Irritable Bowel Disease: Think Malonic and Methylmalonic Aciduria (CMAMMA)!

Abstract

Combined malonic and methylmalonic aciduria (CMAMMA; OMIM 614265) is a rare disorder of mitochondrial fatty acid synthesis caused by pathogenic variants in the ACSF3 gene, which encodes malonyl-CoA synthetase. The clinical presentation is highly heterogeneous and may include seizures, memory impairment, psychiatric manifestations, and cognitive decline. We describe an adult patient with long-standing unexplained fatigue and irritable bowel syndrome who remained undiagnosed for 15 years. Subsequent blood and urine analyses revealed elevated methylmalonic acid levels, and molecular genetic testing identified the biallelic ACSF3 variant c.1672C>T (p.Arg558Trp), confirming the diagnosis of CMAMMA. Functional studies in patient-derived fibroblasts demonstrated altered global protein malonylation together with markedly reduced lipoylation of pyruvate dehydrogenase complex and α-ketoglutarate dehydrogenase, consistent with impaired mitochondrial energy metabolism. Introduction of a diet enriched in carbohydrates and restricted in protein, based on recommendations for methylmalonic aciduria, resulted in a pronounced worsening of gastrointestinal symptoms, which improved after discontinuation of the dietary intervention. This case highlights that CMAMMA may remain unrecognized for many years and should also be considered in adults presenting with unexplained gastrointestinal symptoms. Furthermore, the findings suggest that impaired glucose oxidation plays a central role in disease pathophysiology and that high dietary carbohydrate intake may exacerbate clinical manifestations.