Alpha- Activity ( Type I) Indications for Ordering Symptoms • MPS I subtypes Confirm diagnosis in individuals with clinical and/or o – most severe biochemical evidence of mucopolysaccharidosis type I, also o Hurler- – moderately severe known as MPS I (Hurler, Hurler-Scheie, Scheie syndromes) o Scheie syndrome – least severe (intellect, life span, and Test Description stature can be normal) • Overlap of clinical symptoms among MPS I subtypes Enzyme activity measured by quantitative fluorometry o No biochemical differences have been identified • Symptoms and severity vary widely Tests to Consider o Coarse facial features o Organomegaly Screening o Progressive skeletal dysplasia (dysostosis multiplex) Mucopolysaccharides Screen – Electrophoresis and o Gibbus Quantitation, Urine 0081352 o Short stature • Recommended initial test to screen for all o mucopolysaccharidosis types, including MPS I o Corneal clouding Diagnosis o Hearing loss Alpha-Iduronidase Enzyme Activity in Leukocytes 2011415 o Progressive • Recommended for excluding MPS I following abnormal Pathophysiology screen • GAGs – degraded in by a series of • Recommended for confirming MPS I in patients with a • Alpha-iduronidase enzyme consistent clinical phenotype and/or a positive family o One of several enzymes responsible for the degradation history of the GAGs dermatan and Monitoring o Deficiency of alpha-iduronidase Mucopolysaccharides, Quantitative, Urine 0081357 ▪ Leads to incomplete degradation and accumulation of heparan and in Mucopolysaccharidoses Type 1/2, Total HS and NRE (Sensi- ▪ Causes MPS I Pro®) Quantitative, Urine 3003552 Mucopolysaccharidoses Type 1/2, Total Heparan Sulfate and Genetics NRE (Sensi-Pro®) Quantitative, Serum or Plasma 3003566 • Monitors (GAG) levels in patients with – IDUA a confirmed MPS I diagnosis Inheritance – autosomal recessive Disease Overview Genotype/phenotype correlation Hurler syndrome Incidence • Associated with more severe, nonsense variants • MPS I – ~1/70,000 o Profound alpha-iduronidase deficiency o Subtypes ▪ Hurler syndrome – ~1/100,000 Hurler-Scheie and Scheie syndromes ▪ Hurler-Scheie syndrome – ~1/300,000 • Variants are often milder (eg, single base-pair ▪ Scheie syndrome – ~1/million substitutions) o Some residual enzyme function is retained

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Test Interpretation References

Results • Beck M, Arn P, Giugliani R, et al. The natural history of Alpha-iduronidase enzyme activity in leukocytes MPS I: global perspectives from the MPS I Registry. Genet • Extremely low/undetectable enzyme activity is consistent Med. 2014;16(10):759-65. PubMed with MPS I (Hurler, Hurler-Scheie, Scheie) • Clarke LA. The mucopolysaccharidoses: a success of molecular medicine. Expert Rev Mol Med. 2008;10:e1. Limitations PubMed • Cannot differentiate between Hurler, Hurler-Scheie, and • Clarke LA, Heppner J. Mucopolysaccharidosis type I. In: Scheie syndromes Adam MP, Ardinger HH, Pagon RA, et al., editors. o Categorization depends on clinical and/or molecular GeneReviews, University of Washington; 1993-2021. genetic findings • Enns GM, Steiner RD, et al. Lysosomal disorders. In • Cannot predict carrier status for MPS I Pediatric Endocrinology and Inborn Errors of . • Does not evaluate enzyme deficiencies in other MPS types Sarafoglou K, Hoffman GF, et al, editors. McGraw-Hill • Pseudodeficiency has been shown for this enzyme due to Medical Division; 2009:747-748. specific gene variants affecting the exogenous substrate, • Lawrence R, Brown JR, Al-Mafraji K, et al. Disease-specific but not endogenous substrates non-reducing end carbohydrate biomarkers for o Individuals with pseudodeficiency are not affected with mucopolysaccharidoses. Nat Chem Biol. 2012;8(2):197- MPS I 204. PubMed

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