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Cognitive and adaptive behaviors associated with disease severity and genotype in patients with mucopolysaccharidosis
Karen S Yee1, David Alexanderian2, David Merberg1
1Takeda Development Center Americas, Inc., Cambridge, MA, USA.
Background:
Mucopolysaccharidosis II (MPS II) is a rare, X-linked lysosomal storage disease caused by pathogenic variants of the iduronate-2-sulfatase gene (IDS) and is characterized by a highly variable disease spectrum. MPS II severity is difficult to predict based on IDS variants alone; while some genotypes are associated with specific phenotypes, the disease course of most genotypes remains unknown. This study aims to refine the genotype-phenotype categorization by combining information from the scientific literature with data from two clinical studies in MPS II.
Methods:
Genotype, cognitive, and behavioral data from 88 patients in two clinical studies (NCT01822184, NCT02055118) in MPS II were analyzed post hoc in combination with published information on IDS variants from the biomedical literature through a semi-automated multi-stage review process. The Differential Ability Scales, second edition (DAS-II) and the Vineland Adaptive Behavior Scales™, second edition (VABS-II) were used to measure cognitive function and adaptive behavior.
Results:
The most common category of IDS variant was missense (47/88, 53.4% of total variants). The mean (standard deviation [SD]) baseline DAS-II General Conceptual Ability (GCA) and VABS-II Adaptive Behavior Composite (ABC) scores were 74.0 (16.4) and 82.6 (14.7), respectively. All identified IDS complete deletions/large rearrangements (n = 7) and large deletions (n = 1) were associated with a published 'severe' or 'predicted severe' progressive neuronopathic phenotype, characterized by central nervous system involvement. In categories comprising more than one participant, mean baseline DAS-II GCA scores (SD) were lowest among individuals with complete deletions/large rearrangements 64.0 (9.1, n = 4) and highest among those with splice site variants 83.8 (14.2, n = 4). Mean baseline VABS-II ABC scores (SD) were lowest among patients with unclassifiable variants 79.3 (4.9, n = 3) and highest among those with a splice site variant 87.2 (16.1, n = 5), in variant categories with more than one participant.
Conclusions:
Most patients in the studies had an MPS II phenotype categorized as 'severe' or 'predicted severe' according to classifications, as reported in the literature. Patients with IDS complete deletion/large rearrangement variants had lower mean DAS-II GCA scores than those with other variants, as well as low VABS-II ABC, confirming an association with the early progressive 'severe' (neuronopathic) disease. These data provide a starting point to improve the classification of MPS II phenotypes and the characterization of the genotype-phenotype relationship.
Insights
This study links specific genetic variants in the iduronate-2-sulfatase gene (IDS) to severe Mucopolysaccharidosis II (MPS II) phenotypes, improving genotype-phenotype classification for this rare disease. Findings confirm that complete IDS deletions/large rearrangements correlate with severe neuronopathic MPS II.
Area of Science:
- Genetics
- Rare Diseases
- Biochemistry
Background:
- Mucopolysaccharidosis II (MPS II) is a rare, X-linked lysosomal storage disorder.
- It stems from pathogenic variants in the iduronate-2-sulfatase gene (IDS), presenting a wide spectrum of severity.
- Predicting MPS II severity solely from IDS variants is challenging due to unknown disease courses for most genotypes.
Purpose of the Study:
- To enhance the genotype-phenotype categorization in MPS II.
- To integrate data from scientific literature with clinical study findings.
- To refine the understanding of IDS variant impact on MPS II phenotypes.
Main Methods:
- Post hoc analysis of genotype, cognitive, and behavioral data from 88 MPS II patients across two clinical studies.
- Integration of published IDS variant information from biomedical literature.
- Utilized Differential Ability Scales II (DAS-II) and Vineland Adaptive Behavior Scales II (VABS-II) for assessments.
Main Results:
- Missense variants were most common (53.4%).
- Complete IDS deletions/large rearrangements (n=8) were linked to severe, progressive neuronopathic phenotypes with CNS involvement.
- Individuals with complete deletions/large rearrangements showed the lowest mean DAS-II GCA scores (64.0), while splice site variants had the highest (83.8).
Conclusions:
- The study confirms the association between IDS complete deletion/large rearrangement variants and severe, neuronopathic MPS II.
- Patients with these variants exhibited lower cognitive and adaptive behavior scores.
- These findings offer a foundation for improved MPS II phenotype classification and genotype-phenotype relationship characterization.
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