cobamamide and Vitamin-B-12-Deficiency

Methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl) are coenzymes for methionine synthase and methylmalonyl-CoA mutase, respectively. Hydroxylcobalamin (HOCbl) and cyanocobalamin (CNCbl) are frequently used for supplementation. MeCbl and AdoCbl have recently emerged as alternative forms in supplements. In the light of metabolic transformation of Cbl into its cofactor forms, this review discusses current evidence on efficacy and utility of different Cbl forms in preventing or treating Cbl deficiency. Cbl-transporting proteins bind and mediate the uptake of all aforementioned forms of Cbl. After internalization and lysosomal release, Cbl binds to the cytosolic chaperon MMACHC that is responsible for (i) flavin-dependent decyanation of [CN-Co(3+) Cbl to [Co(2+)]Cbl; (ii) glutathione-dependent dealkylation of MeCbl and AdoCbl to [Co(2+/1+)]Cbl; and (iii) glutathione-dependent decyanation of CNCbl or reduction of HOCbl under anaerobic conditions. MMACHC shows a broad specificity for Cbl forms and supplies the Cbl(2+) intermediate for synthesis of MeCbl and AdoCbl. Cobalamin chemistry, physiology, and biochemistry suggest that MeCbl and AdoCbl follow the same route of intracellular processing as CNCbl does. We conclude that supplementing MeCbl or AdoCbl is unlikely to be advantageous compared to CNCbl. On the other hand, there are obvious advantages of high parenteral doses (1-2 mg) of HOCbl in treating inborn errors of Cbl metabolism.

Topics: Biological Transport; Cobamides; Humans; Hydroxocobalamin; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Amino Acid Isomerases; Amino Acids, Branched-Chain; Anemia, Pernicious; Animals; Clostridium; Cobamides; Humans; Intramolecular Transferases; Kinetics; Leucine; Pentanoic Acids; Plants; Rats; Species Specificity; Tissue Distribution; Valine; Vitamin B 12 Deficiency

Vitamin B12 (cyancobalamin, Cbl) has two active co-enzyme forms, methylcobalamin (MeCbl) and adenosylcobalamin (AdCbl). There has been a paradigm shift in the treatment of vitamin B12 deficiency such that MeCbl is being extensively used and promoted. This is despite the fact that both MeCbl and AdCbl are essential and have distinct metabolic fates and functions. MeCbl is primarily involved along with folate in hematopiesis and development of the brain during childhood. Whereas deficiency of AdCbl disturbs the carbohydrate, fat and amino-acid metabolism, and hence interferes with the formation of myelin. Thereby, it is important to treat vitamin B12 deficiency with a combination of MeCbl and AdCbl or hydroxocobalamin or Cbl. Regarding the route, it has been proved that the oral route is comparable to the intramuscular route for rectifying vitamin B12 deficiency.

Topics: Administration, Oral; Cobamides; Drug Therapy, Combination; Humans; Hydroxocobalamin; India; Injections, Intramuscular; Vitamin B 12; Vitamin B 12 Deficiency

The cobalamin type C deficiency is a rare condition that results from impaired biosynthesis of both methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl). Hemizygous mutations of the HCFC1 gene explain the majority of clinically and biologically compatible cblC patients without MMACHC mutations (OMIM 309541). We report a family with two maternal half-brothers with multiple congenital anomalies and HCFC1 gene mutation in the second Kelch domain. Both presented with dysmorphic features (flat profile, cleft lip for one), increased nuchal translucency, prenatal onset microcephaly and hypospadias. Additionally to early onset intractable epilepsy and profound neurocognitive impairment, this familial observation suggests that HCFC1 gene should be considered in boys with midline malformations, even without proven cobalamin C deficiency.

Topics: Abnormalities, Multiple; Carrier Proteins; Child, Preschool; Cleft Lip; Cobamides; Comparative Genomic Hybridization; Genetic Testing; Host Cell Factor C1; Humans; Karyotyping; Male; Mutation; Oxidoreductases; Vitamin B 12; Vitamin B 12 Deficiency

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.

Topics: Amino Acid Metabolism, Inborn Errors; Anemia, Megaloblastic; Cobamides; Homocysteine; Humans; Hyperhomocysteinemia; Infant, Newborn; Malabsorption Syndromes; Metabolism, Inborn Errors; Methylmalonic Acid; Methylmalonyl-CoA Mutase; Neonatal Screening; Proteinuria; Vitamin B 12; Vitamin B 12 Deficiency

Intracellular cobalamin is converted to adenosylcobalamin, coenzyme for methylmalonyl-CoA mutase and to methylcobalamin, coenzyme for methionine synthase, in an incompletely understood sequence of reactions. Genetic defects of these steps are defined as cbl complementation groups of which cblC, cblD (described in only two siblings), and cblF are associated with combined homocystinuria and methylmalonic aciduria. Here we describe three unrelated patients belonging to the cblD complementation group but with distinct biochemical phenotypes different from that described in the original cblD siblings. Two patients presented with isolated homocystinuria and reduced formation of methionine and methylcobalamin in cultured fibroblasts, defined as cblD-variant 1, and one patient with isolated methylmalonic aciduria and deficient adenosylcobalamin synthesis in fibroblasts, defined as cblD-variant 2. Cell lines from the cblD-variant 1 patients clearly complemented reference lines with the same biochemical phenotype, i.e. cblE and cblG, and the cblD-variant 2 cell line complemented cells from the mutant classes with isolated deficiency of adenosylcobalamin synthesis, i.e. cblA and cblB. Also, no pathogenic sequence changes in the coding regions of genes associated with the respective biochemical phenotypes were found. These findings indicate heterogeneity within the previously defined cblD mutant class and point to further complexity of intracellular cobalamin metabolism.

