Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0917816 (mental retardation)
 15,867 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent work has shown that in phenylketonuria, PKU, in which phenylalanine accumulates in the blood, the damage to the brain, which so often leads to mental retardation, is not solely due to the large quantities of phenylalanine that enter the brain. The raised levels of phenylalanine in the blood lead to a partial exclusion of various other amino acids from the brain and this exclusion in itself damages the brain. Based on this evidence, that in PKU some amino acids are partially excluded from entering the brain, proposals are made for a modified dietary treatment of this disease. In this diet the phenylalainine is not so greatly reduced as in the standard diet for PKU, whilst supplements of other amino acids are added. The rationale for this new diet is that the partial exclusion from the brain of various amino acids (methionine, tryptophan, histidine, tryosine, isoleucine, leucine and valine) by the raised level of phenylalanine in the blood, acting as a competitive inhibitor, can be largely prevented by increasing the blood levels of these excluded amino acids. Raising slightly their blood levels overcomes the excluding effect of moderately raised levels of phenylalanine in the blood. The advantages of the new diet are that not only is it more palatable than a diet very low in phenylalanine, so that it is more likely to continue to prove acceptable to older children and adolescents, as well as to PKU women who expect to become pregnant, but also that its margin of safety is greater if the patient does take unsuitable food.
 ...
PMID:A new approach to the treatment of phenylketonuria. 719 42

A low-phenylalanine diet was given for a period of three weeks to four untreated adult phenylketonurics with mental deficiency. One week before the diet was started, in the course of the diet and one week after its termination, some transamination products of phenylalanine, tryptophan and histidine were determined quantitatively. Each of the transamination products showed a positive correlation to the serum phenylalanine levels of the patients, probably due to the large affinity of 4-hydroxyphenylpyruvic acid and phenylpyruvic acid for the amino groups of the aromatic amino acids. This may also explain the low levels of epinephrine, norepinephrine and serotonine which has been observed by other authors in untreated phenylketonurics. Accordingly, treated phenylketonurics should suffer from a chronic deficiency of biogenic amines after termination of the low-phenylalanine diet.
 ...
PMID:[Excretion of transamination products in hyperphenylalaninemia (author's transl)]. 736 27

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.
 ...
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.
 ...
PMID:Mutations in the galactose-1-phosphate uridyltransferase gene of two families with mild galactosaemia variants. 859 37

Six of nine children born from first-cousin parents presented with the same clinical picture: non-progressive congenital encephalopathy with marked hypertonia resembling the stiff-baby syndrome, delayed milestones, mental deficiency and congenital deafness. Rare, usually reversible, episodes of sudden worsening of the neurological status, with progressive loss of consciousness and increase of hypertonia, occurred spontaneously or during febrile illnesses. During these periods, and sometimes on other occasions, transitory renal dysfunction was observed (nephrotic syndrome and/or tubular abnormalities). Death occurred before age 2 years in 4 patients; 2 are still alive (10 and 13 years old). Electrophysiological, biological and enzymatic investigations remained negative, particularly those concerning mitochondrial and peroxisomal metabolism. The only biochemical anomaly was a massive hyperkynureninuria, seen only during the periods of coma (up to 213 mumol/mmol creatinine; normal < 10) and after an intravenous protein loading test. This suggests an anomaly of tryptophan metabolism which has not been reported up to now.
 ...
PMID:Congenital non-progressive encephalopathy and deafness with intermittent episodes of coma and hyperkynureninuria. 883 Jan 73

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.
 ...
PMID:Stress and self-injurious behavior; hormonal and serotonergic parameters in mentally retarded subjects. 1007 Nov 78

Rec8 syndrome (also known as "recombinant 8 syndrome" and "San Luis Valley syndrome") is a chromosomal disorder found in individuals of Hispanic descent with ancestry from the San Luis Valley of southern Colorado and northern New Mexico. Affected individuals typically have mental retardation, congenital heart defects, seizures, a characteristic facial appearance, and other manifestations. The recombinant chromosome is rec(8)dup(8q)inv(8)(p23.1q22.1), and is derived from a parental pericentric inversion, inv(8)(p23.1q22.1). Here we report on the cloning, sequencing, and characterization of the 8p23.1 and 8q22 breakpoints from the inversion 8 chromosome associated with Rec8 syndrome. Analysis of the breakpoint regions indicates that they are highly repetitive. Of 6 kb surrounding the 8p23.1 breakpoint, 75% consists of repetitive gene family members-including Alu, LINE, and LTR elements-and the inversion took place in a small single-copy region flanked by repetitive elements. Analysis of 3.7 kb surrounding the 8q22 breakpoint region reveals that it is 99% repetitive and contains multiple LTR elements, and that the 8q inversion site is within one of the LTR elements.
 ...
PMID:Cloning, sequencing, and analysis of inv8 chromosome breakpoints associated with recombinant 8 syndrome. 1071 24

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.
 ...
PMID:Degradation of tryptophan in neurodegenerative disorders. 1072 Oct 50

In this work clinical and biochemical findings are presented in three untreated children with phenylketonuria in a family. Their clinical pictures were not typical for classical phenylketonuria. As a result, diagnosis was missed. It has been shown that patterns of large neutral amino acids in serum and urine were somewhat different. Significantly lower serum TRP/LNAA ratio was observed in all patients with phenylketonuria, compared to the control group. These findings suggest that there was subnormal tryptophan availability in the central nervous system leading to its decreased metabolism through the serotonin and kynurenine pathways. These results may explain decreased children's growth and their mental deficiency.
 ...
PMID:Serum tryptophan to large neutral amino acid ratio and urinary tryptophan in three patients with phenylketonuria in a family. A clinical and biochemical study. 1072 Oct 68

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.
 ...
PMID:Arginine:glycine amidinotransferase deficiency: the third inborn error of creatine metabolism in humans. 1155 93


<< Previous 1 2 3 Next >>