1-13C-propionate breath testing as a surrogate endpoint to assess efficacy of liver-directed therapies in methylmalonic acidemia (MMA)

作者：Irini Manoli, Alexandra Pass, Elizabeth A. Harrington, Jennifer L. Sloan, Jack Gagné, Samantha McCoy, Sarah Bell, Jacob D. Hattenbach, Brooks P. Leitner, Courtney J. Duckworth, Laura A. Fletcher, Thomas M. Cassimatis, Carolina I. Galarreta, Audrey Thurm, Joseph Snow, Carol Van Ryzin, Susan Ferry, Nicholas Ah Mew, Oleg A. Shchelochkov, Kong Y. Chen, Charles P. Venditti · 发表于：Genetics in Medicine · 年份：2021 · DOI：10.1038/s41436-021-01143-8 · 被引用次数：17 · 研究领域：Metabolism and Genetic Disorders、Folate and B Vitamins Research、Diet and metabolism studies

Purpose To develop a safe and noninvasive in vivo assay of hepatic propionate oxidative capacity. Methods A modified 1- 13 C-propionate breath test was administered to 57 methylmalonic acidemia (MMA) subjects, including 19 transplant recipients, and 16 healthy volunteers. Isotopomer enrichment ( 13 CO 2 / 12 CO 2 ) was measured in exhaled breath after an enteral bolus of sodium-1- 13 C-propionate, and normalized for CO 2 production. 1- 13 C-propionate oxidation was then correlated with clinical, laboratory, and imaging parameters collected via a dedicated natural history protocol. Results Lower propionate oxidation was observed in patients with the severe mut 0 and cblB subtypes of MMA, but was near normal in those with the cblA and mut − forms of the disorder. Liver transplant recipients demonstrated complete restoration of 1- 13 C-propionate oxidation to control levels. 1- 13 C-propionate oxidation correlated with cognitive test result, growth indices, bone mineral density, renal function, and serum biomarkers. Test repeatability was robust in controls and in MMA subjects (mean coefficient of variation 6.9% and 12.8%, respectively), despite widely variable serum methylmalonic acid concentrations in the patients. Conclusion Propionate oxidative capacity, as measured with 1- 13 C-propionate breath testing, predicts disease severity and clinical outcomes, and could be used to assess the therapeutic effects of liver-targeted genomic therapies for MMA and related disorders of pr...