Clinical characteristics: Mucopolysaccharidosis type I (MPS I) is a progressive multisystem disorder with features ranging over a continuum of severity. While affected individuals have traditionally been classified as having one of three MPS I syndromes (Hurler syndrome, Hurler-Scheie syndrome, or Scheie syndrome), no easily measurable biochemical differences have been identified and the clinical findings overlap; thus, affected individuals are best described as having either severe or attenuated MPS I, a distinction that influences therapeutic options.
Diagnosis/testing: The diagnosis of MPS I is established in a proband with suggestive clinical and laboratory findings and either identification of biallelic pathogenic variants in IDUA on molecular genetic testing or detection of deficient activity of the lysosomal enzyme α-L-iduronidase.
Management: Treatment of manifestations: Infant learning programs/special education for developmental delays; hats with visors/sunglasses to reduce glare; cardiac valve replacement as needed; physical therapy, orthopedic surgery as needed (joint replacement, atlanto-occipital stabilization, early median nerve decompression for carpal tunnel syndrome based on nerve conduction studies before clinical manifestations develop); cerebrospinal fluid (CSF) shunting for hydrocephalus; tonsillectomy and adenoidectomy for eustachian tube dysfunction and/or upper airway obstruction; tracheostomy for sleep apnea, pulmonary hypertension, right heart failure; PE tubes; surgical intervention for cervical myelopathy. Prevention of primary manifestations: Prevention of secondary complications: Bacterial endocarditis prophylaxis for those with cardiac involvement; special attention to anesthetic risks. Surveillance: Early and continuous monitoring of head growth in infants and children; routine median nerve conduction velocity testing; and educational assessment of children with attenuated disease prior to primary school entry. Annual assessment by: orthopedic surgeon, neurologist (for evidence of spinal cord compression), ophthalmologist, cardiologist (including echocardiogram), audiologist, and otolaryngologist. Evaluation of relatives at risk: Early diagnosis prior to significant disease manifestations is warranted in relatives at risk in order to begin therapy as early in the course of disease as possible.
Genetic counseling: MPS I is inherited in an autosomal recessive manner. At conception, each child of a couple in which both parents are heterozygous for a IDUA pathogenic variant has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if both pathogenic IDUA variants have been identified in the family.
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