UMLS:C0025362 - FACTA Search

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Query: UMLS:C0025362 (mental retardation)
15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two half-brothers and their mother had symptomatic pyruvate dehydrogenase complex deficiency. The infants had severe congenital lactic acidosis, seizures, and apneic spells and died at the ages 3 and 4 months. The mother was less symptomatic with mental retardation, truncal ataxia, and dysarthria. The residual pyruvate dehydrogenase activities in cultured skin fibroblasts from the 2 infants and their mother were 7, 15, and 10% of control values. Immunoblot analysis showed negligible amounts of E1 alpha and E1 beta subunits of the complex. Northern blot analysis for the E1 alpha subunit showed normal results. In the 2 sons, complementary DNA sequence analysis revealed a cytosine to thymine mutation in exon 4, resulting in a change of arginine 127 to tryptophan in the E1 alpha subunit. Restriction enzyme analysis of the polymerase chain reaction product representing exon 4 of the E1 alpha gene revealed that the mother was a heterozygotes. Complementary DNA restriction analysis and methylation analysis of the X chromosome DXS255 loci revealed skewed activation of the mutant allele, consistent with the deficient pyruvate dehydrogenase activity in the mother's fibroblasts. The milder maternal phenotype is consistent with variable X-inactivation patterns in different organs of female heterozygotes.
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PMID:Pyruvate dehydrogenase deficiency: molecular basis for intrafamilial heterogeneity. 802 67

Classical galactosaemia, deficiency of galactose-1-phosphate uridyltransferase (GALT), is characterized by acute symptoms of hepatomegaly, jaundice, sepsis, cataracts and growth retardation. Treatment with dietary galactose restriction corrects these complications immediately; however, most of these children develop long-term complications of verbal dyspraxia, mental retardation and ovarian failure. Our previous molecular study showed that the most common mutation of the GALT gene is a missense mutation of Q188R (replacement of glutamine-188 by arginine) in approximately 60-65% of the German galactosaemic population. The coding region of GALT was amplified by the polymerase chain reaction from genomic DNA of classical galactosaemic individuals, who are negative or heterozygous for Q188R, and was further characterized by direct sequencing. Three new disease-causing mutations, two missense and a stop codon mutation, were identified in three patients from two families with mild galactosaemic variants: firstly R67C, replacement of arginine-67 by cysteine and W316X, the stop codon at tryptophan-316 in one male; secondly A330V, replacement of alanine-330 by valine in two female siblings. In the first family the patient was also heterozygous for the polymorphism N314D and in the second family both girls were compound heterozygotes for Q188R and A330V. All three galactosaemic individuals have a considerable amount of the residual GALT activity in RBC and the galactose-1-phosphate (GALP) level decreased much faster on treatment than that of other galactosaemic patients with missense mutations such as Q188R. The clinical and biochemical data of these patients were much more favourable in comparison with those of two female galactosaemic individuals, one homozygous for L195P and the other compound heterozygous for Q188R and L195P. These three missense mutations (R67C, L195P and A330V) also occur in highly conserved regions. These observations suggest that the phenotypic variation in galactosaemic individuals may be due to different molecular aetiologies.
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PMID:Mutations in the galactose-1-phosphate uridyltransferase gene of two families with mild galactosaemia variants. 859 37

Self-injurious behavior (SIB) and stereotyped behavior (SB) are major challenges for professionals in the field of mental retardation. From animal experiments it has become obvious that these behavioral disturbances are not purposeless but may emerge secondary to restrictive environment and may serve de-arousing objectives. In mentally retarded subjects, several hypotheses have been formulated concerning the pathogenesis of SIB, particularly about the involvement of serotonin and beta-endorphin, which are supported by beneficial treatment effects of the opiate antagonist naltrexone and serotonin modulating compounds, respectively. The present study was designed to investigate basal levels of stress-hormonal and serotonergic parameters as well as plasma levels of amino-acids and the beta-carboline norharman in a group of 64 mentally retarded subjects with SB and/or SIB. Allocation to three different groups comprising 17 retarded controls, 26 subjects with mainly SIB and 21 subjects with mainly SB, was originally performed using the scores on the factors Irritability, Stereotypic Behaviour and Hyperactivity of the Aberrant Behavioral Checklist. Because of the overlapping nature of the behavioral parameters, subjects were subsequently divided into three maximally contrasting groups, viz. predominantly SIB, predominantly SB and retarded controls, each comprising 11 subjects. With respect to beta-endorphin, no differences were found either between both the original and maximally contrasting groups or in comparison to nonretarded controls. As compared to retarded controls, a tendency to lower values for total cortisol and cortisol binding globulin appeared to be present in the SIB group, whereas in the SB group a tendency toward higher levels of the major serotonin metabolite 5-HIAA was found. In the contrasting SB group, a trend toward decreased total cortisol level was observed as compared to the retarded control group. In addition, significantly lower values for norharman and tryptophan were demonstrated in the total group of mentally retarded subjects as compared to non-retarded controls. The results of the present study, yielding co-existent disturbances in stress-hormonal and monoaminergic mechanisms as well as in the metabolism of norharman, are in line with the hypothesis that mentally retarded subjects are at risk for the development of stress-related behavioral disorders such as SIB and SB.
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PMID:Stress and self-injurious behavior; hormonal and serotonergic parameters in mentally retarded subjects. 1007 Nov 78

