Genotype-phenotype findings in patients with mucopolysaccharidosis II from the Hunter Outcome Survey.

Purpose: This study investigated the relationship between mucopolysaccharidosis II (MPS II) iduronate-2-sulfatase gene (IDS) variants and phenotypic characteristics, particularly cognitive impairment, using data from the Hunter Outcome Survey (HOS) registry.
Methods: HOS data for male patients (n = 650) aged ≥5 years at latest cognitive assessment with available genetic data were analyzed. Predefined genotype categories were used to classify IDS variants and report phenotypic characteristics by genotype.
Results: At their latest cognitive assessment, 411 (63.2%) of 650 patients had cognitive impairment. Missense variants were the most common MPS II genotype, with about equal frequency for patients with and patients without cognitive impairment. Complete deletions/large rearrangements were associated with cognitive impairment. Cognitive impairment and behavioral issues were most common, and height and weight abnormalities most apparent, in patients with large IDS structural changes. Broadly, missense variants NM-000202.8:c.998C>T p.(Ser333Leu), NM-000202.8:c.1402C>T p.(Arg468Trp), NM-000202.8:c.1403G>A p.(Arg468Gln) and NM-000202.8:c.262C>T p.(Arg88Cys), and splice site variant NM-000202.8:c.257C>T p.(Pro86Leu), were associated with cognitive impairment, and variants NM-000202.8:c.253G>A p.(Ala85Thr), NM-000202.8:c.187 A>G p.(Asn63Asp), NM-000202.8:c.1037C>T p.(Ala346Val), NM-000202.8:c.182C>T p.(Ser61Phe) and NM-000202.8:c.1122C>T were not.
Conclusion: This analysis contributes toward the understanding of MPS II genotype-phenotype relationships, confirming and expanding on existing findings in a large, geographically diverse population.
Competing Interests: Declaration of competing interest J.M. has received consulting fees from and/or has participated in advisory boards for Denali Therapeutics, JCR Pharmaceuticals, REGENXBIO, Sanofi Genzyme, and Shire (a Takeda company). He is a Principal Investigator for a post-trial access program for intrathecal ERT for the neuronopathic form of MPS II (sponsored by Shire, a Takeda company), a Phase 1/2 gene editing trial for adults with MPS II (sponsored by Sangamo Therapeutics), and Phase 1/2 and Phase 2/3 intravenous ERT trials for MPS II (sponsored by Denali Therapeutics). H.A. has received consulting and/or other fees from and/or has participated in advisory boards for Amicus Therapeutics, BioMarin Pharmaceutical, Biopas, Passage Bio, PTC Therapeutics, Sanofi Genzyme, and Takeda. He has performed contracted research for Allievex, Amicus Therapeutics, bluebird bio, PTC Therapeutics, Sanofi Genzyme, and Takeda. B.K.B. has received consulting and/or speaker fees from and/or has participated in advisory boards for Aeglea, Agios, Alexion, AstraZeneca Rare Disease, Alltrna, BioMarin Pharmaceutical, Chiesi Farmaceutici, Horizon Therapeutics, JCR Pharmaceuticals, Jnana Therapeutics, Moderna, Orchard Therapeutics, Passage Bio, REGENXBIO, Sanofi Genzyme, Shire (a Takeda company), Travere, and Ultragenyx. She has performed contracted research for Shire (a Takeda company) and has been involved in company-sponsored clinical trials with BioMarin Pharmaceutical, Denali Therapeutics, Homology Medicines, JCR Pharmaceuticals, Jnana Therapeutics, Sangamo Therapeutics, Shire (a Takeda company), Synlogic, and Ultragenyx. M.S. has received consulting, speaker, and/or other fees from and/or has participated in advisory boards for Actelion, Alexion, AstraZeneca Rare Disease, BioMarin Pharmaceutical, Chiesi Farmaceutici, Orchard Therapeutics, Orphazyme, Paradigm, PTC Therapeutics, Sanofi Genzyme, Takeda, and Ultragenyx. He has performed contracted research for Alexion, AstraZeneca Rare Disease, BioMarin Pharmaceutical, CTD Holdings, Orchard Therapeutics, Orphazyme, Paradigm, PTC Therapeutics, Sanofi Genzyme, and Takeda. A.T.-S. has received consulting and/or other fees from and/or has participated in advisory boards for Alexion, AstraZeneca Rare Disease, BioMarin Pharmaceutical, Chiesi Farmaceutici, Orphazyme, Sanofi Genzyme, Synageva BioPharma, and Takeda. J.A. was an employee of Takeda and stockholder of Takeda Pharmaceuticals Company Limited at the time of this analysis (current affiliation is Ultragenyx Europe GmbH, Allschwil, Basel, Switzerland). J.B. is a full-time employee of Takeda and stockholder of Takeda Pharmaceuticals Company Limited. D.F. was an employee of Takeda and stockholder of Takeda Pharmaceuticals Company Limited at the time of this analysis; and is currently an employee of Denali Therapeutics, Zurich, Switzerland. D.M., D.A.H.W., and M.N. were employees of Takeda and stockholders of Takeda Pharmaceuticals Company Limited at the time of this analysis. M.N. is currently an employee of Crosswalk Therapeutics, Cambridge, MA, USA. R.G. has received consulting fees, fees for service, speaker fees, and/or travel expenses from and/or has participated in advisory boards for Abeona Therapeutics, Alnylam Pharmaceuticals, Amicus Therapeutics, BioMarin Pharmaceutical, Chiesi Farmaceutici, Inventiva Pharma, Janssen, JCR Pharmaceuticals, Novartis, the Orphan Disease Center, Praxis Precision Medicines, PTC Therapeutics, REGENXBIO, Sanofi Genzyme, Shire (a Takeda company), Sigilon Therapeutics, Swedish Orphan Biovitrum, Takeda, and Ultragenyx. He has performed contracted research for or received research grants from Allievex, Amicus Therapeutics, BioMarin Pharmaceutical, GC Pharma, Idorsia, Janssen, JCR Pharmaceuticals, Lysogene, Sanofi Genzyme, Takeda, and Ultragenyx.
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