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 is an inborn error of methionine metabolism, of which cause is mainly deficiency of cystathionine synthetase. The major clinical manifestations of homocystinuria are mental retardation, seizures, ectopia lentis, skeletal deformities and occlusive vascular disease. A case of homocystinuria accompanied with deep cerebral venous thrombosis was reported. A 29-year-old woman was admitted to our hospital with unconsciousness and tetraparesis on December 7, 1984. She was diagnosed as homocystinuria due to cystathionine synthetase deficiency at 13-year-old. Amino acid analysis of serum revealed homocystinaemia (1.37 mg/dl, normal 0), hypermethioninaemia (1.27 mg/dl, normal 0.2-0.48) and low cystathionine content. CT scan revealed intraventricular hemorrhage and diffuse low density in basal ganglia and white matter. Cerebral angiograms showed that deep cerebral veins and superior sagittal sinus can not be recognized clearly in any phase, and Sylvian veins are opacified markedly. It is suggested that intraventricular hemorrhage, and low density area in basal ganglia and white matter is due to hemorrhagic infarction by venous thrombosis of internal cerebral vein. The major clinical manifestations of homocystinuria result from the elevated plasma homocysteine level. The excitotoxic effect of homocysteic acid accounts for mental retardation and seizures.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Homocystinuria accompanied with cerebral deep venous thrombosis--a case report]. 236 35

Homocystinuria (HC) is an inborn error of amino acid metabolism characterized by ectopia lentis, mental retardation, and skeletal abnormalities. Vascular disorders may also occur in HC, although they are less common. Arteriographic studies of two sisters with HC are described. The younger woman's renal arteries showed wall irregularities and aneurysms, narrowing of the celiac and superior mesenteric arteries, and some aneurysmatic changes. In the older patient, irregular right carotid and splenic arteries were seen and a splenic aneurysm was present.
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PMID:Angiographic findings in homocystinuria. 662 57

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

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

Homocystinuria is a rare, inherited metabolic disease frequently associated with severe multisystemic involvement such as dislocated lenses, skeletal deformities, mental retardation, and premature vascular occlusion. Arterial and venous thromboembolic events present frequent and life-threatening complications in homocystinuric patients. It has been suggested that mild homocystinemia would be a risk factor for vascular disease.
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PMID:Homocystinuria presenting with portal vein thrombosis and pancreatic pseudocyst: a case report. 932 45

Severe methylenetetrahydrofolate reductase (MTHFR) deficiency is an inborn error of folate metabolism, and is inherited as an autosomal recessive trait. MTHFR is a key enzyme in folate-dependent remethylation of homocysteine, and reduces 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. Patients with this severe enzymatic deficiency are biochemically characterised by homocystinuria and hypomethioninaemia, and may suffer from neurological abnormalities, mental retardation and premature vascular disease. Here we report the molecular basis of severe MTHFR deficiency in four unrelated families from Turkish/Greek ancestry. By use of reverse-transcriptase (RT)-PCR, subsequently followed by direct sequencing analysis, we were able to identify four novel mutations in the MTHFR gene: two missense (983A-->G; 1027T-->G) and two nonsense (1084C-->T; 1711C-->T) mutations. Furthermore, a splice variant containing a premature termination codon, was observed in one patient, probably as a secondary effect of the 1027T-->G missense mutation. The ongoing identification and characterisation of mutations in the MTHFR gene will provide further insight into the heterogeneity of the clinical phenotype in severe MTHFR deficiency.
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PMID:Identification of four novel mutations in severe methylenetetrahydrofolate reductase deficiency. 978 Oct 30

It is proposed that chronic moderate hyperhomocysteinemia has a causal role in a number of common diseases of late life, including occlusive vascular disease, cognitive decline, senile osteoporosis and presbyopia. These diseases are seen as clinical counterparts of the main manifestations of homocystinuria (vascular occlusions of arteries and veins, mental retardation, osteoporosis and ectopia lentis, respectively) that develop only after many years of exposure to moderately elevated homocysteine (Hcy) levels. The multisystem toxicity of Hcy is attributed to its spontaneous chemical reaction with many biologically important molecules, primarily proteins. The formation of these Hcy-adducts is dependent on time and Hcy concentration and leads to loss or diminution of function of the derivatized molecules. Irreversible homocysteinylation of long-lived proteins should lead to cumulative damage and progressive clinical manifestations. Fibrillin 1 is seen as the paradigm of extracellular connective tissue proteins that are specially susceptible to Hcy (and presumably Hcy thiolactone) attack. The prominent presence of epidermal growth factor (EGF)-like domains in fibrillin and in many other extracellular proteins of the coagulation, anticoagulation, and lipoprotein transport pathways, all of which malfunction in hyperhomocysteinemia, suggests that EGF-like domains may be preferential sites of homocysteinylation.
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PMID:Mechanisms of homocysteine toxicity on connective tissues: implications for the morbidity of aging. 1072 8

