management recommendation; not a controlled outcome comparison.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Other

"Recovery from anesthesia may be slow and postoperative airway obstruction is a common problem."

GeneReviews management recommendation; not a controlled outcome comparison.

Educational and developmental support

Action: Supportive Care NCIT:C15747

Platform: Other

Assess cognition and educational needs over time and provide individualized learning support. Normal early development does not remove the need for later review.

Mechanism Target:

MODULATES Learning disability — Educational support addresses functional learning needs rather than proven CNS substrate clearance.

Show evidence (1 reference)

PMID:20301341 SUPPORT REVIEW SYNTHESIS Other

"Infant learning programs/special education for developmental delay; physical therapy, orthopedic surgery as needed, joint replacement for progressive arthropathy, atlanto-occipital stabilization; spinal cord decompression for cervical myelopathy"

GeneReviews supportive-care summary; the developmental component is relevant when individual needs are identified.

Show evidence (1 reference)

PMID:20301341 SUPPORT REVIEW SYNTHESIS Other

"Infant learning programs/special education for developmental delay; physical therapy, orthopedic surgery as needed, joint replacement for progressive arthropathy, atlanto-occipital stabilization; spinal cord decompression for cervical myelopathy"

GeneReviews supportive-care summary; the developmental component is relevant when individual needs are identified.

Gastrointestinal symptom and hernia care

Action: Supportive Care NCIT:C15747

Platform: Other

Treat constipation or diarrhea individually and assess symptomatic or recurrent hernias. Dietary measures and cautious laxative use may help bowel symptoms; surgical decisions include anesthetic risk assessment.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Other

"Some gastrointestinal symptoms (diarrhea and constipation) can be controlled by diet, including control of the amount of roughage. Increased roughage and the conservative use of laxatives may ease constipation."

GeneReviews management recommendation; not a controlled outcome comparison.

Genetic counseling and pregnancy planning

Action: Supportive Care NCIT:C15747

Platform: Other

Discuss autosomal recessive recurrence and available familial testing. Pregnancy care includes close assessment of cardiorespiratory and spinal disease; disease severity and treatment decisions require individualized multidisciplinary review.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Other

"Women with MPS I who become pregnant require assessment and frequent monitoring of cardiorespiratory and spinal cord involvement."

GeneReviews management recommendation; not a controlled outcome comparison.

PMID:20301341 SUPPORT REVIEW SYNTHESIS Other

"Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if both disease-causing IDUA variants have been identified in the family."

Familial molecular testing recommendation.

🔬

Biochemical Markers

2

Urinary dermatan and heparan sulfate (Elevated)

Context: Quantitative or qualitative urinary GAG analysis supports the diagnosis, but reduced sensitivity, especially in dilute urine, can complicate screening. Urinary GAG reduction after laronidase is a pharmacodynamic response and does not establish correction of all tissue storage or clinical endpoints. In the long-term French attenuated cohort, 11 of 17 patients with relevant measurements reached age-adjusted normal levels, rather than 65% of all 25 attenuated participants.

Show evidence (3 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"Analysis of urine glycosaminoglycans (GAG) (i.e., heparan and dermatan sulfate) may be quantitative (measurement of total urinary GAGs or specific GAG disaccharides) or qualitative (GAG electrophoresis to analyze the specific GAGs excreted)."

Clinical synthesis specific to the described MPS I manifestation.

url:https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a80ac249-cae4-41f3-88bb-344088b20e60 SUPPORT REVIEW SYNTHESIS Other

"The responsiveness of urinary GAG to dosage alterations of ALDURAZYME is unknown, and the relationship of urinary GAG to other measures of clinical response has also not been established"

Current label limits use of urinary GAG as a clinical surrogate.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Other

"Due to the presence of IDUA pseudodeficiency, the establishment of the diagnosis of MPS I requires the demonstration of BOTH deficiency of IDUA enzyme activity AND elevation of urine GAGs."

Biochemical confirmation must distinguish deficient substrate degradation from artificial-substrate pseudodeficiency.

Alpha-L-iduronidase activity (Reduced)

Context: Deficient activity in leukocytes or cultured fibroblasts supports MPS I. Routine assays do not reliably separate severe from attenuated disease, and activity can be undetectable in either. Artificial-substrate pseudodeficiency requires interpretation with GAG metabolism and molecular findings. Specialized residual-activity assays show overlapping ranges and remain insufficient to establish a universal CNS-protection threshold.

Show evidence (2 references)

PMID:23786846 SUPPORT PRIMARY RESULT In Vitro

"Mean residual IDUA activity was 0.18% (range 0-0.6) of the control value in MPS IH fibroblasts (n=5); against 0.27% (range 0.2-0.3) in MPS IH/S cells (n=3); and 0.79% (range 0.3-1.8) in MPS IS fibroblasts (n=5)."

Small cultured-fibroblast study using an artificial substrate; activity ranges overlap and do not measure brain activity.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"Pseudodeficiency relates to the finding of reduced or undetectable IDUA enzyme activity with the use of artificial substrates, but no evidence of altered glycosaminoglycan metabolism with the use of radiolabeled"

Artificial-substrate deficiency can occur without the metabolic disease.

🔬

Diagnosis

4

Biochemical and molecular confirmation

Assess urinary dermatan/heparan sulfate and IDUA enzyme activity, then interpret biallelic pathogenic or likely pathogenic IDUA variants with the biochemical findings. Urinary screening is neither subtype-specific nor perfectly sensitive; a reassuring screen alone should not terminate evaluation when clinical suspicion persists. Enzyme pseudodeficiency and variants of uncertain significance are important pitfalls. Parent testing can clarify phase.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Other

"Due to the presence of IDUA pseudodeficiency, the establishment of the diagnosis of MPS I requires the demonstration of BOTH deficiency of IDUA enzyme activity AND elevation of urine GAGs."

Biochemical confirmation must distinguish deficient substrate degradation from artificial-substrate pseudodeficiency.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"Neither the quantitative nor the qualitative method can diagnose a specific lysosomal enzyme deficiency, including MPS I; however, an abnormality detected by either or both methods indicates the likely presence of an MPS disorder."

Clinical synthesis specific to the described MPS I manifestation.

Clinical severity assessment

Integrate age at onset, developmental trajectory, organ involvement and genotype. Severe and attenuated MPS I form a continuum; neither detectable residual enzyme activity nor normal early cognition independently establishes the long-term phenotype.

Show evidence (2 references)

PMID:20301341 SUPPORT REVIEW SYNTHESIS Other

"An essential component of management is the determination of whether the proband has severe or attenuated MPS I."

Management requires a clinical severity assessment.

PMID:31194252 SUPPORT PRIMARY RESULT Human Clinical

"A total of 24 patients were homozygous for P533R; seven classified as severe and 17 classified as attenuated."

The same homozygous genotype occurred in both clinical categories.

Multisystem baseline evaluation and surveillance

Arrange coordinated neurologic, ophthalmologic, auditory, cardiac, respiratory, gastrointestinal and musculoskeletal assessment. The management guideline recommends follow-up every six to twelve months with individualized intervals. Include echocardiography, pulmonary and sleep assessment, nerve-conduction studies, spinal examination and developmental or educational review; symptoms alone may miss carpal-tunnel or cord disease.

Show evidence (1 reference)

PMID:19117856 SUPPORT REVIEW SYNTHESIS Other

"All patients with mucopolysaccharidosis I should receive a comprehensive baseline evaluation, including neurologic, ophthalmologic, auditory, cardiac, respiratory, gastrointestinal, and musculoskeletal assessments, and should be monitored every 6 to 12 months with individualized specialty..."

Expert guidance across MPS I, with assessments individualized to phenotype.

At-risk family and reproductive testing

Offer testing to at-risk siblings so disease can be identified before substantial progression. Known familial pathogenic variants enable carrier, prenatal and preimplantation testing; carrier enzyme assays alone are unreliable.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Other

"Testing of all at-risk sibs of any age is warranted in order to initiate therapy as early in the course of disease as possible."

GeneReviews management recommendation; not a controlled outcome comparison.

PMID:20301341 SUPPORT REVIEW SYNTHESIS Other

"Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if both disease-causing IDUA variants have been identified in the family."

Familial molecular testing recommendation.

📈

Progression

1

Variable attenuated course

Age: Usually childhood onset, with later recognition possible

Symptoms commonly begin between three and ten years. Progression ranges from life-threatening cardiorespiratory complications in early adulthood to a near-normal lifespan with substantial joint and multisystem disability. Normal early development is not a guarantee of lifelong preserved cognition.

Show evidence (2 references)

PMID:20301341 SUPPORT REVIEW SYNTHESIS Human Clinical

"Attenuated MPS I: Clinical onset is usually between ages three and ten years."

Attenuated-specific clinical synthesis.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"The rate of disease progression can range from serious life-threatening complications leading to death in the second to third decade, to a normal life span (albeit with significant disease morbidity)."

Clinical synthesis specific to the described MPS I manifestation.

📊

Prevalence

1

Populations summarized in GeneReviews

0.2 per 100,000 1–9 per 1,000,000

Historical summary estimate of approximately one in 500,000 for attenuated MPS I. This is not a contemporary worldwide surveillance denominator; ascertainment of mild or late-recognized disease varies. The cited chapter does not specify an observation period or birth denominator for this estimate, so no measure type is imposed.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"MPS I is seen in all populations at a frequency of approximately 1:100,000 for the severe form and 1:500,000 for the attenuated form"

Clinical synthesis specific to the described MPS I manifestation.

🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Attenuated Mucopolysaccharidosis Type I:

Severe MPS I MONDO:0011758

Overlapping Features The severe end of the same IDUA spectrum. Early progressive developmental impairment and somatic disease support severe classification, but genotype and longitudinal examination are needed; normal early development or any single assay threshold cannot guarantee attenuated disease.

Distinguishing Features

The clinical trajectory and predicted allele effects inform severity rather than a categorical detectable-versus-absent enzyme rule.

Show evidence (2 references)

PMID:20301341 SUPPORT REVIEW SYNTHESIS Other

"An essential component of management is the determination of whether the proband has severe or attenuated MPS I."

Management requires a clinical severity assessment.

PMID:31194252 SUPPORT PRIMARY RESULT Human Clinical

"A total of 24 patients were homozygous for P533R; seven classified as severe and 17 classified as attenuated."

The same homozygous genotype occurred in both clinical categories.

Other mucopolysaccharidoses

Overlapping Features MPS II, VI and VII can overlap clinically. Disease-specific enzyme assays distinguish IDUA deficiency from iduronate-2-sulfatase, arylsulfatase B or beta-glucuronidase deficiency. Corneal and inheritance patterns help direct testing but do not replace biochemical confirmation.

Distinguishing Features

A urinary GAG pattern alone does not identify the deficient enzyme.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"Neither the quantitative nor the qualitative method can diagnose a specific lysosomal enzyme deficiency, including MPS I; however, an abnormality detected by either or both methods indicates the likely presence of an MPS disorder."

Clinical synthesis specific to the described MPS I manifestation.

Juvenile idiopathic arthritis

Overlapping Features Progressive noninflammatory joint limitation can lead to an arthritis referral. Evaluate the joint pattern together with corneal, skeletal, cardiac and other storage-disease signs; no universal inflammatory-marker or treatment-response rule is assumed.

Distinguishing Features

Multisystem storage-disease findings and deficient IDUA-mediated GAG degradation favor MPS I.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"Persons with attenuated MPS I may present with noninflammatory arthritis at any age; thus, MPS I should be considered in the differential diagnosis of juvenile idiopathic arthritis"

Clinical synthesis specific to the described MPS I manifestation.

IDUA pseudodeficiency

Overlapping Features Low activity against an artificial substrate can occur without disturbed GAG metabolism or clinical MPS I. Interpret enzyme results with substrate biomarkers, molecular classification and the clinical picture.

Distinguishing Features

Reduced artificial-substrate activity without abnormal GAG metabolism is not sufficient to diagnose disease.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/ SUPPORT REVIEW SYNTHESIS Human Clinical

"Pseudodeficiency relates to the finding of reduced or undetectable IDUA enzyme activity with the use of artificial substrates, but no evidence of altered glycosaminoglycan metabolism with the use of radiolabeled"

Artificial-substrate deficiency can occur without the metabolic disease.

🔬

Clinical Trials

2

NCT00912925 PHASE_III COMPLETED

Completed pivotal 26-week randomized placebo-controlled trial in 45 participants, including 37 Hurler-Scheie, seven Scheie and one Hurler participant. The FVC result favored laronidase; walking-distance significance differed between unadjusted and prespecified adjusted analyses. The registry record and current label describe the same trial, not independent replications.

Target Phenotypes: Reduced vital capacity HP:0002792

Show evidence (2 references)

clinicaltrials:NCT00912925 SUPPORT BACKGROUND Other

"This study is being conducted to demonstrate the safety and clinical efficacy of Aldurazyme treatment in MPS I patients"

Official registry study-design description. Phase, status and enrollment were separately checked in the live structured registry record; this summary does not report efficacy results.

PMID:31211405 SUPPORT REVIEW SYNTHESIS Human Clinical

"The laronidase group achieved statistically significant improvements in per cent predicted forced vital capacity compared to placebo, MD 5.60 (95% confidence intervals 1.24 to 9.96) (low-quality evidence) and in the six-minute-walk test (mean improvement of 38.1 metres in the laronidase group; P..."

Cochrane synthesis of one 45-person, 26-week trial; walk-test significance depends on the prespecified adjusted analysis.

NCT00852358 NOT_APPLICABLE COMPLETED

Completed open-label randomized delayed-treatment intrathecal laronidase study. The registry reports nine enrolled, whereas the published randomized analysis contains eight participants, four per group. Existing intravenous ERT continued. No significant between-group cognitive benefit was demonstrated; stable controls, small sample size and limited controlled duration constrain inference.

Target Phenotypes: Cognitive impairment HP:0100543

Show evidence (2 references)

clinicaltrials:NCT00852358 SUPPORT BACKGROUND Other

"This is a 24-month study of the use of laronidase administered into the spinal fluid to treat cognitive decline in mucopolysaccharidosis I (MPS I). MPS I is a rare genetic condition due to deficiency of the enzyme alpha-l-iduronidase. Laronidase is the manufactured form of the enzyme alpha-l-iduronidase."

Official registry study-design description. Phase, status and enrollment were separately checked in the live structured registry record; this summary does not report efficacy results.

PMID:31839529 SUPPORT PRIMARY RESULT Human Clinical

"Nor was there a significant difference between treatment and control groups in any of the neuropsychological tests. Subjects in the control group did not experience any significant decline over the 12 month untreated period in any neuropsychological test except the Brief Visuospatial Memory..."

Eight-person randomized open-label pilot with ongoing intravenous ERT; no demonstrated cognitive benefit in this design.

🧫

Experimental Models

1

Patient fibroblast residual-IDUA and thermal-stability assays PRIMARY_CELL_CULTURE

Cultured fibroblast homogenates from severe, intermediate and mild MPS I were assayed with an artificial fluorogenic substrate under high-protein and prolonged-incubation conditions. The E276K-associated activity was unstable at 37 degrees Celsius and more stable at 23 degrees Celsius. The study proposes a residual-function approach but does not validate an individual prognostic classifier.

Organism

Homo sapiens NCBITaxon:9606

Cell source

Patient-derived skin fibroblasts and control fibroblasts

Publication

PMID:23786846

Pathograph links

Reduced Alpha-L-Iduronidase Activity measures fidelity: moderate observes: molecular Residual activity was markedly reduced, with overlapping clinical-subtype ranges.

