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Combined malonic and methylmalonic acidemia (CMAMMA) is a rare autosomal recessive metabolic disorder characterized by elevations of malonic acid (MA) and methylmalonic acid (MMA) due to deficient mitochondrial malonyl‐CoA synthetase activity. Biallelic variants in ACSF3 (HGNC:27288) have been identified as the genetic basis for CMAMMA (Nature Genetics • 2011) and confirmed in multiple cohorts worldwide. Affected individuals often present in infancy or childhood with metabolic acidosis, seizures, developmental delay and variable severity of infections or organ involvement. The benign clinical course described in several reports underlines phenotypic heterogeneity, ranging from asymptomatic to life‐threatening infections. Functional studies in murine and cellular models demonstrate that loss of ACSF3 activity disrupts lipoylation and mitochondrial fatty acid synthesis, supporting a loss‐of‐function disease mechanism.
The ACSF3–CMAMMA association meets ClinGen criteria for a Definitive gene–disease relationship based on identification of >50 unrelated probands across at least 6 publications, segregation of compound heterozygous or homozygous variants in multiple families, and concordant functional data in both a canine model and human cell knockdown studies (PMID:21841779; PMID:28986507). Segregation in consanguineous and non‐consanguineous pedigrees further solidifies causality.
CMAMMA follows autosomal recessive inheritance with reports of compound heterozygous and homozygous ACSF3 variants. Initial exome sequencing in nine unrelated probands identified a spectrum of loss‐of‐function alleles (nonsense, frameshift, canonical splice site) and missense variants (PMID:21841779). Subsequent case series and singleton reports describe at least 30 distinct ACSF3 variants, including recurrent c.689G>A (p.Trp230Ter) and founder alleles in specific populations (PMID:37987109; PMID:34900860). Population allele frequencies (MAF ~0.0058) predict an incidence of ~1:30,000, consistent with observed case numbers.
Segregation analyses in multiple families, including two affected siblings and several consanguineous pedigrees, confirm biallelic inheritance (affected relatives = 2). Phenotypes range from benign neonatal fever and lymphadenitis (HP:0001945) to global developmental delay (HP:0001263), cardiomyopathy (HP:0001638), seizures (HP:0001250), metabolic acidosis (HP:0001942), anemia (HP:0001903) and jaundice (HP:0000952) (PMID:21785126; PMID:26915364).
ACSF3 deficiency disrupts mitochondrial fatty acid synthesis by depleting malonyl‐CoA required for lipoic acid cofactor production. Knockdown of ACSF3 in human cells leads to ablation of protein lipoylation and mitochondrial fragmentation, phenocopied by simultaneous ACACA mitochondrial isoform disruption (PMID:28986507). Canine models harboring ACSF3 ortholog mutations recapitulate biochemical accumulations, supporting loss‐of‐function as the pathogenic mechanism.
Collectively, robust genetic evidence, consistent segregation patterns, and mechanistic functional studies fulfill ClinGen definitive criteria for ACSF3 as the causative gene for CMAMMA. Diagnostic sequencing of ACSF3 should be implemented in patients with unexplained elevations of MMA and MA. Early molecular diagnosis enables tailored metabolic monitoring, prognostic counseling, and avoidance of unnecessary immunological work‐ups.
Key Take-home: Biallelic loss‐of‐function ACSF3 variants definitively cause CMAMMA, a clinically heterogeneous but often benign autosomal recessive metabolic disorder amenable to genetic diagnosis.
Gene–Disease AssociationDefinitive
Genetic EvidenceStrongNine cases in initial exome study plus >30 distinct alleles in subsequent cohorts; autosomal recessive segregation Functional EvidenceModerateCellular knockdown and animal models demonstrate loss-of-function mechanism with impaired lipoylation |