Methlymalonyl-CoA Epimerase Deficiency via the MCEE Gene

Methylmalonic acidemia (MMA) without homocystinuria is caused either by errors in the biochemical pathway in which propionyl-CoA is converted to succinyl-CoA, or by defects in the generation of the enzymatic cofactor adenosylcobalamin (AdoCbl) (Dobson et al 2006; Manoli et al. 2016). The vast majority of diagnosed cases of MMA are caused by variants in the MUT gene, followed by the MMAA, MMAB, MMADHC and MCEE genes. Very few patients have been reported to have variants in the MCEE gene, so a cohesive clinical picture has yet to emerge. Symptoms reported in the few MCEE patients thus far include failure to gain weight, gastroesophageal reflux, tachypnea, vomiting and diarrhea. Biochemically, these patients have been found to exhibit mild to moderately increased levels of serum methylmalonic acid and methylcitric acid, as well as severe metabolic acidosis. Plasma total homocysteine levels have been reported to be normal (Bikker et al. 2006; Dobson et al 2006; Gradinger et al. 2007; Manoli et al. 2016). One patient presented with progressive delayed motor development; however, this patient was the child of consanguineous parents and was also diagnosed with sepiapterin deficiency, to which the motor delays were largely attributed (Bikker et al. 2006). MCEE deficiency has also been reported to occur in asymptomatic individuals (Bikker et al. 2006; Dobson et al 2006; Gradinger et al. 2007).

Treatment of the reported patients has included a protein-restricted diet and vitamin B12 supplementation, although too few reports exist to be certain of the efficacy of this regimen (Bikker et al. 2006; Dobson et al 2006).

Methlymalonyl-CoA Epimerase Deficiency is thought to be an autosomal recessive disorder, and MCEE is the only gene in which defects occur. To date, fewer than five causative variants have been reported in the MCEE gene (Human Gene Mutation Database; Gradinger et al. 2007). Two of these variants (p.Arg47* and p.Lys60Gln) have been reported in the homozygous state, while the third (p.Arg143Cys) has been reported in the heterozygous state in two patients for whom a second variant was not identified. Of these variants, the p.Arg47* variant appears to be the most common as it has been reported in at least three families (Bikker et al. 2006; Dobson et al 2006; Gradinger et al. 2007).

Methlymalonyl-CoA Epimerase Deficiency is caused by defects in the Methlymalonyl-CoA Epimerase enzyme, which is responsible for the interconversion of the D- and L-methylmalonyl-CoA. The D- and L-methylmalonyl-CoA products are intermediates in the pathway whereby propionyl-CoA is converted to succinyl-CoA (Dobson et al. 2007).

At this time, the sensitivity of this test is difficult to estimate due to the low number of cases reported in the literature. Analytical sensitivity may be high as the only reported causative variants are detectable by sequencing.

This test provides full coverage of all coding exons of the MCEE 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).

This testing also includes coverage for the following intronic variant, as well as ~10 bp of adjacent sequence: c.379-644A>G.

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).