Limitations: Artificial 4-methylumbelliferyl substrate, high protein loading and extended incubation measure residual catalytic activity. Severe and attenuated ranges overlap. No neuronal activity threshold, natural-GAG turnover, intracellular protein half-life or clinical rescue was established. The abstract labels the Scheie group n=5, whereas the main Results and Table 1 include seven Scheie cell lines across five genotypes, including three E276K siblings. Those siblings are not independent genotype replications.

Divergences from the human mechanism

proxy quantity qualifying

Artificial-substrate activity in cultured-cell homogenates stands in for lysosomal hydrolysis in patient tissues; CNS protection and intact-cell protein turnover were not measured.

Readouts

Fluorogenic IDUA activity

Direction: DECREASED

Interpretation: Residual activity was markedly reduced, with overlapping clinical-subtype ranges.

Show evidence (1 reference)

PMID:23786846 SUPPORT PRIMARY RESULT In Vitro

"Mean residual IDUA activity was 0.18% (range 0-0.6) of the control value in MPS IH fibroblasts (n=5); against 0.27% (range 0.2-0.3) in MPS IH/S cells (n=3); and 0.79% (range 0.3-1.8) in MPS IS fibroblasts (n=5)."

Small cultured-fibroblast study using an artificial substrate; activity ranges overlap and do not measure brain activity.

Show evidence (1 reference)

PMID:23786846 SUPPORT PRIMARY RESULT In Vitro

"Mean residual IDUA activity was 0.18% (range 0-0.6) of the control value in MPS IH fibroblasts (n=5); against 0.27% (range 0.2-0.3) in MPS IH/S cells (n=3); and 0.79% (range 0.3-1.8) in MPS IS fibroblasts (n=5)."

Small cultured-fibroblast study using an artificial substrate; activity ranges overlap and do not measure brain activity.

Variant-Dependent IDUA Functional Instability measures fidelity: moderate observes: molecular E276K-associated activity decayed faster at 37 degrees Celsius than at 23 degrees Celsius.

Limitations: Artificial 4-methylumbelliferyl substrate, high protein loading and extended incubation measure residual catalytic activity. Severe and attenuated ranges overlap. No neuronal activity threshold, natural-GAG turnover, intracellular protein half-life or clinical rescue was established. The abstract labels the Scheie group n=5, whereas the main Results and Table 1 include seven Scheie cell lines across five genotypes, including three E276K siblings. Those siblings are not independent genotype replications.

Divergences from the human mechanism

proxy quantity qualifying

Artificial-substrate activity in cultured-cell homogenates stands in for lysosomal hydrolysis in patient tissues; CNS protection and intact-cell protein turnover were not measured.

Readouts

Temperature-dependent retention of IDUA activity

Direction: ALTERED

Interpretation: E276K-associated activity decayed faster at 37 degrees Celsius than at 23 degrees Celsius.

Show evidence (1 reference)

PMID:23786846 SUPPORT PRIMARY RESULT In Vitro

"IDUA(E276K) was very unstable at 37°C, but more stable at 23°C, suggesting thermal instability."

Temperature-dependent loss of enzyme activity in patient fibroblast homogenates; not protein-turnover measurement or a universal allele mechanism.

Show evidence (1 reference)

PMID:23786846 SUPPORT PRIMARY RESULT In Vitro

"IDUA(E276K) was very unstable at 37°C, but more stable at 23°C, suggesting thermal instability."

Temperature-dependent loss of enzyme activity in patient fibroblast homogenates; not protein-turnover measurement or a universal allele mechanism.

Show evidence (3 references)

PMID:23786846 SUPPORT PRIMARY RESULT In Vitro

"Mean residual IDUA activity was 0.18% (range 0-0.6) of the control value in MPS IH fibroblasts (n=5); against 0.27% (range 0.2-0.3) in MPS IH/S cells (n=3); and 0.79% (range 0.3-1.8) in MPS IS fibroblasts (n=5)."

Small cultured-fibroblast study using an artificial substrate; activity ranges overlap and do not measure brain activity.

PMID:23786846 SUPPORT PRIMARY RESULT In Vitro

"IDUA(E276K) was very unstable at 37°C, but more stable at 23°C, suggesting thermal instability."

Temperature-dependent loss of enzyme activity in patient fibroblast homogenates; not protein-turnover measurement or a universal allele mechanism.

url:https://repub.eur.nl/pub/112929/Opmaak-Esmee-Oussoren-mindiscussie.pdf SUPPORT PRIMARY RESULT In Vitro

"Fibroblast homogenates were prepared by resuspending one cell pellet in 100 µL water followed by sonication for 10 sec at 130 W."

Methods of the 2013 article reproduced in chapter 3 of Oussoren’s 2018 thesis, Studies on Cartilage and Bone Disease in Mucopolysaccharidoses and Mucolipidoses. This measures fibroblast-homogenate activity, not intact-brain or natural-substrate flux.

