Metabolic dysfunction related to specific genetic variant sites of methylmalonic acidemia

Methylmalonic acidemia (MMA) is a genetic metabolic disease, with mut (mut-MMA, caused by MMUT gene variation) and cblC (cblC-MMA, caused by MMACHC gene variation) being the predominant subtypes. MMA patients carrying c.729_730insTT and c.609G>A exhibit severe clinical manifestations and have poorer outcomes. Little information is known on the potential mechanism. The metabotypes of MMA patients carrying c.729_730insTT and c.609G>A were profiled. The potential effect of genetic variation sites on the metabolism were explored. Leveraging the gene variation spectrum and the targeted metabolomics, propionic acid, indolelactic acid, myristoleic acid, tetradecenoic acid, tridecanoic acid, and oxoadipic acid showed strong enrichment in c.729_730insTT carrying mut-MMA patients. Whereas mutation c.609G>A caused adipic acid, pimelic acid, fructose, AMP, hexanylcarnitine, and methionine significnatly altered in cblC-MMA patients. Furthermore, the metabolomic profiles were obviously different in c.729_730insTT and non-c.729_730insTT carrying mut-MMA patients after treatment. Different metabolic alterations in cblC-MMA patients carrying c.609G > A and non-c.609G > A under treatment were also observed. Our findings provide unique insights into the metabolic basis of MMA specific subtypes and its implications across different variants.