Methylmalonic Acidemia, cblB type, via the MMAB 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 cblB disorder, the vital cobalamin-dependent cofactor adenosylcobalamin (AdoCbl) cannot be produced. As a result, cblB 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). CblB type MMA results from deficiency of cob(I)alamin adenosyltransferase, the enzyme that catalyzes the final step in synthesis of adenosylcobalamin (Fenton et al. 2014).

Methylmalonic acidemia cblB type is an autosomal recessive disease. The MMAB gene on chromosome 12 encodes the cob(I)alamin adenosyltransferase enzyme, which catalyzes the final step in synthesis of adenosylcobalamin (Fenton et al. 2014). Over 30 causative MMAB sequence variants have been reported to date (Lerner-Ellis et al. 2006; Human Gene Mutation Database). Of these, approximately two-thirds are missense and nonsense, although splicing and regulatory variants, small deletions, insertions and indels have been reported as well (Martinez et al. 2005; Lerner-Ellis et al. 2006; Human Gene Mutation Database). The majority of pathogenic variants reported today seem to cluster in exon 7 of the MMAB gene, and overall three variants seem to be the most commonly reported (p.Arg186Trp, p.Gln234*, and the splice variant c.197-1G>T) (Lerner-Ellis et al. 2006).

Dobson et al. (2002) found two MMAB pathogenic variants in all six cblB patients studied. Lerner-Ellis et al. (2006) identified two pathogenic variants in the MMAB gene in 34 of 35 cblB patients, and a single pathogenic variant in the last patient. Thus, the clinical sensitivity of this test appears to be near 100%, and analytical sensitivity is also expected to be high as all variants reported to date should be detectable via direct gene sequencing.

To date, no large deletions or duplications have been reported in MMAB (Human Gene Mutation Database).

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