ENOrphanet Journal of Rare Diseases | A Novel Strategy for Patient-Reported Outcome Assessment in Alpha-Mannosidosis
Date: February 14, 2026
Classification: Frontiers
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This study proposes a patient-reported outcome (PRO) assessment and validation strategy applicable to ultra-rare diseases, effectively overcoming challenges of small sample sizes by integrating qualitative interviews with standardized scales, enabling comprehensive capture of multidimensional disease impacts.
Literature Overview
The article titled 'Exemplifying a measurement validation strategy for rare- and ultra-rare diseases: measuring what matters in alpha-mannosidosis', published in Orphanet Journal of Rare Diseases, reviews and summarizes the development and validation of a patient-reported outcome (PRO) assessment tool for the ultra-rare disease alpha-mannosidosis (AM). The study constructed a core symptom model based on literature review and clinical observations, and combined semi-structured video interviews with standardized proxy-reported scales to systematically evaluate the multidimensional impact of AM on patients' quality of life. The applicability of the measurement tool was validated under extremely small sample sizes using effect-size-driven multidimensional validity analysis. This approach offers a scalable solution to the lack of specific outcome measures in the rare disease field. The study ultimately proposes a comprehensive assessment toolkit applicable to natural history studies, clinical trials, and real-world effectiveness evaluations.Background Knowledge
Alpha-mannosidosis (AM) is an extremely rare lysosomal storage disorder caused by mutations in the MAN2B1 gene, leading to reduced or absent alpha-mannosidase enzyme activity and the accumulation of mannose-rich oligosaccharides in cells, affecting multiple systems. Clinical manifestations are highly heterogeneous, including cognitive impairment, hearing loss, motor dysfunction, immunodeficiency, psychiatric and behavioral abnormalities, and skeletal deformities, significantly reducing patients’ quality of life, with most adult patients requiring care. Current treatments include hematopoietic stem cell transplantation (BMT), enzyme replacement therapy (ERT, e.g., Velmanase alfa), and supportive care, but long-term efficacy assessment is limited by the lack of sensitive and comprehensive outcome measures. In rare disease research, traditional PRO scales are often difficult to validate due to small sample sizes and lack of disease-specific content, while generic scales (e.g., EQ-5D) facilitate economic modeling but fail to capture the true impact of AM-specific symptoms on patients and families. Therefore, constructing and validating assessment tools with content validity and clinical relevance under extremely small samples remains a core challenge. This study uses AM as a model to propose a mixed-methods approach integrating symptom-guided interviews and proxy-reported scales, aiming to systematically capture health dimensions that matter to patients, providing methodological innovation for outcome assessment in ultra-rare diseases.
Methods and Experiment
The study employed a mixed-methods design, recruiting 16 primary caregivers (mostly parents) of AM patients, representing 20 patients aged 4 to 49 years. The research tools included two components: first, semi-structured interviews conducted via video conferencing, covering four domains—activities of daily living (ADL), emotions, cognition/development, and clinical symptoms—with 38 Likert-scale items (0–4 points) and an 'other' option to capture symptoms not previously listed; second, standardized proxy-reported (Parent Proxy) scales based on the PROMIS and Neuro-QoL systems, assessing functional domains including mobility, pain, sleep, emotions, and social functioning. EQ-5D-5L proxy reports were also collected as a criterion measure. Data analysis used descriptive statistics and effect sizes (e.g., correlation coefficients, η²) instead of p-values to accommodate small sample characteristics. Validity assessments included content validity (via 'other' symptom mention rates and coverage of important symptoms), criterion validity (correlations with EQ-5D utility and VAS), known-groups validity (comparisons by age group), convergent and discriminant validity (inter-scale correlations), and potential longitudinal validity (comparisons by treatment group).Key Findings and Insights
Research Significance and Outlook
This study provides a replicable methodological framework for outcome assessment in ultra-rare diseases, emphasizing the prioritization of effect sizes and content coverage over statistical significance in small samples. By integrating qualitative interviews with standardized scales, the study successfully developed an assessment toolkit that comprehensively reflects the multisystem impacts of AM, addressing the content validity shortcomings of generic scales. This strategy is not only applicable to AM but also generalizable to other rare diseases, offering more sensitive and clinically meaningful endpoints for natural history studies, clinical trial design, and real-world evidence collection.
Future research can further optimize the tool, such as conducting factor analysis on interview items to refine dimensionality or developing AM-specific CAT (Computerized Adaptive Testing) to improve measurement precision. Additionally, the tool’s reliability and longitudinal validity need validation in larger samples, especially its ability to detect changes before and after treatment interventions. Exploring consistency between patient self-reports (e.g., in higher-functioning individuals) and caregiver reports would provide a more comprehensive understanding of the patient perspective. This method could also be integrated with biomarkers and clinical assessments to build a multidimensional efficacy evaluation system, advancing precision medicine in rare diseases.
Conclusion
This study proposes and validates an innovative patient-reported outcome (PRO) assessment strategy for the ultra-rare disease alpha-mannosidosis. By integrating semi-structured caregiver interviews with standardized proxy-reported scales, the study achieved comprehensive capture of multidimensional disease impacts in an extremely small sample (n=20). Analysis shows that generic scales like EQ-5D reflect only partial functional status but significantly underestimate emotional burden and disease-specific symptoms, while the interview-based tool developed in this study effectively supplements this information. Validity analysis emphasizes effect sizes over p-values, accommodating the reality of small samples and supporting the tool’s sensitivity to disease progression and treatment response. This strategy provides a feasible solution to the long-standing lack of outcome measures in the rare disease field, applicable not only to natural history studies and clinical trials in AM but also serving as a methodological blueprint for developing assessment tools in other rare diseases. Future work should further validate its reliability and longitudinal responsiveness in larger cohorts, promoting its application in real-world research and ultimately enabling patient-centered efficacy evaluation in rare diseases.
