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

Joseph Muenzer1, Hernan Amartino2, Barbara K Burton3

  • 1University of North Carolina at Chapel Hill, 101 Manning Drive CB# 7487, Medical School Wing E Room 117, Chapel Hill, NC 27599-7487, USA.

Molecular Genetics and Metabolism
|September 20, 2024
PubMed
Abstract

Insights

Genetic variants in the iduronate-2-sulfatase gene (IDS) are linked to mucopolysaccharidosis II (MPS II) severity. Large IDS deletions/rearrangements correlate with cognitive impairment, while missense variants show varied effects in MPS II patients.

Area of Science:

  • Genetics
  • Biochemistry
  • Rare Diseases

Background:

  • Mucopolysaccharidosis II (MPS II) is a rare genetic disorder caused by deficiency of the enzyme iduronate-2-sulfatase (IDS).
  • Understanding the relationship between specific IDS gene variants and clinical manifestations is crucial for predicting disease progression and guiding treatment.

Purpose of the Study:

  • To investigate the genotype-phenotype correlations in MPS II, focusing on the association between IDS variants and cognitive impairment.
  • To analyze data from the Hunter Outcome Survey (HOS) registry to identify patterns in a large, diverse MPS II patient cohort.

Main Methods:

  • Analysis of genetic data and phenotypic characteristics from 650 male MPS II patients aged ≥5 years in the HOS registry.
  • Classification of patients based on predefined IDS genotype categories to assess phenotypic variability.

Main Results:

  • Cognitive impairment was observed in 63.2% of the analyzed MPS II patients.
  • Complete IDS deletions or large rearrangements were significantly associated with cognitive impairment.
  • Specific missense variants (e.g., c.998C>T, c.1402C>T) and a splice site variant (c.257C>T) were linked to cognitive impairment, while others were not.
  • Height and weight abnormalities were most pronounced in patients with large IDS structural changes.

Conclusions:

  • This study confirms and expands the understanding of genotype-phenotype relationships in MPS II using a large, diverse patient population.
  • The findings highlight the importance of specific IDS variants, particularly large structural changes, in predicting cognitive outcomes in MPS II.
Keywords:
Cognitive impairmentHunter Outcome SurveyIduronate-2-sulfatase gene (IDS) variantsMPS IIMucopolysaccharidosis IIPhenotypic characteristics

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