Transcobalamin Deficiency Research Articles

Prenatal diagnosis for methylmalonic acidemia and inborn errors of vitamin B 12 metabolism and transport

Vitamin B 12 (cobalamin) is an essential cofactor for two enzymes: methionine synthase (MS), which requires methylcobalamin (MeCbl), and methylmalonyl-CoA mutase (MUT), which requires adenosylcobalamin (AdoCbl). A number of individually rare inborn errors of cobalamin metabolism are known and are distinguished by complementation analysis ( mut, cblA-cblH). From 1984 to 2005, we have performed prenatal diagnosis for 117 high-risk pregnancies. We identified a total of 21 affected pregnancies (18%): cblA, 2/8; cblB, 0/5; cblC, 10/52; cblE, 2/3; cblF, 0/5; cblG, 0/5; transcobalamin deficiency, 0/2; methylmalonyl-CoA mutase ( mut) deficiency, 7/30; and unclassified MMA, 0/7. Studies were performed on amniotic fluid, cultured chorionic villus cells (CCVC), cultured amniocytes (CA), or various combinations of these three types of sample. Analyses done include propionate and methyltetrahydrofolate incorporation into protein and cobalamin cofactor levels (CA: 92%, CCVC: 18%), amniotic fluid metabolite measurement either by gas chromatography/mass spectrometry (GC/MS) or by liquid chromatography–tandem mass spectrometry (LC–MS/MS) (49%), and direct mutation analysis (5%). There was one false negative CCVC result in a pregnancy at risk for cblC and one false positive CCVC in a pregnancy at risk for mutase deficiency. One unaffected pregnancy at risk for an unclassified form of MMA and another unaffected pregnancy at risk for cblC, had higher than control MMA amniotic fluid levels. Our experience suggests that prenatal diagnosis for these disorders should be done by application of two independent methods, and that CA studies appear more reliable than CCVC studies.

Nutritional vitamin B 12 deficiency and folate deficiency in an adolescent patient presenting with anemia, weight loss, and poor school performance

Vitamin B/12 is an essential vitamin for hematopoiesis and neurologic and psychiatric health. Because it is not synthesized in the human body it must be supplied exogenously in the diet. Deficiency of cobalamin is rare and usually results from malabsorption. Other rare causes include the use of nitrous oxide transcobalamin deficiency and inadequate dietary intake. Vitamin B/12 is primarily found in meat and dairy products. The recommended dietary allowance for adults is 2-4 µg/day; however most adults consume approximately 1-2 mg/day. Because the body also stores approximately 4-5 mg of vitamin B/12 predominantly in the liver it takes 3-6 years before dietary vitamin B/12 deficiency may become clinically evident. Of the few reported adult and neonatal cases of symptomatic deficiency secondary to inadequate dietary intake vegetarian diets are usually implicated although cobalamin deficiency has also been associated with nonvegetarian diets. (excerpt)

血しょう蛋白欠乏症とその臨床 トランスコバラミン欠乏症

血しょう蛋白欠乏症とその臨床 トランスコバラミン欠乏症

Transcobalamin II deficiency presenting with methylmalonic aciduria and homocystinuria and abnormal absorption of cobalamin

An infant with deficiency of transcobalamin II (TCII) presented with virtually complete failure to thrive and life-threatening pancytopenia. Methylmalonic acid and homocystine were found in the urine. The concentration of B12 in the serum was 26 pg/ml. Fibroblasts derived from the patient failed to take up labeled cobalamin in the absence of a source of TCII. Uptake was normal in the presence of TCII. Treatment with parenteral cobalamin reversed the clinical and hematological manifestations of the disease but she developed glossitis when the interval between injections was lengthened. Intestinal absorption of 57Co-cobalamin was less than 1% and remained abnormal when highly purified human intrinsic factor was given along with the labeled B12. Absorption improved when the labeled B12 was given together with rabbit TCII. The data suggest that TCII as well as intrinsic factor is required for transport of cobalamin from the intestine to the blood.

Congenital Transcobalamin II Deficiency Presenting Atypically With a Low Serum Cobalamin Level: Studies Demonstrating the Coexistence of a Circulating Transcobalamin I (R Binder) Complex

A case of transcobalamin II deficiency with several unique features is described. The clinical presentation was typical, except for a slightly delayed age at presentation and the occurrence of apparent neurologic dysfunction from the beginning. The unusual biochemical feature was a low serum cobalamin level (97 pg/ml). Several cobalamin-binding protein abnormalities coexisted and antedated cobalamin therapy. Chief among these was the complexing of all serum R binder (transcobalamin I), leaving the patient with no detectable R binder. This defect appeared to be transient. Noteworthy, too, was a prominent binder of 70,000 mol wt that also carried the bulk of his serum cobalamin after therapy; it was prominent in his presumably heterozygous relatives too. The interrelationship between all these abnormalities is intriguing but unclear. The abnormality in transcobalamin II deficiency is clearly not limited solely to deficiency of transcobalamin II. It is also evident that this entity must now be considered in the differential diagnosis of low serum cobalamin levels in infancy.