Homocysteine is a sulphur-containing amino acid that is derived primarily from protein of animal origin. Classical homocystinuria is an inherited metabolic disorder that arises from defects in either the re-methylation or trans-sulphuration pathways of homocysteine metabolism and leads to skeletal abnormalities, mental retardation and a high risk of vascular disease. In contrast, moderate hyperhomocysteinaemia is associated with an increased risk of both arterial and venous thrombotic disease but no other abnormalities. This increased risk appears to be independent of other conventional risk factors. Many cases of hyperhomocysteineaemia have been attributed to defects in the enzyme cystathionine-beta-synthase (CBS) but this accounts for less than 1.5% of cases. A thermolabile variant of the enzyme methylenetetrahydrofolate reductase (MTHFR) arises from a C --> T transition at nucleotide 677 in the MTHFR gene resulting in an alanine-to-valine substitution. While the mutation does not appear to be associated with an increased risk of vascular disease, it results in excessively high homocysteine levels in response to a low or low-normal serum folate. Supplementation of the diet with folate, B6 and B12 can reduce homocysteine levels and this is the mainstay of treatment. Supplementation of grain with folate is undertaken in the USA to reduce the risk of neural tube defects in pregnant women. However, by reducing plasma homocysteine levels, it is estimated that this will save up to 50,000 lives per annum.
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PMID:Hyperhomocysteinaemia. 1085 81

The influence of the genotype on the phenotypic expression of homocystinuria due to cystathionine beta-synthase (CBS) deficiency is frequently unclear. We therefore investigated the genotype and the phenotype of CBS deficiency in two Austrian families also considering genetic polymorphisms with a putative association with vascular disease (MTHFR 677C-->T, MTHFR 1298A-->C, F5 1691G-->A, F2 20210G-->A) and response to therapy. We identified the CBS 833T-->C/1058C-->T and CBS 828ins104/1358del134 compound heterozygous genotype in our index patients. Both patients showed mental retardation and ectopia lentis. CBS 833T-->C/1058C-->T was associated with severe vascular complications, which was not the case for CBS 828ins104/1358del134. The patient with CBS 828ins104/1358del134 was negative for F5 1691G-->A, F2 20210G-->A, MTHFR 677C-->T, and MTHFR 1298A-->C, while the patient with CBS 833T-->C/1058C-->T was heterozygous for MTHFR 1298A-->C. A combination therapy including pyridoxine, folic acid, hydroxycobalamin, and betaine failed to lower total homocysteine plasma levels below 50 mumol/L in both patients. In summary, our study demonstrates that the CBS 833C/1058T-MTHFR 1298AC genotype can be related to severe vascular disease, while the CBS 828ins104/1358del134-MTHFR 1298AA genotype presents with a somewhat milder clinical phenotype. Both genotypes do not allow for normalisation of total homocysteine plasma levels following vitamin therapy.
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PMID:Molecular and clinical characterisation of homocystinuria in two Austrian families with cystathionine beta-synthase deficiency. 1177 77

Homocystinuria due to cystathionine beta-synthase deficiency is the second most treatable aminoacidopathy. The reported incidence varies from 1 in 344,000 worldwide to 1 in 65,000 in Ireland. Untreated patients with homocystinuria have severe hyperhomocysteinaemia. Amongst its pathological sequelae, which include mental retardation, ectopia lentis and osteoporosis, vascular events remain the major cause of morbidity and mortality in untreated patients. Recognized modalities of treatment include pyridoxine, in combination with folic acid and vitamin B12; methionine-restricted, cystine-supplemented diet; and betaine. The natural history of vascular events is such that half will have an event before age 30 years and there is a predicted one event per 25 years at the time of maximal risk. In 158 patients with 2822 patient-years of treatment, there would be a predicted 112 events if left untreated, but instead only 17 vascular events were recorded during treatment (relative risk 0.09, 95% CI 0.036 to 0.228; p < 0.0001). Appropriate chronic treatment to lower hyperhomocysteinaemia is effective in reducing the potentially life-threatening vascular risk in patients with homocystinuria. These findings may also have relevance to the significance of mild hyperhomocysteinaemia that is commonly found in patients with premature vascular disease.
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PMID:Classical homocystinuria: vascular risk and its prevention. 1288 65


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