Conclusions

We describe a symptomatic CMAMMA patient with fatigue and irritable bowel syndrome, expanding the clinical spectrum of the disease. Our case reinforces that CMAMMA is a clinically heterogeneous disorder whose manifestations span from the neonatal period to adulthood and affect multiple organ systems, with severely reduced lipoylation of PDC and αKGDH subunits as a unifying biochemical hallmark. Abdominal symptoms emerged during puberty but remained undiagnosed for years, illustrating that CMAMMA is easily overlooked when not included in standard diagnostic algorithms for fatigue and gastrointestinal presentations. Viewed through the lens of the recently described evolutionary model of ACSF3 [13, 14], the pathophysiology of CMAMMA reflects a breakdown of a metabolic axis that has been under positive selection in modern humans for hundreds of thousands of years, one optimized for high‐protein, meat‐based nutrition and elevated mitochondrial energy homeostasis. The observation that our patient improved most markedly on a higher‐protein diet with essential amino acid support is consistent with this evolutionary framework and points to the value of prospective, CMAMMA‐specific dietary studies to inform evidence‐based nutritional recommendations for this distinct disorder. Nothing is currently known about riboflavin use in CMAMMA. Ongoing studies in patient‐derived cell lines aim to evaluate the effects of riboflavin and amino acid load on mitochondrial energy homeostasis, with the goal of informing therapeutic strategies for affected individuals.