Cobalamin disease

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... 

In cobalamin-E (cblE) disease there is a failure of methyl-B12 to bind to methionine synthase. It is not known if this reflects a primary defect of methionine synthase or the absence of a separate enzyme activity. Patients manifest megaloblastic changes with a pancytopenia, homocystinuria and hypomethioninemia. There is no methylmalonic aciduria. Patients usually become clinically manifest during infancy with vomiting, developmental retardation and lethargy. They respond well to injections of hydroxocobalamin. 

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. 

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. 

Rosenblatt DS, Erbe RW (2001) Inherited disorders of folate and cobalamin transport and metabolism. In Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The Metabolic and Molecular Bases of Inherited Disease, 8th edn. McGraw-Hill, New York, NY, pp 3897-3933... 

Vitamins B6, B12, and folate An elevated plasma homocysteine level is associated with increased cardiovascular risk (see p. 263). Homocysteine, which is thought to be toxic to the vascular endothelium, is converted into harmless amino acids by the action of enzymes that require the B vitamins—folate, B6 (pyridoxine), and B12 (cobalamin). Ingesting foods rich in these vitamins can lower homocysteine levels and possibly decrease the risk of car diovascular disease. Folate and B6 are found in leafy green veg etables, whole grains, some fruits, and fortified breakfast cereals. B12 comes from animal food, for example, meat, fish, and eggs. 

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... 

Measurement of blood tHcy is usually performed for one of three reasons (1) to screen for inborn errors of methionine metabolism (2) as an adjunctive test for cobalamin deficiency (3) to aid in the prediction of cardiovascular risk. Hyperhomocysteinemia, defined as an elevated level of tHcy in blood, can be caused by dietary factors such as a deficiency of B vitamins, genetic abnormalities of enzymes involved in homocysteine metabolism, or kidney disease. All of the major metabolic pathways involved in homocysteine metabolism (the methionine cycle, the transsulfuration pathway, and the folate cycle) are active in the kidney. It is not known, however, whether elevation of plasma tHcy in patients with kidney disease is caused by decreased elimination of homocysteine in the kidneys or by an effect of kidney disease on homocysteine metabolism in other tissues. Additional factors that also influence plasma levels of tHcy include diabetes, age, sex, lifestyle, and thyroid disease (Table 21-1). 

Regulation of homocysteine metabolism appears to be especially important in the central nervous system, presumably because of the critical role of methyl transfer reactions in the production of neurotransmitters and other methylated products. It has been known for decades that mental retardation is a feature of the genetic diseases, such as CBS deficiency, that cause severe hyperhomocysteinemia and ho-mocystinuria. Impaired cognitive function is also seen in pernicious anemia, which causes hyperhomocysteinemia due to deficiency of cobalamin (see Chapter 28). Hyperhomocysteinemia also may be linked to depression, schizophrenia, multiple sclerosis, and Alzheimer s disease. The molecular mechanisms underlying these clinical associations have not yet been delineated. 

Metz J Cobalamin deficiency and the pathogenesis of nervous system disease. Annu Rev Nutr 12 59-79,1992. 

Cobalamin is not significantly metabolised and passes into the bile (there is enterohepatic circulation which can be interrupted by intestinal disease and hastens the onset of clinical deficiency), and is excreted via the kidney. Body stores amount to about 5 mg (mainly in the liver) and are sufficient for 2-4 years if absorption ceases. 

Savage DG, Lindenbaum J. Folate-cobalamin interactions. In Bailey LB, editor. Folate in Health and Disease. New York Marcel Dekker Inc, 1994 237-85. 

Intestinal malabsorption of vitamin B12 may be caused by gastrectomy or ileal resection, with an inverse relationship between the length of ileum resected and the absorption of vitamin B12. Other causes of malabsorption are tropical sprue, inflammatory disease of the small intestine, intestinal stasis with overgrowth of colonic bacteria, which consume the vitamin 6,2 ingested by the host, and HIV infection. Another cause of vitamin B malabsorption is failure to extract cobalamin from food. Some patients fail to absorb cobalamin bound to food, whereas absorption of nonfood-bound cobalamin in the Schilling test is unimpaired. This is particularly a problem in patients with compromised gastric status or early in the course of development of pernicious anemia. 

For iron, iodine, cobalt (as cobalamins), selenium, copper, and zinc there are clinical examples of reversible deficiency disease. For these elements there is enough known about their biochemical functions to explain their importance in human nutrition. For others, such as manganese, chromium, molybdenum, and vanadium, their importance remains to be fuUy accepted in clinical practice. Stfll other elements such as bromine, fluorine, cadmium, lead, strontium, lithium, and tin have been claimed by at least one investigator to be essential for one or more animal species as demonstrated by dietary deprivation studies. 

