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

Content of phenylalanine and tyrosine was increased in blood serum in mongolism. When 4 patients with mongolism and 10 healthy persons were loaded with 1-phenylalanine, content of the amino acid in blood serum of patients exceeded 1.5--2-fold that found in healthy persons within 4 and 6 hrs after the treatment. The hydroxylation rate of phenylalanine was lower in mongolism as compared to normal state; it corresponded to the rate of phenylalanine hydroxylation in atypical homo- and heterozygote patients bearing "phenylketonuria" gene and in patients with viral hepatitis. Concentration of tyrosine was distinctly higher in the impaired patients within 2--6 hrs after the loading as compared with the healthy persons. But content of tyrosine was increased only slightly in patients with mongolism during the loading and excretion of homogentisinic acid with urine was decreased. These data suggest that activity of phenylalanine hydroxylase system is impaired in liver tissue in mongolism. Excretion of phenylpyruvic acid with urine was not observed in the patients and healthy persons both before and during the amino acid loading. The data obtained suggest that impairment of phenylalanine and tyrosine turnover in mongolism appears to be one of the factors responsible for disturbance of neurotransmitter synthesis and to be related to development of mental retardation.
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PMID:[Disorders of phenylalanine and tyrosine metabolism in Down's syndrome]. 15 71

The hyperphenylalaninemias are caused by the defect of either phenylalanine hydroxylase (PAH) or tetrahydrobiopterin (BH4) cofactor. The former is diagnosed as phenylketonuria (PKU) or benign hyperphenylalaninemia, based on the serum phenylalanine values. The latter, so called malignant hyperphenylalaninemia, includes three enzyme defects, dihydropteridine reductase (DHPR), 6-pyruvoyl tetrahydropterin synthase (PT PS) and guanosine triphosphate cyclohydrolase (GTP-CH). Excess phenylalanine and its metabolites cause brain damage before 6 years of age. Deficiency of BH4 impairs two other hydroxylases (tyrosine and tryptophan), and severe neurological symptoms develop because of the lack of neurotransmitters. Tyrosinemia I, II, and III are different enzyme defects, fumarylacetoacetate hydrolyase (FAH), hepatic tyrosine aminotransferase (TAT), and 4-hydroxyphenylpyruvate acid oxidase, respectively. Tyrosinemia I is associated with severe involvement of the liver, kidney and central nervous system. Tyrosinemia II has mental retardation, palmar hyperkeratosis and corneal ulcers. Tyrosinemia III has mild mental retardation but no eye or skin manifestations.
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PMID:[The metabolic basis of the hyperphenylalaninemias and tyrosinemia]. 135 1

Intrauterine growth retardation, microcephaly, and developmental delay in two first cousins lead to the recognition of phenylketonuria (PKU) in their mothers, 24- and 23 year-old sisters with blood phenylalanine concentrations of approx. 1.2 mmol/l who had never been treated and had no overt mental retardation. Both mothers were shown to be homozygous for a point mutation leading to an Arg-to-Gln substitution at codon 261 of the phenylalanine hydroxylase gene, a mutation which has been recently identified and tentatively associated with a mild variant of PKU. Our observation suggests that homozygosity for the Arg-261-Gln mutation can indeed result in "mild" PKU with little or perhaps no mental retardation, but also indicates that in such women, who may go unrecognized if not screened for, blood phenylalanine is elevated enough to cause the maternal PKU syndrome in their offspring.
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PMID:Maternal phenylketonuria syndrome in cousins caused by mild, unrecognized phenylketonuria in their mothers homozygous for the phenylalanine hydroxylase Arg-261-Gln mutation. 191 2

Phenylketonuria (PKU) has become a paradigm of a disease that can be identified by screening in the newborn period and treated to prevent serious complications. After many years of experience treating PKU, new challenges have emerged. It has become apparent that defective activity of phenylalanine hydroxylase leads to a spectrum of clinical presentations that has led to subclassifications of PKU. Blood phenylalanine greater than 1200 mumol/L usually indicates severe deficiency of phenylalanine hydroxylase and is often called "classical PKU." Blood phenylalanine levels between 600 and 1200 mumol/L lead to "atypical PKU." Cases where blood phenylalanine remains between 120 and 480 mumol/L on a normal diet are termed "benign hyperphenylalaninemia." A deficiency of the cofactor tetrahydrobiopterin (BH4), which is required for phenylalanine hydroxylase activity, leads to hyperphenylalaninemia. This cofactor is also required for the enzymatic hydroxylation of tyrosine and tryptophan. Cofactor defects account for only 1-3% of hyperphenylalaninemia, which has been termed "malignant PKU", but they must be identified so that appropriate treatment can be established. Long-term treatment of PKU is currently advised because loss of IQ, poor school performance, and behavior problems occur when blood phenylalanine levels increase. Therefore, there is reason to continue the diet as patients become older. When blood phenylalanine levels are elevated during pregnancy a "maternal PKU syndrome" may result. Babies born to untreated mothers with PKU are at risk for being small for gestational age with microcephaly, mental retardation and congenital heart defects. A national collaborative study for the treatment of maternal PKU is underway. The characterization of the gene for phenylalanine hydroxylase has added a new exciting chapter to the study of PKU.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Phenylketonuria: screening, treatment and maternal PKU. 195 25

Identification of mutations within the phenylalanine hydroxylase gene which cause phenylketonuria has introduced the possibility of diagnosing phenylketonuria by direct analysis of the genome. Genotypic analysis could be used for identifying homozygotes in the newborn period, for prenatal diagnosis, or for heterozygote detection in general populations. Establishing the clinical utility of genotypic diagnosis, however, will require characterization of the cohort of patients identified by genotypic diagnosis, correlation of mutant genotypes with specific biochemical and developmental phenotypes, and consideration of how genotypic diagnosis might contribute to improving the clinical outcome in individuals at risk for mental retardation due to hyperphenylalaninemia.
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PMID:Clinical application of genotypic diagnosis for phenylketonuria: theoretical considerations. 195 35

