Cobalamin Status and Its Biochemical Markers Methylmalonic Acid and Homocysteine in Different Age Groups from 4 Days to 19 Years Anne-Lise Bjørke Monsen, 1 Helga Refsum, 2,4 Trond Markestad, 1 and Per Magne Ueland 3* Background: Recent data indicate that cobalamin and folate status, including the metabolic markers methyl- malonic acid (MMA) and total homocysteine (tHcy), undergo marked changes during childhood, particularly during the first year. Methods: Serum cobalamin, serum and whole-blood folate, and plasma MMA and tHcy were determined in a cross-sectional study of 700 children, ages 4 days to 19 years. Results: During the first 6 months, serum cobalamin was lower than and plasma MMA, tHcy, and serum folate were higher than the concentrations detected in the other age groups. In infants 6 weeks to 6 months of age, median MMA and tHcy concentrations were >0.78 and >75 mol/L, respectively. In older children (>6 months), serum cobalamin peaked at 3–7 years and then decreased, median plasma MMA remained low (<0.26 mol/L), median plasma tHcy was low (<6 mol/L) and increased from the age of 7 years on, and serum folate gradually decreased. Plasma MMA was inversely asso- ciated with cobalamin (r 0.4) in both age groups, but across the whole range of cobalamin concentrations, MMA was markedly higher in infants (<6 months) than in older children. Plasma tHcy showed a strong negative correlation to cobalamin (r 0.52) but not to serum folate in infants <6 months. In older children, tHcy showed the expected association with both cobalamin (r 0.48) and folate (r 0.51). Conclusions: In infants 6 weeks to 6 months, concentra- tions of the metabolic markers MMA and tHcy were higher than in the other age groups and strongly corre- lated to cobalamin, whereas in older children, both makers showed correlations to cobalamin and folate concentrations documented in adults. Whether this met- abolic profile in infants is explained by impaired cobal- amin status, which in turn may have long-term effects on psychomotor development, remains to be addressed in intervention studies. © 2003 American Association for Clinical Chemistry During the first year of life, cobalamin uptake may be limited because of a low cobalamin content in breast milk (1) and an immature intrinsic factor system (2, 3), but the estimated cobalamin stores in the neonatal liver are as- sumed to be sufficient for normal growth (1). In older children, an omnivorous diet is thought to ensure the daily dietary requirement for cobalamin. Consequently, nutritional cobalamin deficiency in childhood is consid- ered rare and limited to infants born to cobalamin- deficient mothers or children adhering to a strict vegetar- ian diet low in cobalamin (1, 4). Several case reports, mainly from developing countries (1, 5, 6), demonstrate the importance of maintaining ade- quate cobalamin concentrations during periods of rapid growth and development. In infancy, cobalamin defi- ciency may present as failure to thrive, developmental delay and regression, progressive neurologic disorders, or hematologic changes. The symptoms may be evident as early as 3– 4 months of age (7), but are often nonspecific and difficult to detect. Cobalamin is a coenzyme in a methyl transfer reaction that converts homocysteine to methionine and in a sepa- rate reaction converts l-methylmalonyl-CoA to succinyl- CoA (8). This explains why increased total homocysteine (tHcy) and/or methylmalonic acid (MMA) in the blood are measures of impaired cobalamin status, which may Departments of 1 Pediatrics and 2 Pharmacology, and 3 LOCUS for Homo- cysteine and Related Vitamins, University of Bergen, N-5021 Bergen, Norway. 4 Department of Pharmacology, University of Oxford, Oxford, UK. *Address correspondence to this author at: Department of Pediatrics, Haukeland University Hospital, N-5021 Bergen, Norway. Fax 47-55-975147; e-mail albm@online.no. Received April 6, 2003; accepted September 23, 2003. DOI: 10.1373/clinchem.2003.019869 Clinical Chemistry 49:12 2067–2075 (2003) Pediatric Clinical Chemistry 2067 Downloaded from https://academic.oup.com/clinchem/article/49/12/2067/5642079 by guest on 13 February 2023