Orphanet Journal of Rare Diseases | Clinical Significance and Minimal Important Difference of BSITD-III in Developmental Assessment of Children with Neuronopathic MPS II

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This study, from the caregiver perspective, established that a 1–2 month gain in age-equivalent scores on the BSITD-III represents a minimally important difference in children with neuronopathic MPS II. The tool's items are highly correlated with daily functioning, supporting its use as a sensitive endpoint in clinical trials.

 

Literature Overview

The article titled 'Defining Bayley Scales of Infant and Toddler Development Third Edition (BSITD-III) meaningful change and item relevance in children with neuronopathic MPS II: a caregiver interview-based study,' published in Orphanet Journal of Rare Diseases, reviews and summarizes the clinical significance of using the BSITD-III scale to assess developmental changes in children with neuronopathic Mucopolysaccharidosis type II (MPS II, Hunter syndrome) during treatment. Through semi-structured interviews, the study collected subjective evaluations from primary caregivers to systematically analyze whether changes in BSITD-III subtests were perceived by families as functionally meaningful, and quantified the threshold for 'meaningful improvement.' Results showed that even a 1–2 month gain in age-equivalent scores was widely recognized as clinically significant progress, particularly in cognitive, expressive communication, and fine motor domains. This study provides empirical support from patient families for selecting appropriate outcome measures in rare disease clinical trials. The article emphasizes that maintaining existing skills is an important therapeutic goal when assessing progressive neurodevelopmental disorders. Additionally, the study validates the association between BSITD-III items and children's daily functional abilities, enhancing the tool’s validity in real-world settings. The paragraph ends with a Chinese period and concludes with

Background Knowledge

Neuronopathic Mucopolysaccharidosis type II (neuronopathic MPS II) is an X-linked recessive lysosomal storage disorder caused by mutations in the IDS gene, leading to deficient activity of iduronate-2-sulfatase (I2S) and accumulation of glycosaminoglycans in multiple systems, particularly affecting the central nervous system. Affected children exhibit progressive cognitive decline, behavioral abnormalities, and global developmental delay, typically experiencing neurological deterioration after reaching a plateau at ages 2–4. Currently, there is no cure, and enzyme replacement therapy struggles to cross the blood-brain barrier, prompting exploration of novel therapeutic strategies such as gene therapy. In interventional clinical trials, developmental function must serve as a key efficacy endpoint with both sensitivity and clinical interpretability. The Bayley Scales of Infant and Toddler Development, Third Edition (BSITD-III), is a standardized tool for assessing cognitive, language, and motor development in infants and toddlers (1–42 months), and its age-equivalent scores (AEq) are widely used to track developmental trajectories in children with MPS II. However, the magnitude of AEq change that constitutes a 'meaningful' improvement has long lacked empirical data from the family perspective. Previous studies suggest that children’s developmental trajectories in the natural history of the disease are significantly below those of age-matched peers and exhibit individual heterogeneity. Therefore, defining the minimal important difference (MID) is crucial for appropriately designing clinical trials, interpreting efficacy results, and supporting regulatory approval. This study fills that gap by establishing clinically meaningful thresholds for BSITD-III changes through caregiver interviews, thereby strengthening the tool’s application foundation in MPS II research. The paragraph ends with

 

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Research Methods and Experiment

The study employed a mixed-methods design, using semi-structured interviews to collect caregiver perceptions of BSITD-III changes in hypothetical treatment scenarios. Twelve caregivers (representing 11 children) from the US and UK, all primary caregivers of children aged 2–6 years with neuronopathic MPS II, participated; families currently involved in interventional studies were excluded. Interviews were conducted via video or in person, presenting four hypothetical clinical vignettes constructed from real-world data. Each vignette described a child's baseline and one-year follow-up performance on the three BSITD-III subtests (cognitive, expressive communication, fine motor), including raw scores, age-equivalent values (AEq), and specific skill changes. Caregivers were asked to rate the magnitude of change using the Caregiver Global Impression of Change (CaGI-C) scale and discuss the functional relevance of these skills in daily life. All interview recordings were transcribed and analyzed thematically, with frequency statistics used to assess the proportion of meaningful improvements. Data analysis was independently conducted by Rare Disease Research Partners using NVivo software for coding and theme extraction.

