Combined Malonic and Methylmalonic Aciduria (CMAMMA) via the ACSF3 Gene

Combined malonic and methylmalonic aciduria (CMAMMA) is an inborn error of metabolism that is characterized by elevated levels of malonic and methylmalonic acid in the urine. To date, the majority of cases have been found to be caused by variants in the MLYCD gene, which encodes the enzyme malonyl-CoA decarboxylase. However, recent research has shown that CMAMMA is a genetically heterogeneous disorder, and that pathogenic variants in the ACSF3 gene can lead to a non-classical form of CMAMMA (Alfares et al. 2011; Sloan et al. 2011). Patients with the non-classical form have been found to excrete both malonic and methylmalonic acid in the urine, but the level of methylmalonic acid is significantly higher than that of malonic acid. In contrast, in classical CMAMMA the level of malonic acid is higher. As fewer than 20 patients have been described to date, the clinical spectrum of non-classical CMAMMA is not fully understood. Patients have been reported to be clinically asymptomatic (Alfares et al. 2011), or to have clinical symptoms ranging from childhood to adult onset (Sloan et al. 2011; Pupavac et al. 2016). The patients with childhood onset of disease have exhibited symptoms suggestive of a metabolic disorder, such as ketoacidosis, hypoglycemia, coma, failure to thrive, increased transaminases, microcephaly, dystonia, hypotonia and developmental delay. In contrast, the patients with adult onset disease presented with solely neurologic symptoms, such as seizures, memory problems, psychiatric disease and/or cognitive decline (Sloan et al. 2011). A late-onset patient was recently reported to have progressive generalized weakness without psychiatric disease and/or cognitive decline (Pupavac et al. 2016).

Patients with non-classical CMAMMA may be detected by newborn screening programs due to elevated levels of malonic and methylmalonic acid.

Current knowledge about non-classical CMAMMA suggests that this is an autosomal recessive disorder, and ACSF3 is the only gene known to be involved (Alfares et al. 2011; Sloan et al. 2011). To date, the majority of reported pathogenic variants have been missense variants, although one small deletion, two nonsense variants and one splice variant have been reported. In addition, one gross deletion has been detected, though it should be noted that this deletion included several other genes as well (Pupavac et al. 2016). The R558W missense variant has been reported in multiple unrelated individuals, and recently a patient was identified with an R558Q variant. This suggests that variants at this site may be a common cause of disease (Alfares et al. 2011; Sloan et al. 2011; Pupavac et al. 2016).

The ACSF3 gene encodes an acyl-CoA synthetase protein of uncertain function. Initial functional studies have suggested that it may act as a malonyl-CoA and methylmalonyl-CoA synthetase. The ACSF3 protein has been shown to be localized to the mitochondria (Sloan et al. 2011).

Clinical sensitivity is difficult to estimate because only a small number of patients have been reported. Analytical sensitivity should be high because nearly all variants reported are detectable by direct sequencing.

To date, a single gross deletion encompassing the ACSF3 gene has been reported in the literature (Pupavac et al. 2016).

This test provides full coverage of all coding exons of the ACSF3 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).