{ }

Source YAML

click to show

name: Attenuated Mucopolysaccharidosis Type I
creation_date: '2026-08-27T00:00:00Z'
category: Mendelian
description: >-
  Attenuated mucopolysaccharidosis type I comprises the historically named Hurler-Scheie and Scheie phenotypes within
  the continuous spectrum of biallelic IDUA-related disease. Deficient alpha-L-iduronidase impairs lysosomal degradation
  of dermatan and heparan sulfate. Progressive skeletal, joint, corneal, valvular, respiratory and peripheral neurologic
  disease can cause substantial disability despite slower progression than severe Hurler syndrome. Onset is commonly
  between three and ten years, with variable diagnostic delay. Normal early development does not exclude later learning
  difficulties or cognitive impairment. Laronidase treats selected somatic manifestations; neither residual enzyme
  activity nor a mild early presentation guarantees an unaffected CNS or reversal of established structural disease.
classifications:
  lysosomal_storage_category:
    classification_value: mucopolysaccharidosis
    notes: >-
      Attenuated MPS I is a mucopolysaccharidosis: lysosomal accumulation of the glycosaminoglycans dermatan sulfate
      and heparan sulfate arising from partial alpha-L-iduronidase deficiency.
  icimd_category:
  - classification_value: glycosaminoglycan_degradation
    notes: >-
      ICIMD (Ferreira et al. 2021, PMID:33340416): group "Glycosaminoglycan degradation" under category "Disorders
      of complex molecule degradation". Attenuated MPS I is alpha-L-iduronidase deficiency, the same enzyme defect
      as Hurler syndrome, with residual activity.
  isds_skeletal_category:
  - classification_value: lysosomal_storage_with_skeletal_involvement
    notes: >-
      ISDS Nosology and Classification of Genetic Skeletal Disorders, 2019 revision (Mortier et al., PMID:31633310),
      Table 1 group 27 "Lysosomal storage diseases with skeletal involvement (dysostosis multiplex group)"; MPS
      type 1 is listed there, and the attenuated forms carry the dysostosis multiplex phenotype that defines the
      group.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0011759
      label: Hurler-Scheie syndrome
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: >-
      Hurler-Scheie syndrome is the intermediate attenuated MPS I phenotype and is one of the two MONDO concepts
      this entry covers. narrowMatch rather than exactMatch because this entry deliberately spans both attenuated
      concepts; the Hurler-Scheie subtype is curated in has_subtypes.
  - term:
      id: MONDO:0011760
      label: Scheie syndrome
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: >-
      Scheie syndrome is the mildest attenuated MPS I phenotype and is the second MONDO concept this entry covers.
      narrowMatch for the same reason; the Scheie subtype is curated in has_subtypes.
  - term:
      id: MONDO:0001586
      label: mucopolysaccharidosis type 1
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO
    mapping_justification: >-
      MPS type 1 is the parent concept spanning the whole IDUA-deficiency spectrum. It is broader than this entry
      because it also subsumes Hurler syndrome, which dismech curates separately; recorded as broadMatch so it is
      not retired from the curation queue by this entry alone.
parents:
- Mucopolysaccharidosis
- Lysosomal Storage Disorder
synonyms:
- attenuated MPS I
- attenuated mucopolysaccharidosis type I
- MPS I H/S
- MPS I S
- Hurler-Scheie syndrome
- Scheie syndrome
notes: >-
  This entry covers the attenuated MPS I spectrum, retaining Hurler-Scheie and Scheie as historical subtypes. Their
  clinical boundary is imprecise. The parent MPS I concept also includes severe Hurler syndrome, so it remains a
  broad mapping rather than an exact disease binding. Subtype-specific observations are distinguished from mixed
  MPS I data. In particular, the 2026 carpal-tunnel series contains 31 Hurler and only two Hurler-Scheie patients,
  all treated with transplantation, and cannot define attenuated phenotype frequencies or onset. The institutional
  PDF is Esmeralda Oussoren’s 2018 thesis, Studies on Cartilage and Bone Disease in Mucopolysaccharidoses and Mucolipidoses.
  Its chapter 3 reproduces the 2013 residual-IDUA study (PMID:23786846). The generated PDF cache records its URL
  as the title; citation metadata retains that value to satisfy authoritative title validation, while this note
  identifies the work by its actual title.
has_subtypes:
- name: Hurler-Scheie
  display_name: Hurler-Scheie syndrome (MPS I H/S)
  subtype_term:
    preferred_term: Hurler-Scheie syndrome
    term:
      id: MONDO:0011759
      label: Hurler-Scheie syndrome
  genes:
  - preferred_term: IDUA
    term:
      id: hgnc:5391
      label: IDUA
  description: >-
    Historical intermediate phenotype with progressive somatic disease and variable neurologic involvement. It overlaps
    with Scheie syndrome and is usually grouped with it as attenuated MPS I for clinical management.
  evidence:
  - &id001
    reference: PMID:32764324
    reference_title: 'Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Three MPS I subtypes have been classified that differ in the severity of disease, ranging from mild (Scheie
      syndrome) to moderate (Hurler–Scheie) to severe (Hurler syndrome or MPS-IH)
    explanation: Historical clinical categories within one disease spectrum.
- name: Scheie
  display_name: Scheie syndrome (MPS I S, formerly MPS V)
  subtype_term:
    preferred_term: Scheie syndrome
    term:
      id: MONDO:0011760
      label: Scheie syndrome
  genes:
  - preferred_term: IDUA
    term:
      id: hgnc:5391
      label: IDUA
  description: >-
    Historical mildest phenotype, sometimes recognized only in adulthood. Significant progressive joint, ocular
    and cardiac disease may occur despite relatively preserved cognition. The label does not specify an individual
    prognosis.
  evidence:
  - *id001
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic pathogenic IDUA variants cause disease. When both parents are confirmed carriers, each pregnancy has
    a 25% recurrence risk. Carrier enzyme testing is unreliable; familial molecular testing supports reproductive
    counseling.
  evidence:
  - &id011
    reference: PMID:20301341
    reference_title: Mucopolysaccharidosis Type I.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: MPS I is inherited in an autosomal recessive manner.
    explanation: Inheritance mode summarized in GeneReviews.
pathophysiology:
- name: Biallelic IDUA Pathogenic Variants
  description: >-
    Pathogenic variants in both IDUA alleles underlie the attenuated clinical spectrum. Allele-specific residual
    function varies, and clinical severity is not determined by a single enzyme-activity cutoff.
  biological_scale: MOLECULAR
  evidence:
  - &id002
    reference: PMID:32764324
    reference_title: 'Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive inherited disease, caused by deficiency
      of the enzyme α-L-iduronidase, resulting in accumulation of the glycosaminoglycans (GAGs) dermatan and heparan
      sulfate in organs and tissues
    explanation: Established MPS I enzyme and storage mechanism; not a subtype-specific activity threshold.
  - &id012
    reference: PMID:31194252
    reference_title: >-
      Genotype-phenotype relationships in mucopolysaccharidosis type I (MPS I): Insights from the International
      MPS I Registry.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      A total of 24 patients were homozygous for P533R; seven classified as severe and 17 classified as attenuated.
    explanation: The same homozygous genotype occurred in both clinical categories.
  gene: &id003
    preferred_term: IDUA
    term:
      id: hgnc:5391
      label: IDUA
  downstream:
  - target: Reduced Alpha-L-Iduronidase Activity
    description: >-
      Pathogenic variants reduce the amount or catalytic function of IDUA through allele-dependent effects.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32764324
      reference_title: 'Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive inherited disease, caused by deficiency
        of the enzyme α-L-iduronidase, resulting in accumulation of the glycosaminoglycans (GAGs) dermatan and heparan
        sulfate in organs and tissues
      explanation: Established MPS I enzyme and storage mechanism; not a subtype-specific activity threshold.
    - reference: PMID:23786846
      reference_title: >-
        Residual α-L-iduronidase activity in fibroblasts of mild to severe Mucopolysaccharidosis type I patients.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        Mean residual IDUA activity was 0.18% (range 0-0.6) of the control value in MPS IH fibroblasts (n=5); against
        0.27% (range 0.2-0.3) in MPS IH/S cells (n=3); and 0.79% (range 0.3-1.8) in MPS IS fibroblasts (n=5).
      explanation: >-
        Small cultured-fibroblast study using an artificial substrate; activity ranges overlap and do not measure
        brain activity.
  - target: Variant-Dependent IDUA Functional Instability
    description: The E276K-associated experimental finding illustrates one possible allele-dependent contribution.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23786846
      reference_title: >-
        Residual α-L-iduronidase activity in fibroblasts of mild to severe Mucopolysaccharidosis type I patients.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: IDUA(E276K) was very unstable at 37°C, but more stable at 23°C, suggesting thermal instability.
      explanation: >-
        Temperature-dependent loss of enzyme activity in patient fibroblast homogenates; not protein-turnover measurement
        or a universal allele mechanism.
  - target: Learning disability
    description: >-
      Learning difficulties occur in attenuated MPS I, but no validated residual-enzyme threshold or specific neuronal
      intermediate explains individual risk.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
      reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Although development may be normal in early childhood, children and adults with attenuated MPS I may have
        detectable learning disabilities.
      explanation: >-
        Clinical synthesis specific to the described MPS I manifestation. The genotype-to-phenotype relationship
        does not identify all intermediate mechanisms.
      directness: INDIRECT
  - target: Cognitive impairment
    description: >-
      Some attenuated patients have cognitive impairment. The observed phenotype does not establish a uniform storage-to-neurodegeneration
      route or a protective residual-activity threshold.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41353341
      reference_title: >-
        Clinical outcomes of exclusive enzyme therapy (laronidase) in a cohort of patients with mucopolysaccharidosis
        type I.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Before ERT, 4 (16%) patients had cognitive impairment since the median age of 7.3 years.
      explanation: >-
        Attenuated subset of an uncontrolled treated cohort, not population prevalence. The genotype-to-phenotype
        relationship does not identify all intermediate mechanisms.
      directness: INDIRECT
- name: Reduced Alpha-L-Iduronidase Activity
  description: >-
    IDUA hydrolytic activity is markedly reduced. Specialized fibroblast assays may detect residual activity, but
    routine diagnostic assays can show little or no activity in both severe and attenuated disease.
  biological_scale: MOLECULAR
  evidence:
  - *id002
  - &id010
    reference: PMID:23786846
    reference_title: >-
      Residual α-L-iduronidase activity in fibroblasts of mild to severe Mucopolysaccharidosis type I patients.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      Mean residual IDUA activity was 0.18% (range 0-0.6) of the control value in MPS IH fibroblasts (n=5); against
      0.27% (range 0.2-0.3) in MPS IH/S cells (n=3); and 0.79% (range 0.3-1.8) in MPS IS fibroblasts (n=5).
    explanation: >-
      Small cultured-fibroblast study using an artificial substrate; activity ranges overlap and do not measure
      brain activity.
  gene: *id003
  molecular_functions:
  - preferred_term: L-iduronidase activity
    term:
      id: GO:0003940
      label: L-iduronidase activity
  downstream:
  - target: Impaired Dermatan and Heparan Sulfate Degradation
    description: Insufficient iduronidase activity limits the required hydrolytic step.
    causal_link_type: DIRECT
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
      reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        encodes alpha-L-iduronidase, a glycosidase that removes nonreducing terminal &#x003b1;-L-iduronide residues
        during the lysosomal degradation of heparan sulfate and dermatan sulfate, which are glycosaminoglycans in
        mammalian cells
      explanation: >-
        Enzymatic role of IDUA summarized in the molecular-pathogenesis section; the cached HTML entity is preserved.
- name: Variant-Dependent IDUA Functional Instability
  description: >-
    For the E276K allele, enzyme activity rapidly decays during incubation of fibroblast homogenates at 37 degrees
    Celsius and is more stable at lower temperature. This is an allele-specific experimental route to loss of activity,
    not evidence of accelerated intracellular protein degradation for all patients.
  biological_scale: MOLECULAR
  evidence:
  - &id019
    reference: PMID:23786846
    reference_title: >-
      Residual α-L-iduronidase activity in fibroblasts of mild to severe Mucopolysaccharidosis type I patients.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: IDUA(E276K) was very unstable at 37°C, but more stable at 23°C, suggesting thermal instability.
    explanation: >-
      Temperature-dependent loss of enzyme activity in patient fibroblast homogenates; not protein-turnover measurement
      or a universal allele mechanism.
  downstream:
  - target: Reduced Alpha-L-Iduronidase Activity
    description: Loss of retained enzyme activity during incubation reduces measured catalytic output.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23786846
      reference_title: >-
        Residual α-L-iduronidase activity in fibroblasts of mild to severe Mucopolysaccharidosis type I patients.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: IDUA(E276K) was very unstable at 37°C, but more stable at 23°C, suggesting thermal instability.
      explanation: >-
        Temperature-dependent loss of enzyme activity in patient fibroblast homogenates; not protein-turnover measurement
        or a universal allele mechanism.
- name: Impaired Dermatan and Heparan Sulfate Degradation
  description: >-
    Deficient IDUA interrupts sequential lysosomal degradation of dermatan and heparan sulfate at terminal iduronic-acid
    residues.
  biological_scale: MOLECULAR
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      encodes alpha-L-iduronidase, a glycosidase that removes nonreducing terminal &#x003b1;-L-iduronide residues
      during the lysosomal degradation of heparan sulfate and dermatan sulfate, which are glycosaminoglycans in
      mammalian cells
    explanation: >-
      Enzymatic role of IDUA summarized in the molecular-pathogenesis section; the cached HTML entity is preserved.
  - *id002
  cellular_components:
  - preferred_term: lysosome
    term:
      id: GO:0005764
      label: lysosome
  biological_processes:
  - preferred_term: glycosaminoglycan catabolic process
    modifier: DECREASED
    term:
      id: GO:0006027
      label: glycosaminoglycan catabolic process
  downstream:
  - target: Lysosomal Glycosaminoglycan Accumulation
    description: Failure to complete degradation permits substrate storage.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32764324
      reference_title: 'Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive inherited disease, caused by deficiency
        of the enzyme α-L-iduronidase, resulting in accumulation of the glycosaminoglycans (GAGs) dermatan and heparan
        sulfate in organs and tissues
      explanation: Established MPS I enzyme and storage mechanism; not a subtype-specific activity threshold.
- name: Lysosomal Glycosaminoglycan Accumulation
  conforms_to: "lysosomal_substrate_accumulation#Lysosomal Substrate Accumulation"
  description: >-
    Partially degraded substrates accumulate in lysosomes across tissues. The amount and consequences vary by cell
    type and disease stage; urine GAG excretion is not a direct measurement of every tissue pool.
  biological_scale: CELLULAR
  evidence:
  - *id002
  cellular_components:
  - preferred_term: lysosome
    term:
      id: GO:0005764
      label: lysosome
  downstream:
  - target: Extracellular Matrix Disorganization
    description: >-
      Lysosomal storage accompanies extracellular substrate deposition and altered matrix organization; the cellular
      export and remodeling sequence is incompletely resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32764324
      reference_title: 'Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        GAG deposits and GAG-laden cells also interfere with the organization of collagen and elastin fibers
      explanation: >-
        General MPS I tissue-pathology synthesis; the relative contribution to each attenuated manifestation is
        not quantified.
  - target: Growth Plate Disorganization
    description: Storage and secondary tissue changes disturb growth-plate architecture.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32764324
      reference_title: 'Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        The epiphyseal growth plates in patients affected by MPS I ... and in animal models of MPS I ... are disorganized
        and show large chondrocytes with large vacuolar contents
      explanation: Human and model pathology summarized together; not an attenuated-specific longitudinal experiment.
  - target: Periarticular Tissue Remodeling
    description: Storage in periarticular tissues contributes to tissue remodeling and reduced compliance.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32764324
      reference_title: 'Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Joint symptoms, such as joint stiffness and limited range of joint mobility, stem from GAG accumulation
        and secondary pathogenic cascades in the ligaments and capsule around the joints
      explanation: Review synthesis linking periarticular tissue disease to joint dysfunction.
  - target: Cardiac Valve Thickening
    description: Storage-associated interstitial and matrix changes thicken valve tissue.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32764324
      reference_title: 'Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        The most commonly affected valves are the mitral and the aortic valves that are significantly thickened
        ... by progressive infiltration of GAG-laden activated valvular interstitial cells into the valvular tissues
        ... and excessive deposits of collagen ... Functional outcomes are poor mobility of the valves, regurgitation,
        and, to a lesser extent, stenosis
      explanation: Review synthesis of valve tissue pathology and mechanical dysfunction.
  - target: Upper Airway Narrowing
    description: Storage-associated soft-tissue enlargement contributes to upper airway narrowing.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
      reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Storage of GAGs within the oropharynx with associated enlargement of the tonsils and adenoids can contribute
        to upper airway complications, along with narrowed trachea, thickened vocal cords, redundant tissue in the
        upper airway, and an enlarged tongue.
      explanation: General MPS I airway mechanism; attenuated obstructive sleep apnea is separately documented.
  - target: Dural Thickening
    description: >-
      Storage-associated meningeal disease contributes to dural thickening; the full cellular sequence is not demonstrated
      here.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
      reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Progressive compression of the spinal cord with resulting cervical myelopathy caused by thickening of the
        dura (hypertrophic pachymeningitis cericalis) is common in individuals with attenuated MPS I.
      explanation: Attenuated-specific clinical mechanism; the source spelling is preserved in the quote.
  - target: Hepatosplenomegaly
    description: >-
      Storage expands liver and spleen tissue; attenuated enlargement is variable.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
      reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: <b>Hepatosplenomegaly</b> is variable in individuals with attenuated MPS I.
      explanation: >-
        Attenuated-specific clinical synthesis.
      directness: INDIRECT
    - reference: PMID:32764324
      reference_title: 'Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Protuberance of the abdomen caused by progressive hepatosplenomegaly is common .... Although the organs
        may be vastly enlarged, storage of GAGs in the liver and spleen does not lead to organ dysfunction.
      explanation: >-
        General MPS I tissue-pathology synthesis; the contribution to attenuated disease and each individual outcome
        remains indirect.
      directness: INDIRECT
  - target: Reduced vital capacity
    description: >-
      Storage-associated airway and thoracic skeletal disease can impair pulmonary function. Reduced vital capacity
      is not attributed solely to upper-airway narrowing.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
      reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Progressive pulmonary disease may manifest as abnormalities of forced vital capacity. Respiratory complications
        (and cardiac involvement) are among the leading causes of premature death.
      explanation: >-
        Clinical synthesis specific to the described MPS I manifestation.
      directness: INDIRECT
    - reference: PMID:32764324
      reference_title: 'Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Finally, skeletal deformities of the thoracic cage predispose MPS I patients for restrictive lung disease
        ....
      explanation: >-
        General MPS I tissue-pathology synthesis; the contribution to attenuated disease and each individual outcome
        remains indirect.
      directness: INDIRECT
  - target: Hearing impairment
    description: >-
      Storage-associated middle- and inner-ear abnormalities can impair hearing; the eustachian, ossicular and neural
      contributions vary.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
      reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Hearing impairment, most commonly in the high frequency range, is likely caused by a combination of eustachian
        tube dysfunction, dysostosis of the ossicles of the middle ear, and eighth nerve involvement.
      explanation: >-
        Clinical synthesis specific to the described MPS I manifestation.
      directness: INDIRECT
  - target: Coarse facial features
    description: >-
      Storage in craniofacial soft tissues and bones contributes to coarse facial appearance; no growth-plate-only
      mechanism is asserted.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
      reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Coarseness of facial features is less obvious than in individuals with severe MPS I. Findings can include
        a short neck, wide mouth, and square jaw.
      explanation: >-
        Clinical synthesis specific to the described MPS I manifestation.
      directness: INDIRECT
    - reference: PMID:32764324
      reference_title: 'Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        These characteristic features are caused by GAG deposits in the soft tissues and bones.
      explanation: >-
        General MPS I tissue-pathology synthesis; the contribution to attenuated disease and each individual outcome
        remains indirect.
      directness: INDIRECT
  - target: Short neck
    description: >-
      Storage-associated skeletal and soft-tissue abnormalities contribute to the short-neck appearance; their individual
      contributions are not resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
      reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Coarseness of facial features is less obvious than in individuals with severe MPS I. Findings can include
        a short neck, wide mouth, and square jaw.
      explanation: >-
        Clinical synthesis specific to the described MPS I manifestation.
      directness: INDIRECT
    - reference: PMID:32764324
      reference_title: 'Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Musculoskeletal deformities such as nasal dysmorphism, short neck, abnormal cervical vertebrae, and mandible
        predispose the patient for the development of upper airway obstructions.
      explanation: >-
