Inborn errors of cobalamin absorption and metabolism

Abstract

Derivatives of cobalamin (vitamin B(12)) are required for activity of two enzymes in humans. Adenosylcobalamin is required for activity of mitochondrial methylmalonylCoA mutase and methylcobalamin is required for activity of cytoplasmic methionine synthase. Deficiency in cobalamin, or inability to absorb cobalamin normally, can result in accumulation of methylmalonic acid and homocysteine in blood and urine. Methylmalonic acidemia can result in metabolic acidosis which in severe cases may be fatal. Hyperhomocysteinemia along with hypomethioninemia can result in hematologic (megaloblastic anemia, neutropenia, thrombocytopenia) and neurologic (subacute combined degeneration of the cord, dementia, psychosis) defects. Inborn errors affecting cobalamin absorption (inherited intrinsic factor deficiency, Imerslund–Gra¨ sbeck syndrome) and transport (transcobalamin deficiency) have been described. A series of inborn errors of intracellular cobalamin metabolism, designated cblA-cblG, have been differentiated by complementation analysis. These can give rise to isolated methylmalonic acidemia (cblA, cblB, cblD variant 2), isolated hyperhomocysteinemia (cblD variant 1, cblE, cblG) or combined methylmalonic acidemia and hyperhomocysteinemia (cblC, classic cblD, cblF). All these disorders are inherited as autosomal recessive traits. The genes underlying each of these disorders have been identified. Two other disorders, haptocorrin deficiency and transcobalamin receptor deficiency, have been described, but it is not clear that they have any consistent clinical phenotype.

Degenerative Liver Disease in Young Beagles with Hereditary Cobalamin Malabsorption Because of a Mutation in the Cubilin Gene

“…Neutropenia had been noted in both dogs and, mild macrocytosis in the absence of anemia was detected in 1 dog at some point. These are typical findings described in children with congenital cobalamin deficiency 2, 14. Neutropenia was also reported in the only previously published case of a cobalamin‐deficient Beagle 4.…”

The Human Knockout Gene CLYBL Connects Itaconate to Vitamin B12

“…To date, mutations in genes for 10 cellular complementation groups based on patient-derived fibroblasts have been identified, thereby providing insight into the intracellular trafficking and biochemistry of B 12 (Watkins and Rosenblatt, 2011, 2016). A recent GWAS studies for low circulating B 12 levels in human have revealed its association with 11 loci (Grarup et al, 2013).…”

Cellular uptake of cobalamin: Transcobalamin and the TCblR/CD320 receptor

“…The advances in biology have led to the identification of pathways, proteins and genes involved (119). The structural and functional characterization of proteins involved and the metabolic consequences of gene defects have provided a better understanding of clinical disorders of Cbl metabolism (120) to implement strategies to manage these disorders.…”