Methylmalonic Aciduria and Homocystinuria, cblJ Type, via the ABCD4 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 cblJ deficiency, cobalamin accumulates in lysosomes and cannot be used to synthesize the cofactors adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl). As a result, methylmalonyl CoA mutase cannot convert L-methylmalonyl-CoA to succinyl CoA, and methionine synthase cannot convert homocysteine to methionine. Patients have elevated methylmalonic acid and homocysteine concentrations in blood and urine, and some patients with increased propionylcarnitine concentrations are identified through newborn screening (Coelho et al. 2012). Clinical presentations are variable, but include being small for gestational age, feeding difficulties, hypotonia, lethargy, developmental delay, macrocytic anemia, and cardiovascular defects of variable severity (Coelho et al. 2012; Carrillo-Carrasco et al. 1993). Typically, presentation is within the first year and a half of life, but an 8 year-old patient was also diagnosed with a milder phenotype (Kim et al. 2012). Cultured fibroblasts from patients are phenotypically indistinguishable from that of patients with the cblF disorder (LMBRD1 gene) (Coelho et al. 2012).

Mutations in ABCD4 on chromosome 14q24 are responsible for autosomal recessive methylmalonic aciduria and homocystinuria, cblJ type. The ABCD4 gene consists of 19 coding exons and encodes the 606 amino acid ABCD4 protein. ABCD4 contains a transmembrane domain and an ABC transporter or nucleotide-binding domain. This protein localizes to the lysosome and interacts with LMBD1 (deficient protein in cblF type) (Coelho et al. 2012). It is unknown how the LMBD1 and ABCD4 proteins function in transporting cobalamin across the lysosomal membrane. Reported causative mutations include missense, splicing, and a small insertion detectable by sequencing. Two reported mutations occur in the predicted transmembrane domain, whereas two others have been reported in the predicted nucleotide-binding domain (Coelho et al. 2012; Kim et al. 2012).

Clinical sensitivity cannot be estimated because only a small number of patients have been reported. Analytical sensitivity should be almost 100% because all reported mutations thus far are detectable by sequencing.

This test provides full coverage of all coding exons of the ABCD4 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).