Clinical spectrum of acyl-CoA synthetase family member 3-related combined malonic and methylmalonic aciduria: insights from four cases

BACKGROUND: Acyl-conezyme A (CoA) synthetase family member 3 (ACSF3) related combined malonic and methylmalonic aciduria (CMAMMA) is an inborn error of metabolism involving defective activation of malonic and methylmalonic acids to CoA derivatives. The resulting deficiency of malonyl-CoA disrupts mitochondrial fatty acid synthesis, lipid metabolism, and protein malonylation. Although regarded as a benign condition, studies have demonstrated that ACSF3 deficiency may lead to variable manifestations. OBJECTIVE: This study aimed to expand the spectrum of ACSF3-related CMAMMA. METHODS: Four patients with biochemically and genetically confirmed ACSF3-related CMAMMA were retrospectively analyzed for clinical, biochemical, neuroimaging, and molecular features. RESULTS: All patients showed elevated urinary malonic and methylmalonic acids. Two presented with mild metabolic findings such as vomiting, hypoglycemia, or growth retardation, while two exhibited neurodevelopmental phenotypes with regression, ataxia, and refractory epilepsy. One patient developed ketotic hypoglycemia during illness, and two had growth failure despite nutritional interventions. One patient carried a homozygous deletion consistent with neuronal ceroid lipofuscinosis type 7, indicating a dual diagnosis. CONCLUSION: This case series broadens the clinical spectrum of ACSF3-related CMAMMA and reinforces that the condition extends beyond a benign biochemical abnormality. The presence of genotypes and variable neurological involvement underscores the need for comprehensive genomic testing and long-term multidisciplinary monitoring to define prognosis and guide individualized management.