biostudies-literatureForny PSwiss National Science Foundation80-95https://www.ebi.ac.uk/biostudies/studies/S-EPMC9886552biostudies-literatureUnknown5(1)Methylmalonic aciduria (MMA) is an inborn error of metabolism with multiple monogenic causes and a poorly understood pathogenesis, leading to the absence of effective causal treatments. Here we employ multi-layered omics profiling combined with biochemical and clinical features of individuals with MMA to reveal a molecular diagnosis for 177 out of 210 (84%) cases, the majority (148) of whom display pathogenic variants in methylmalonyl-CoA mutase (MMUT). Stratification of these data layers by disease severity shows dysregulation of the tricarboxylic acid cycle and its replenishment (anaplerosis) by glutamine. The relevance of these disturbances is evidenced by multi-organ metabolomics of a hemizygous Mmut mouse model as well as through identification of physical interactions between MMUT anNature metabolismIntegrated multi-omics reveals anaplerotic rewiring in methylmalonyl-CoA mutase deficiency.PMC9886552175779192505211038310030Xenarios IRatsch GWollscheid BLamparter DHowald CZamboni NShao WBurer CHarshman KFrei CDermitzakis ETPoms MCherkaoui STraversi FMorscher RJSimmons LGoetze SPedrioli PGAvan Drogen ABaumgartner MRBingisser ABonilla XPlessl TAebersold RFroese DSForny MForny PfalseIntegrated multi-omics reveals anaplerotic rewiring in methylmalonyl-CoA mutase deficiency.Methylmalonic aciduria (MMA) is an inborn error of metabolism with multiple monogenic causes and a poorly understood pathogenesis, leading to the absence of effective causal treatments. Here we employ multi-layered omics profiling combined with biochemical and clinical features of individuals with MMA to reveal a molecular diagnosis for 177 out of 210 (84%) cases, the majority (148) of whom display pathogenic variants in methylmalonyl-CoA mutase (MMUT). Stratification of these data layers by disease severity shows dysregulation of the tricarboxylic acid cycle and its replenishment (anaplerosis) by glutamine. The relevance of these disturbances is evidenced by multi-organ metabolomics of a hemizygous Mmut mouse model as well as through identification of physical interactions between MMUT an2023-01-01T00:00:00Z2023 Jan2026-05-10T06:51:33.818Z2025-04-19T17:17:21.211ZS-EPMC98865523671775210.1038/s42255-022-00720-8