Abnormal cobalamin metabolism in a case of juvenile pernicious anaemia with neurological symptoms

Abstract

Studies of cobalamin metabolism in a case of juvenile pernicious anaemia during haematological remission showed that while plasma cobalamins were normal there was some depletion of erythrocyte cobalamins. In addition, the plasma distribution of apo-and holo-transcobalamins was markedly abnormal, holo-TCII being increased, yet the patient's plasma promoted less cellular synthesis of adenosylcobalamin by cultured lymphocytes than did plasma from a control subject. The results suggest that hoto-TCII may in this case have been ineffective and provide further evidence for the importance of TCII in intracellular synthesis of adenosylcobalamin.Cobalamin deficiency in pernicious anaemia (PA) results from genetically absent or ineffective gastric intrinsic factor with impaired intestinal absorption and loss of biliary cobalamins. Regular parenteral administration ofhydroxocobalamin (OH-Cbl) normally restores cellular and tissue levels of the two coenzymes adenosylcobalamin (Ado-Cbl) and methylcobalamin (Me-Cbl), maintaining the patient in haematological remission.We have investigated cobalamin metabolism in a case of juvenile PA diagnosed by Schilling test, who, despite continued therapy with parenteral OH-Cbl and oral folate, developed neurological symptoms with ataxia, parasthesiae, impaired dexterity and some visual loss. METHODSCobalamins in plasma and erythrocytes were estimated , by chromatography and bioautography (Linnell et al., 1974). Transcobalamins TC0, TCI and TCII were separated on Sephadex G.200 and the total Cbl attached to each TC was estimated by radioisotopic assay (England et al., 1976). Uptake and conversion of [57Co]CN-Cbl in phytohaemagglutinin (PHA)-stimulated lymphocytes in vitro was measured as previously described (Quadros et al., 1976). RESULTS Estimation of plasma cobalamins 4 weeks after OH-Cbl(1 mg i.m.) showed no marked abnormality, but in erythrocytes OH-Cbl was low and the level of Ado-Cbl was close to the lower limit ()f normal (Table 1). Similarly low levels of OH-Cbl and Ado-Cbl were detected in erythrocyte samples 4 and 6 months later, despite continuing OH-Cbl therapy and daily oral folate.Plasma Cbt binding capacity (UBBC) was normal (920 pg/ml), but binding of [57Co]CN-Cbl to each transcobalamin showed a markedly disturbed distribution, more being attached to TCI and less to TCII than normal (Figure 1). Analysis of the endogenous Cbl distribution showed that the total Cbl carried by TCII (334 pg/ml) was more than four times the upper limit of normal (normal range 7-82pg/ml) and, in addition, about 10% was.bound to a protein of the molecular weight of albumin.