        General MPS I tissue-pathology synthesis; the contribution to attenuated disease and each individual outcome
        remains indirect.
      directness: INDIRECT
  - target: Wide mouth
    description: >-
      Craniofacial tissue storage contributes to the reported facial spectrum; the pathway to a wide mouth is inferred
      rather than directly assayed.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
      reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Coarseness of facial features is less obvious than in individuals with severe MPS I. Findings can include
        a short neck, wide mouth, and square jaw.
      explanation: >-
        Clinical synthesis specific to the described MPS I manifestation.
      directness: INDIRECT
    - reference: PMID:32764324
      reference_title: 'Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        These characteristic features are caused by GAG deposits in the soft tissues and bones.
      explanation: >-
        General MPS I tissue-pathology synthesis; the contribution to attenuated disease and each individual outcome
        remains indirect.
      directness: INDIRECT
  - target: Glaucoma
    description: >-
      Storage can impair aqueous drainage through trabecular or angle abnormalities; corneal stromal disorganization
      is not a necessary intermediary.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
      reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Corneal clouding can lead to significant visual disability. Glaucoma, retinal degeneration, and optic atrophy
        can occur.
      explanation: >-
        Clinical synthesis specific to the described MPS I manifestation.
      directness: INDIRECT
    - reference: PMID:32764324
      reference_title: 'Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        In MPS I, drainage may be impaired by GAG accumulation in the trabecular meshwork (open-angle glaucoma)
        or by GAG deposits in the iris and cornea, which bring the lens and the iris into contact and eventually
        prevents drainage (closed-angle glaucoma).
      explanation: >-
        General MPS I tissue-pathology synthesis; the contribution to attenuated disease and each individual outcome
        remains indirect.
      directness: INDIRECT
  - target: Retinal degeneration
    description: >-
      Retinal storage-associated injury is distinct from the corneal stromal pathway.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
      reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Corneal clouding can lead to significant visual disability. Glaucoma, retinal degeneration, and optic atrophy
        can occur.
      explanation: >-
        Clinical synthesis specific to the described MPS I manifestation.
      directness: INDIRECT
    - reference: PMID:32764324
      reference_title: 'Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        GAG deposits within retinal pigment epithelial cells and in the photoreceptor matrix leads to progressive
        photoreceptor loss, retinal degeneration, and dysfunction ....
      explanation: >-
        General MPS I tissue-pathology synthesis; the contribution to attenuated disease and each individual outcome
        remains indirect.
      directness: INDIRECT
  - target: Optic atrophy
    description: >-
      Several storage-associated ocular and intracranial processes can injure the optic nerve; the relative route
      is unresolved in attenuated disease.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
      reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Corneal clouding can lead to significant visual disability. Glaucoma, retinal degeneration, and optic atrophy
        can occur.
      explanation: >-
        Clinical synthesis specific to the described MPS I manifestation.
      directness: INDIRECT
    - reference: PMID:32764324
      reference_title: 'Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Ocular manifestations of MPS I are caused by GAG deposits in the majority of ocular tissues and include
        corneal clouding, ocular hypertension/glaucoma, retinal degeneration, optic nerve swelling/atrophy ...,
        refractive errors, and ocular motility abnormalities ...
      explanation: >-
        General MPS I tissue-pathology synthesis; the contribution to attenuated disease and each individual outcome
        remains indirect.
      directness: INDIRECT
  - target: Hydrocephalus
    description: >-
      Storage may interfere with cerebrospinal-fluid absorption. This proposed cranial route is distinct from the
      modeled cervical dural thickening.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
      reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        The risk of communicating hydrocephalus and its complications are lower in attenuated MPS I than severe
        MPS I. However, hydrocephalus may occur with insidious onset.
      explanation: >-
        Clinical synthesis specific to the described MPS I manifestation.
      directness: INDIRECT
    - reference: PMID:32764324
      reference_title: 'Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Anatomically, MPS IH patients display abnormalities in the white matter ... dilated perivascular spaces
        (PVS), atrophy ..., cervical spinal cord compression, and hydrocephalus .... The latter may be caused by
        interference with CSF absorption by GAG-laden cells and extracellular GAG deposits.
      explanation: >-
        The proposed absorption mechanism is described for Hurler disease; extension to the separately documented
        attenuated hydrocephalus is indirect, not a cervical-dura mechanism.
      directness: INDIRECT
- name: Extracellular Matrix Disorganization
  conforms_to: "mps_gag_storage#Dermatan Sulfate-Driven Connective-Tissue and ECM Storage"
  description: >-
    Accumulated GAGs and storage-laden cells alter tissue hydration and organization of structural fibers. This
    is not equivalent to an inherited collagen defect or proof that normal decorin biology explains every manifestation.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: extracellular matrix organization
    modifier: DYSREGULATED
    term:
      id: GO:0030198
      label: extracellular matrix organization
  evidence:
  - reference: PMID:32764324
    reference_title: 'Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      GAG deposits and GAG-laden cells also interfere with the organization of collagen and elastin fibers
    explanation: >-
      General MPS I tissue-pathology synthesis; the relative contribution to each attenuated manifestation is not
      quantified.
  downstream:
  - target: Corneal Stromal Disorganization
    description: Corneal matrix changes disturb the orderly architecture needed for transparency.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32764324
      reference_title: 'Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Corneal clouding is caused by aberrant GAG deposits in stromal keratocytes and disruption of normal collagen
        alignment in the corneal stroma ... The usually highly uniform collagen fibrils show great variations in
        diameter, and the fibrils are spaced further apart
      explanation: >-
        Corneal pathology synthesis across MPS I; the severe infant timing elsewhere in this review is not assigned
        to attenuated disease.
  - target: Inguinal hernia
    description: >-
      Altered abdominal-wall connective tissue is a proposed contribution to herniation; the complete tissue-failure
      sequence is not demonstrated.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
      reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Many have also had inguinal hernias during infancy, often requiring repeated surgical correction.
      explanation: >-
        Clinical synthesis specific to the described MPS I manifestation.
      directness: INDIRECT
    - reference: PMID:32764324
      reference_title: 'Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Recurrent umbilical and inguinal hernias are common in MPS I patients and are attributed to an aberrant
        collagen state in the abdominal wall ....
      explanation: >-
        General MPS I tissue-pathology synthesis; the contribution to attenuated disease and each individual outcome
        remains indirect.
      directness: INDIRECT
- name: Growth Plate Disorganization
  description: >-
    Abnormal chondrocyte morphology and growth-plate organization contribute to skeletal dysplasia and impaired
    longitudinal growth. Specific cathepsin-K and TLR4 routes remain proposed or model-derived and are not imposed
    as a proven attenuated human cascade.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:32764324
    reference_title: 'Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The epiphyseal growth plates in patients affected by MPS I ... and in animal models of MPS I ... are disorganized
      and show large chondrocytes with large vacuolar contents
    explanation: Human and model pathology summarized together; not an attenuated-specific longitudinal experiment.
  downstream:
  - target: Dysostosis multiplex
    description: This tissue process contributes to the clinical finding; severity and timing vary.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32764324
      reference_title: 'Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        The epiphyseal growth plates in patients affected by MPS I ... and in animal models of MPS I ... are disorganized
        and show large chondrocytes with large vacuolar contents
      explanation: Human and model pathology summarized together; not an attenuated-specific longitudinal experiment.
  - target: Short stature
    description: This tissue process contributes to the clinical finding; severity and timing vary.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32764324
      reference_title: 'Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        The epiphyseal growth plates in patients affected by MPS I ... and in animal models of MPS I ... are disorganized
        and show large chondrocytes with large vacuolar contents
      explanation: Human and model pathology summarized together; not an attenuated-specific longitudinal experiment.
  - target: Kyphosis
    description: This tissue process contributes to the clinical finding; severity and timing vary.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32764324
      reference_title: 'Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        The epiphyseal growth plates in patients affected by MPS I ... and in animal models of MPS I ... are disorganized
        and show large chondrocytes with large vacuolar contents
      explanation: Human and model pathology summarized together; not an attenuated-specific longitudinal experiment.
  - target: Scoliosis
    description: This tissue process contributes to the clinical finding; severity and timing vary.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32764324
      reference_title: 'Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        The epiphyseal growth plates in patients affected by MPS I ... and in animal models of MPS I ... are disorganized
        and show large chondrocytes with large vacuolar contents
      explanation: Human and model pathology summarized together; not an attenuated-specific longitudinal experiment.
  - target: Spondylolisthesis
    description: This tissue process contributes to the clinical finding; severity and timing vary.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32764324
      reference_title: 'Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        The epiphyseal growth plates in patients affected by MPS I ... and in animal models of MPS I ... are disorganized
        and show large chondrocytes with large vacuolar contents
      explanation: Human and model pathology summarized together; not an attenuated-specific longitudinal experiment.
- name: Periarticular Tissue Remodeling
  description: >-
    GAG storage and secondary changes in ligaments and joint capsules restrict joint movement. Clinical noninflammatory
    arthropathy does not imply the absence of all molecular inflammatory signaling.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:32764324
    reference_title: 'Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Joint symptoms, such as joint stiffness and limited range of joint mobility, stem from GAG accumulation and
      secondary pathogenic cascades in the ligaments and capsule around the joints
    explanation: Review synthesis linking periarticular tissue disease to joint dysfunction.
  downstream:
  - target: Median Nerve Compression
    description: >-
      Hand connective-tissue changes can contribute to tunnel crowding, alongside bony factors; the dominant mechanism
      was not isolated in the surgical cohort.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41656624
      reference_title: >-
        Carpal tunnel syndrome in mucopolysaccharidosis type I: clinical, surgical and histopathological findings.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: The flexor retinaculum was thickened and synovial tissues appeared swollen in six cases.
      explanation: >-
        Intraoperative observation in a mostly Hurler post-HSCT cohort; extrapolation to attenuated disease is indirect.
      directness: INDIRECT
  - target: Limitation of joint mobility
    description: This tissue process contributes to the clinical finding; severity and timing vary.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32764324
      reference_title: 'Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Joint symptoms, such as joint stiffness and limited range of joint mobility, stem from GAG accumulation
        and secondary pathogenic cascades in the ligaments and capsule around the joints
      explanation: Review synthesis linking periarticular tissue disease to joint dysfunction.
  - target: Joint contracture
    description: This tissue process contributes to the clinical finding; severity and timing vary.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32764324
      reference_title: 'Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Joint symptoms, such as joint stiffness and limited range of joint mobility, stem from GAG accumulation
        and secondary pathogenic cascades in the ligaments and capsule around the joints
      explanation: Review synthesis linking periarticular tissue disease to joint dysfunction.
  - target: Claw hand deformity
    description: >-
      Periarticular remodeling and stiffness contribute to hand contractures; osseous and neural contributions are
      not excluded.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
      reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Poor hand function resulting from the characteristic claw hand deformity, carpal tunnel syndrome, and interphalangeal
        joint stiffness is often observed.
      explanation: >-
        Clinical synthesis specific to the described MPS I manifestation.
      directness: INDIRECT
    - reference: PMID:32764324
      reference_title: 'Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Joint symptoms, such as joint stiffness and limited range of joint mobility, stem from GAG accumulation
        and secondary pathogenic cascades in the ligaments and capsule around the joints
      explanation: >-
        General MPS I tissue-pathology synthesis; the contribution to attenuated disease and each individual outcome
        remains indirect.
      directness: INDIRECT
- name: Corneal Stromal Disorganization
  description: Keratocyte storage and altered stromal fibril spacing impair corneal transparency.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:32764324
    reference_title: 'Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Corneal clouding is caused by aberrant GAG deposits in stromal keratocytes and disruption of normal collagen
      alignment in the corneal stroma ... The usually highly uniform collagen fibrils show great variations in diameter,
      and the fibrils are spaced further apart
    explanation: >-
      Corneal pathology synthesis across MPS I; the severe infant timing elsewhere in this review is not assigned
      to attenuated disease.
  downstream:
  - target: Corneal opacity
    description: This tissue process contributes to the clinical finding; severity and timing vary.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32764324
      reference_title: 'Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Corneal clouding is caused by aberrant GAG deposits in stromal keratocytes and disruption of normal collagen
        alignment in the corneal stroma ... The usually highly uniform collagen fibrils show great variations in
        diameter, and the fibrils are spaced further apart
      explanation: >-
        Corneal pathology synthesis across MPS I; the severe infant timing elsewhere in this review is not assigned
        to attenuated disease.
- name: Cardiac Valve Thickening
  description: >-
    Storage-laden valve interstitial cells and matrix accumulation thicken valve leaflets and restrict normal movement,
    particularly in the mitral and aortic valves.
  biological_scale: TISSUE
  evidence:
  - &id005
    reference: PMID:32764324
    reference_title: 'Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The most commonly affected valves are the mitral and the aortic valves that are significantly thickened ...
      by progressive infiltration of GAG-laden activated valvular interstitial cells into the valvular tissues ...
      and excessive deposits of collagen ... Functional outcomes are poor mobility of the valves, regurgitation,
      and, to a lesser extent, stenosis
    explanation: Review synthesis of valve tissue pathology and mechanical dysfunction.
  downstream:
  - target: Mitral regurgitation
    description: This tissue process contributes to the clinical finding; severity and timing vary.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32764324
      reference_title: 'Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        The most commonly affected valves are the mitral and the aortic valves that are significantly thickened
        ... by progressive infiltration of GAG-laden activated valvular interstitial cells into the valvular tissues
        ... and excessive deposits of collagen ... Functional outcomes are poor mobility of the valves, regurgitation,
        and, to a lesser extent, stenosis
      explanation: Review synthesis of valve tissue pathology and mechanical dysfunction.
  - target: Mitral stenosis
    description: This tissue process contributes to the clinical finding; severity and timing vary.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32764324
      reference_title: 'Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        The most commonly affected valves are the mitral and the aortic valves that are significantly thickened
        ... by progressive infiltration of GAG-laden activated valvular interstitial cells into the valvular tissues
        ... and excessive deposits of collagen ... Functional outcomes are poor mobility of the valves, regurgitation,
        and, to a lesser extent, stenosis
      explanation: Review synthesis of valve tissue pathology and mechanical dysfunction.
  - target: Aortic regurgitation
    description: This tissue process contributes to the clinical finding; severity and timing vary.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32764324
      reference_title: 'Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        The most commonly affected valves are the mitral and the aortic valves that are significantly thickened
        ... by progressive infiltration of GAG-laden activated valvular interstitial cells into the valvular tissues
        ... and excessive deposits of collagen ... Functional outcomes are poor mobility of the valves, regurgitation,
        and, to a lesser extent, stenosis
      explanation: Review synthesis of valve tissue pathology and mechanical dysfunction.
  - target: Aortic valve stenosis
    description: This tissue process contributes to the clinical finding; severity and timing vary.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32764324
      reference_title: 'Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        The most commonly affected valves are the mitral and the aortic valves that are significantly thickened
        ... by progressive infiltration of GAG-laden activated valvular interstitial cells into the valvular tissues
        ... and excessive deposits of collagen ... Functional outcomes are poor mobility of the valves, regurgitation,
        and, to a lesser extent, stenosis
      explanation: Review synthesis of valve tissue pathology and mechanical dysfunction.
  - target: Left ventricular hypertrophy
    description: >-
      Valve dysfunction can impose ventricular loading and contribute to hypertrophy. This is one possible route
      and does not establish that every registry case is secondary to valve disease.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37850463
      reference_title: >-
        Natural history of cardiac findings in mucopolysaccharidosis type I: report from an international registry.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        Left ventricular hypertrophy of the posterior wall was the most common finding in both phenotypes (47.7
        and 31% in severe and attenuated, respectively).
      explanation: >-
        Attenuated posterior-wall abnormality was measured in 27 of 87 with available data before ERT/HSCT; no histologic
        infiltration assay.
      directness: INDIRECT
    - reference: PMID:32764324
      reference_title: 'Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Functional outcomes are poor mobility of the valves, regurgitation, and, to a lesser extent, stenosis ....
        Both can lead to atrial and/or ventricular volume overload, ventricular dilatation, ventricular hypertrophy,
        and ultimately to systolic and diastolic dysfunction ....
      explanation: >-
        General MPS I tissue-pathology synthesis; the contribution to attenuated disease and each individual outcome
        remains indirect.
      directness: INDIRECT
- name: Upper Airway Narrowing
  description: >-
    Oropharyngeal soft-tissue storage and altered airway anatomy can obstruct airflow, particularly during sleep.
    The relative roles of obstruction and central contributions vary.
  biological_scale: TISSUE
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Storage of GAGs within the oropharynx with associated enlargement of the tonsils and adenoids can contribute
      to upper airway complications, along with narrowed trachea, thickened vocal cords, redundant tissue in the
      upper airway, and an enlarged tongue.
    explanation: General MPS I airway mechanism; attenuated obstructive sleep apnea is separately documented.
  downstream:
  - target: Obstructive sleep apnea
    description: This tissue process contributes to the clinical finding; severity and timing vary.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
      reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Storage of GAGs within the oropharynx with associated enlargement of the tonsils and adenoids can contribute
        to upper airway complications, along with narrowed trachea, thickened vocal cords, redundant tissue in the
        upper airway, and an enlarged tongue.
      explanation: General MPS I airway mechanism; attenuated obstructive sleep apnea is separately documented.
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
      reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Sleep apnea as a result of obstructive airway disease and possibly central nervous system involvement occurs
        in individuals with attenuated MPS I.
      explanation: Clinical synthesis specific to the described MPS I manifestation.
- name: Median Nerve Compression
  description: >-
    Restricted space and altered connective tissues within the carpal tunnel compress the median nerve. The precise
    contributions of bony anatomy, tendons and retinaculum remain unresolved; storage-positive foam cells are not
    necessary in every sampled case.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:41656624
    reference_title: >-
      Carpal tunnel syndrome in mucopolysaccharidosis type I: clinical, surgical and histopathological findings.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: The flexor retinaculum was thickened and synovial tissues appeared swollen in six cases.
    explanation: >-
      Intraoperative observation in a mostly Hurler post-HSCT cohort; extrapolation to attenuated disease is indirect.
    directness: INDIRECT
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Poor hand function resulting from the characteristic claw hand deformity, carpal tunnel syndrome, and interphalangeal
      joint stiffness is often observed.
    explanation: Clinical synthesis specific to the described MPS I manifestation.
  downstream:
  - target: Constrictive median neuropathy