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Adolescent; Alkyl and Aryl Transferases; Child; Child, Preschool; Cobamides; DNA, Complementary; Fibroblasts; Genetic Complementation Test; Homocysteine; Homocystinuria; Humans; Male; Methionine; Methylmalonyl-CoA Mutase; Models, Biological; Mutation; Phenotype; Vitamin B 12; Vitamin B 12 Deficiency

The early onset type of cobalamin (Cbl) C/D deficiency is characterised by feeding difficulties, failure to thrive, hypotonia, seizures, microcephaly and developmental delay. It has an unfavourable outcome, often with early death and significant neurological impairment in survivors. While clinical and biochemical features of Cbl C/D deficiency are well known, only a few isolated case reports are available concerning neurophysiological and neuroimaging findings. We carried out clinical, biochemical, neurophysiological and neuroradiologic investigations in 14 cases with early-onset of the Cbl CID defect. Mental retardation was identified in most of the cases. A variable degree of supratentorial white matter atrophy was detected in 11 cases by MR imaging and tetraventricular hydrocephalus was present in the remaining 3 patients. Waking EEG showed a clear prevalence of epileptiform abnormalities, possibly related to the high incidence of seizures in these cases. Increased latency of evoked responses and/or prolongation of central conduction time were the most significant neurophysiological abnormalities. The selective white matter involvement, shown both by neuroradiologic and neurophysiological studies, seems to be the most consistent finding of Cbl C/D deficiency and may be related to a reduced supply of methyl groups, possibly caused by the dysfunction in the methyl-transfer pathway.

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Atrophy; Brain; Brain Diseases, Metabolic, Inborn; Child; Child, Preschool; Cobamides; Cytosol; Electroencephalography; Evoked Potentials; Female; Follow-Up Studies; Homocystinuria; Humans; Infant; Intellectual Disability; Magnetic Resonance Imaging; Male; Methylmalonic Acid; Methylmalonyl-CoA Mutase; Seizures; Vitamin B 12; Vitamin B 12 Deficiency

Several of the inborn errors of vitamin B12 (cobalamin, Cbl) metabolism (cblC, cblD, cblE, cblF, cblG) are associated with homocystinuria and hypomethioninemia due to a functional deficiency of the cytoplasmic enzyme methionine synthase which requires methylcobalamin (MeCbl) as a cofactor. We compared the growth of cultured fibroblasts from controls, from patients with a selective deficiency of MeCbl (cblE and cblG), with those with a defect in both MeCbl and adenosylcobalamin (AdoCbl) (cblC, cblD and cblF), in methionine and folic acid-free media to their growth in fully supplemented medium. Control cells were able to grow in deficient medium supplied with homocysteine, cobalamin and folate, while mutant cells were not, due to their inability to synthesize methionine from its immediate metabolic precursor, homocysteine. This differential growth is useful in screening for genetic defects of methionine biosynthesis.

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Cell Division; Cell Line; Cobamides; Fibroblasts; Homocysteine; Humans; Metabolism, Inborn Errors; Methionine; Vitamin B 12; Vitamin B 12 Deficiency

This study was designed to investigate a postulated relationship between vitamin B-12 and leucine metabolism in mature domestic chickens. Plasma amino acid analysis revealed the presence of beta-leucine at a concentration of 60 to 80 mumol/l. After 425 d on a vitamin B-12-deficient diet, plasma beta-leucine was 133% higher (P less than 0.06) and plasma leucine and methionine lower (P less than 0.03) than values in plasma from hens fed a diet adequate in vitamin B-12. Branched-chain-amino-acid aminotransferase (EC 2.6.1.42) (BCAT) activity was not enhanced by vitamin B-12 deprivation (P greater than 0.05). In contrast to leucine, beta-leucine was not utilized as substrate by BCAT for the formation of alpha-ketoisocaproate. Kidney extracts possessed leucine 2,3-aminomutase (EC 5.4.3.7) (LAM) activity, as evidenced by enhanced conversion of beta-leucine to alpha-leucine in the presence of adenosylcobalamin. LAM activity could not be demonstrated in liver or muscle extract, while leucine formation by pancreas extract was negligible. These data represent the first evidence of the presence of the amino acid beta-leucine in chicken plasma. In addition, the data support vitamin B-12-dependent leucine synthesis from beta-leucine in the chicken and highlight the kidney's role in leucine synthesis.

Topics: Amino Acid Isomerases; Amino Acids; Animals; Chickens; Cobamides; Enzyme Activation; Female; Intramolecular Transferases; Kidney; Leucine; Poultry Diseases; Transaminases; Vitamin B 12 Deficiency

Topics: Carrier Proteins; Cobamides; Humans; Radioisotopes; Transcobalamins; Vitamin B 12; Vitamin B 12 Deficiency