Screening newborns for phenylketonuria (PKU) is a mandatory practice based on measuring a raised blood phenylalanine level. Many factors influence the rate of blood phenylalanine rise so that there are many pitfalls in detecting the 1:10,000 affected infant. About one percent of all babies tested proves to be "false positives." Two-thirds of those with persistent hyperphenylalaninemia prove to have classic PKU. Non-classic PKU with less intense, persistent hyperphenylalaninemia is due to different alterations in the enzyme, phenylalanine hydroxylase. Additionally, about one percent of the confirmed positive patients is due to either a defect in the synthesis or regeneration of the cofactor, tetrahydrobiopterin; these latter forms are not amenable to treatment with the low phenylalanine diet. Screening programs have developed directives regarding the timing and conditions for obtaining the specimens for testing. Specific confirmatory tests of those with positive results must be performed. Even so, about one in 70 affected babies is "missed," resulting in mental retardation, seizures, and neurologic deficits.
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PMID:Phenylketonuria: contemporary screening and diagnosis. 207 89

The mRNA for phenylalanine hydroxylase (phenylalanine 4-monooxygenase, EC 1.14.16.1) has been purified from total rat liver mRNAs, of which it constitutes less than 0.25%, to greater than 10% purity in a single step by specific polysome immunoprecipitation. The purified mRNA was used for synthesis and cloning of its cDNA. Recombinant colonies containing phenylalanine hydroxylase DNA sequences were identified by differential hybridization, hybrid-selected translation, and blot hybridization analysis. The rat cDNA clone was capable of hybridizing with human phenylalanine hydroxylase mRNA, which will permit the isolation of the corresponding human gene for analysis of phenylketonuria, a hereditary disorder in phenylalanine metabolism that causes permanent mental retardation in humans.
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PMID:Polysome immunoprecipitation of phenylalanine hydroxylase mRNA from rat liver and cloning of its cDNA. 675 Jun 7

The history of PKU is one of science in the discovery of an inborn error of metabolism and a chemical cause of mental retardation; and also one of technology with the development of methods to prevent disease. PKU is the classic example of success in the prevention of a genetic disease. Meanwhile, the science has continued to evolve over the 60 years since the discovery of PKU, generating new understanding of its clinical and metabolic phenotypes and about phenylalanine hydroxylation. At least five known genes are involved in hydroxylation of phenylalanine, synthesis of tetrahybrobiopterin and regeneration of this cofactor. The genes have been cloned and mutations characterized for several enzymes (GTPCH, 6-PTPS, PHS/DoCH, DHPR, PAH). A new animal model (the enu mouse) is contributing to knowledge about pathogenesis of brain disease and potential new treatments. The human phenylalanine hydroxylase gene (PAH) itself harbors 99% of the mutations causing hyperphenylalaninemia, over 170 different mutations have been identified at this locus. They cause loss of function; none affecting regulation has been identified. The aggregate PKU gene frequency at 1% is polymorphic in many human populations and mutations are highly stratified by region and population reflecting a variety of mechanisms (founder effect, genetic drift, hypermutability and, perhaps, selection) for their occurrence and distribution.
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PMID:Whatever happened to PKU? 762 72

The binding of the muscarinic acetylcholine antagonist quinuclinidylbensilate to its specific receptors was measured by quantitative autoradiography in the brain of the HPH-5 mouse, a phenylalanine hydroxylase-deficient mouse mutant, as a model for human PKU. Three types of response to a hyperphenylalaninemic condition were observed: no effect as in the putamen; a gradual decrease over time such as in several areas of the cerebral cortex and the hippocampus; a transient increase, followed by a decrease, such as in the frontal area of the cerebral cortex. Of particular significance is the effect on the CA1 and CA3 layer of the hippocampus, since this structure has been implicated in the acquisition and storage of long-term memory. Hyperphenylalaninemia leads to a decrease in neurotransmitter receptor density and, therefore, to a decrease in connectivity, which may form the basis for the mental retardation in this condition.
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PMID:Loss of neurotransmitter receptors by hyperphenylalaninemia in the HPH-5 mouse brain. 776 46

Phenylketonuria (PKU) is an autosomal recessive genetic disorder caused by phenylalanine hydroxylase (PAH) deficiency. Individuals afflicted with PKU develop irreversible mental retardation that can be largely prevented by the administration of a low-phenylalanine diet. A number of restriction fragment-length polymorphisms (RFLPs) have been identified in the PAH gene. Combinations of RFLPs constitute unique haplotypes that can be used to identify mutant PAH chromosomes for prenatal diagnostic purpose in PKU families. Unfortunately, the utility of haplotype analysis is limited in populations with a single predominant haplotype. We have identified a novel short tandem repeat (STR) within the PAH gene that has an average level of heterozygosity of about 75% in Orientals and about 80% in European Caucasian populations. This single marker is as informative as haplotype analysis in Europeans and nearly twice as informative as haplotype analysis in Orientals. Although there is statistically significant disequilibrium between STR alleles and RFLP-based haplotypes, there is a relatively low degree of disequilibrium between STR alleles and certain RFLP sites. Nevertheless, the combined use of the STR and RFLP haplotype systems increases the informativity of linkage-based tests for prenatal diagnosis and carrier screening in PKU families.
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PMID:A single polymorphic STR system in the human phenylalanine hydroxylase gene permits rapid prenatal diagnosis and carrier screening for phenylketonuria. 810 Jan 64


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