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)

Homocystinuria with elevated plasma homocysteine and methionine levels is the result of deficient activity of cystathionine synthetase, the enzyme catalyzing conversion of homocysteine to cystathionine. It is inherited as an autosomal recessive trait with a worldwide distribution. The major clinical manifestations result from the elevated plasma homocysteine level. The excitotoxic effect of homocysteic acid accounts for mental retardation and seizures. Interference with collagen cross-linking by sulfhydryl groups of homocysteine causes ectopia lentis and skeletal deformities. Sulfation factor-like effects contribute to disruption of vascular endothelium, which is followed by platelet thrombosis and widespread arterial and venous occlusions. Low methionine homocystinuria, with deficient remethylation of homocysteine, results from deranged vitamin B(12) metabolism and from deficient 5,10-methylene-tetrahydrofolate reductase. Administration of azaribine produces homocystinuria by mechanism not yet elucidated.
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PMID:Homocystinuria: pathogenetic mechanisms. 32 77

In congenital methemoglobinemia associated with mental retardation a generalized deficiency of NADH-cytochrome beta 5 reductase (NADH : ferricytochrome beta 5 oxidoreductase, EC 1.6.2.2) has been found in soluble extracts of red blood cells, as well as in deoxycholate-treated extracts of leukocytes, muscle, liver and fibroblasts (Leroux et al. (1975) Nature 258, 619-620). In the present study the relationship between the microsomal (I) and the soluble (II) NADH-cytochrome beta 5 reductase was investigated, using human placenta as a source of enzyme. Both forms were compared to the human red-cell soluble NADH-methemoglobin reductase (III) and NADH-cytochrome beta 5 reductase (IV). The four entities exhibited great immunological similarities. It is concluded that the three soluble enzymes (II, III and IV) are identical. The detergent-solubilized microsomal NADH-cytochrome beta 5 reductase (I) is immunologically very similar to the soluble enzymes, but presents distinct features possibly due to the presence of a hydrophobic part.
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PMID:Soluble and microsomal forms of NADH-cytochrome beta 5 reductase from human placenta. Similarity with NADH-methemoglobin reductase from human erythrocytes. 40 44

We report an unusual case of variegate porphyria in a young girl with epilepsy, mental retardation and premature adrenarche. Symptoms of porphyria commenced about the age of 12 years and death occurred about 18 months later. The patient had very low protoporphyrinogen oxidase activity in her cultured fibroblasts. Both parents had half the normal activity of this enzyme in lymphocytes and are heterozygous for the abnormal gene for variegate porphyria. Therefore, it is possible that the patient was a homozygous variant. Anticonvulsant therapy and low hepatic 5 alpha reductase activity were probably other contributing factors to the severity of the condition in this patient.
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PMID:An unusual case of variegate porphyria with possible homozygous inheritance. 222 53

We have recently shown that cytoplasmic malate dehydrogenase (MDH-s) from several non-human species catalyses the reduction of aromatic alpha-keto acids in the presence of NADH (Friedrich et al. 1987), an activity previously attributed to the enzyme aromatic alpha-keto acid reductase (KAR E.C.1.1.1.96). Here we present evidence that this also occurs in humans, and that the previously characterized human KAR is not the product of a genetically distinct locus. Human MDH-s and KAR activities co-migrate after starch gel electrophoresis, and electrophoretic variants of human MDH-s exhibited identical variation for KAR. Both enzymes show almost no electrophoretic variation among human populations of diverse origin. The reduction of aromatic alpha-keto acids is substantially inhibited by malate, the end-product of the MDH reaction. Antibodies raised against purified chicken MDH-s equally inhibited both MDH-s and KAR in chickens and humans. The bulk of the KAR activity in human blood appears to be due to MDH-s, with a minor fraction catalysed by LDH, as is the case in most other species studied. The previous assignment of a gene for KAR to human chromosome 12 in human/Chinese hamster somatic cell hybrids is questioned because interspecific hybrid bands of both MDH-s and LDH appear with slightly different mobility approximately midway between the human and hamster controls in somatic cell hybrid studies, and the meaning of this artifact is discussed. The discovery that MDH reacts with intermediate metabolites of phenylalanine and tyrosine has implications in relation to the mechanism by which mental retardation may be produced in phenylketonuria (PKU), and the effect of MDH inhibition on oxidative phosphorylation in the various tyrosinaemias is discussed.
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PMID:Biochemical and genetic identity of alpha-keto acid reductase and cytoplasmic malate dehydrogenase from human erythrocytes. 305 44

