Discussion

CMAMMA is a rare disease caused by ACSF3 variants and characterized by accumulation of MA and MMA [1]. Its clinical relevance remains controversial [6], and late symptom onset suggests chronic, progressive metabolic dysfunction [2, 7, 8, 9, 11]. A strength of this report is the detailed longitudinal characterization of clinical course, biochemical markers, and genetic findings, with systematic documentation of dietary interventions and patient‐reported outcomes. Limitations include the non‐controlled nature of dietary interventions and reliance on patient self‐report without standardized scales.

Placed in a broader biological context, the pathogenicity of ACSF3 mutations gains further significance from the recent finding that ACSF3 has been subject to positive selection in anatomically modern humans. Zhang et al. demonstrated that a human‐specific regulatory variant (rs34590044‐A), emerging approximately 653 000 years ago and under strong positive selection over the past 20 000 years, upregulates ACSF3 expression, enhances mitochondrial respiratory capacity, and reduces MMA accumulation, effects that translated into greater body length and higher energy expenditure in mice fed threonine‐rich, meat‐based diets [14]. This evolutionary model implies that the ACSF3‐mtFAS axis has been critical for sustaining the elevated metabolic demands of anatomically modern humans consuming animal protein. Conversely, our patient's data illustrate what happens when this axis is disrupted by a coding variant. Indeed, MMA accumulates, mitochondrial respiratory complexes are depleted, and the organism's capacity to oxidize dietary substrates, particularly carbohydrates via PDH, is severely compromised. The symptomatic improvement observed with higher protein and essential amino acid intake, rather than carbohydrate loading, is fully consistent with the evolutionary logic identified by Zhang et al., in that ACSF3 function is most critical precisely when the diet is rich in the essential amino acids, including threonine, that characterize meat‐based nutrition [13, 14].

Although serum malonic acid was never detected, altered lysine malonylation in patient fibroblasts supports metabolic dysregulation in ACSF3‐deficient cells. Previous studies showed that exogenous malonic acid exposure increased lysine malonylation in ACSF3 knockout cells [19]. Interestingly, Zhang et al. reported that CRISPR‐mediated suppression of ACSF3 in hepatocytes (HepG2 cells) did not significantly alter malonate, malonyl‐CoA, or lysine malonylation, but did elevate MMA, suggesting cell‐type‐specific consequences of ACSF3 deficiency. Our patient's fibroblasts seemed to show a selective increase in specific protein subsets (Figure S1C), suggesting redistribution rather than uniform upregulation, indicating that the malonylation consequences of ACSF3 loss may be tissue‐dependent and appear progressively over time.

The connection between mitochondrial dysfunction and neurodegeneration is well established [20]. Given the neurological manifestations in adult CMAMMA patients [2, 8], it is plausible that the enteric nervous system (ENS) may experience similar metabolic alterations. Previous studies have implicated mitochondrial DNA alterations in irritable bowel syndrome, suggesting mitochondrial diseases should be considered in patients with intestinal motility disorders [21, 22].

The dramatic reduction in lipoylation of PDC and αKGDH subunits, also independently observed by Gragnaniello et al. [12] in a neonatal CMAMMA patient presenting with hyperinsulinemic hypoglycemia, indicates that mitochondrial ACC1 cannot fully compensate for ACSF3 loss, suggesting these enzymes act synergistically and cannot substitute for each other's function [23]. The convergence of severely impaired lipoylation across independent CMAMMA cases of different ages and phenotypes reinforces that reduced mtFAS‐dependent lipoic acid synthesis is a core biochemical feature of ACSF3 deficiency. Reduced lipoylation was functionally reflected in a 50% decrease in PDH activity in our patient. In the neonatal case reported by Gragnaniello et al., the same impairment was proposed to contribute to dysregulated insulin secretion, since lipoic acid plays a known modulatory role in pancreatic β‐cell function.

Following diagnosis, the patient adopted a protein‐restricted, carbohydrate‐rich diet based on methylmalonic aciduria guidelines, as no CMAMMA‐specific guidelines exist [24, 25]. Symptoms worsened, accompanied by accumulation of potentially toxic glycine and serine [26]. We hypothesize that increased carbohydrate load, hindered by reduced PDH activity, enhances serine and glycine biosynthesis from glucose (Figure S1A) [27] while impairing the glycine cleavage system [28]. Reducing carbohydrates while increasing protein normalized amino acid levels and improved symptoms, likely by providing anaplerotic substrates for the citric acid cycle [29]. This dietary response pattern aligns with the evolutionary framework proposed by Zhang et al., in which ACSF3 function is optimally engaged by protein‐rich, meat‐based diets. Glutamine remained elevated regardless of dietary intervention, likely due to redirection of excess α‐ketoglutarate toward endogenous glutamine synthesis secondary to partial αKGDH dysfunction [27].