Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
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All of vitamin B12 in nature is of microbial origin. Cobalamin, as vitamin B12 should correctly be termed, is a large polar molecule that must be bound to specialized transport proteins to gain entry into cells. Entry from the lumen of the intestine under physiological conditions occurs only in the ileum and only when bound to intrinsic factor. It is transported into all other cells only when bound to another transport protein, transcobalamin II. Congenital absence or defective synthesis of intrinsic factor or transcobalamin II result in megaloblastic anemia. The Immerslund-Graesbeck syndrome, a congenital defect in the transcellular transport of cobalamin through the ileal cell during absorption, also presents with megaloblastic anemia, but with accompanying albuminuria. In most bacteria and in all mammals, cobalamin regulates DNA synthesis indirectly through its effect on a step in folate metabolism, the conversion of N5-methyltetrahydrofolate to tetrahydrofolate, which in turn is linked to the conversion of homocysteine to methionine. This reaction occurs in the cytoplasm, and it is catalyzed by methionine synthase, which requires methyl cobalamin (MeCbl), one of the two coenzyme forms of the vitamin, as a cofactor. Defects in the generation of MeCbl (cobalamin E and G diseases) result in homocystinuria; affected infants present with megaloblastic anemia, retardation, and neurological and ocular defects. 5'-Deoxyadenosyl cobalamin (AdoCbl), the other coenzyme form of cobalamin, is present within mitochondria, and it is an essential cofactor for the enzyme Methylmalonyl-CoA mutase, which converts L-methylmalonyl CoA to succinyl CoA. This reaction is in the pathway for the metabolism of odd chain fatty acids via propionic acid, as well as that of the amino acids isoleucine, methionine, threonine, and valine. Impaired synthesis of AdoCbl (cobalamin A or B disease) results in infants with methylmalonic aciduria who are mentally retarded, hypotonic, and who present with metabolic acidosis, hypoglycemia, ketonemia, hyperglycinemia, and hyperammonemia. Megaloblastic anemia does not develop in these children because adequate amounts of MeCbl are present, but the effect of methylmalonic acid on marrow stem cells may give rise to pancytopenia. Congenital absence of reductases in the cytoplasm, which normally reduce the cobalt atom in cobalamin from its oxidized to its reduced state (cobalamin C and D diseases), results in impaired synthesis of both MeCbl and AdoCbl. Both methylmalonic aciduria and homocystinuria therefore develop in these children, and they present with megaloblastosis, mental retardation, a host of neurological and ocular disorders, and failure to thrive; however, they do not have hyperglycinemia or hyperammonemia. A similar biochemical profile and clinical presentation is also seen in cobalamin F disease, which results from a defect in the release of cobalamin from lysosomes, following receptor-mediated endocytosis of the transcobalamin II-cobalamin complex into cells. It is important to recognize these inborn errors of cobalamin absorption, transport, or function as soon after birth as possible, because most respond (in some patients more fully than others) to parenteral administration of cobalamin. Delays in diagnosis can lead to grave clinical consequences.
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PMID:Vitamin B12 in health and disease: part I--inherited disorders of function, absorption, and transport. 877 94

Alterations in homocysteine, methionine, folate, and/or B12 homeostasis have been associated with neural tube defects, cardiovascular disease, and cancer. Methionine synthase, one of only two mammalian enzymes known to require vitamin B12 as a cofactor, lies at the intersection of these metabolic pathways. This enzyme catalyzes the transfer of a methyl group from 5-methyl-tetrahydrofolate to homocysteine, generating tetrahydrofolate and methionine. Human patients with methionine synthase deficiency exhibit homocysteinemia, homocysteinuria, and hypomethioninemia. They suffer from megaloblastic anemia with or without some degree of neural dysfunction and mental retardation. To better study the pathophysiology of methionine synthase deficiency, we utilized gene-targeting technology to inactivate the methionine synthase gene in mice. On average, heterozygous knockout mice from an outbred background have slightly elevated plasma homocysteine and methionine compared to wild-type mice but seem to be otherwise indistinguishable. Homozygous knockout embryos survive through implantation but die soon thereafter. Nutritional supplementation during pregnancy was unable to rescue embryos that were completely deficient in methionine synthase. Whether any human patients with methionine synthase deficiency have a complete absence of enzyme activity is unclear. These results demonstrate the importance of this enzyme for early development in mice and suggest either that methionine synthase-deficient patients have residual methionine synthase activity or that humans have a compensatory mechanism that is absent in mice.
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PMID:Targeted disruption of the methionine synthase gene in mice. 1115 93