In patients with neurodegenerative disorders, namely Alzheimer's disease and Huntington's disease, we compared serum concentrations of tryptophan, kynurenine and the kynurenine per tryptophan ratio with concentrations of soluble immune activation markers. Significantly lower tryptophan concentrations were observed in the patients, and lower tryptophan levels as well as higher kynurenine levels and higher kynurenine per tryptophan ratios correlated with higher concentrations of neopterin, and soluble receptors for TNF and interleukin-2. In both groups of patients tryptophan concentrations correlated inversely with the degree of mental retardation. No such association existed for the duration of the disease. The data show that systemic chronic immune activation in patients with Alzheimer's disease and Huntington's disease is associated with significant degradation of tryptophan, which is most likely due to activation of indoleamine (2,3)-dioxygenase by immunologic stimuli. Further studies will be necessary to investigate a potential role of tryptophan degradation in the pathogenesis of neurodegenerative disorders.
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PMID:Degradation of tryptophan in neurodegenerative disorders. 1072 Oct 50

Arginine:glycine amidinotransferase (AGAT) catalyzes the first step of creatine synthesis, resulting in the formation of guanidinoacetate, which is a substrate for creatine formation. In two female siblings with mental retardation who had brain creatine deficiency that was reversible by means of oral creatine supplementation and had low urinary guanidinoacetate concentrations, AGAT deficiency was identified as a new genetic defect in creatine metabolism. A homozygous G-A transition at nucleotide position 9297, converting a tryptophan codon (TGG) to a stop codon (TAG) at residue 149 (T149X), resulted in undetectable cDNA, as investigated by reverse-transcription PCR, as well as in undetectable AGAT activity, as investigated radiochemically in cultivated skin fibroblasts and in virus-transformed lymphoblasts of the patients. The parents were heterozygous for the mutant allele, with intermediate residual AGAT activities. Recognition and treatment with oral creatine supplements may prevent neurological sequelae in affected patients.
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PMID:Arginine:glycine amidinotransferase deficiency: the third inborn error of creatine metabolism in humans. 1155 93

Hyperammonemia is mainly found in hepatic encephalopathy and in genetic defects of the urea cycle or other pathways of the intermediary metabolism. Clinically a difference has to be made between chronic moderate hyperammonemia and acutely increased concentrations. Pathogenetic mechanisms of ammonia toxicity to the brain are partly unraveled. In some animal models confounding variables, such as the reduced intake of food and amino acid imbalance due to liver insufficiency, do not allow to establish unequivocal causal relationships between the ammonia concentration and measured effects. In chronic moderate hyperammonemia an increased flux through the serotonin pathway is a key factor. It is caused by an increased transport of large neutral amino acids (including tryptophan) through the blood-brain barrier, accentuated by the imbalance of plasma amino acids in hepatic insufficiency. It is stimulated by D- or L-glutamine. Evidence is presented showing that a functioning gamma-glutamyl cycle (glutathione formation) is a prerequisite. In acute hyperammonemia involvement of NMDA receptors, glutamate, NO and cGMP plays an additional role. In hyperammonemic crises the increased cerebral blood flow leads to brain edema; factors discussed here are increased osmolytes in astrocytes and serotoninergic activity. Recent data indicate that axonal development is affected by ammonia and can be normalized in vitro by creatine supplementation in developing mixed brain cell aggregate cultures, thus reviving the old hypothesis of the impact of hyperammonemia on energy metabolism in the developing brain that could cause mental retardation.
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PMID:Mechanisms of hyperammonemia. 1224 Oct 9

