Cobalamins (Cbls) are complex organometallic substances that include a central cobalt atom. The basic structure, known as vitamin B12, is synthesized exclusively by microorganisms found in soil and water or in the rumen and intestine of animals. Mammals convert this vitamin into two required coenzyme forms, adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl). AdoCbl is needed to assist the enzyme methylmalonyl CoA mutase convert methylmalonyl CoA to succinyl CoA. MeCbl is needed to assist the enzyme methionine synthase convert homocysteine to methionine.
Dietary Cbl is acquired mostly from animal sources (e.g. meat and milk) and is absorbed in a series of steps that includes proteolytic release from its associated proteins, binding to a gastric secretory protein known as intrisic factor (IF), recognition of the IF-Cbl complex by cubilin, a receptor on ileal mucosal cells, transport across those cells, and release into the portal circulation bound to transcobalamin II (TC II), the serum protein that carries newly absorbed Cbl throughout the body.
The cellular metabolism by which the coenzymes are formed involves receptor-mediated binding of the TC II-Cbl complex to the cell surface, adsorptive endocytosis of the complex, intralysosomal degradation of the TC II, release of the Cbl into the cytoplasm, enzyme-mediated reduction of the central cobalt atom, and cytosolic methylation to form MeCbl or mitochondrial adenosylation to form AdoCbl.
Ten different inherited defects are known to impair the pathways of Cbl transport and metabolism in humans: three affect absorption and transport; the other seven alter cellular utilization and coenzyme production. The clinical manifestations of deficiencies in cellular Cbl utilization and metabolism vary depending on whether one or both coenzymes are affected.
Two abnormalities in AdoCbl synthesis (designated cblA and cblB) lead to impaired methylmalonyl CoA mutase activity and result in the accumulation of methylmalonate in the blood and urine.
One abnormality, cblE, involves a defect of the enzyme methionine synthase reductase, which leads to impaired MeCbl production, decreased activity of the enzyme methionine synthase, and the subsequent accumulation of homocysteine. Another defect, cblG, affects the enzyme methionine synthase itself, which again leads to the accumulation of homocysteine in the blood and urine.
Three distinct mutations (designated cblC, cblD, cblF) lead to impaired synthesis of both AdoCbl and MeCbl and, accordingly, to deficient activity of both methylmalonyl CoA mutase and methionine synthase. Children from these groups have mathylmalonic aciduria and homocystinuria.
Children with the cblC mutation appear to be more severely affected clinically than the two known siblings in the cblD group or those in the cblF group (6 unrelated patients). Over one hundred patients have been diagnosed with cblC, which usually presents in the first few months of life with failure to thrive, poor feeding, and lethargy. Rarely, some patients have presented with a delayed onset of symptoms (a 4-year-old with fatigue, delirium, and spasticity, and a 14-year-old with sudden dementia and myelopathy). Most, but not all, of these patients have had hematologic abnormalities characterized by megaloblastic and macrocytic anemia. Many patients suffer from a characteristic pigmentary retinopathy with perimacular degeneration, as well as other ophthalmologic changes. Moderate to severe developmental delay has been common in the early onset patients, and about a third of early onset patients have died (most commonly from hemolytic anemia and congestive failure) despite treatment.
At this time, there are three major treatment strategies. The first involves the administration of large amounts of exogenous Cobalamin by intramuscular injection. While patients with Cbl deficiency and Cbl transport defects respond dramatically to small amounts of Cobalamin, patients with cblC, cblD, and cblF require large doses of intramuscular hydroxycobalamin (OH-Cbl). Such treatment has resulted in dramatic decreases in urinary methylmalonate and in less dramatic, but significant, decreases in urinary homocysteine. The second treatment strategy involves moderate dietary protein restriction to reduce the load of metabolic end products and, hence, the amount of methylmalonate produced. Finally, a number of adjunctive medicines (carnitine, folate and betaine) have been used to improve organic acid excretion, improve hematologic function, and provide alternate pathways (betaine:homocysteine methyltransferase) for homocysteine metabolism.
Evidence suggests that cblC is inherited as an autosomal recessive trait (the number of cblD and cblF patients remains too small to definitively determine a mode of inheritance). Because normal amniotic fluid cells appear to carry out all of the steps of Cbl metabolism observed in cultures fibroblasts, it is possible to detect all of the defects prenatally by assaying any of these parameters in cultures amniocytes. Successful diagnosis can also be determined via chorionic villi sampling (CVS).
Reference: The Metabolic & Molecular Bases of Inherited Disease – eighth edition