Combined malonic and methylmalonic aciduria

Combined malonic and methylmalonic aciduria is an inherited metabolic disorder marked by elevated malonic and methylmalonic acids, usually caused by pathogenic variants in ACSF3.

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ACSF3: ACSF3 is a mitochondrial acyl-CoA synthetase that activates malonate and methylmalonate. Pathogenic variants in this gene cause most cases by impairing organic-acid activation.
Organic acid: An organic acid is a carbon-containing compound with acidic properties, often formed or used in metabolism. Both diagnostic metabolites belong to this broad chemical class.
Urine organic acid analysis: Urine organic acid analysis measures small organic acids to help identify metabolic disorders. It can reveal the paired elevations that define this condition.
Isolated malonic aciduria: Isolated malonic aciduria is an inherited metabolic disorder characterized primarily by elevated malonic acid. It shares malonic acid elevation but lacks the defining combined pattern.
Malonyl-CoA: Malonyl-CoA is a coenzyme A thioester involved in fatty-acid synthesis and mitochondrial metabolism. Deficient malonate activation alters the balance of metabolites connected to this thioester.
Fatty acid synthesis: Fatty acid synthesis is the pathway that builds fatty acids from acetyl-CoA-derived units. Malonate metabolism intersects with this pathway through malonyl-CoA.
ACSF3 genetic testing: ACSF3 genetic testing identifies sequence variants in the gene associated with combined malonic and methylmalonic aciduria. Finding pathogenic variants can confirm the suspected molecular cause.
Methylmalonic acidemia: Methylmalonic acidemia is a group of inherited disorders causing methylmalonic acid accumulation and potentially severe metabolic illness. Unlike this usually milder biochemical phenotype, it often reflects defects in methylmalonate metabolism.
Methylmalonyl-CoA: Methylmalonyl-CoA is a coenzyme A thioester formed during the breakdown of certain amino acids and fatty acids. Its associated pathway helps explain why methylmalonic acid accumulates alongside malonic acid.
Propionate metabolism: Propionate metabolism converts propionyl-CoA into intermediates that enter central metabolism. Methylmalonate is connected to the pathway’s methylmalonyl-CoA intermediates.