We evaluated testicular function in 15 men with the Martin-Bell (fragile-X) mental retardation syndrome. Macro-orchidism was present in all subjects. Their mean serum LH and FSH levels and plasma testosterone and dihydrotestosterone levels were normal. The mean plasma levels of androstenedione, 17-hydroxyprogesterone, and progesterone were slightly elevated above the normal range, whereas the plasma levels of dehydroepiandrosterone and dehydroepiandrosterone-sulfate were normal. The response in the levels of plasma testosterone following a 5 day period of hCG stimulation was normal in 8 subjects and there was no abnormal accumulation of androgen precursors. The level of 5 alpha-reductase activity and androgen receptor binding was normal in genital skin fibroblasts derived from 3 of these patients. The response of gonadotropin secretion to GnRH stimulation was normal in the 8 men who were tested. Therefore, our data are consistent with the hypothesis that testicular enlargement in men with the Martin-Bell syndrome is not mediated by hormonal factors.
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PMID:Gonadal function in men with the Martin-Bell (fragile-X) syndrome. 308 5

Normal levels of NADH-cytochrome b5 reductase activity in platelets, lymphocytes and granulocytes were determined. The homogenate of each cell was treated with Triton X-100 after incubation with lipoprotein lipase. The reductase was extracted very well from the cells by this treatment. Moreover, the assay of the reductase activity in the cells became accurate and reproducible by the treatment. The reductase level of each cell was also determined in cases of hereditary methemoglobinemia. It was normal in the case of the disease without mental retardation, and low with mental retardation. This latter case might be due to the deficiency of cytochrome b5 reductase in the whole tissue.
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PMID:NADH-cytochrome b5 reductase in platelets and leukocytes with special reference to normal levels and to levels in carriers of hereditary methemoglobinemia with or without neurological symptoms. 676 12

We investigated the enzyme defect in late cholesterol biosynthesis in the Smith-Lemli-Opitz syndrome, a recessively inherited developmental disorder characterized by facial dysmorphism, mental retardation, and multiple organ congenital anomalies. Reduced plasma and tissue cholesterol with increased 7-dehydrocholesterol concentrations are biochemical features diagnostic of the inherited enzyme defect. Using isotope incorporation assays, we measured the transformation of the precursors, [3 alpha- 3H]lathosterol and [1,2-3H]7-dehydrocholesterol into cholesterol by liver microsomes from seven controls and four Smith-Lemli-Opitz homozygous subjects. The introduction of the double bond in lathosterol at C-5[6] to form 7-dehydrocholesterol that is catalyzed by lathosterol-5-dehydrogenase was equally rapid in controls and homozygotes liver microsomes (120 +/- 8 vs 100 +/- 7 pmol/mg protein per min, P = NS). In distinction, the reduction of the double bond at C-7 [8] in 7-dehydrocholesterol to yield cholesterol catalyzed by 7-dehydrocholesterol-delta 7-reductase was nine times greater in controls than homozygotes microsomes (365 +/- 23 vs 40 +/- 4 pmol/mg protein per min, P < 0.0001). These results demonstrate that the pathway of lathosterol to cholesterol in human liver includes 7-dehydrocholesterol as a key intermediate. In Smith-Lemli-Opitz homozygotes, the transformation of 7-dehydrocholesterol to cholesterol by hepatic microsomes was blocked although 7-dehydrocholesterol was produced abundantly from lathosterol. Thus, lathosterol 5-dehydrogenase is equally active which indicates that homozygotes liver microsomes are viable. Accordingly, microsomal 7-dehydrocholesterol-delta 7-reductase is inherited abnormally in Smith-Lemli-Opitz homozygotes.
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PMID:Markedly inhibited 7-dehydrocholesterol-delta 7-reductase activity in liver microsomes from Smith-Lemli-Opitz homozygotes. 756 69

