Goal attainment in PMM2-CDG: A new approach measuring meaningful clinical outcomes

Patient-centered outcomes, including patient-reported outcomes (PROs), are increasingly important in healthcare and research, though their use in rare diseases remains limited. In disorders with significant phenotypic variation, selecting appropriate outcome measures is crucial to ensuring the relevance of clinical trials for the patient population. Phosphomannomutase 2-CDG (PMM2-CDG) involves a complex genotype-phenotype relationship, making it challenging to predict clinical outcomes and select reliable measures for clinical trials. Caused by biallelic pathogenic variants in the PMM2, PMM2-CDG displays highly variable clinical severity, underscoring the need for personalized outcome measures. One such so far unexplored, individualized approach is Goal Attainment Scaling (GAS), which allows patients to set and track personal goals over time. We evaluated 93 PMM2-CDG patients enrolled in the Frontiers in Congenital Disorders of Glycosylation Consortium (FCDGC) Natural History study, classifying patient goals using the International Classification of Functioning, Disability, and Health (ICF) model, and assessing goal achievement prospectively. We also analyzed potential associations between GAS and factors such as age, sex, genetic background, and disease severity measured by the Nijmegen Progression CDG Rating Scale (NPCRS). The most common goals set by patients were related to mobility (31.5 %) and communication (26.8 %), with additional goals focused on body function (22.8 %) and independence (18.8 %). Of the 68 patients with follow-up data, 23.5 % showed no improvement in their goals, while 20.6 % improved in all three personal goals. Patients with pathogenic variants affecting the PMM2 dimerization domain had lower GAS improvement scores (M = 1.3 [SD = 1.1]) compared to those without such variants (M = 2.2 [SD = 1.7], p = 0.03). There was no significant correlation between NPCRS score changes and GAS improvement (r = -0.18, p = 0.19). GAS is a valuable additional outcome measure that ensures clinical improvements are meaningful for patients and their representatives, helping to assess individual goals and overall wellbeing.