Key Conclusions and Insights

• Caregivers widely regarded the items in BSITD-III’s cognitive, expressive communication, and fine motor subtests as highly functionally relevant, reflecting the child’s actual abilities in daily life, such as problem-solving, imitation, communication needs, and manual dexterity
• An increase of 1–2 months in BSITD-III age-equivalent scores (AEq) was considered clinically meaningful: across all subtests, 97.1% of caregivers rated a 2-month gain as 'minimal improvement' or better; for expressive communication and fine motor subtests, 90.9% and 81.8% of caregivers, respectively, considered a 1-month gain meaningful
• Maintaining existing skills was viewed by caregivers as equally important as acquiring new ones, suggesting that stabilizing developmental trajectories is itself a sign of treatment success in progressive diseases
• Improvements in expressive communication (e.g., using two-word phrases, naming objects) were seen as critical for reducing frustration, improving behavior, and enhancing social engagement
• Fine motor skills (e.g., stacking blocks, drawing lines) were closely linked to daily living activities such as dressing and eating independently; improvements can reduce caregiver burden and promote social integration
• Cognitive items such as pretend play and solving hidden object tasks were described by caregivers as 'major milestones' due to their reflection of higher-order mental functions and environmental adaptation

Research Significance and Outlook

This study is the first to quantify the minimal important difference (MID) of BSITD-III in children with neuronopathic MPS II from the caregiver perspective, providing key parameters for clinical trial design. Endpoints previously based on statistical significance or group-average changes may underestimate individual-level clinical value. This study confirms that even small gains in AEq are perceived as meaningful by families, supporting the use of more sensitive thresholds in efficacy assessments. The findings reinforce the rationale for using BSITD-III as a primary or secondary endpoint in MPS II intervention trials, especially for children over 42 months or with developmental levels below -2SD, where other standardized scores may not be applicable.

Future research could further validate the predictive value of these thresholds in real interventional trials and explore associations between BSITD-III changes and other functional outcome measures (e.g., adaptive behavior scales). Additionally, extending the observation period to assess the clinical significance of long-term maintenance effects will help fully understand the real-world benefits of treatment. This methodology can also be extended to other rare neurodevelopmental disorders, promoting the development of patient-centered outcome assessment systems.

 

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Conclusion

Through in-depth interviews with primary caregivers of children with neuronopathic MPS II, this study systematically evaluated the clinical significance and functional relevance of skill changes measured by the BSITD-III developmental scale. It found that even a 1–2 month gain in age-equivalent scores is regarded by the majority of families as a meaningful improvement, particularly in cognitive, expressive communication, and fine motor domains. The maintenance of existing skills was emphasized as a critical treatment goal, reflecting the unique clinical reality within the context of disease progression. The study further confirmed that items covered by BSITD-III—such as stacking blocks, naming objects, and pretend play—are closely tied to children’s abilities in problem-solving, expressive communication, and independent activities in daily life, validating the tool’s content and ecological validity. These results provide strong caregiver-based evidence supporting the use of BSITD-III in MPS II clinical trials, affirming its role as a sensitive and relevant clinical outcome assessment tool. Furthermore, the study highlights that in evaluating rare neurodevelopmental disorders, even small but sustained progress should be valued, and patient and family experiences should be integrated into efficacy evaluation criteria, promoting more patient-centered drug development and regulatory decision-making. This work offers methodological guidance for the design of studies on similar conditions, emphasizing the importance of integrating subjective reports with objective measurements.

 

Dawn Phillips, Catherine Wilson, and Vivian Fernandez. Defining Bayley Scales of Infant and Toddler Development Third Edition (BSITD-III) meaningful change and item relevance in children with neuronopathic MPS II: a caregiver interview-based study. Orphanet Journal of Rare Diseases.