Inborn Errors of Cobalamin Metabolism

There are several known but rare inherited molecular defects resulting in absence or structural defects in proteins required for normal absorption, transport. or metabolism of cobalamin. These include the intestinal binding proteins gastric intrinsic factor and its ileal receptor complex cubulin and amnionless, the plasma binders trans-cobalamin and haptocorrin, the enzymes that are required for conversion of cobalamin to its coenzy-matically active methyl and deoxyadenosyl forms, and enzyme complexes involved in the catalysis of the two cobalamin-dependent reactions responsible for conversion of homocysteine to methionine and methylmalonate to succinate, respectively. Individuals who inherit a defective gene from each parent for any one of these proteins that are critical for cobalamin metabolism suffer from varying degrees of impairment of normal cobalamin-related status (see Table 4), closely mimicking the various

Test Finding Major limitations

Serum/plasma cobalamin concentration Low (<150pmolT1) Normal levels in some deficient subjects; slight to moderately low levels may not connote deficiency Serum/plasma holotranscobalamin (holo TC II) Low (<35pmolr1) Test not yet widely available; insufficient validation of usefulness

Serum/plasma or urine methylmalonic acid Raised (>350nmolr1) Levels raised in renal insufficiency

Plasma homocysteine Raised (>12 mmol r1) Levels raised in folate and in vitamin B6 deficiencies, renal insufficiency, hypothyroidism

Table 4 Inherited disorders affecting cobalamin metabolism and their effects

Cobalamin protein

Effects of deletion or mutation

Intrinsic factor

Cubulin/amnionless complex



Cobalamin reducing and activating enzymes (mut+ and mut-, cobalamin mutants C-G)

Cobalamin malabsorption

(juvenile pernicious anemia) Cobalamin malabsorption (Immerslund-Grasbeck syndrome) Severe cobalamin deficiency No apparent abnormality Varying degrees of disruption in one or both cobalamin-dependent pathways manifestations of cobalamin deficiency described above. These disorders usually become manifest at an early age.

See also: Amino Acids: Chemistry and Classification; Metabolism; Specific Functions. Anemia: Iron-Deficiency Anemia; Megaloblastic Anemia. Folic Acid. Homocysteine. Inborn Errors of Metabolism: Classification and Biochemical Aspects.

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