Methylmalonic Acidemia via the MMUT/MUT Gene

Methylmalonic acidemia is caused by a deficiency in the activity of the enzyme methylmalonyl-CoA mutase. Methylmalonyl-CoA mutase catalyzes the last step in the breakdown of certain amino acids (met, ile, thr, val), odd-numbered chain length fatty acids, and propionic acid from gut flora (Fenton et al. 2014). Methylmalonic acidemia is typically a severe disease with onset in infancy. Patients may present with lethargy, vomiting, hepatomegaly, acidosis, hypoglycemia and neutropenia. Many patients die in childhood; those that survive often have neurological and renal complications. Milder forms of the disease are also known (Fenton et al. 2014; Manoli et al. 2016). Today, many cases are detected through routine neonatal screening with tandem mass spectrometry.

Methylmalonic acidemia is an autosomal recessive disease. The MMUT/MUT gene on chromosome 6 encodes the methylmalonyl-CoA mutase enzyme. Over 250 causative MMUT sequence variants have been reported to date (Acquaviva et al. 2005; Worgan et al. 2006; Human Gene Mutation Database). Of these, nearly 60% are missense, ~20% frameshift, ~15% nonsense, and ~10% splicing. Although founder mutations are known in specific populations, no pathogenic variants are common in the mixed American population.

Methylmalonyl-CoA mutase requires adenosylcobalamin (a vitamin B12 derivative) as a cofactor. Methylmalonic acidemia can be caused pathogenic variants in the MMUT, MMAA, MMAB, MMADHC or MCEE genes, as well as by vitamin B12 deficiency, or by defects in vitamin B12 metabolism. Two types of MUT deficiency are known to exist, and are termed complete (mut⁰) or partial (mut ^-) enzyme deficiency based on the amount of detectable residual methylmalonyl-CoA mutase activity (Fenton et al. 2014; Manoli et al. 2016).

Lempp et al. (2007) detected by genomic DNA sequencing 97% of possible MMUT pathogenic variants in 32 mutase apoenzyme-deficient patients. Similarly, Worgan et al. (2006) detected 96% of pathogenic variants in 160 patients. The fraction of patients with isolated methylmalonic acidemia due to sequence variants in the MMUT gene is estimated to be approximately 60% (Worgan et al. 2006; Hörster et al. 2007; Manoli et al. 2016).

It is difficult to estimate the clinical sensitivity of CNV detection as to date, only one gross deletion has been reported in the MMUT gene (Acquaviva et al. 2005), and no gross insertions have been reported. However, the clinical sensitivity appears to be relatively low.

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