Cerebrotendinous xanthomatosis (CTX) is a hereditary disorder, which is inherited as an autosomally recessive disease, causing production of cholesterol and cholestanol xanthomas and mental retardation. The disease is caused by mutations in the gene for sterol 27-hydroxylase (CYP27A1). The only CTX patients diagnosed in Scandinavia are two Norwegian sisters from a consanguineous marriage. Here we have characterized the mutation and its functional consequences for the enzyme. Analysis of genomic DNA from cultured fibroblasts identified a base exchange C > T in position 1441, causing arginine at amino acid position 441 to be replaced by tryptophan. The same mutation was introduced by mutagenesis in the complimentary DNA (cDNA) for CYP27, ligated into the expression vector pcDNA4/HisMax and transfected into HEK293 cells. The mutated enzyme had less than 5% of the enzyme activity compared with the native enzyme. No abnormal catalytic products could be identified in the cell culture medium. Probably the mutation affects the haem binding within the holoenzyme. The mutation has also previously been reported in a Japanese family. This is the second example of a CTX-causing mutation that has been recognized in more than one population.
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PMID:Cerebrotendinous xanthomatosis: molecular characterization of two Scandinavian sisters. 1227 7

Arginine:glycine amidinotransferase (AGAT, EC 2.1.4.1) deficiency is a recently recognized autosomal recessive inborn error of creatine biosynthesis, characterized by mental retardation and severe language impairment. We extensively investigated a third 5-year-old patient with AGAT deficiency, discovered in the pedigree of the same Italian family as the two index cases. At the age of 2 years he presented with psychomotor and language delay, and autistic-like behavior. Brain MRI was normal, but brain 1H-MRS disclosed brain creatine depletion, which almost completely normalized following creatine monohydrate supplementation. A remarkable clinical improvement paralleled the restoration of brain creatine concentration. AGAT and GAMT (guanidinoacetate:methyltransferase) genes were analyzed in the proband and in 26 relatives, including the two cousins with AGAT deficiency. Sequencing of the proband's AGAT gene disclosed the same homozygous mutation at nt position 9093 converting a tryptophan (TGG) to a stop codon (TAG) at residue 149 (W149X), as already described in the two previously reported cases. The proband's parents and 10 additional subjects of the pedigree were carriers for this mutation. AGAT deficiency was further confirmed by undetectable AGAT activity in the patient's lymphoblasts. Mutation analysis of the GAMT gene revealed a sequence variation in exon 6 (T209M), not in the proband, but in 15 additional subjects from the pedigree. The silent nature of this sequence variation is supported by its homozygosity in one AGAT deficient cousin and in one asymptomatic adult, both with normal GAMT activity.
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PMID:Creatine depletion in a new case with AGAT deficiency: clinical and genetic study in a large pedigree. 1246 79

Although hyperphenylalaninemia causes neurological disturbances and mental retardation, the neuropathological effects of phenylalanine excess are still poorly understood. Brain serotonin depletion may play a major role in such disturbances and is a possible target for feasible pharmacotherapies. In the present study, we investigated hyperphenylalaninemia-related brain serotonin depletion using a genetic mouse model of phenylketonuria, the Pah(enu2) mutant. Mutant mice showed severe depletion of whole brain serotonin, a mild reduction in the brain level of tryptophan, its amino acid precursor, and major deficits in the brain level of 5-hydroxytryptophan, the second rate-limiting factor in serotonin synthesis. These results suggest that interference with brain 5-hydroxytryptophan synthesis may be the major cause of serotonin deficits in hyperphenylalaninemia.
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PMID:Deficits in brain serotonin synthesis in a genetic mouse model of phenylketonuria. 1249 68

