Cobalamin deficiency

Methionine synthase deficiency (cobalamin-E disease) produces homocystinuria without methylmalonic aciduria 677 Cobalamin-c disease remethylation of homocysteine to methionine also requires an activated form of vitamin B12 677 Hereditary folate malabsorption presents with megaloblastic anemia, seizures and neurological deterioration 678... 

Homocyst(e)ine CBS deficiency Cobalamin defects/defi-ciency MTHFR deficiency Methionine adenosyltrans-ferase deficiency Hyperhomocysteinemia Sulfite oxidase deficiency... 

Methionine Methionine adenosyltrans-ferase deficiency Cobalamin defects... 

Patients with MMA can either have a deficiency of the mutase enzyme (mut° or muf) or a defect in cobalamin synthesis or utilization (e.g., cobalamin A or cobalamin B deficiency). Cobalamin defects are not covered in this chapter. Those with the mut° form of MMA have absent mutase activity and often develop a more severe phenotype than those with the mur deficiency who have some residual enzyme activity [2]. There is a wide range of clinical severity in both PROP and MMA and nutrition management needs to be individualized (Box 20.1). Further discussion of organic acidemias, including PROP and MMA, is found in Chap. 17. 

Cobalamin deficiency. Cobalamin deficiency is a common condition caused by an insufficient intake of cobalamin or an inability to absorb the vitamin. If left untreated, the condition may result in irreversible neurological damage and eventually death caused by a severe anaemia. Measurement of serum cobalamin is the most commonly employed test in order to confirm or rule out the presence of cobalamin deficiency. 

Methylmalonic acid (MMA) in semm is an estabUshed marker of cobalamine deficiency. MMA and other short-chain dicarboxyhc acids react with... 

Dietary deficiency in the absence of absorption defects can be effectively reversed with oral supplementation of 1 p.m of vitamin B 2 daily. If deficiency is related to a defect in vitamin absorption, daily doses of 1 pg adininistered subcutaneously or intramuscularly are effective (33). However, a single intramuscular dose of 100 pg of cobalamin once per month is adequate in patients with chronic gastric or ileal damage. Larger doses are generally rapidly cleared from the plasma into the urine and are not effective unless the patient demonstrates poor vitamin retention. 

Bellou A, Aimone-Gastin I, De Korwin JD, Bronowicki JP, Moneret-Vautrin A, Nicolas JP, et al Cobalamin deficiency with megaloblastic anaemia in one patient under long-term omeprazole therapy. J Intern Med 1996 240 161-164. 

Cobalamin-c disease remethylation of homocysteine to methionine also requires an activated form of vitamin B12. In the absence of normal B12 activation, homocystinuria results from a failure of normal vitamin B12 metabolism. Complementation analysis classifies defects in vitamin B12 metabolism into three groups cblC (most common), cblD and cblF. Most individuals become ill in the first few months or weeks of life with hypotonia, lethargy and growth failure. Optic atrophy and retinal changes can occur. Methylmalonate excretion is excessive, but less than in methylmalonyl-CoA mutase deficiency, and without ketoaciduria or metabolic acidosis. 

There are many causes of the clinical condition referred to as anaemia. One particular type, whose cause can be traced to a genuine metabolic defect is megaloblastic anaemia and is due to a deficiency of the vitamins B12 (cobalamin) and/or folate. These vitamins are required for normal cell division in all tissues, but the rapid production of red cells makes them more susceptible to deficiency. In megaloblastic anaemia the blood haemoglobin concentration falls the synthesis of haem is not impaired. Examination of the blood reveals the appearance of larger then normal cells called macrocytes and megaloblasts are found in the bone marrow. 

Very small amounts of cobalamin are required each day (<5 i.g) and the diet normally provides plenty more than the minimum, so dietary B12 deficiency is uncommon, except in very strict vegetarians. Pernicious anaemia arises when a defect in the stomach results in too little secretion of a protein called intrinsic factor, without which, cobalamin cannot be absorbed in the ileum of the small intestine. 

