Introduction

Combined malonic and methylmalonic aciduria (CMAMMA) is an inherited metabolic disorder caused by pathogenic variants in the ACSF3 gene [1]. ACSF3 encodes the mitochondrial enzyme malonyl‐CoA synthetase, which converts malonic acid to malonyl‐CoA, the starter substrate of mitochondrial fatty acid biosynthesis (mtFAS) [1]. CMAMMA is biochemically characterized by accumulation of malonic acid (MA) and methylmalonic acid (MMA) in body fluids, with normal malonyl‐CoA decarboxylase activity and mild lactic and pyruvic aciduria. ACSF3 mutations may cause symptoms suggestive of intermediary metabolic disorders, including vomiting and diarrhea in children or neurological manifestations later in life [2]. Although symptomatic patients with seizures, memory impairment, psychiatric symptoms, and cognitive decline have been reported [2, 3, 4, 5], the clinical relevance of CMAMMA remains debated [6]. Because many patients are diagnosed only in adulthood after years of misdiagnosis, long‐term disturbances in metabolic flexibility and secondary cellular dysfunction have been proposed [7, 8, 9]. The pathophysiology of CMAMMA remains poorly understood [9, 10]. Accumulation of MA and MMA, together with adaptive mitochondrial energy mechanisms, likely contribute to disease development but do not fully explain the broad clinical spectrum [2, 8, 9, 11]. The biological significance of ACSF3 extends beyond rare disease. A recent evolutionary genomics study identified a human‐specific regulatory variant (rs34590044‐A) in an enhancer region of ACSF3, which upregulates its expression, enhances mitochondrial activity, reduces MMA accumulation, and is associated with increased stature and basal metabolic rate (BMR) in anatomically modern humans, particularly under meat‐enriched, threonine‐rich diets [12, 13, 14]. This finding places ACSF3‐dependent mitochondrial metabolism at the intersection of human metabolic evolution and disease, and underscores that even partial loss of ACSF3 function, as in CMAMMA, may profoundly disrupt the metabolic homeostasis that this gene has helped shape over hundreds of thousands of years. A recent case report further expanded the CMAMMA clinical spectrum by describing neonatal hyperinsulinemic hypoglycemia, with reduced lipoylation of the pyruvate dehydrogenase (PDH) and α‐ketoglutarate dehydrogenase (αKGDH) suggesting that impaired mitochondrial lipoic acid biosynthesis may contribute to diverse clinical presentations [12]. We recently showed that impaired metabolic flexibility and increased reliance on mitochondrial fatty acid oxidation in ACSF3‐deficient fibroblasts are associated with dysregulated mitochondrial dynamics and enhanced mitochondrial fragmentation [7]. Here, we describe a young adult with fatigue, irritable bowel symptoms, and anxiety who underwent a long diagnostic journey before receiving a diagnosis of CMAMMA, and we investigate the effects of an ACSF3 variant on mitochondrial metabolism in patient‐derived fibroblasts.