Methylmalonic Acidemia, cblA type, via the MMAA Gene

Cobalamin (Cbl or vitamin B12) is an important cofactor in homocysteine metabolism and in branched-chain amino acid and odd-chain fatty acid catabolism. A series of inherited inborn errors of cobalamin metabolism have been identified, designated cblA through cblJ. In cblA disorder, the vital cobalamin-dependent cofactor adenosylcobalamin (AdoCbl) cannot be produced. As a result, cblA disorder leads to elevated levels of methylmalonic acid in the blood (Fenton et al. 2014; Manoli et al. 2016).

Methylmalonic acidemia (MMA) 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 experience neurological and renal complications. Milder forms of the disease are also known. Today, many cases are detected through routine neonatal screening with tandem mass spectrometry (Fenton et al. 2014; Manoli et al. 2016).

AdoCbl is the cofactor for methylmalonyl-CoA mutase, which is encoded by the MUT gene. In addition to defects in the MUT gene itself, MMA can be caused by defects in genes that encode proteins involved in the generation of AdoCbl. MMA caused by defects in genes other than MUT are generally referred to as cbl types of MMA. Thus far, three distinct genetic variants of cbl type MMA have been identified: cblA, cblB and cblD variant 2 (Martinez et al. 2005; Fenton et al. 2014). Of these three variants, cblA type MMA has the most favorable clinical outcome (Fenton et al. 2014; Manoli et al. 2016), and is thought to be caused by defective mitochondrial transport of cbl (Yang et al. 2004). CblA patients may be responsive to treatment with vitamin B12 (Manoli et al. 2016).

Methylmalonic acidemia cblA type is an autosomal recessive disease. The MMAA gene on chromosome 4 encodes a protein that is thought to play a role in transport of adenosylcobalamin (AdoCbl) into the mitochondria (Yang et al. 2004; Fenton et al. 2014). Over 40 causative MMAA sequence variants have been reported to date (Lerner-Ellis et al. 2004; Human Gene Mutation Database). Of these, approximately two-thirds are missense and nonsense, although splicing variants, small deletions and insertions and one gross deletion have been reported as well (Human Gene Mutation Database). Variants are spread throughout the MMAA gene, with the most commonly reported variant being the nonsense variant p.Arg145*. This variant has been reported to account for over 40% of causative variants in some patient cohorts (Lerner-Ellis et al. 2004).

The MMAA gene product is thought to be required for transport of cbl into mitochondria where adenosylcobalamin synthesis occurs (Yang et al. 2004; Fenton et al. 2014).

Martinez et al. (2005) evaluated 25 MMA patients and found MUT pathogenic variants in 13 patients, MMAA pathogenic variants in 7, and MMAB pathogenic variants in 2. Among 37 patients with biochemically diagnosed cblA type MMA, Lerner-Ellis et al. (2004) found two MMAA pathogenic variants in 95% of their cohort and a single pathogenic variant in the remaining 2 individuals. Dempsey-Nunez et al. (2012) found two MMAA pathogenic variants in ~92% of their cohort, a single pathogenic variant in ~6% and no pathogenic variants in the remaining patients. Thus, the clinical sensitivity of this test is quite high. The analytical sensitivity should also be high as the vast majority of MMAA pathogenic variants that have been reported are detectable by direct sequencing.

Only a single gross deletion has been reported in the MMAA gene (Nizon et al. 2013). Therefore, the sensitivity of duplication/deletion testing for this rare disorder, although not precisely known, is low.

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