It is the role of jV5-methyl THF which is key to understanding the involvement of cobalamin in megaloblastic anaemia. The metabolic requirement for N-methyl THF is to maintain a supply of the amino acid methionine, the precursor of S-adenosyl methionine (SAM), which is required for a number of methylation reactions. The transfer of the methyl group from jV5-methyl THF to homocysteine is cobalamin-dependent, so in B12 deficiency states, the production of SAM is reduced. Furthermore, the reaction which brings about the formation of Ns-methyl THF from N5,N10-methylene THF is irreversible and controlled by feedback inhibition by SAM. Thus, if B12 is unavailable, SAM concentration falls and Ah -methyl THF accumulates and THF cannot be re-formed. The accumulation of AT-methyl THF is sometimes referred to as the methyl trap because a functional deficiency of folate is created. 

Cobalamin deficiency can create a secondary deficiency of active THF by preventing its release from the storage pool through the AT-methyl THF-homocysteine methyltransferase reaction, and thus also result in megaloblastic anemia. Progressive peripheral neuropathy also results from cobalamin deficiency. TTeating a cobalamin deficiency with folate corrects the megaloblastic anemia but does not halt the neuropathy. 

The most likely reason for cobalamin deficiency is pernicious anemia (failure to absorb vitamin B 2 in the absence of intrinsic factor from parietal cells). Vitamin Bjj absorption also decreases with aging and in individuals with chronic pancreatitis. Less common reasons for Bjj deficiency include a long-term completely vegetarian diet (plants don t contain vitamin Bjj) and infection with Diphyllobothrium latum, a parasite found in raw fish. Excess vitamin B,2 is stored in the body, so deficiencies develop slowly. 

Vitamin Bn deficiency Deficiency, although rare, results in two serious problems megaloblastic anaemia (which is identical to that caused by folate deficiency) and a specific neuropathy called Bi2-associated neuropathy or cobalamin-deficiency-associated neuropathy (previously called, subacute combined degeneration of the cord). A normal healthy adult can survive more than a decade without dietary vitamin B12 without any signs of deficiency since it is synthesised by microorganisms in the colon and then absorbed. However, pernicious anaemia develops fairly rapidly in patients who have a defective vitamin B12 absorption system due to a lack of intrinsic factor. It results in death in 3 days. Minot and Murphy discovered that giving patients liver, which contains the intrinsic factor, and which is lightly cooked to avoid denaturation, cured the anaemia. For this discovery they were awarded the Nobel Prize in Medicine in 1934. 

Cobalamine can only be resorbed in the small intestine when the gastric mucosa secretes what is known as intrinsic factor—a glycoprotein that binds cobalamine (the extrinsic factor) and thereby protects it from degradation. In the blood, the vitamin is bound to a special protein known as trans-cobalamin. The liver is able to store vitamin Bi2 in amounts suf cient to last for several months. Vitamin B12 deficiency is usually due to an absence of intrinsic factor and the resulting resorption disturbance. This leads to a disturbance in blood formation known as pernicious anemia. 

Strict vegetarian diet or after diseases affecting cobalamin absorption. The main effects of vitamin deficiency are pernicious anemia, macrocytosis, and neurological problems. A particularity of this vitamin is that it can be stored especially in the liver and kidneys. 

The answer is D. Several vitamin deficiencies can cause anemia due to reduced DNA synthesis in the erythropoietic cells of the bone marrow, especially folic acid and vitamin Bj2 (cobalamin), which are particularly prevalent among elderly patients due to poor diet and reduced absorption. In addition, deficiencies of either folic acid or vitamin Bj2 could produce the megaloblastic anemia seen in this patient. However, the absence of neurologic symptoms, a hallmark of vitamin Bj2 deficiency, makes that diagnosis less likely than folic acid deficiency. 

Cyanocobalamin and the derivative hydroxo-cobalamin, given IM or deep subcutaneously, are indicated for treating vitamin B12 deficiency. Only in strict vegetarians oral preparations may be effective. Oral preparations with added intrinsic factor mostly are not reliably in patients with pernicious anemia. More than half the dose of cyanocobalamin injected is excreted in the urine within 48 hours and the therapeutic advantages of doses higher than 100 pg are questionable because of this rapid eiimination. As... 

Physiologically, distinction from folate deficiency is often clinically and haematologically difficult because vitamin B12, also known as cobalamin, functions as an essential cofactor for folate metabolism in the evenmal synthesis of deoxyribonucleic acid. 

Contraindications Folic acid deficiency anemia, hereditary optic nerve atrophy, history of allergy to cobalamins... 