    description: This tissue process contributes to the clinical finding; severity and timing vary.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41656624
      reference_title: >-
        Carpal tunnel syndrome in mucopolysaccharidosis type I: clinical, surgical and histopathological findings.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: The flexor retinaculum was thickened and synovial tissues appeared swollen in six cases.
      explanation: >-
        Intraoperative observation in a mostly Hurler post-HSCT cohort; extrapolation to attenuated disease is indirect.
      directness: INDIRECT
- name: Dural Thickening
  description: >-
    Dural thickening is one route to cervical canal compromise in attenuated MPS I. Skeletal stenosis and instability
    can also contribute.
  biological_scale: TISSUE
  evidence:
  - &id004
    reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Progressive compression of the spinal cord with resulting cervical myelopathy caused by thickening of the
      dura (hypertrophic pachymeningitis cericalis) is common in individuals with attenuated MPS I.
    explanation: Attenuated-specific clinical mechanism; the source spelling is preserved in the quote.
  downstream:
  - target: Cervical Spinal Cord Compression
    description: Thickened dura narrows the space around the spinal cord.
    causal_link_type: DIRECT
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
      reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Progressive compression of the spinal cord with resulting cervical myelopathy caused by thickening of the
        dura (hypertrophic pachymeningitis cericalis) is common in individuals with attenuated MPS I.
      explanation: Attenuated-specific clinical mechanism; the source spelling is preserved in the quote.
- name: Cervical Spinal Cord Compression
  description: >-
    Mechanical compression of the cervical cord can cause progressive myelopathy and irreversible neurologic injury
    if unrecognized.
  biological_scale: TISSUE
  evidence:
  - *id004
  downstream:
  - target: Spinal cord compression
    description: This tissue process contributes to the clinical finding; severity and timing vary.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
      reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Progressive compression of the spinal cord with resulting cervical myelopathy caused by thickening of the
        dura (hypertrophic pachymeningitis cericalis) is common in individuals with attenuated MPS I.
      explanation: Attenuated-specific clinical mechanism; the source spelling is preserved in the quote.
phenotypes:
- name: Limitation of joint mobility
  category: Musculoskeletal
  description: >-
    Progressive stiffness and restricted movement affect multiple joints. This is a major cause of disability, including
    hand dysfunction.
  phenotype_term:
    preferred_term: Limitation of joint mobility
    term:
      id: HP:0001376
      label: Limitation of joint mobility
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Progressive arthropathy affecting all joints and eventually leading to loss of or severe restriction in range
      of motion is universal.
    explanation: Clinical synthesis specific to the described MPS I manifestation.
- name: Joint contracture
  category: Musculoskeletal
  description: >-
    Fixed limitation can develop with progressive arthropathy; no subtype-specific numerical frequency is inferred
    from treatment cohorts.
  phenotype_term:
    preferred_term: Joint contracture
    term:
      id: HP:0034392
      label: Joint contracture
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Progressive arthropathy affecting all joints and eventually leading to loss of or severe restriction in range
      of motion is universal.
    explanation: Attenuated-specific fixed and progressive joint limitation.
- name: Constrictive median neuropathy
  category: Neurologic
  description: >-
    Carpal tunnel syndrome may be present without typical pain or paresthesia. The attenuated registry median age
    was about ten years; the much younger pooled post-HSCT series is predominantly severe Hurler disease.
  phenotype_term:
    preferred_term: Constrictive median neuropathy
    term:
      id: HP:0012185
      label: Constrictive median neuropathy
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Carpal tunnel syndrome was present at a median age of nine years 11 months in 138 individuals with attenuated
      MPS I included in the MPS I Registry
    explanation: Clinical synthesis specific to the described MPS I manifestation.
- name: Corneal opacity
  category: Ophthalmologic
  description: >-
    Progressive bilateral clouding may impair vision. The GeneReviews attenuated registry synthesis reports approximately
    82% at a median recognition age of 9.1 years, not an invariant finding at birth.
  phenotype_term:
    preferred_term: Corneal opacity
    term:
      id: HP:0007957
      label: Corneal opacity
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Corneal clouding, exhibited by approximately 82% of children with attenuated MPS I, was identified at a median
      age of 9.1 years
    explanation: Clinical synthesis specific to the described MPS I manifestation.
- name: Mitral regurgitation
  category: Cardiovascular
  description: >-
    Progressive mitral valve dysfunction can become hemodynamically important. Frequency depends on age and ascertainment.
    It was recorded in 196 of 264 attenuated patients with valve data during variable untreated follow-up; this
    is not a lifetime risk or valve-severity estimate.
  phenotype_term:
    preferred_term: Mitral regurgitation
    term:
      id: HP:0001653
      label: Mitral regurgitation
  evidence:
  - *id005
  - reference: PMID:37850463
    reference_title: >-
      Natural history of cardiac findings in mucopolysaccharidosis type I: report from an international registry.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Mitral regurgitation was the most common and earliest finding for individuals with both severe (58.3%, median
      age 1.2 years) and attenuated (74.2%, median age 8.0 years) disease.
    explanation: >-
      Voluntary registry; 196 of 264 attenuated patients with valve data had an ever-recorded finding before ERT
      or HSCT.
- name: Aortic valve stenosis
  category: Cardiovascular
  description: Aortic stenosis can develop during the attenuated course, sometimes requiring valve replacement.
  phenotype_term:
    preferred_term: Aortic valve stenosis
    term:
      id: HP:0001650
      label: Aortic valve stenosis
  evidence:
  - *id005
- name: Aortic regurgitation
  category: Cardiovascular
  description: Aortic valve involvement may cause regurgitation as well as stenosis.
  phenotype_term:
    preferred_term: Aortic regurgitation
    term:
      id: HP:0001659
      label: Aortic regurgitation
  evidence: &id006
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Cardiac involvement can present as progressive disease of the mitral and aortic valves with regurgitation
      and/or stenosis, for which valve replacement may be necessary.
    explanation: Clinical synthesis specific to the described MPS I manifestation.
- name: Mitral stenosis
  category: Cardiovascular
  description: Mitral valve thickening can produce stenosis in addition to regurgitation.
  phenotype_term:
    preferred_term: Mitral stenosis
    term:
      id: HP:0001718
      label: Mitral stenosis
  evidence: *id006
- name: Short stature
  category: Growth
  description: >-
    Growth deceleration is variable and may emerge later in childhood. Registry models associate laronidase with
    slower decline in height z scores, but growth often remains below population standards.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:35869927
    reference_title: >-
      Growth in individuals with attenuated mucopolysaccharidosis type I during untreated and treated periods: Data
      from the MPS I registry.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      While median height remained below CDC standards during both the natural history and ERT-treated periods for
      individuals with attenuated MPS I, laronidase ERT was associated with slower declines in height z-scores.
    explanation: >-
      Observational attenuated growth registry; treatment and untreated periods overlap within participants.
- name: Dysostosis multiplex
  category: Skeletal
  description: >-
    Multifocal skeletal dysplasia commonly involves vertebrae and femora and may persist despite systemic treatment.
  phenotype_term:
    preferred_term: Dysostosis multiplex
    term:
      id: HP:0000943
      label: Dysostosis multiplex
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The MPS I Registry showed that more than 85% of persons with attenuated MPS I have dysostosis, primarily in
      the vertebrae and femur
    explanation: Clinical synthesis specific to the described MPS I manifestation.
- name: Kyphosis
  category: Skeletal
  description: Spinal deformity is reported in attenuated disease and contributes to orthopedic morbidity.
  phenotype_term:
    preferred_term: Kyphosis
    term:
      id: HP:0002808
      label: Kyphosis
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Kyphosis, scoliosis, and severe back pain are common. Spondylolisthesis of the lower spine leading to spinal
      cord compression can occur.
    explanation: Clinical synthesis specific to the described MPS I manifestation.
- name: Scoliosis
  category: Skeletal
  description: Spinal deformity is reported in attenuated disease and contributes to orthopedic morbidity.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence: &id007
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Kyphosis, scoliosis, and severe back pain are common. Spondylolisthesis of the lower spine leading to spinal
      cord compression can occur.
    explanation: Clinical synthesis specific to the described MPS I manifestation.
- name: Spondylolisthesis
  category: Skeletal
  description: Lower spinal spondylolisthesis can contribute to cord compression.
  phenotype_term:
    preferred_term: Spondylolisthesis
    term:
      id: HP:0003302
      label: Spondylolisthesis
  evidence: *id007
- name: Hepatosplenomegaly
  category: Gastrointestinal
  description: >-
    Liver and spleen enlargement varies across attenuated patients. Reduction with therapy does not imply restoration
    of all affected tissues.
  phenotype_term:
    preferred_term: Hepatosplenomegaly
    term:
      id: HP:0001433
      label: Hepatosplenomegaly
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: <b>Hepatosplenomegaly</b> is variable in individuals with attenuated MPS I.
    explanation: >-
      Attenuated-specific clinical synthesis; the balanced inline HTML preserves the diagnostic subject exactly.
- name: Obstructive sleep apnea
  category: Respiratory
  description: Obstructive airway disease can cause sleep apnea; central contributions may coexist.
  phenotype_term:
    preferred_term: Obstructive sleep apnea
    term:
      id: HP:0002870
      label: Obstructive sleep apnea
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Sleep apnea as a result of obstructive airway disease and possibly central nervous system involvement occurs
      in individuals with attenuated MPS I.
    explanation: Clinical synthesis specific to the described MPS I manifestation.
- name: Reduced vital capacity
  category: Respiratory
  description: >-
    Pulmonary restriction and other disease burdens may reduce forced vital capacity. Decline can occur despite
    laronidase.
  phenotype_term:
    preferred_term: Reduced vital capacity
    term:
      id: HP:0002792
      label: Reduced vital capacity
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Progressive pulmonary disease may manifest as abnormalities of forced vital capacity. Respiratory complications
      (and cardiac involvement) are among the leading causes of premature death.
    explanation: Clinical synthesis specific to the described MPS I manifestation.
- name: Spinal cord compression
  category: Neurologic
  description: >-
    Cervical compression may initially present as reduced activity or exercise intolerance; skeletal disease can
    also compress other levels.
  phenotype_term:
    preferred_term: Spinal cord compression
    term:
      id: HP:0002176
      label: Spinal cord compression
  evidence:
  - *id004
- name: Hearing impairment
  category: Otologic
  description: >-
    Conductive and sensorineural contributors include eustachian-tube dysfunction, ossicular dysostosis and eighth-nerve
    involvement.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Hearing impairment, most commonly in the high frequency range, is likely caused by a combination of eustachian
      tube dysfunction, dysostosis of the ossicles of the middle ear, and eighth nerve involvement.
    explanation: Clinical synthesis specific to the described MPS I manifestation.
- name: Coarse facial features
  category: Craniofacial
  description: Coarsening can be mild or subtle compared with severe Hurler syndrome.
  phenotype_term:
    preferred_term: Coarse facial features
    term:
      id: HP:0000280
      label: Coarse facial features
  evidence: &id008
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Coarseness of facial features is less obvious than in individuals with severe MPS I. Findings can include
      a short neck, wide mouth, and square jaw.
    explanation: Clinical synthesis specific to the described MPS I manifestation.
- name: Short neck
  category: Craniofacial
  description: Reported within the variable attenuated facial appearance.
  phenotype_term:
    preferred_term: Short neck
    term:
      id: HP:0000470
      label: Short neck
  evidence: *id008
- name: Wide mouth
  category: Craniofacial
  description: Reported within the variable attenuated facial appearance.
  phenotype_term:
    preferred_term: Wide mouth
    term:
      id: HP:0000154
      label: Wide mouth
  evidence: *id008
- name: Inguinal hernia
  category: Gastrointestinal
  description: Hernias may occur in infancy before other manifestations are recognized and may recur after surgery.
  phenotype_term:
    preferred_term: Inguinal hernia
    term:
      id: HP:0000023
      label: Inguinal hernia
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Many have also had inguinal hernias during infancy, often requiring repeated surgical correction.
    explanation: Clinical synthesis specific to the described MPS I manifestation.
- name: Glaucoma
  category: Ophthalmologic
  description: >-
    Glaucoma can contribute to visual morbidity; corneal abnormalities complicate pressure interpretation.
  phenotype_term:
    preferred_term: Glaucoma
    term:
      id: HP:0000501
      label: Glaucoma
  evidence: &id009
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Corneal clouding can lead to significant visual disability. Glaucoma, retinal degeneration, and optic atrophy
      can occur.
    explanation: Clinical synthesis specific to the described MPS I manifestation.
- name: Retinal degeneration
  category: Ophthalmologic
  description: Retinal disease may limit vision independently of corneal clouding.
  phenotype_term:
    preferred_term: Retinal degeneration
    term:
      id: HP:0000546
      label: Retinal degeneration
  evidence: *id009
- name: Optic atrophy
  category: Ophthalmologic
  description: Optic-nerve disease may limit visual recovery after corneal treatment.
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence: *id009
- name: Hydrocephalus
  category: Neurologic
  description: Communicating hydrocephalus is less frequent than in severe MPS I but may develop insidiously.
  phenotype_term:
    preferred_term: Hydrocephalus
    term:
      id: HP:0000238
      label: Hydrocephalus
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The risk of communicating hydrocephalus and its complications are lower in attenuated MPS I than severe MPS
      I. However, hydrocephalus may occur with insidious onset.
    explanation: Clinical synthesis specific to the described MPS I manifestation.
- name: Learning disability
  category: Neurologic
  description: >-
    Learning difficulties can emerge despite normal early development. They do not imply the rapid early neurodegenerative
    course of severe Hurler disease.
  phenotype_term:
    preferred_term: Learning disability
    term:
      id: HP:0001328
      label: Specific learning disability
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Although development may be normal in early childhood, children and adults with attenuated MPS I may have
      detectable learning disabilities.
    explanation: Clinical synthesis specific to the described MPS I manifestation.
- name: Cognitive impairment
  category: Neurologic
  description: >-
    Cognition is variable. Four of 25 attenuated participants in the French long-term cohort had impairment before
    ERT; absence of observed regression in that cohort does not exclude cognitive decline in other patients.
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - &id020
    reference: PMID:41353341
    reference_title: >-
      Clinical outcomes of exclusive enzyme therapy (laronidase) in a cohort of patients with mucopolysaccharidosis
      type I.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Before ERT, 4 (16%) patients had cognitive impairment since the median age of 7.3 years.
    explanation: Attenuated subset of an uncontrolled treated cohort, not population prevalence.
- name: Left ventricular hypertrophy
  category: Cardiovascular
  description: >-
    Ventricular wall thickening occurs in a subset of attenuated patients. A normal cohort mean or stable average
    trajectory does not exclude myocardial abnormalities in individuals.
  phenotype_term:
    preferred_term: Left ventricular hypertrophy
    term:
      id: HP:0001712
      label: Left ventricular hypertrophy
  evidence:
  - reference: PMID:37850463
    reference_title: >-
      Natural history of cardiac findings in mucopolysaccharidosis type I: report from an international registry.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Left ventricular hypertrophy of the posterior wall was the most common finding in both phenotypes (47.7 and
      31% in severe and attenuated, respectively).
    explanation: >-
      Attenuated posterior-wall abnormality was measured in 27 of 87 with available data before ERT/HSCT; no histologic
      infiltration assay.
- name: Claw hand deformity
  category: Musculoskeletal
  description: >-
    Phalangeal and periarticular disease can produce a claw-hand appearance, contributing to hand dysfunction.
  phenotype_term:
    preferred_term: Claw hand deformity
    term:
      id: HP:0034337
      label: Claw hand deformity
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Poor hand function resulting from the characteristic claw hand deformity, carpal tunnel syndrome, and interphalangeal
      joint stiffness is often observed.
    explanation: Clinical synthesis specific to the described MPS I manifestation.
biochemical:
- name: Urinary dermatan and heparan sulfate
  presence: Elevated
  context: >-
    Quantitative or qualitative urinary GAG analysis supports the diagnosis, but reduced sensitivity, especially
    in dilute urine, can complicate screening. Urinary GAG reduction after laronidase is a pharmacodynamic response
    and does not establish correction of all tissue storage or clinical endpoints. In the long-term French attenuated
    cohort, 11 of 17 patients with relevant measurements reached age-adjusted normal levels, rather than 65% of
    all 25 attenuated participants.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Analysis of urine glycosaminoglycans (GAG) (i.e., heparan and dermatan sulfate) may be quantitative (measurement
      of total urinary GAGs or specific GAG disaccharides) or qualitative (GAG electrophoresis to analyze the specific
      GAGs excreted).
    explanation: Clinical synthesis specific to the described MPS I manifestation.
  - reference: url:https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a80ac249-cae4-41f3-88bb-344088b20e60
    reference_title: DailyMed - ALDURAZYME- laronidase injection, solution, concentrate
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The responsiveness of urinary GAG to dosage alterations of ALDURAZYME is unknown, and the relationship of
      urinary GAG to other measures of clinical response has also not been established
    explanation: Current label limits use of urinary GAG as a clinical surrogate.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Due to the presence of IDUA pseudodeficiency, the establishment of the diagnosis of MPS I requires the demonstration
      of BOTH deficiency of IDUA enzyme activity AND elevation of urine GAGs.
    explanation: >-
      Biochemical confirmation must distinguish deficient substrate degradation from artificial-substrate pseudodeficiency.
- name: Alpha-L-iduronidase activity
  presence: Reduced
  context: >-
    Deficient activity in leukocytes or cultured fibroblasts supports MPS I. Routine assays do not reliably separate
    severe from attenuated disease, and activity can be undetectable in either. Artificial-substrate pseudodeficiency
    requires interpretation with GAG metabolism and molecular findings. Specialized residual-activity assays show
    overlapping ranges and remain insufficient to establish a universal CNS-protection threshold.
  evidence:
  - *id010
  - &id018
    reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Pseudodeficiency relates to the finding of reduced or undetectable IDUA enzyme activity with the use of artificial
      substrates, but no evidence of altered glycosaminoglycan metabolism with the use of radiolabeled
    explanation: Artificial-substrate deficiency can occur without the metabolic disease.
genetic:
- name: IDUA pathogenic variants
  gene_term: *id003
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  inheritance:
  - name: Autosomal recessive
    evidence:
    - *id011
  features: >-
    Attenuated disease is often associated with at least one missense allele, but splice, in-frame deletion and
    stop-loss alleles also occur. Genotype contributes to severity assessment alongside clinical trajectory. Novel
    variants, incomplete phase information and variable phenotypes for recurrent alleles limit individual prediction;
    a variant of uncertain significance is not diagnostic.
  evidence:
  - reference: PMID:31194252
    reference_title: >-
      Genotype-phenotype relationships in mucopolysaccharidosis type I (MPS I): Insights from the International
      MPS I Registry.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The genotype/ phenotype relationships identified in this large series of patients shows that many MPS I patients
      have unique variants and that certain variants have variable phenotypic effects.
    explanation: Registry association with clinician-assigned severity; no direct activity assay.
  - *id012
  review_notes: >-
    The registry reports inconsistent proportions for attenuated patients with a missense allele across abstract,
    Results, Discussion and Table 4; no exact proportion is adopted. Genotyping methods, parental phase confirmation
    and laboratory classifications were not collected. The nonsense variant p.Tyr343Ter can have an attenuating
    splice consequence, so all stop variants cannot be classified as null from their names alone.
diagnosis:
- name: Biochemical and molecular confirmation
  description: >-
    Assess urinary dermatan/heparan sulfate and IDUA enzyme activity, then interpret biallelic pathogenic or likely
    pathogenic IDUA variants with the biochemical findings. Urinary screening is neither subtype-specific nor perfectly
    sensitive; a reassuring screen alone should not terminate evaluation when clinical suspicion persists. Enzyme
    pseudodeficiency and variants of uncertain significance are important pitfalls. Parent testing can clarify phase.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Due to the presence of IDUA pseudodeficiency, the establishment of the diagnosis of MPS I requires the demonstration
      of BOTH deficiency of IDUA enzyme activity AND elevation of urine GAGs.
    explanation: >-
      Biochemical confirmation must distinguish deficient substrate degradation from artificial-substrate pseudodeficiency.
  - &id017
    reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Neither the quantitative nor the qualitative method can diagnose a specific lysosomal enzyme deficiency, including
      MPS I; however, an abnormality detected by either or both methods indicates the likely presence of an MPS
      disorder.
    explanation: Clinical synthesis specific to the described MPS I manifestation.
- name: Clinical severity assessment
  description: >-
    Integrate age at onset, developmental trajectory, organ involvement and genotype. Severe and attenuated MPS
    I form a continuum; neither detectable residual enzyme activity nor normal early cognition independently establishes
