CME/CE Mucopolysaccharidosis I Diagnosing MPS I Paul Orchard, MD Medical Director, Inherited Metabolic and Storage Disease Program Professor of Pediatrics, Division of Blood and Marrow Transplantation University of Minnesota Medical School Mucopolysaccharidosis type I (MPS I) is a Lysosomal Storage Disorder Lysosomal Storage Disorders (>50 identified) Overall Incidence of ~ 1:8,000 MPS Disorders (7 types) Incidence 1:25,000 – 50,000 MPS I Incidence 1:100,000 NIH Rare Disease Database: MPS. 2019. https://rarediseases.info.nih.gov/diseases/7065/mucopolysaccharidosis Mucopolysaccharidoses MPS Type Common Name Gene Mutation MPS I Hurler, Hurler-Scheie, Scheie syndrome IDUA MPS II Hunter syndrome IDS MPS III Sanfilippo syndrome GNS, HGSNAT, NAGLU, SGSH MPS IV Morquio syndrome GALNS, GLB1 MPS VI Maroteaux-Lamy syndrome ARSB MPS VII Sly syndrome GUSB NIH Rare Disease Database: MPS. 2019. https://rarediseases.info.nih.gov/diseases/7065/mucopolysaccharidosis What is MPS I? Mucopolysaccharidosis I (MPS I) • Lysosomal “storage disease” • Mutations in a-L-iduronidase (IDUA) gene, leading to: • increased glycosaminoglycans (dermatan sulphate and heparan sulphate) • An autosomal recessive disease • Disease severity and symptom onset varies • Two subtypes • Hurler syndrome (Severe MPS I, or MPS IH) • Attenuated MPS I (previously Scheie, or Hurler-Scheie syndrome • 1 in 100,000 births (Severe MPS I) • 1 in 500,000 births (Attenuated MPS I) Jameson et al. Cochrane Rev. 2016; CD009354. Kabuska et al. Diagnostics. 2020;10: 161. Mucopolysaccharidosis type I. US National Library of Medicine website. Multiple Symptoms Macrosomia Developmental delay Chronic rhinitis/otitis Corneal clouding Obstructive airway disease Hearing loss Umbilical/inguinal hernia Enlarged tongue Skeletal deformities Cardiovascular disease Hepatosplenomegaly Carpal tunnel syndrome Joint stiffness Adapted from Neufeld et al. 2001; 3421-3452. MPS I Phenotypes Jameson et al. Cochrane Rev. 2016; CD009354. Kabuska et al. Diagnostics. 2020;10: 161. Image courtesy Kabuska et al. 2020. Licensed under: https://creativecommons.org/licenses/by-nc-nd/4.0/. Early Symptoms Leading to Diagnosis: Attenuated MPS I • Survey of 60 MPS I patients with attenuated phenotype Bruni et al. Mol Gen Metab Rep. 2016; 8: 67-73. Image licensed under: https://creativecommons.org/licenses/by-nc-nd/4.0/. Early Symptoms Leading to Diagnosis: Severe MPS I • Survey of 93 MPS I patients with severe phenotype Bruni et al. Mol Gen Metab Rep. 2016; 8: 67-73. Image licensed under: https://creativecommons.org/licenses/by-nc-nd/4.0/. Early Symptoms Leading to Diagnosis: Severe MPS I a. Course facial a b d features b. Claw hands c. Umbilical e hernia d. Spine c abnormalities e. Corneal clouding Kabuska et al. Diagnostics. 2020;10: 161. Image licensed under: https://creativecommons.org/licenses/by-nc-nd/4.0/. Which Physicians Were Consulted? Attenuated (N=60) Severe (N=93) • Patients with severe MPS I saw a mean of 4.7 specialists before diagnosed (left) • Mean age at diagnosis; 8.2 yrs (range 1 month to 48 yrs) • Attenuated MPS I saw a mean of 4.5 specialists before diagnosed (right) • Mean age at diagnosis; 1.7 yrs (range birth to 8.5 yrs) Bruni et al. Mol Gen Metab Rep. 2016; 8: 67-73. Image licensed under: https://creativecommons.org/licenses/by-nc-nd/4.0/. Phenotype-Genotype Connection • MPS I Registry: Numerous mutations linked to MPS I. Most are nonsense or missense mutations. Nonsense Missense Hurler Attenuated Image courtesy Clarke et al. Clin Genet. 2019;96: 281-9. Licensed under: https://creativecommons.org/licenses/by-nc-nd/4.0/. Phenotype-Genotype Correlation Image courtesy Clarke et al. Clin Genet. 2019;96: 281-9. Licensed under: https://creativecommons.org/licenses/by-nc-nd/4.0/. Diagnosis • GAG analysis • IDUA assay (gold standard) • Genetic testing • NBS (module 4) Kabuska et al. Diagnostics. 2020;10: 161. Image licensed under: https://creativecommons.org/licenses/by-nc-nd/4.0/. Newborn Screening of MPS-I https://www.newsteps.org/resources/newborn-screening-status-all-disorders Summary • MPS I is a rare, genetic lysosomal storage disorder • Untreated, severe MPSI is lethal in the first decade • Part of the MPS family of diseases • Due to mutations in IDUA gene that leads to increased GAGs • Variability in symptoms, disease onset, and severity • Severe (Hurler) – most common form • Attenuated (Hurler-Scheie, Scheie) • Long delays in diagnosis involving multiple specialists • Newborn screening advised but not universal (see module 3 of this program) • Available treatments include enzyme therapy and blood/marrow transplantation (see module 2 of this program).