Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Congenital errors of folate metabolism can be related either to defective transport of folate through various cells or to defective intracellular utilization of folate due to some enzyme deficiencies. Defective transport of folate across the intestine and the blood-brain barrier was reported in the condition 'Congenital Malabsorption of Folate'. This disease is characterized by a severe megaloblastic anaemia of early appearance associated with mental retardation. Anaemia is folate-responsive, but neurological symptoms are only poorly improved because of the inability to maintain adequate levels of folate in the CSF. A familial defect of cellular uptake was described in a family with a high frequency of aplastic anaemia or leukaemia. An isolated defect in folate transport into CSF was identified in a patient suffering from a cerebellar syndrome and pyramidal tract dysfunction. Among enzyme deficiencies, some are well documented, others still putative. Methylenetetrahydrofolate reductase deficiency is the most common. The main clinical findings are neurological signs (mental retardation, seizures, rarely schizophrenic syndromes) or vascular disease, without any haematological abnormality. Low levels of folate in serum, red blood cells and CSF associated with homocystinuria are constant. Methionine synthase deficiency is characterized by a megaloblastic anaemia occurring early in life that is more or less folate-responsive and associated with mental retardation. Glutamate formiminotransferase-cyclodeaminase deficiency is responsible for massive excretion of formiminoglutamic acid but megaloblastic anaemia is not constant. The clinical findings are a more or less severe mental or physical retardation. Dihydrofolate reductase deficiency was reported in three children presenting with a megaloblastic anaemia a few days or weeks after birth, which responded to folinic acid. The possible relationship between congenital disorders such as neural tube defects or dihydropteridine reductase deficiency and disturbances of folate metabolism are discussed. Neurological symptoms present in most of these congenital disorders highlight the role of folate in the central nervous system.
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PMID:Congenital errors of folate metabolism. 853 63

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

Deficiency of 5,10-methylenetetrahydrofolate reductase (MTHFR), the very rare methionine synthase reductase (CblE) and methionine synthase (CblG) defects, and the recently identified CblD-variant-1 defect are primary remethylation defects characterized by an isolated defect in methionine synthesis without methylmalonic aciduria. The clinical signs are mainly neurological, and hematological signs are seen in CblE, CblG, and CblD-variant-1 defects. Patients with neonatal or early-onset disease exhibit acute neurological distress. Infants and children have unspecific mental retardation, often with acquired microcephaly. Without appropriate therapy, they may experience acute or rapidly progressive neurological deterioration, which may be fatal. Adolescents and adults show normal development or mild developmental delay initially and then experience rapid neurological or behavioral deterioration. A few patients may have signs of subacute combined degeneration of the spinal cord. Adults may be asymptomatic or present with isolated thromboembolism. All patients with suspected remethylation disorders should receive emergency treatment with parenteral administration of hydroxocobalamin and folate supplements combined with betaine orally. The long-term treatment of CblE, CblG, and CblD-variant-1 defects consists of parenterally administered hydroxocobalamin and orally administered folate and betaine supplements, whereas patients with MTHFR deficiency require long-term oral folate and betaine supplements. Long-term oral methionine therapy should also be considered. Early treatment may lead to a favorable outcome with developmental recovery and prevention of further neurological deterioration. In contrast, most late-treated patients have severe and irreversible neuromotor impairments. Hematological abnormalities are easily corrected.
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PMID:Isolated remethylation disorders: do our treatments benefit patients? 2049 Sep 23