    the long-term phenotype.
  evidence:
  - &id016
    reference: PMID:20301341
    reference_title: Mucopolysaccharidosis Type I.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      An essential component of management is the determination of whether the proband has severe or attenuated
      MPS I.
    explanation: Management requires a clinical severity assessment.
  - *id012
- name: Multisystem baseline evaluation and surveillance
  description: >-
    Arrange coordinated neurologic, ophthalmologic, auditory, cardiac, respiratory, gastrointestinal and musculoskeletal
    assessment. The management guideline recommends follow-up every six to twelve months with individualized intervals.
    Include echocardiography, pulmonary and sleep assessment, nerve-conduction studies, spinal examination and developmental
    or educational review; symptoms alone may miss carpal-tunnel or cord disease.
  evidence:
  - reference: PMID:19117856
    reference_title: 'Mucopolysaccharidosis I: management and treatment guidelines.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      All patients with mucopolysaccharidosis I should receive a comprehensive baseline evaluation, including neurologic,
      ophthalmologic, auditory, cardiac, respiratory, gastrointestinal, and musculoskeletal assessments, and should
      be monitored every 6 to 12 months with individualized specialty assessments, to monitor disease progression
      and effects of intervention.
    explanation: Expert guidance across MPS I, with assessments individualized to phenotype.
- name: At-risk family and reproductive testing
  description: >-
    Offer testing to at-risk siblings so disease can be identified before substantial progression. Known familial
    pathogenic variants enable carrier, prenatal and preimplantation testing; carrier enzyme assays alone are unreliable.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Testing of all at-risk sibs of any age is warranted in order to initiate therapy as early in the course of
      disease as possible.
    explanation: GeneReviews management recommendation; not a controlled outcome comparison.
  - &id015
    reference: PMID:20301341
    reference_title: Mucopolysaccharidosis Type I.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible
      if both disease-causing IDUA variants have been identified in the family.
    explanation: Familial molecular testing recommendation.
treatments:
- name: Intravenous laronidase enzyme replacement
  description: >-
    Weekly intravenous laronidase supplies recombinant IDUA for somatic disease. The current US label covers Hurler
    and Hurler-Scheie forms and Scheie disease with moderate-to-severe symptoms; efficacy and safety for mildly
    affected Scheie patients are not established. In the pivotal 26-week trial, 44 of 45 participants had attenuated
    disease. FVC improved; the walking-distance result was significant in a prespecified adjusted analysis but not
    the unadjusted comparison. Long-term observational data suggest some somatic benefit, but skeletal, corneal,
    valvular and spinal disease can persist or progress. CNS effects have not been established. Earlier treatment
    may help, but no validated age-nine cutoff follows from the uncontrolled growth cohorts.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: laronidase
      term:
        id: NCIT:C83864
        label: Laronidase
  evidence:
  - &id021
    reference: PMID:31211405
    reference_title: >-
      Enzyme replacement therapy with laronidase (Aldurazyme(®)) for treating mucopolysaccharidosis type I.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The laronidase group achieved statistically significant improvements in per cent predicted forced vital capacity
      compared to placebo, MD 5.60 (95% confidence intervals 1.24 to 9.96) (low-quality evidence) and in the six-minute-walk
      test (mean improvement of 38.1 metres in the laronidase group; P = 0.039, when using a prospectively planned
      analysis of covariance) (low-quality evidence).
    explanation: >-
      Cochrane synthesis of one 45-person, 26-week trial; walk-test significance depends on the prespecified adjusted
      analysis.
  - reference: url:https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a80ac249-cae4-41f3-88bb-344088b20e60
    reference_title: DailyMed - ALDURAZYME- laronidase injection, solution, concentrate
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The safety and effectiveness of treating mildly affected patients with the Scheie form have not been established.
    explanation: Current regulatory indication boundary.
  - reference: url:https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a80ac249-cae4-41f3-88bb-344088b20e60
    reference_title: DailyMed - ALDURAZYME- laronidase injection, solution, concentrate
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The effect of ALDURAZYME on central nervous system manifestations of the disorder has not been determined.
    explanation: Current regulatory CNS limitation.
  - reference: PMID:35869927
    reference_title: >-
      Growth in individuals with attenuated mucopolysaccharidosis type I during untreated and treated periods: Data
      from the MPS I registry.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      While median height remained below CDC standards during both the natural history and ERT-treated periods for
      individuals with attenuated MPS I, laronidase ERT was associated with slower declines in height z-scores.
    explanation: Observational association, not a randomized age threshold.
  - reference: PMID:15126990
    reference_title: >-
      Enzyme replacement therapy for mucopolysaccharidosis I: a randomized, double-blinded, placebo-controlled,
      multinational study of recombinant human alpha-L-iduronidase (laronidase).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      After 26 weeks, patients receiving laronidase compared with placebo showed mean improvements of 5.6 percentage
      points in percent of predicted normal FVC (median, 3.0; P=.009) and 38.1 meters in 6MWT distance (median,
      38.5; P=.066; P=.039, analysis of covariance).
    explanation: Primary trial results; adjusted and unadjusted walk analyses differ.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6581069/
    reference_title: >-
      Enzyme replacement therapy with laronidase (Aldurazyme®) for treating mucopolysaccharidosis type I - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      No measures of systolic and diastolic function, hypertrophy and valve disease were reported on in the included
      study
    explanation: Full Cochrane review specifies the cardiac outcomes absent from the pivotal trial.
  - reference: url:https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a80ac249-cae4-41f3-88bb-344088b20e60
    reference_title: DailyMed - ALDURAZYME- laronidase injection, solution, concentrate
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Hypersensitivity reactions including anaphylaxis have been reported in patients during or up to 3 hours after
      ALDURAZYME infusions. Some of these reactions were life-threatening
    explanation: Boxed safety concern, including events after prior exposure.
  - reference: url:https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a80ac249-cae4-41f3-88bb-344088b20e60
    reference_title: DailyMed - ALDURAZYME- laronidase injection, solution, concentrate
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Neutralizing antibodies that inhibited cellular uptake of laronidase were detected in 38 of 70 (54%) patients
      who developed ADA.
    explanation: Neutralizing uptake antibodies in the label population; not an attenuated-only prevalence.
  target_mechanisms:
  - target: Reduced Alpha-L-Iduronidase Activity
    treatment_effect: RESTORES
    description: >-
      Replacement enzyme adds lysosomal hydrolase activity; distribution and clinical correction remain incomplete.
    evidence:
    - reference: url:https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a80ac249-cae4-41f3-88bb-344088b20e60
      reference_title: DailyMed - ALDURAZYME- laronidase injection, solution, concentrate
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        The rationale of ALDURAZYME therapy in MPS I is to provide exogenous enzyme for uptake into lysosomes and
        increase the catabolism of GAG. ALDURAZYME uptake by cells into lysosomes is most likely mediated by the
        mannose-6-phosphate-terminated oligosaccharide chains of laronidase binding to specific mannose-6-phosphate
        receptors.
      explanation: >-
        Label mechanism: lysosomal delivery of replacement enzyme; receptor contribution is qualified by the source.
  notes: >-
    Infusion reactions can be severe, including anaphylaxis and cardiorespiratory decompensation; label-directed
    monitoring and individualized premedication are required. Anti-drug antibodies are common. Cell-uptake neutralization
    and associations with reduced urinary-GAG response have been reported, so the absence of an FVC/6MWT correlation
    in trials does not establish that antibodies are always clinically irrelevant.
- name: Individualized transplantation assessment
  description: >-
    HSCT is primarily standard care for selected children with severe MPS I. For attenuated disease, decisions require
    specialist assessment of progression, genotype, development, age and transplant risk. Its potential benefits
    are not confined to cognition, but it does not reliably reverse established skeletal, corneal or valve disease.
    A universal preserved-cognition rationale for excluding transplantation is inappropriate.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: Hematopoietic Cell Transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Due to the morbidity and mortality associated with HSCT, it is currently recommended primarily for children
      with severe MPS I.
    explanation: GeneReviews management recommendation; not a controlled outcome comparison.
  - reference: PMID:19117856
    reference_title: 'Mucopolysaccharidosis I: management and treatment guidelines.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The patient's age (>2 years or < or =2 years), predicted phenotype, and developmental quotient help define
      the risk/benefit profile for hematopoietic stem cell transplantation (higher risk but can preserve central
      nervous system function) versus enzyme replacement therapy (low risk but cannot cross the blood-brain barrier).
    explanation: Expert risk-benefit framework, not proof of benefit in all attenuated patients.
- name: Physical and occupational therapy
  description: >-
    Early range-of-motion work and functional support may preserve mobility and hand function. Established contractures
    may not reverse; tailor activity and assistive support to skeletal and neurologic limitations.
  therapeutic_modality: OTHER
  treatment_term: &id014
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Range of motion exercises appear to offer some benefits in preserving joint function and should be started
      early. Once significant joint limitation has occurred, increased range of motion may not be achieved without
      HSCT.
    explanation: GeneReviews management recommendation; not a controlled outcome comparison.
  target_mechanisms:
  - target: Limitation of joint mobility
    treatment_effect: MODULATES
    description: Exercises aim to preserve available movement rather than remove stored substrate.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
      reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Range of motion exercises appear to offer some benefits in preserving joint function and should be started
        early. Once significant joint limitation has occurred, increased range of motion may not be achieved without
        HSCT.
      explanation: GeneReviews management recommendation; not a controlled outcome comparison.
- name: Individualized orthopedic surgery
  description: >-
    Joint replacement or spinal stabilization may be appropriate for selected progressive structural problems. Decisions
    account for other organ disease and major anesthetic risk; surgery does not correct the underlying enzyme deficiency.
  therapeutic_modality: SURGERY
  treatment_term: &id013
    preferred_term: Surgical Procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Various orthopedic approaches can be undertaken, particularly in individuals with attenuated disease. Joint
      replacement and atlanto-occipital stabilization may be necessary. These procedures must be performed at appropriate
      times in the individual's clinical course and must take into account the presence of other disease complications.
    explanation: GeneReviews management recommendation; not a controlled outcome comparison.
  target_mechanisms:
  - target: Limitation of joint mobility
    treatment_effect: MODULATES
    description: Selected joint replacement addresses a structural contributor to disability.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
      reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Various orthopedic approaches can be undertaken, particularly in individuals with attenuated disease. Joint
        replacement and atlanto-occipital stabilization may be necessary. These procedures must be performed at
        appropriate times in the individual's clinical course and must take into account the presence of other disease
        complications.
      explanation: GeneReviews management recommendation; not a controlled outcome comparison.
- name: Carpal tunnel decompression
  description: >-
    Use early nerve-conduction assessment and specialist evaluation because typical sensory symptoms may be absent.
    Release can improve function, but recovery varies and surveillance continues for recurrence. The 13 recurrences
    among 21 operated patients in the 2026 series predominantly concern transplanted Hurler disease and are not
    an attenuated-specific rate.
  therapeutic_modality: SURGERY
  treatment_term: *id013
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      thus, nerve conduction studies should be used early in the course of disease to identify persons with carpal
      tunnel syndrome at a time when surgical release may be most beneficial. Surgical decompression of the median
      nerve results in variable restoration of motor hand activity
    explanation: GeneReviews management recommendation; not a controlled outcome comparison.
  - reference: PMID:41656624
    reference_title: >-
      Carpal tunnel syndrome in mucopolysaccharidosis type I: clinical, surgical and histopathological findings.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Twenty-one patients underwent carpal tunnel release and 13 patients experienced recurrence.
    explanation: Mostly severe post-HSCT cohort; scope does not establish attenuated recurrence probability.
  target_mechanisms:
  - target: Median Nerve Compression
    treatment_effect: INHIBITS
    description: Surgical release relieves pressure on the median nerve.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
      reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        thus, nerve conduction studies should be used early in the course of disease to identify persons with carpal
        tunnel syndrome at a time when surgical release may be most beneficial. Surgical decompression of the median
        nerve results in variable restoration of motor hand activity
      explanation: GeneReviews management recommendation; not a controlled outcome comparison.
- name: Evaluation and decompression of cervical myelopathy
  description: >-
    Urgently evaluate progressive activity loss, gait change or other myelopathic signs, with spinal imaging and
    neurosurgical assessment. Early decompression can limit further injury; established deficits may persist.
  therapeutic_modality: SURGERY
  treatment_term: *id013
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Progressive compression of the spinal cord with resulting cervical myelopathy should be aggressively and quickly
      evaluated in individuals with attenuated disease or those who have had HSCT. Early surgical intervention may
      prevent severe complications.
    explanation: GeneReviews management recommendation; not a controlled outcome comparison.
  target_mechanisms:
  - target: Cervical Spinal Cord Compression
    treatment_effect: INHIBITS
    description: Decompression addresses mechanical cord compromise.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
      reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Progressive compression of the spinal cord with resulting cervical myelopathy should be aggressively and
        quickly evaluated in individuals with attenuated disease or those who have had HSCT. Early surgical intervention
        may prevent severe complications.
      explanation: GeneReviews management recommendation; not a controlled outcome comparison.
- name: Corneal and visual care
  description: >-
    Reduce glare and assess glaucoma, retinal and optic-nerve disease. Selected corneal transplantation may improve
    transparency, but graft clouding can recur and noncorneal disease can limit visual benefit.
  therapeutic_modality: OTHER
  treatment_term: *id014
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Wearing peaked caps or eye shades can help reduce glare resulting from corneal clouding. Corneal transplantation
      is successful for individuals with attenuated disease, although donor grafts eventually become cloudy. Individuals
      with clear grafts may still experience poor vision because of involvement of the retina and/or optic nerve
    explanation: GeneReviews management recommendation; not a controlled outcome comparison.
  target_mechanisms:
  - target: Corneal opacity
    treatment_effect: MODULATES
    description: Symptom aids and selected transplantation address the consequences of corneal clouding.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
      reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Wearing peaked caps or eye shades can help reduce glare resulting from corneal clouding. Corneal transplantation
        is successful for individuals with attenuated disease, although donor grafts eventually become cloudy. Individuals
        with clear grafts may still experience poor vision because of involvement of the retina and/or optic nerve
      explanation: GeneReviews management recommendation; not a controlled outcome comparison.
- name: Cardiac assessment and selected valve replacement
  description: >-
    Monitor valve and ventricular disease with cardiology and echocardiography. Hemodynamically important valve
    disease may require replacement. The untreated registry describes valve and myocardial abnormalities and cannot
    establish that laronidase prevents progression. Endocarditis prophylaxis should follow current indication-specific
    cardiology guidance rather than a blanket disease rule from older literature.
  therapeutic_modality: SURGERY
  treatment_term: *id013
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Cardiac involvement can present as progressive disease of the mitral and aortic valves with regurgitation
      and/or stenosis, for which valve replacement may be necessary.
    explanation: Clinical synthesis supporting specialist consideration of valve surgery.
  target_mechanisms:
  - target: Mitral regurgitation
    treatment_effect: BYPASSES
    description: >-
      Replacing a dysfunctional valve addresses its mechanical lesion, without correcting systemic storage.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
      reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Cardiac involvement can present as progressive disease of the mitral and aortic valves with regurgitation
        and/or stenosis, for which valve replacement may be necessary.
      explanation: Clinical synthesis supporting specialist consideration of valve surgery.
  - target: Mitral stenosis
    treatment_effect: BYPASSES
    description: >-
      Replacing a dysfunctional valve addresses its mechanical lesion, without correcting systemic storage.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
      reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Cardiac involvement can present as progressive disease of the mitral and aortic valves with regurgitation
        and/or stenosis, for which valve replacement may be necessary.
      explanation: Clinical synthesis supporting specialist consideration of valve surgery.
  - target: Aortic regurgitation
    treatment_effect: BYPASSES
    description: >-
      Replacing a dysfunctional valve addresses its mechanical lesion, without correcting systemic storage.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
      reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Cardiac involvement can present as progressive disease of the mitral and aortic valves with regurgitation
        and/or stenosis, for which valve replacement may be necessary.
      explanation: Clinical synthesis supporting specialist consideration of valve surgery.
  - target: Aortic valve stenosis
    treatment_effect: BYPASSES
    description: >-
      Replacing a dysfunctional valve addresses its mechanical lesion, without correcting systemic storage.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
      reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Cardiac involvement can present as progressive disease of the mitral and aortic valves with regurgitation
        and/or stenosis, for which valve replacement may be necessary.
      explanation: Clinical synthesis supporting specialist consideration of valve surgery.
- name: Audiologic and ENT support
  description: >-
    Identify conductive and sensorineural contributors, offer hearing aids, and consider ventilation tubes or upper-airway
    surgery where indicated. ENT procedures require disease-experienced anesthesia planning.
  therapeutic_modality: OTHER
  treatment_term: *id014
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Tonsillectomy and adenoidectomy correct eustachian tube dysfunction and decrease upper airway obstruction.
      Early placement of ventilating tubes is recommended in severely affected individuals. Hearing aids should
      also be considered.
    explanation: GeneReviews management recommendation; not a controlled outcome comparison.
  target_mechanisms:
  - target: Hearing impairment
    treatment_effect: MODULATES
    description: Hearing aids and treatment of selected conductive contributors support hearing.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
      reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Tonsillectomy and adenoidectomy correct eustachian tube dysfunction and decrease upper airway obstruction.
        Early placement of ventilating tubes is recommended in severely affected individuals. Hearing aids should
        also be considered.
      explanation: GeneReviews management recommendation; not a controlled outcome comparison.
- name: Sleep and airway support
  description: >-
    Evaluate obstructive and possible central sleep-disordered breathing. Selected patients require positive airway
    pressure, supplementary oxygen or tracheostomy; requirements are individualized rather than inferred from a
    pooled MPS I frequency.
  therapeutic_modality: OTHER
  treatment_term: *id014
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Sleep apnea may require tracheotomy or high-pressure continuous positive airway pressure with supplemented
      oxygen. Tracheostomy is often required to maintain the airway and control pulmonary hypertension and right
      heart failure.
    explanation: GeneReviews management recommendation; not a controlled outcome comparison.
  target_mechanisms:
  - target: Upper Airway Narrowing
    treatment_effect: BYPASSES
    description: Positive airway pressure supports patency, while tracheostomy can bypass an obstructed upper airway.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
      reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Sleep apnea may require tracheotomy or high-pressure continuous positive airway pressure with supplemented
        oxygen. Tracheostomy is often required to maintain the airway and control pulmonary hypertension and right
        heart failure.
      explanation: GeneReviews management recommendation; not a controlled outcome comparison.
- name: CSF diversion for progressive hydrocephalus
  description: >-
    Consider shunting when pressure and progressive ventricular enlargement support clinically important hydrocephalus.
    Ventriculomegaly alone is not equivalent to raised pressure; treatment is palliative and requires specialist
    assessment.
  therapeutic_modality: SURGERY
  treatment_term: *id013
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Cerebrospinal fluid (CSF) pressure and progressive ventricular enlargement indicate need for a shunting procedure.