Vitamin B12 (cobalamin) serves as a cofactor for several essential biochemical reactions in humans. Deficiency of vitamin B12 leads to megaloblastic anemia (Table 33-2), gastrointestinal symptoms, and neurologic abnormalities. Although... 

Fig. 2.2.1 Outline of homocysteine metabolism in man. BMT Betaine methyltransferase, cblC cobalamin defect type C, cblD cobalamin defect type D, GNMT def glycine N-methyltransferase deficiency, MAT methionine adenosyl transferase, MeCbl methylcobalamin, Met Synth methionine synthase, MTHFR methylenetetrahydrofolate reductase, SAH Hyd dc/S-adenosylhomocys-...

A large elevation of Hey in body fluids and tissues is found in several genetic enzyme deficiencies, the homocystinurias. These include cystathionine /3-synlhase deficiency [9], the remethylation defects due to deficiency of MTHF reductase [10], methionine synthase and methionine synthase reductase deficiencies, as well as defects of intracellular cobalamin metabolism [11], namely the cblF, cblC and cblD defects. It is noteworthy that low levels of total Hey (tHcy) have been described in sulphite oxidase deficiency [12]. 

Elevated Hey levels can also occur in nutritional deficiencies of vitamin B12 (cobalamin) and folate. Folate or vitamin B12 deficiency can even lead to tHcy levels as high as those seen in the genetic homocystinurias [13]. In addition, a reciprocal relationship between blood levels or intake of these vitamins and tHcy concentrations... 

Stabler SP, Marcell PD, Podell ER, Allen RH, Savage DG, Lindenbaum J (1988) Elevation of total homocysteine in the serum of patients with cobalamin or folate deficiency detected by capillary gas chromatography-mass spectrometry. J Clin Invest 81 466-474... 

The effects of cobalamin deficiency are most pronounced in rapidy dividing cells, such as the erythropoietic tissue of bone marrow and the mucosal cells of the intestine. Such tissues need both Die N5-N10-methylene and N10-formyl forms of tetrahydrofolate for Ihe synthesis of nucleotides required for DNA replication (see pp. 291, 301). However, in vitamin B12 deficiency, the N5-methyl form of tetrahydrofolate is not efficiently used. Because the methylated fonn cannot be converted directly to other forms of tetrahydrofolate, tie Ns-methyl form accumulates, whereas the levels of the other forms decrease. Thus, cobalamin deficiency is hypothesized to lead to a deficiency of the tetrahydrofolate forms needed in purine and thymine synthesis, resulting in the symptoms of megaloblastic anemia. 

Vitamin B12 (cobalamin) has as its active forms, methylcobalamin and deoxyadenosyl cobalamin. It serves as a cofactor for the conversion of homocysteine to methionine, and methylmalonyl CoA to succinyl CoA. A deficiency of cobalamin results in pernicious (megaloblastic) anemia, dementia, and spinal degeneration. The anemia is treated with IM or high oral doses of vitamin B12. There is no known toxicity for this vitamin. 

The human body contains only about 1.5 mg of cobalt, almost all of it is in the form of cobalamin, vitamin B12. Ruminant animals, such as cattle and sheep, have a relatively high nutritional need for cobalt and in regions with a low soil cobalt content, such as Australia, cobalt deficiency in these animals is a serious problem. This need for cobalt largely reflects the high requirement of the microorganisms of the rumen (paunch) for vitamin B12. All bacteria require vitamin B12 but not all are able to synthesize it. For example, E. coli lacks one enzyme in the biosynthetic... 

In this hereditary disease up to 1 - 2 g of methylmalonic acid per day (compared to a normal of <5 mg/day) is excreted in the urine, and a high level of the compound is present in blood. Two causes of the rare disease are known/ One is the lack of functional vitamin B12-containing coenzyme. This can be a result of a mutation in any one of several different genes involved in the synthesis and transport of the cobalamin coenzyme.6 Cultured fibroblasts from patients with this form of the disease contain a very low level of the vitamin B12 coenzyme (Chapter 16), and addition of excess vitamin B12 to the diet may restore coenzyme synthesis to normal. Among elderly patients a smaller increase in methylmalonic acid excretion is a good indicator of vitamin B12 deficiency. A second form of the disease, which does not respond to vitamin B12, arises from a defect in the methylmalonyl mutase protein. Methylmalonic aciduria is often a very severe disease, frequently resulting in death in infancy. Surprisingly, some children with the condition are healthy and develop normally.3 1... 

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