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. 2021 Apr 5;23(8):1522–1533. doi: 10.1038/s41436-021-01143-8

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© This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2021, corrected publication 2021

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Fig. 3 — The lowest 1-¹³C-propionate oxidation rates were mostly observed in mut MMA patients, who harbored two loss-of-function (LOF) variants in MMUT. Comparisons reached significance for the area under the curve at 120 minutes (adjusted P = 0.0154), but with significant overlap with the compound heterozygous carrying LOF/missense or two missense variants. (b) 1-¹³C-propionate oxidation rates showed a positive correlation with renal function, with higher propionate oxidation subjects having a near normal estimated glomerular filtration rate (eGFR) (mL/min/1.73 m²) calculated with the combined equation using creatinine and cystatin C values (correlation coefficient r = 0.436, R² = 0.1909, P = 0.0098). (c) Age of onset for stage 3 chronic kidney disease (CKD) (eGFR based on the bedside Schwartz equation ≤60 mL/min/1.73m²) was censored in a Kaplan–Meier curve for mut⁰ MMA patients stratified by their 1-¹³C-propionate oxidation rate. Fifty percent of patients with the lowest (<10%) propionate oxidation reached stage 3 CKD at age 8.3 years, as opposed to 15 years in patients with oxidation >20% (marked in red and blue, respectively, P = 0.0574). (d, e) Patients with the lowest 1-¹³C-propionate oxidation (<10%, red) had more severe intellectual impairment, based on standardized age-appropriate neurocognitive evaluations (full-scale IQ [FSIQ]) compared with patients with >20% oxidation rates (adjusted P = 0.0325, blue). Bivariate correlation coefficient r = 0.455, R² = 0.2078, P = 0.0129. (f–i) Significant correlations are shown between 1-¹³C-propionate oxidation rates and clinical disease-specific serum biomarkers, including serum methylmalonic acid (r = −0.739, R² = 0.547, P < 0.0001, log transformed values were used for skewed variables); acyl/free carnitine ratio (r = −0.584, R² = 0.341, P < 0.0004), as well as biomarkers of hepatic or multisystem mitochondrial dysfunction (FGF21, fibroblast growth factor 21: r = −0.486, R² = 0.237, P < 0.0064 and GDF15, growth differentiation factor 15: r = −0.664, R² = 0.4418, P < 0.0001).