      Ventriculoperitoneal shunting in individuals with MPS I who have moderate-to-severe hydrocephalus is generally
      palliative and improves quality of life.
    explanation: GeneReviews management recommendation; not a controlled outcome comparison.
  target_mechanisms:
  - target: Hydrocephalus
    treatment_effect: MODULATES
    description: CSF diversion treats pressure and fluid accumulation.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
      reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Cerebrospinal fluid (CSF) pressure and progressive ventricular enlargement indicate need for a shunting
        procedure. Ventriculoperitoneal shunting in individuals with MPS I who have moderate-to-severe hydrocephalus
        is generally palliative and improves quality of life.
      explanation: GeneReviews management recommendation; not a controlled outcome comparison.
- name: Anesthetic precautions
  description: >-
    Use centers experienced with mucopolysaccharidoses. Anticipate a difficult narrowed airway, cervical instability,
    slow recovery and postoperative obstruction; plan positioning and airway equipment accordingly.
  therapeutic_modality: OTHER
  treatment_term: *id014
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Dysostosis multiplex can lead to instability of the spine, including the atlanto-axial joint. Careful positioning
      and avoidance of hyperextension of the neck are necessary.
    explanation: GeneReviews management recommendation; not a controlled outcome comparison.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Recovery from anesthesia may be slow and postoperative airway obstruction is a common problem.
    explanation: GeneReviews management recommendation; not a controlled outcome comparison.
- name: Educational and developmental support
  description: >-
    Assess cognition and educational needs over time and provide individualized learning support. Normal early development
    does not remove the need for later review.
  therapeutic_modality: OTHER
  treatment_term: *id014
  evidence:
  - reference: PMID:20301341
    reference_title: Mucopolysaccharidosis Type I.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Infant learning programs/special education for developmental delay; physical therapy, orthopedic surgery as
      needed, joint replacement for progressive arthropathy, atlanto-occipital stabilization; spinal cord decompression
      for cervical myelopathy
    explanation: >-
      GeneReviews supportive-care summary; the developmental component is relevant when individual needs are identified.
  target_mechanisms:
  - target: Learning disability
    treatment_effect: MODULATES
    description: Educational support addresses functional learning needs rather than proven CNS substrate clearance.
    evidence:
    - reference: PMID:20301341
      reference_title: Mucopolysaccharidosis Type I.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Infant learning programs/special education for developmental delay; physical therapy, orthopedic surgery
        as needed, joint replacement for progressive arthropathy, atlanto-occipital stabilization; spinal cord decompression
        for cervical myelopathy
      explanation: >-
        GeneReviews supportive-care summary; the developmental component is relevant when individual needs are identified.
- name: Gastrointestinal symptom and hernia care
  description: >-
    Treat constipation or diarrhea individually and assess symptomatic or recurrent hernias. Dietary measures and
    cautious laxative use may help bowel symptoms; surgical decisions include anesthetic risk assessment.
  therapeutic_modality: OTHER
  treatment_term: *id014
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Some gastrointestinal symptoms (diarrhea and constipation) can be controlled by diet, including control of
      the amount of roughage. Increased roughage and the conservative use of laxatives may ease constipation.
    explanation: GeneReviews management recommendation; not a controlled outcome comparison.
- name: Genetic counseling and pregnancy planning
  description: >-
    Discuss autosomal recessive recurrence and available familial testing. Pregnancy care includes close assessment
    of cardiorespiratory and spinal disease; disease severity and treatment decisions require individualized multidisciplinary
    review.
  therapeutic_modality: OTHER
  treatment_term: *id014
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Women with MPS I who become pregnant require assessment and frequent monitoring of cardiorespiratory and spinal
      cord involvement.
    explanation: GeneReviews management recommendation; not a controlled outcome comparison.
  - *id015
differential_diagnoses:
- name: Severe MPS I
  disease_term:
    preferred_term: Hurler syndrome
    term:
      id: MONDO:0011758
      label: Hurler syndrome
  description: >-
    The severe end of the same IDUA spectrum. Early progressive developmental impairment and somatic disease support
    severe classification, but genotype and longitudinal examination are needed; normal early development or any
    single assay threshold cannot guarantee attenuated disease.
  distinguishing_features:
  - The clinical trajectory and predicted allele effects inform severity rather than a categorical detectable-versus-absent enzyme rule.
  evidence:
  - *id016
  - *id012
- name: Other mucopolysaccharidoses
  description: >-
    MPS II, VI and VII can overlap clinically. Disease-specific enzyme assays distinguish IDUA deficiency from iduronate-2-sulfatase,
    arylsulfatase B or beta-glucuronidase deficiency. Corneal and inheritance patterns help direct testing but do
    not replace biochemical confirmation.
  distinguishing_features:
  - A urinary GAG pattern alone does not identify the deficient enzyme.
  evidence:
  - *id017
- name: Juvenile idiopathic arthritis
  description: >-
    Progressive noninflammatory joint limitation can lead to an arthritis referral. Evaluate the joint pattern together
    with corneal, skeletal, cardiac and other storage-disease signs; no universal inflammatory-marker or treatment-response
    rule is assumed.
  distinguishing_features:
  - Multisystem storage-disease findings and deficient IDUA-mediated GAG degradation favor MPS I.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Persons with attenuated MPS I may present with noninflammatory arthritis at any age; thus, MPS I should be
      considered in the differential diagnosis of juvenile idiopathic arthritis
    explanation: Clinical synthesis specific to the described MPS I manifestation.
- name: IDUA pseudodeficiency
  description: >-
    Low activity against an artificial substrate can occur without disturbed GAG metabolism or clinical MPS I. Interpret
    enzyme results with substrate biomarkers, molecular classification and the clinical picture.
  distinguishing_features:
  - Reduced artificial-substrate activity without abnormal GAG metabolism is not sufficient to diagnose disease.
  evidence:
  - *id018
prevalence:
- population: Populations summarized in GeneReviews
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.2
  notes: >-
    Historical summary estimate of approximately one in 500,000 for attenuated MPS I. This is not a contemporary
    worldwide surveillance denominator; ascertainment of mild or late-recognized disease varies. The cited chapter
    does not specify an observation period or birth denominator for this estimate, so no measure type is imposed.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      MPS I is seen in all populations at a frequency of approximately 1:100,000 for the severe form and 1:500,000
      for the attenuated form
    explanation: Clinical synthesis specific to the described MPS I manifestation.
references:
- reference: PMID:32764324
  title: 'Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.'
- reference: PMID:20301341
  title: Mucopolysaccharidosis Type I.
  tags:
  - GeneReviews
- reference: PMID:31194252
  title: >-
    Genotype-phenotype relationships in mucopolysaccharidosis type I (MPS I): Insights from the International MPS
    I Registry.
- reference: PMID:23786846
  title: >-
    Residual α-L-iduronidase activity in fibroblasts of mild to severe Mucopolysaccharidosis type I patients.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
  title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
  tags:
  - GeneReviews
- reference: PMID:41656624
  title: >-
    Carpal tunnel syndrome in mucopolysaccharidosis type I: clinical, surgical and histopathological findings.
- reference: PMID:35869927
  title: >-
    Growth in individuals with attenuated mucopolysaccharidosis type I during untreated and treated periods: Data
    from the MPS I registry.
- reference: PMID:41353341
  title: >-
    Clinical outcomes of exclusive enzyme therapy (laronidase) in a cohort of patients with mucopolysaccharidosis
    type I.
- reference: PMID:37850463
  title: >-
    Natural history of cardiac findings in mucopolysaccharidosis type I: report from an international registry.
- reference: url:https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a80ac249-cae4-41f3-88bb-344088b20e60
  title: DailyMed - ALDURAZYME- laronidase injection, solution, concentrate
- reference: PMID:19117856
  title: 'Mucopolysaccharidosis I: management and treatment guidelines.'
- reference: PMID:31211405
  title: >-
    Enzyme replacement therapy with laronidase (Aldurazyme(®)) for treating mucopolysaccharidosis type I.
- reference: PMID:15126990
  title: >-
    Enzyme replacement therapy for mucopolysaccharidosis I: a randomized, double-blinded, placebo-controlled, multinational
    study of recombinant human alpha-L-iduronidase (laronidase).
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6581069/
  title: >-
    Enzyme replacement therapy with laronidase (Aldurazyme®) for treating mucopolysaccharidosis type I - PMC
- reference: url:https://repub.eur.nl/pub/112929/Opmaak-Esmee-Oussoren-mindiscussie.pdf
  title: >-
    https://repub.eur.nl/pub/112929/Opmaak-Esmee-Oussoren-mindiscussie.pdf
- reference: PMID:31839529
  title: >-
    Intrathecal enzyme replacement for cognitive decline in mucopolysaccharidosis type I, a randomized, open-label,
    controlled pilot study.
- reference: PMID:28119823
  title: >-
    Pilot study of the safety and effect of adalimumab on pain, physical function, and musculoskeletal disease in
    mucopolysaccharidosis types I and II.
- reference: clinicaltrials:NCT00912925
  title: >-
    A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Multinational, Clinical Study of Recombinant Human
    Alpha L-Iduronidase In Patients With Mucopolysaccharidosis I
- reference: clinicaltrials:NCT00852358
  title: >-
    A Study of Intrathecal Enzyme Replacement for Cognitive Decline in Mucopolysaccharidosis I
progression:
- phase: Variable attenuated course
  age_range: Usually childhood onset, with later recognition possible
  notes: >-
    Symptoms commonly begin between three and ten years. Progression ranges from life-threatening cardiorespiratory
    complications in early adulthood to a near-normal lifespan with substantial joint and multisystem disability.
    Normal early development is not a guarantee of lifelong preserved cognition.
  evidence:
  - reference: PMID:20301341
    reference_title: Mucopolysaccharidosis Type I.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: 'Attenuated MPS I: Clinical onset is usually between ages three and ten years.'
    explanation: Attenuated-specific clinical synthesis.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/
    reference_title: Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The rate of disease progression can range from serious life-threatening complications leading to death in
      the second to third decade, to a normal life span (albeit with significant disease morbidity).
    explanation: Clinical synthesis specific to the described MPS I manifestation.
experimental_models:
- name: Patient fibroblast residual-IDUA and thermal-stability assays
  experimental_model_type: PRIMARY_CELL_CULTURE
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Patient-derived skin fibroblasts and control fibroblasts
  description: >-
    Cultured fibroblast homogenates from severe, intermediate and mild MPS I were assayed with an artificial fluorogenic
    substrate under high-protein and prolonged-incubation conditions. The E276K-associated activity was unstable
    at 37 degrees Celsius and more stable at 23 degrees Celsius. The study proposes a residual-function approach
    but does not validate an individual prognostic classifier.
  publication: PMID:23786846
  evidence:
  - *id010
  - *id019
  - reference: url:https://repub.eur.nl/pub/112929/Opmaak-Esmee-Oussoren-mindiscussie.pdf
    reference_title: >-
      https://repub.eur.nl/pub/112929/Opmaak-Esmee-Oussoren-mindiscussie.pdf
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      Fibroblast homogenates were prepared by resuspending one cell pellet in 100 µL water followed by sonication
      for 10 sec at 130 W.
    explanation: >-
      Methods of the 2013 article reproduced in chapter 3 of Oussoren’s 2018 thesis, Studies on Cartilage and Bone
      Disease in Mucopolysaccharidoses and Mucolipidoses. This measures fibroblast-homogenate activity, not intact-brain
      or natural-substrate flux.
  modeled_mechanisms:
  - target: Reduced Alpha-L-Iduronidase Activity
    relationship: MEASURES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: Residual activity was markedly reduced, with overlapping clinical-subtype ranges.
    limitations: >-
      Artificial 4-methylumbelliferyl substrate, high protein loading and extended incubation measure residual catalytic
      activity. Severe and attenuated ranges overlap. No neuronal activity threshold, natural-GAG turnover, intracellular
      protein half-life or clinical rescue was established. The abstract labels the Scheie group n=5, whereas the
      main Results and Table 1 include seven Scheie cell lines across five genotypes, including three E276K siblings.
      Those siblings are not independent genotype replications.
    divergences:
    - divergence_type: PROXY_QUANTITY
      description: >-
        Artificial-substrate activity in cultured-cell homogenates stands in for lysosomal hydrolysis in patient
        tissues; CNS protection and intact-cell protein turnover were not measured.
      materiality: QUALIFYING
    evidence:
    - *id010
    readouts:
    - name: Fluorogenic IDUA activity
      target: Reduced Alpha-L-Iduronidase Activity
      direction: DECREASED
      interpretation: Residual activity was markedly reduced, with overlapping clinical-subtype ranges.
      evidence:
      - *id010
  - target: Variant-Dependent IDUA Functional Instability
    relationship: MEASURES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: E276K-associated activity decayed faster at 37 degrees Celsius than at 23 degrees Celsius.
    limitations: >-
      Artificial 4-methylumbelliferyl substrate, high protein loading and extended incubation measure residual catalytic
      activity. Severe and attenuated ranges overlap. No neuronal activity threshold, natural-GAG turnover, intracellular
      protein half-life or clinical rescue was established. The abstract labels the Scheie group n=5, whereas the
      main Results and Table 1 include seven Scheie cell lines across five genotypes, including three E276K siblings.
      Those siblings are not independent genotype replications.
    divergences:
    - divergence_type: PROXY_QUANTITY
      description: >-
        Artificial-substrate activity in cultured-cell homogenates stands in for lysosomal hydrolysis in patient
        tissues; CNS protection and intact-cell protein turnover were not measured.
      materiality: QUALIFYING
    evidence:
    - *id019
    readouts:
    - name: Temperature-dependent retention of IDUA activity
      target: Variant-Dependent IDUA Functional Instability
      direction: ALTERED
      interpretation: E276K-associated activity decayed faster at 37 degrees Celsius than at 23 degrees Celsius.
      evidence:
      - *id019
discussions:
- evidence:
  - *id020
  - &id022
    reference: PMID:31839529
    reference_title: >-
      Intrathecal enzyme replacement for cognitive decline in mucopolysaccharidosis type I, a randomized, open-label,
      controlled pilot study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Nor was there a significant difference between treatment and control groups in any of the neuropsychological
      tests. Subjects in the control group did not experience any significant decline over the 12 month untreated
      period in any neuropsychological test except the Brief Visuospatial Memory Test, where the treatment group
      also experienced decline.
    explanation: >-
      Eight-person randomized open-label pilot with ongoing intravenous ERT; no demonstrated cognitive benefit in
      this design.
  discussion_id: cognitive_and_treatment_heterogeneity
  rationale: >-
    Attenuated disease is not synonymous with absence of CNS involvement. In the French cohort, 21 of 25 had normal
    cognition, but four had pre-ERT impairment. The small intrathecal laronidase trial found no treatment-associated
    cognitive improvement; it does not establish that intrathecal delivery can never work. Eight participants, short
    controlled follow-up, stable controls and lack of a human brain-uptake assay limit interpretation.
  prompt: What predicts cognitive involvement and treatment responsiveness within attenuated MPS I?
  kind: INTERPRETATION
  status: OPEN
- evidence:
  - reference: PMID:37850463
    reference_title: >-
      Natural history of cardiac findings in mucopolysaccharidosis type I: report from an international registry.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: All available echocardiography assessments completed prior to treatment initiation were used.
    explanation: Treatment censoring defines the natural-history period.
  - reference: PMID:37850463
    reference_title: >-
      Natural history of cardiac findings in mucopolysaccharidosis type I: report from an international registry.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Left ventricular hypertrophy of the posterior wall was the most common finding in both phenotypes (47.7 and
      31% in severe and attenuated, respectively).
    explanation: Primary echo finding; wall thickening is not histologic proof of infiltration.
  - reference: PMID:37850463
    reference_title: >-
      Natural history of cardiac findings in mucopolysaccharidosis type I: report from an international registry.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Cardiac data elements did not include other components of more recent interest such as aortic dimensions,
      aortic root dilation, strain, and diastolic function.
    explanation: Missing cardiac domains limit mechanistic and prognostic inference.
  discussion_id: cardiac_natural_history_and_source_limitations
  rationale: >-
    The cardiac registry uses echocardiograms obtained before ERT or HSCT. It therefore does not demonstrate treatment-related
    stabilization. Valve findings are ever-observed during irregular follow-up, not graded incident events. Among
    attenuated patients, posterior-wall hypertrophy occurred in 27 of 87 with measurements, septal hypertrophy in
    14 of 86 and low shortening fraction in seven of 104. Normal group averages and stable modeled trajectories
    do not exclude individual myocardial involvement; histology, cardiac MRI, strain and diastolic measurements
    were unavailable.
  prompt: >-
    What can untreated echocardiographic registry findings establish about myocardial disease and treatment effects?
  kind: INTERPRETATION
  status: OPEN
- evidence:
  - *id010
  - *id012
  discussion_id: residual_activity_genotype_and_evidence_boundaries
  rationale: >-
    The enzyme-activity study uses a small number of cultured-cell lines and overlapping residual ranges, while
    the genotype registry uses clinician-assigned severity and incomplete phase information. Neither establishes
    a universal enzyme threshold that protects the human brain. The French treatment cohort has inconsistent mortality-by-treatment-age
    statements between narrative and Table 2; no claim that all attenuated deaths followed adult treatment initiation
    is adopted. Its growth, antibody and organ outcomes are uncontrolled observations, and follow-up denominators
    vary by measurement.
  prompt: How well do residual-activity assays and genotype predict individual outcomes?
  kind: INTERPRETATION
  status: OPEN
- evidence:
  - reference: PMID:28119823
    reference_title: >-
      Pilot study of the safety and effect of adalimumab on pain, physical function, and musculoskeletal disease
      in mucopolysaccharidosis types I and II.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      We found comparable changes of 13° and 28° in the participant with MPS type IH (Subject  # 1), who had been
      previously treated with hematopoietic stem cell transplantation, over just 16 weeks of treatment with adalimumab.
    explanation: The MPS I participant had severe Hurler disease, not attenuated MPS I.
  - reference: PMID:28119823
    reference_title: >-
      Pilot study of the safety and effect of adalimumab on pain, physical function, and musculoskeletal disease
      in mucopolysaccharidosis types I and II.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      However, additional clinical trials are needed before this therapy should be recommended as part of clinical
      care.
    explanation: The exploratory study does not establish routine-care efficacy.
  discussion_id: inflammatory_therapy_evidence_is_not_attenuated_specific
  rationale: >-
    A small adalimumab crossover pilot in the tissue review enrolled one post-transplant Hurler patient and one
    patient with attenuated MPS II. It did not demonstrate treatment efficacy in attenuated MPS I. Parent-reported
    pain and some range-of-motion findings favored active treatment, but another pain measure, walking distance
    and handgrip did not improve, one family was effectively unblinded and safety follow-up was short. This supports
    further research rather than routine anti-TNF care or a proven human TLR4-to-TNF causal cascade.
  prompt: Does anti-inflammatory treatment benefit attenuated MPS I beyond existing care?
  kind: INTERPRETATION
  status: OPEN
clinical_trials:
- name: NCT00912925
  phase: PHASE_III
  status: COMPLETED
  description: >-
    Completed pivotal 26-week randomized placebo-controlled trial in 45 participants, including 37 Hurler-Scheie,
    seven Scheie and one Hurler participant. The FVC result favored laronidase; walking-distance significance differed
    between unadjusted and prespecified adjusted analyses. The registry record and current label describe the same
    trial, not independent replications.
  target_phenotypes:
  - preferred_term: Reduced vital capacity
    term:
      id: HP:0002792
      label: Reduced vital capacity
  evidence:
  - reference: clinicaltrials:NCT00912925
    reference_title: >-
      A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Multinational, Clinical Study of Recombinant
      Human Alpha L-Iduronidase In Patients With Mucopolysaccharidosis I
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: >-
      This study is being conducted to demonstrate the safety and clinical efficacy of Aldurazyme treatment in MPS
      I patients
    explanation: >-
      Official registry study-design description. Phase, status and enrollment were separately checked in the live
      structured registry record; this summary does not report efficacy results.
  - *id021
- name: NCT00852358
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: >-
    Completed open-label randomized delayed-treatment intrathecal laronidase study. The registry reports nine enrolled,
    whereas the published randomized analysis contains eight participants, four per group. Existing intravenous
    ERT continued. No significant between-group cognitive benefit was demonstrated; stable controls, small sample
    size and limited controlled duration constrain inference.
  target_phenotypes:
  - preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - reference: clinicaltrials:NCT00852358
    reference_title: >-
      A Study of Intrathecal Enzyme Replacement for Cognitive Decline in Mucopolysaccharidosis I
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: >-
      This is a 24-month study of the use of laronidase administered into the spinal fluid to treat cognitive decline
      in mucopolysaccharidosis I (MPS I). MPS I is a rare genetic condition due to deficiency of the enzyme alpha-l-iduronidase.
      Laronidase is the manufactured form of the enzyme alpha-l-iduronidase.
    explanation: >-
      Official registry study-design description. Phase, status and enrollment were separately checked in the live
      structured registry record; this summary does not report efficacy results.
  - *id022

