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

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. 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. 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. 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.

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Journal
Orphanet Journal of Rare Diseases
Published
2026-03-09
DOI
https://doi.org/10.1186/s13023-026-04251-3
Primary Topic
Metabolism and Genetic Disorders
Type
article
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article

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

Manuel Schiff, Bernd Schwahn, Stephanie Grünewald, Thomas Morgan et al.
Orphanet Journal of Rare Diseases
Metabolism and Genetic Disorders
article

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

Manuel Schiff, Bernd Schwahn, Stephanie Grünewald, Thomas Morgan, Vanja Sikirica, Sue Perera, Husain Attarwala, Javier De las Heras, Hilary J. Vernon, Can FIÇICIOĞLU, Caroline Guat Lay Lee, Min Liang, Barbara K. Burton, D.D. Koeberl, George A. Diaz, Junxiang Luo, J. Lawrence Merritt II, Hong Li, Brigitte Chabrol, Gerard T. Berry, Jerry Vockley
article en

Abstract

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. 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. 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. 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.

Orphanet Journal of Rare Diseases
Délégation Paris 5 (FR), West Virginia University (US), Boston Children's Hospital (US), Seattle Children's Hospital (US), Children's Hospital of Philadelphia (US), Johns Hopkins University (US), Emory University (US), Inserm (FR), University of Pittsburgh (US), Duke University (US), Vanderbilt University (US), University of Washington (US), Université Paris Cité (FR), Great Ormond Street Hospital (GB), University of Manchester (GB), Assistance Publique Hôpitaux de Marseille (FR), BioCruces Health research Institute (ES), Manchester University NHS Foundation Trust (GB), Assistance Publique – Hôpitaux de Paris (FR), St Mary's Hospital (GB), Moderna Therapeutics (United States) (US), Lurie Children's Hospital (US), Institut des Maladies Génétiques Imagine (FR), Robert H. Lurie Comprehensive Cancer Center of Northwestern University, University College London (GB), Stanford University (US), Icahn School of Medicine at Mount Sinai (US)
Openalex Percentile: Top 26%
Metabolism and Genetic Disorders
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