Multiple cases with various types of pediatric malabsorption syndromes were evaluated. The clinical manifestations, laboratory findings, pathophysiology, and histopathological descriptions of each patient were analyzed in an effort to clear the pathogenesis of the malabsorption syndromes and the treatments were undertaken. The cases studied, included one patient with cystic fibrosis, two with lactose intolerance with lactosuria (Durand type), one with primary intestinal lymphangiectasia, two with familial hypobetalipoproteinemia, one with Hartnup disease, one with congenital chroride diarrhea, one with acrodermatitis enteropathica, one with intestinal nodular lymphoid hyperplasia (NLH), five with intractable diarrhea of early infancy and four with glycogenosis type Ia. Each case description and outcome is described below: 1. A 15-year-old Japanese boy with cystic fibrosis presented with severe symptoms, including pancreatic insufficiency, bronchiectasis, pneumothorax and hemoptysis. His prognosis was poor. Analysis of the CFTR genes of this patient revealed a homozygous large deletion from intron 16 to 17b. 2. In the sibling case of Durand type lactose intolerance, the subjects'disaccaridase activity of the small bowel, including lactase, were within normal limits. The results of per oral and per intraduodenal lactose tolerance tests confirmed lactosuria in both. These observations suggested, not only an abnormal gastric condition, but also duodenal and intestinal mucosal abnormal permeability of lactose. 3. In the case of primary intestinal lymphangiectasia, the subject had a lymphedematous right arm and hand, a grossly coarsened mucosal pattern of the upper gastrointestinal tract (identified via radiologic examination) and the presence of lymphangiectasia (confirmed via duodenal mucosal biopsy). The major laboratory findings were hypoalbuminemia, decreased immunoglobulin levels and lymphopenia resulting from loss of lymph fluid and protein into the gastro-intestinal tract. 4. In two cases of heterozygous familial hypobetalipoproteinemia, serum total cholesterol and betalipoprotein levels were very low. The subjects presented with symptoms and signs of acanthocytosis and fat malabsorption. Further, one subject had neurological abnormalities such as mental retardation and severe convulsions. Treatment with MCT formula diet corrected the lipid malabsorption. 5. A 5-year-old girl presented with pellagra-like rashes, mental retardation and cerebellar ataxia. An oral tryptophan (Trp) and dipeptide (Trp-Phe) loading test were conducted and the renal clearance of amino acids was also evaluated in this patient and in controls. Following the oral Trp loading test, plasma levels of Trp indicated a lower peak in the case, reaching a maximum at 60 minutes. On the other hand, the oral dipeptide (Trp-Phe) loading test in the Hartnup patient showed the peak Trp plasma level was the same as the control subjects. The renal clearance of neutral amino acids in this case increased to levels 5 to 35 times normal. 6. In the case of congenital chloride diarrhea, the subject had secondary lactose intolerance, dehydration, hyponatremia, hypokalemia, hypochloremia, hyperreninemia and metabolic alkalosis. The chloride content of her fecal fluid was very high. The concentrations were 89-103 mEq/l. In contrast, her urine was chloride-free. The subject's growth and development improved after treatment with lactose free formura and oral replacement of the fecal loses of water, NaCl and KCl. Unfortunately, the patient died of a small bowel intussusception. The kidney histopathological finding was juxtaglomerular hyperplasia by a necropsy. 7. In the case of acrodermatitis enteropathica, the subject had characteristic skin lesions, low serum zinc levels and ALPase activity. An oral ZnSO4 loading test and intestinal mucosal histology by a peroral biopsy were conducted. The serum zinc peak level was 2 hours after the oral ZnSO4 loading test. Infant formula alone could not maintain normal serum zinc ranges. Light microscopic studies of the intestinal villous architecture showed a normal pattern. However, ultrastructual examination of several epithelial cells revealed numerous intracellular vesicles. After zinc therapy, these changes were decreased. The lesions were postulated as the secondary result of zinc deficiency. 8. A 12-year-old girl presented with hypogammaglobulinemia, recurrent infections, chronic diarrhea and intestinal NLH. A barium meal and follow-through examination showed multiple nodules throughout the stomach and intestine. The nodules, all uniform in size, were 2 mm diameter. The barium enema did not show NLH in the colon. Mucosal biopsy of the stomach and jejunum revealed the typical histology of NLH in the lamina propria. Also, achlorhydria was present in this patient and her serum gastrin levels were very high; 315-775 pg/ml. 9. In 4 cases of intractable diarrhea in early infancy (by Avery G B), a jejunal biopsy showed shortening villi and nonspecific enterocolitis. Some patients were found with only low lactase or low lactase and sucrase levels. An electron microscope analysis of the small bowel in 2 cases showed alterations: increased pinocytosis in microvillus membranes and lysosomes by endocytosis of undigested macromolecular substances. I postulated that the stated evidence was causative of this clinical profile. 10. I frequently observed diarrhea as a clinical manifestation in glycogenosis type Ia and lipid malabsorption in one case. The light and electron photomicrographs showed intestinal absorption cells with the glycogen deposits in the inferior devision of nuclei.
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PMID:[Clinical studies of pediatric malabsorption syndromes]. 1722 86

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