Assessment of adaptive functioning in Angelman syndrome using the Vineland Adaptive Behavior Scales, Third Edition

Technical Summary: Assessment of Adaptive Functioning in Angelman Syndrome Using the Vineland Adaptive Behavior Scales, Third Edition

Problem Statement
Angelman syndrome (AS) is a rare neurogenetic disorder characterized by severe intellectual disability, minimal to absent speech, motor impairments, and a distinctive behavioral profile. Adaptive functioning—the conceptual, social, and practical skills used in daily life—remains profoundly impaired in individuals with AS, necessitating lifelong care. While previous natural history studies have utilized the Vineland Adaptive Behavior Scales, Second Edition (Vineland-II), several limitations persist. These include significant floor effects in specific subdomains (e.g., Domestic and Community skills) and the inability of the Vineland-II to account for augmentative and alternative communication (AAC) modalities, which are critical for accurately assessing communication in this population. Furthermore, the Vineland-II data primarily covered childhood and early adolescence, leaving a gap in understanding adaptive trajectories into adulthood. As the Vineland-3 (released in 2016) becomes a core outcome measure in recent and upcoming AS clinical trials, updated natural history benchmarks using this instrument are required to contextualize treatment effects and guide trial design.

Methodology
This study analyzed longitudinal data from 331 individuals with genetically confirmed Angelman syndrome (ages 6 months to 52 years) assessed between 2018 and 2025. The cohort included 156 females (47%) and was stratified by molecular subtype: deletion (n=207, ~63%), UBE3A point mutation (n=61, ~18%), and uniparental disomy (UPD) or imprinting defect (ImpD) (n=63, ~19%). The latter two groups were combined for analysis due to similar neurodevelopmental profiles.

Adaptive functioning was assessed using the Comprehensive Interview Form of the Vineland-3, covering Communication, Daily Living Skills, Socialization, and Motor Skills domains. The study excluded the Written Communication subdomain due to the scarcity of relevant skills in the AS population. To address floor effects and the limitations of Age Equivalent (AE) scores (where multiple raw scores map to a single AE value), the authors utilized Growth Scale Values (GSVs). GSVs provide an equal-interval scale, offering greater sensitivity to detect small changes over time compared to standard scores or AE scores.

Statistical analysis employed linear mixed-effects models (LMM) with restricted maximum likelihood. The models included random effects for participants to account for repeated measures and fixed effects for molecular subtype, age, and the interaction between subtype and age. Age was log2-transformed to model the nonlinear relationship between age and skill acquisition, where growth is typically faster in early life and slows over time. The deletion subtype served as the reference group.

Key Results

1. Genotype-Phenotype Gradient: Individuals with the deletion subtype demonstrated significantly lower adaptive functioning across all Vineland-3 domains compared to non-deletion subtypes. Within the non-deletion group, individuals with UBE3A mutations generally exhibited higher adaptive skills than those with UPD/ImpD, though the latter two groups were often statistically similar depending on the specific subdomain.
2. Nonlinear Developmental Trajectories: Adaptive skills increased with age across all domains, but the rate of growth was nonlinear. The log2 transformation of age confirmed that skill acquisition occurs more rapidly in early life and decelerates over time. This pattern held true across all molecular subtypes, with largely parallel trajectories.
3. Domain-Specific Findings:
   • Communication: Both non-deletion subtypes showed significantly higher Growth Scale Values (GSVs) than the deletion group at age 11. Notably, the study identified significant age-by-subtype interactions in Expressive Communication, where non-deletion groups showed steeper age-related increases compared to the deletion group—a nuance not detected in previous Vineland-II analyses.
   • Daily Living Skills: Non-deletion groups outperformed the deletion group in Personal, Domestic, and Community subdomains. Significant age-by-subtype interactions were observed in the Personal subdomain for the UBE3A mutation group.
   • Socialization and Motor Skills: Non-deletion groups consistently scored higher than the deletion group. While most trajectories were parallel, the UPD/ImpD group showed a steeper increase in Play and Leisure Time skills relative to the deletion group.
4. Floor Effects: Despite the inclusion of additional early-skill items in the Vineland-3, floor effects remained substantial, particularly in the Domestic subdomain (nearly 46% of observations at the floor). However, the use of GSVs allowed for the modeling of growth even in the presence of these floor effects, avoiding the compression issues inherent in AE scores.

Significance and Claims
The authors claim that this study provides updated natural history benchmarks for Angelman syndrome using the Vineland-3, a tool increasingly central to clinical trial endpoints. The primary significance lies in demonstrating that:

• Vineland-3 Utility: The Vineland-3, with its inclusion of AAC modalities and expanded item pools for early skills, offers improved sensitivity for assessing communication and adaptive functioning in AS compared to the Vineland-II.
• Longitudinal Modeling: GSVs are a practical and necessary metric for modeling longitudinal change in AS, particularly given the persistent floor effects and the nonlinear nature of development in this population.
• Subtype Differentiation: The study reinforces the genotype-phenotype correlation, confirming that deletion subtypes are associated with the most severe adaptive impairments, while also identifying subtle differences in developmental slopes between subtypes in specific domains (e.g., Expressive Communication).
• Trial Readiness: These findings offer critical data for power calculations, endpoint selection, and the interpretation of clinical meaningfulness in ongoing and future AS therapeutic trials, particularly those targeting adolescents and adults where data has historically been sparse.

The paper concludes that while adaptive functioning in AS improves slowly into adulthood, the rate of growth varies by molecular subtype. These updated benchmarks are essential for setting realistic expectations for intervention outcomes and for designing robust clinical trials.