Organic acidemias such as methylmalonic acidemia (MMA) are a group of inborn errors of metabolism that typically arise from defects in the catabolism of amino and fatty acids. Accretion of acyl-CoA species is postulated to underlie disease pathophysiology, but the mechanism(s) remain unknown. Here, we surveyed hepatic explants from patients with MMA and unaffected donors, in parallel with samples from various mouse models of methylmalonyl-CoA mutase deficiency. We found a widespread posttranslational modification, methylmalonylation, that inhibited enzymes in the urea cycle and glycine cleavage pathway in MMA. Biochemical studies and mouse genetics established that sirtuin 5 (SIRT5) controlled the metabolism of MMA-related posttranslational modifications. SIRT5 was engineered to resist acylation-driven inhibition via lysine to arginine mutagenesis. The modified SIRT5 was used to create an adeno-associated viral 8 (AAV8) vector and systemically delivered to mutant and control mice. Gene therapy ameliorated hyperammonemia and reduced global methylmalonylation in the MMA mice.

Methylmalonic Acidemia (MMA) is a heterogenous group of inborn errors of metabolism caused by a defect in the methylmalonyl‐CoA mutase (MMUT) enzyme or the synthesis and transport of its cofactor, 5′‐deoxy‐adenosylcobalamin. It is characterized by life‐threatening episodes of ketoacidosis, chronic kidney disease, and other multiorgan complications. Liver transplantation can improve patient stability and survival and thus provides clinical and biochemical benchmarks for the development of hepatocyte‐targeted genomic therapies. Data are presented from a US natural history protocol that evaluated subjects with different types of MMA including mut‐type (N = 91), cblB‐type (15), and cblA‐type MMA (17), as well as from an Italian cohort of mut‐type (N = 19) and cblB‐type MMA (N = 2) subjects, including data before and after organ transplantation in both cohorts. Canonical metabolic markers, such as serum methylmalonic acid and propionylcarnitine, are variable and affected by dietary intake and renal function. We have therefore explored the use of the 1‐13C‐propionate oxidation breath test (POBT) to measure metabolic capacity and the changes in circulating proteins to assess mitochondrial dysfunction (fibroblast growth factor 21 [FGF21] and growth differentiation factor 15 [GDF15]) and kidney injury (lipocalin‐2 [LCN2]). Biomarker concentrations are higher in patients with the severe mut0‐type and cblB‐type MMA, correlate with a decreased POBT, and show a significant response postliver transplant. Additional circulating and imaging markers to assess disease burden are necessary to monitor disease progression. A combination of biomarkers reflecting disease severity and multisystem involvement will be needed to help stratify patients for clinical trials and assess the efficacy of new therapies for MMA.

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