📚

References & Deep Research

References

19

PMID:32764324

Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.

No top-level findings curated for this source.

PMID:20301341

Mucopolysaccharidosis Type I.

No top-level findings curated for this source.

PMID:31194252

Genotype-phenotype relationships in mucopolysaccharidosis type I (MPS I): Insights from the International MPS I Registry.

No top-level findings curated for this source.

PMID:23786846

Residual α-L-iduronidase activity in fibroblasts of mild to severe Mucopolysaccharidosis type I patients.

No top-level findings curated for this source.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1162/

Mucopolysaccharidosis Type I - GeneReviews® - NCBI Bookshelf

No top-level findings curated for this source.

PMID:41656624

Carpal tunnel syndrome in mucopolysaccharidosis type I: clinical, surgical and histopathological findings.

No top-level findings curated for this source.

PMID:35869927

Growth in individuals with attenuated mucopolysaccharidosis type I during untreated and treated periods: Data from the MPS I registry.

No top-level findings curated for this source.

PMID:41353341

Clinical outcomes of exclusive enzyme therapy (laronidase) in a cohort of patients with mucopolysaccharidosis type I.

No top-level findings curated for this source.

PMID:37850463

Natural history of cardiac findings in mucopolysaccharidosis type I: report from an international registry.

No top-level findings curated for this source.

url:https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a80ac249-cae4-41f3-88bb-344088b20e60

DailyMed - ALDURAZYME- laronidase injection, solution, concentrate

No top-level findings curated for this source.

PMID:19117856

Mucopolysaccharidosis I: management and treatment guidelines.

No top-level findings curated for this source.

PMID:31211405

Enzyme replacement therapy with laronidase (Aldurazyme(®)) for treating mucopolysaccharidosis type I.

No top-level findings curated for this source.

PMID:15126990

Enzyme replacement therapy for mucopolysaccharidosis I: a randomized, double-blinded, placebo-controlled, multinational study of recombinant human alpha-L-iduronidase (laronidase).

No top-level findings curated for this source.

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC6581069/

Enzyme replacement therapy with laronidase (Aldurazyme®) for treating mucopolysaccharidosis type I - PMC

No top-level findings curated for this source.

url:https://repub.eur.nl/pub/112929/Opmaak-Esmee-Oussoren-mindiscussie.pdf

https://repub.eur.nl/pub/112929/Opmaak-Esmee-Oussoren-mindiscussie.pdf

No top-level findings curated for this source.

PMID:31839529

Intrathecal enzyme replacement for cognitive decline in mucopolysaccharidosis type I, a randomized, open-label, controlled pilot study.

No top-level findings curated for this source.

PMID:28119823

Pilot study of the safety and effect of adalimumab on pain, physical function, and musculoskeletal disease in mucopolysaccharidosis types I and II.

No top-level findings curated for this source.

clinicaltrials:NCT00912925

A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Multinational, Clinical Study of Recombinant Human Alpha L-Iduronidase In Patients With Mucopolysaccharidosis I

No top-level findings curated for this source.

clinicaltrials:NCT00852358

A Study of Intrathecal Enzyme Replacement for Cognitive Decline in Mucopolysaccharidosis I

No top-level findings curated for this source.

Attenuated Mucopolysaccharidosis Type I

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