Methylmalonic Aciduria and/or Homocystinuria via the CD320 Gene

Methylmalonic aciduria due to defects in the transcobalamin receptor appears to be a rare disorder, with fewer than 10 cases reported to date. Based on current knowledge, the majority of affected individuals have no overt clinical symptoms, although one patient presented in early infancy with bilateral central retinal artery occlusions (Quadros et al. 2010; Karth et al. 2012; Watkins and Rosenblatt 2014). Biochemically, all patients identified to date have been found to exhibit moderately elevated methylmalonic acid in plasma and/or urine, and most have also been found to have elevated serum homocysteine levels (Quadros et al. 2010; Karth et al. 2012). All patients identified in the study by Quadros et al. (2010) were also found to have elevated levels of C3-acylcarnitine. Additionally, the index patient reported by Quadros et al. (2010) was found to have elevated vitamin B12 in the plasma by 9 months of age.

To date, none of the identified patients have shown the hematological or neurological symptoms that are often associated with cobalamin deficiency, but the long-term outcome of this disorder is not currently known. While it is possible this may be primarily a benign disorder, patients with CD320 variants may be identified by newborn screening programs and flagged for follow up studies. In individuals with pathogenic variants in the CD320 gene, treatment with pharmacological doses of vitamin B12 has been shown to lower methylmalonic acid and homocysteine to normal levels, and thus it may be important to distinguish such individuals from those with the more clinically severe intracellular cobalamin deficiency disorders (Quadros et al. 2010).

Current knowledge of the transcobalamin receptor deficiency disorder suggests that this is an autosomal recessive disorder, and CD320 is the only gene known to be involved. To date, only a single variant has been reported in this gene (p.Glu88del), and all affected patients have been reported to be homozygous for this variant (Quadros et al. 2010; Karth et al. 2012).

Cobalamin is transported to different tissues in the body via the bloodstream, while bound to the protein transcobalamin. The transcobalamin cobalamin receptor is a glycoprotein found on the plasma membrane of cells. The receptor has a large extracellular domain, a single transmembrane domain, and a cytoplasmic domain, and is responsible for mediating the uptake of transcobalamin-bound cobalamin into cells. The Glu88 amino acid is located in the extracellular domain of this protein, in the region thought to be directly involved in interacting with transcobalamin (Quadros et al. 2010; Karth et al. 2012; Watkins and Rosenblatt 2014).

At this time, the sensitivity of this test is difficult to estimate due to the low number of cases reported in the literature. Analytical sensitivity may be high as the only reported causative variant is detectable by sequencing.

This test provides full coverage of all coding exons of the CD320 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).