OBJECTIVES: To develop a conceptual model and clinical outcome assessment (COA) measurement strategy in propionic acidemia (PA) and methylmalonic acidemia (MMA).

METHODS: Concept elicitation interviews were conducted with patients with PA/MMA and their caregivers, supplemented by discussions with clinical experts/patient advocates. Thematic analysis identified important concepts, including signs/symptoms and health-related quality-of-life (HRQoL) impacts, for patients/caregivers. Concepts in the PA/MMA conceptual model were mapped to the PedsQL™ Generic Core Scales (GCS) [covering ages 13 months to 18 years] and Family Impact Module, on a per-item basis. Gap analysis assessed potential COAs measuring relevant concepts to PA/MMA.

RESULTS: Twenty-six interviews were conducted in total (caregivers: n=14 PA, n=7 MMA; patients: n=3 PA, n=2 MMA), representing 22 patients ages 0.5-34 years. Key sign/symptom domains included metabolic crises, developmental delays (communication, motor functioning), and diet/feeding. HRQoL impacts included negative emotional impact, sleep difficulties, decreased endurance, limits on activities/sports, impacts on peer relationships, and missing school; caregiver/family impacts were also identified. The PedsQL™ GCS mapped closely to HRQoL impacts in the PA/MMA conceptual model, with the exception of additional physical symptom and cognitive functioning items in the infant version. The PedsQL™ Family Impact module also showed good overlap with the PA/MMA conceptual model. The Cogstate computerized battery, NIH Toolbox Motor Battery, and Bayley Scales of Infant and Toddler Development (Bayley™-4) were determined to be fit-for-purpose for measuring cognitive and/or motor function (depending on age of patient).

CONCLUSIONS: This is the first conceptual model for PA/MMA identifying core concepts of patient/caregiver importance. Symptoms and impacts were broad-ranging and the PedsQL™ GCS and Family Impact modules map appropriately to assess HRQoL in the PA/MMA patients and caregivers, respectively. The Cogstate, NIH Toolbox Motor Battery, and Bayley™-4 appropriately measure cognitive and/or motor function impacts. Future research should aim to develop a measure of core signs/symptoms in PA/MMA.