Fig. 2. 1-¹³C-propionate oxidation in methylmalonic acidemia (MMA) patients: correlations with subtype severity and response after organ transplantation.

(a) The cumulative percent dose of administered sodium 1-¹³C-propionate metabolized by 120 minutes is depicted for controls (n = 8) and MMA subjects, per disease subtype (mut⁰ n = 26, mut^– n = 6, cblB n = 2, cblA n = 9). The severe mut⁰ patients (marked in red) had a range of oxidative capacity with a mean ± SD of 21.77 ± 9.50% at 120 minutes (P < 0.0001 compared with the controls 47.96 ± 4.26% and cblA 47.75 ± 5.91%; P = 0.0002 compared with mut^– individuals, 42.88 ± 9.02%, and P = NS to cblB 31.78 ± 21.82%). (b) The delta over baseline ¹³C enrichment in exhaled breath samples is depicted in controls and MMA subjects per subtype. A slower time to maximum enrichment was observed in mut⁰ subjects, 46.59 ± 18.25 minutes, as opposed to 22.5 ± 11.81 in controls, 23.18 ± 6.8 in cblA patients, and 32.50 ± 11.65 in mut^–. Asterisks correspond to P values compared with controls for each time point. (c) A receiver operating curve (ROC) is depicted for the cumulative dose oxidized in 120 minutes between controls and mut⁰ (area under the curve [AUC]= 1, P < 0.0001) as well as between mut⁰ and mut^– (AUC: 0.9345 ± 0.0655, P = 0.001). Method sensitivity between controls and mut^– patients was low (AUC: 0.687, P = NS). (d) Three patients were tested before and after combined liver/kidney transplant (LT/LKT), and three before and after kidney transplant (KT). One subject was tested before and after a second KT procedure after failure of the first kidney graft. On average pre- and post-transplant values were significant even for the kidney transplant recipients. (e, f) Cumulative percent dose metabolized and enrichment curves are depicted for mut⁰ patients without and with a LT/LKT transplant (marked in red and blue, respectively) or isolated KT procedure. LT/LKT but not KT resulted in complete restoration of propionate oxidation to control values. (g) 1-¹³C-propionate oxidation breath test result in controls and MMA patients per subtype and transplant status are depicted as areas under the curve, for patients with more than one test, the average value is represented (scatter plot of individual values, boxes and error bars represent mean ± SD). (h) An adult with cblA defect unable to comply with his hydroxocobalamin intramuscular injections was tested before and 2 months after B₁₂ therapy, showing improved oxidation. (****P < 0.0001. ***P < 0.001, **P < 0.01, *P < 0.05).