Submission Details

ACSF3 was first reported in relation to autosomal recessive combined malonic and methylmalonic acidemia (CMAMMA) in 2011 (Alfares et al., PMID: 21785126), with cases identifying the causal enzyme, malonyl coenzyme A decarboxylase, having been reported since 1984 (Brown et al., PMID: 6145813). At least 19 unique variants (e.g. missense, in-frame indel, nonsense, frameshift, etc) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and some experimental data. Variants in this gene have been reported in at least 26 probands in six publications (PMIDs: 21785126, 26915364, 30740739, 26827111, 27604308, 21841779). All of these probands show evidence of the biochemical abnormalities characteristic of this disorder, however many of them do not demonstrate any additional phenotypic abnormalities. Additionally, many of these variants have high population frequencies that would not befit a deleterious function when affected as well as a high recorded pLOF (https://gnomad.broadinstitute.org/gene/ENSG00000176715). As such, this disorder has been asserted to be a benign metabolic phenotype in the literature (PMIDs: 21841779, 30740739). Functional studies into the effects of these variants in vitro or to determine any residual enzyme activity have not yet been performed. The mechanism for disease is biallelic loss of function, with disruption of the encoded mitochondrial malonyl-CoA and methylmalonyl-CoA synthetase causing a backup in intramitochondrial fatty acid synthesis and resulting buildup of malonic and methylmalonic acid in urine and tissues. This gene-disease association is supported by functional studies performed on patient tissue, with MMA production significantly lowered in patient fibroblasts compared to controls and the expression of WT ACSF3 cDNA, but not GFP, rescuing the metabolic phenotype and returning the production levels to near the controls. A natural canine model exhibiting the deficency also exists with homozygous variants in this gene, although there are other unexplained severe neurological symptoms in the line as well. In summary, ACSF3 is definitively associated with autosomal recessive combined malonic and methylmalonic acidemia (CMAMMA). Although more functional data examining the residual activity of variants and more experimental data could be acquired, the evidence currently provided is sufficent and has been upheld over time.