Congenital transcobalamin II deficiency presenting atypically with a low serum cobalamin level: studies demonstrating the coexistence of a circulating transcobalamin I (R binder) complex

A case of transcobalamin II deficiency with several unique features is described. The clinical presentation was typical, except for a slightly delayed age at presentation and the occurrence of apparent neurologic dysfunction from the beginning. The unusual biochemical feature was a low serum cobalamin level (97 pg/ml). Several cobalamin-binding protein abnormalities coexisted and antedated cobalamin therapy. Chief among these was the complexing of all serum R binder (transcobalamin I), leaving the patient with no detectable R binder. This defect appeared to be transient. Noteworthy, too, was a prominent binder of 70,000 mol wt that also carried the bulk of his serum cobalamin after therapy; it was prominent in his presumably heterozygous relatives too. The interrelationship between all these abnormalities is intriguing but unclear. The abnormality in transcobalamin II deficiency is clearly not limited solely to deficiency of transcobalamin II. It is also evident that this entity must now be considered in the differential diagnosis of low serum cobalamin levels in infancy.

Atypical cobalamin binding in the serum of congenital deficiency of transcobalamin II.

The serum cobalamin (Cb 1) binding patterns were described in nine children with congenital deficiency of transcobalamin II (TC II). Immunoreactive TC II was less than 100 pg/ml TC II-Cb 1 equivalent in eight and 150 pg/ml in the ninth. There was neither endogenous TC II-Cb 1 (holo TC II) nor apo TC II. Thus, the defect was characterized by the absence of any binding of Cb 1 to TC II either in vivo or in vitro and either non-detectable or much reduced immunoreactive TC II. Only the serum from an untreated infant bound any added Cb 1 at all, but in every sera there was binding of endogenous Cb 1 to a substance of the molecular size of albumin. Native Cb 1 was also bound to R binder and in some instances was incorporated into large complexes. The precise nature, cause and consequences of this atypical binding are unknown.

Transport of therapeutic cyanocobalamin in the congenital deficiency of transcobalamin II (TC II)

Transport of therapeutic cyanocobalamin in the congenital deficiency of transcobalamin II (TC II)

Transport of Therapeutic Cyanocobalamin in the Congenital Deficiency of Transcobalamin II (TC II)

Cobalamin (Cbl) transport was studied in the circulation of a child deficient in transcobalamin II (TC II) after 1.0 mg of cyanocobalamin (CN-Cbl) either intramuscularly or orally. Pertinent observations include the following: (1) There was no detectable TC II in the serum as measured immunologically or by binding capacities in vivo or in vitro. (2) Transcobalamin I (TC I) was present in at least normal amounts, but, in contrast to the normal, TC I was completely saturated with Cbl. (3) The TC I of the child was qualitatively the same as that of normal persons and there was no evidence that TC I, or any other R-type binder, assumed the functions of the apparently absent TC II. (4) There was, however, an incompletely characterized circulating large molecular sized complex containing R-type binder. (5) After intake of 1.0 mg CN-Cbl orally, the usual daily therapeutic dose and route in this child, free Cbl was present in the serum. HeLa cells in culture took up free Cbl much less efficiently than Cbl bound to TC II, but the free Cbl followed the normal sequence in being bound to an intracellular binder and converted from CN-Cbl to the functioning forms adenosyl and methyl Cbl. Therefore entry to free Cbl into the child's tissues was considered to be a therapeutic possibility.

Vitamin B12 transport in blood. I. Congenital deficiency of transcobalamin II

Some characteristics of vitamin B12 binding and transport in the serum of an infant with congenital hereditary transcobalamin II (TC II) deficiency were studied using the following parameters and methods: vitamin B12 level and binding capacity; electrophoretic mobility in polyacrylamide gel electrophoresis; various immunodiffusion and absorption experiments, using a specific anti-TC II antiserum and the patient's serum as antigen. The results of these studies point to a deficient synthesis of TC II. Parenteral administration of high doses of vitamin B12 was followed by rapid and complete clinical remission and the appearance of vitamin B12 binder in the alpha 2 region which is similar to “fetal binder.” Thus, very high concentrations of vitamin B12, either carrier free or bound to this alpha 2 binder, were able to correct the disturbed physiology of TC II deficiency, presumably by normalization of DNA-thymine synthesis.