3-Methylcrotonyl-CoA Carboxylase Deficiency via the MCCC2 Gene

3-methylcrotonyl-CoA carboxylase (MCC) deficiency (OMIM 210200 and 210210) is a defect in the catabolism of the amino acid leucine. MCC is the next enzyme after isovaleryl-CoA dehydrogenase in the degradation pathway. MCC deficiency leads to abnormally high levels of 3-methylcrotonylglycine in the urine and 3- hydroxyisovalerylcarnitine in the blood. MCC deficiency is one of the most frequent disorders detected through neonatal screening with tandem mass spectrometry. The most severe forms of MCC deficiency have onset in infancy and are characterized by episodes of vomiting, lethargy, and muscle weakness. These episodes can lead to seizures, coma, and death. A variety of other, mostly neurological, symptoms have been reported.

3-methylcrotonyl-CoA carboxylase (MCC) deficiency is an autosomal recessive disorder. The MCC enzyme has two subunits, α and β, encoded by the MCCC1 (also called MCCA) and MCCC2 (MCCB) genes, respectively. Variants in either gene can lead to MCC deficiency. No differences in clinical features have been reported for variants in MCCC1 versus MCCC2. About 30 different causative variants have been reported in MCCC1 and 45 in MCCC2 (Gallardo et al. Am J Hum Genet 68:334-346, 2001; Baumgartner et al. J Clin Invest 107:495-504, 2001; Dantas et al. Hum Mut 26:164, 2005; Stadler et al. Hum Mut 27:748-59,2006). In both genes, the causative variants are about equally split between missense and nonsense/frameshift/splicing. No common variants have been reported. Variants are distributed throughout the lengths of the genes. Although nearly all MCC deficiency patients detected by neonatal screening carry likely causative variants, it appears that many such patients, perhaps even the great majority, will not experience significant health problems (Dantas et al. 2005; Stadler et al. 2006). The genetic or non-genetic factors which exert such strong control over the expressivity of the variants are currently unknown.

Stadler et al. 2006 reported detecting two causative variants by sequencing the MCCC1 and MCCC2 genes in 28 out of 28 patients.

This test provides full coverage of all coding exons of the MCCC2 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).