Homocyst(e)ine [H(e)], the sum of homocysteine, homocystine, and the homocysteine-cysteine mixed disulfide, free and protein-bound, has been shown to be associated in retrospective case control studies, and in one prospective study, with vascular disease, including coronary artery disease (CAD), cerebrovascular disease, and peripheral vascular disease. Elevated levels of homocyst(e)ine severe enough to cause homocystinuria are seen in severe nutritional deficiencies of vitamin B12, folic acid and vitamin B6. Rare genetic disorders of vitamin B12 synthesis of 5'-10'-methylene tetrahydrofolate reductase, or the pyridoxal phosphate-dependent enzyme cystathionine beta-synthase may cause severe hyperhomocyst(e)inemia and homocystinuria. The clinical manifestation of these disorders are mental retardation, neurological disorders, and widespread thromboembolic phenomena. The measurement of H(e) is currently performed using high-pressure liquid chromatography with fluorescence detection. Other methods, especially mass spectroscopy, are also used. Internal standards using increasing concentrations of homocystine and acetylcysteine and several external standards are used to ensure accuracy of the assay. Milder elevations of H(e) have recently been associated with vascular disease, in both men and women. The strength of this association appears to be stronger for peripheral and cerebrovascular disease than for CAD. Nevertheless, several case control studies in Europe, Canada, and the United States have shown that H(e) levels are elevated in CAD patients compared with controls, and H(e) levels are independent of the conventional cardiovascular risk factors (age, gender, lipid and lipoprotein cholesterol levels, hypertension, or cigarette smoking). One prospective study, the Physicians' Health Study, has shown that H(e) levels are slightly but significantly higher in CAD cases vs controls in a population of US physicians.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Measurement of homocyst(e)ine in the prediction of arteriosclerosis. 762 74

Until recently, the diagnosis of Smith-Lemli-Opitz syndrome (SLOS), an autosomal recessive malformation/mental retardation syndrome, was made on the basis of clinical criteria alone. As a result, prenatal diagnosis has been possible only if sonography disclosed distinct fetal malformations in a subsequent pregnancy. However, the recent description of increased levels of 7-dehydrocholesterol (cholesta-5,7-dien-3 beta-ol) in patients with SLOS, most likely caused by a deficiency of 3 beta-hydroxysteroid-delta 7-reductase, has provided an apparently reliable biochemical marker for diagnosis of SLOS. To determine if this abnormality of sterol metabolism has utility for prenatal diagnosis of SLOS, we measured the levels of neutral sterols in stored amniotic fluid samples from two SLOS pregnancies. In both cases, the diagnosis of SLOS was made in the neonatal period by clinical criteria and the finding of markedly increased levels of 7-dehydrocholesterol in plasma. Quantitative analysis by gas chromatography of sterols extracted from the amniotic fluid of both pregnancies revealed similar, markedly increased levels of 7-dehydrocholesterol and its precursor, lathosterol (cholest-7-en-3 beta-ol), both of which were undetectable in reference amniotic fluids. These findings suggest that abnormalities of cholesterol biosynthesis in SLOS may be sufficiently expressed in fetal life to permit prenatal diagnosis of this disorder by measurement of 7-dehydrocholesterol in amniotic fluid.
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PMID:Smith-Lemli-Opitz syndrome: prenatal diagnosis by quantification of cholesterol precursors in amniotic fluid. 777 88

In order to understand the mechanisms responsible for the generation of different isoforms (membrane-bound and soluble) of NADH-cytochrome b5 reductase, and the different clinical forms of recessive congenital methemoglobinemia due to the deficiency of this enzyme in humans (type I, without mental retardation; type II, with mental retardation), we have looked for mRNA heterogeneity in various rat tissues. We have found four types of mRNAs, each with a different first exon (1L, 1R, 1X and 1Y), all of which were precisely spliced to join the common second exon. Our results are consistent with a 5'-->3' 'scanning' mechanism for splice-site selection. The previously characterized 1L and 1R transcripts arise from the alternative use of either a ubiquitous promoter (Pr-L) or an erythroid-specific promoter (Pr-R). In addition, the X and Y RNA species are novel transcripts which are expressed ubiquitously and at a relatively low level. The first alternative exons 1X and 1Y are noncoding, such that the AUG codon present in the common second exon is functional, as it is in the R mRNA. Thus, the X and Y mRNAs are expected to be translated in vivo into a ubiquitous soluble enzyme. Consequently, the rat NADH-cytochrome-b5-reductase gene is expressed through the use of at least four different promoters, which are probably subjected to different forms of regulation. This model of gene expression in rat could be important in understanding the basis for the different types of the NADH-cytochrome-b5-reductase enzyme and their deficiency in man.
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PMID:Heterogeneity of the rat NADH-cytochrome-b5-reductase transcripts resulting from multiple alternative first exons. 814 27


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