Characterizing the frequency of clinical events and assessing biomarkers in propionic acidemia: a natural history study.

BACKGROUND: Propionic acidemia (PA) is a rare disease resulting in toxic accumulation of metabolites that cause metabolic decompensation events (MDEs). Natural history characterization of PA is limited partly due to its rarity and complexity. This study examined clinical events in participants with PA and their correlation with biomarkers to better understand the disease. METHODS: Participants diagnosed with PA (early- versus late-onset) were evaluated every 6 months from baseline to month 36. Outcome measures included annualized MDEs and changes in 3-hydroxypropionic acid (3-HP), 2-methylcitrate (2-MC), and propionylcarnitine (C3) concentrations. Blood samples were collected at each visit and during MDEs for plasma biomarker analyses. Relative risk (RR) was calculated based on MDE rates and biomarker levels. RESULTS: Most participants (n/N = 49/50, 98.0%) reported MDEs. Annualized MDE rates were highest in participants aged 0 to ≤ 1 and > 1 to ≤ 2 versus > 12 to ≤ 18 years (2.6 and 2.4, respectively, vs 0.2) and for early-onset versus late-onset PA (1.2 vs 0.3). A 50% decrease in plasma biomarkers was associated with a statistically significant reduction in RR of MDEs for 3-HP (RR: 0.7, 95% CI: 0.6–0.9; p < 0.01) and a substantial reduction for C3 (RR: 0.6, 95% CI: 0.4–0.9; p = 0.017); no effect was observed for 2-MC. CONCLUSIONS: MDE rates were higher in the youngest participants (0 to ≤ 2 years) versus participants aged > 12 years, and with early- versus late-onset PA. Lower concentrations of 3-HP and C3 were associated with a reduced MDE risk. These findings may guide biomarker or clinical endpoints in future treatment trials.