There is reason to conclude that vitamin deficiency might contribute to arteriosclerosis. There is a correlation between elevated homocysteine levels and incidence of cardiovascular disease (59). There is debate as to whether homocysteine contributesto the dam e of cells on the interior of blood vessel or whether homocysteine is a marker of intensive cell repair and formation of replacement cells. Nevertheless, administration of pyridoxine, folic acid, and (yanocobalamin are being recommended along with the two antioxidant vitamins, a-tocopherol and ascorbic acid for arteriosclerosis. Vitamin Bg is required for two of the steps in the catabolism of homocysteine to succinyl CoA (Fig. 8.52). Note in Fig. 8.52 (bottom) that biotin and a coenzyme form of cobalamin also are required for... 

Cobalmin Deficiency. Pernicious anemia is the disease associated with vitamin Bi2 deficiency. It is usually caused by the inability to produce intrinsic factor. Indeed, many times the vitamin must be administered by injection. The blood picture, a megaloblastic anemia, is indistinguishable from that caused by folic acid deficiency. Indeed folic acid supplements can mask the blood picture. This is illustrated in Fig. 8.53. Removal of ad-enosyl cobalamin eliminates the regeneration of tetrahydrofolate during the methylation of homocysteine to methionine. Folic acid supplements provide a fresh source of tetrahydrofolate coenzymes. DNA synthesis can continue and new erythrocytes form. Excess folic acid also may compete for the available vitamin, further exacerbating vitamin deficiency. 

Vitamers are chemically similar substances that have a qualitatively similar vitamin activity. Thus, vitamin D refers to ergocalciferol (Da) and cholecalciferol (D3) and sometimes to their 25-hydroxy- and 1,25-dihydroxy derivatives (Chapter 37). Similarly, pyridoxine (pyri-doxol), pyridoxal, and pyridoxamine are vitamin Be vitamers, riboflavin is the active form of vitamin Ba and cobalamin is vitamin Bia- The members of a particular vitamin family are functionally interchangeable and protect against deficiency symptoms for that vitamin. A vitamin and its corresponding deficiency disease are related as follows ... 

Vitamin B12 is stable to temperatures up to 250°C (482°F) in acidic or neutral solutions. Dietary B12 deficiency is rare among meat eaters but not in strict vegetarians. The average total body content of vitamin B12 is about 2.5 mg, most of which is in the liver (1 /u,g of Bi2 per gram of hepatic tissue). There is extensive reutilization of cobalamin and an active enterohepatic circulation. The principal disease caused by vitamin B12 deficiency is megaloblastic anemia. Deficiency also causes neurological abnormalities that become irreversible if allowed to persist. 

The answer is e. (Murray, pp 627-661. Sciiver, pp 3897-3964. Sack, pp 121-138. Wilson, pp 287-320.) Ascorbic acid (vitamin C) is found in fresh fruits and vegetables. Deficiency of ascorbic acid produces scurvy, the sailor s disease. Ascorbic acid is necessary for the hydroxylation of proline to hydroxyproline in collagen, a process required in the formation and maintenance of connective tissue. The failure of mesenchymal cells to form collagen causes the skeletal, dental, and connective tissue deterioration seen in scurvy. Thiamine, niacin, cobalamin, and pantothenic acid can all be obtained from fish or meat products. The nomenclature of vitamins began by classifying fat-soluble vitamins as A (followed by subsequent letters of the alphabet such as D, E, and K) and water-soluble vitamins as B. Components of the B vitamin fraction were then given subscripts, e.g., thiamine (Bi), riboflavin (B2), niacin [nicotinic acid (B3)], panthothenic acid (B5), pyridoxine (Bg), and cobalamin (B ). The water-soluble vitamins C, biotin, and folic acid do not follow the B nomenclature. 

Other potentially useful tests include antibody testing and serum gastrin levels. Positive anti-intrinsic factor antibodies may be present in approximately half of patients with pernicious anemia, but is highly specific for the disease. Additionally, an estimated 85% of patients have anti-parietal cell antibodies, but they are nonspecific, as 3% to 10% of healthy patients have these antibodies. Fasting serum gastrin levels are elevated in more than 70% of patients with cobalamin deficiency and may be useful in assessing patients with borderline... 

Another common problem in the elderly is vitamin B12 deficiency, with the most common causes of clinically overt deficiency due to pernicious anemia, small bowel disease, and food-cobalamin malabsorption. A preclinical deficiency in vitamin B12 is seen in 5% to 30% of all seemingly healthy elderly patients and is predominantly metabolic in expression, although subtle neurologic and cognitive defects may be present. " ... 

Cobalt is found in vitamin Bn, its only apparent biological site. The vitamin is a cyano complex, but a methyl or methylene group replaces CN in native enzymes. Vitamin-Bi2 deficiency causes the severe disease of pernicious anemia in humans, which indicates the critical role of cobalt. The most common type of reaction in which cobalamin enzymes participate results in the reciprocal exchange of hydrogen atoms if they are on adjacent carbon atoms, yet not with hydrogen in solvent water ... 

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