Methylmalonic Aciduria and Homocystinuria, cblD Type, via the MMADHC 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 cblG. The rare cblD disorder shows clinical and biochemical variability, as this disorder may be associated with either isolated or combined deficiency of methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl) synthesis (Suormala et al. 2004). In classic cblD disorder, patients have combined homocystinuria and methylmalonic aciduria. However, in cblD variant 1, patients have isolated homocystinuria, and in cblD variant 2, patients have isolated methylmalonic aciduria. Whether patients present with classic cblD, cblD variant 1 or cblD variant 2 seems to depend on the type and location of variants in the MMADHC gene (Carrillo-Carrasco et al. 2013; Watkins and Rosenblatt 2014). Presenting features of cblD deficiency include developmental delay, focal neurologic signs, megaloblastic anemia, marfanoid appearance, venous thrombosis, cerebral atrophy, and hydrocephalus (Miousse et al. 2009; Carrillo-Carrasco et al. 2013; Watkins and Rosenblatt 2014).

Pathogenic variants in MMADHC on chromosome 2q23.2 are responsible for autosomal recessive methylmalonic aciduria and homocystinuria, cblD type. The MMADHC gene consists of eight exons (seven of which encode protein). While the exact function of the gene product remains unknown, it appears to be a cobalamin-binding mitochondrial protein which shows homology to the putative ATPase component of a bacterial ABC transporter (Miousse et al. 2009). To date, fewer than 20 pathogenic variants have been reported in the MMADHC gene. It has been hypothesized that Met62 is capable of acting as a second start codon for reinitiation of translation in patients with an initiation codon or early chain termination variant. These patients would produce a shorter functional protein lacking mitochondrial sequence, but capable of normal methylcobalamin synthesis (Coelho et al. 2008).

In two studies which examined a total of 10 patients with cblD defect, all individuals were found to have MMADHC pathogenic variants in either a compound heterozygous or homozygous state (Coelho et al. 2008; Miousse et al. 2009).

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

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