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

Child health and life expectancy improved together in many societies in the 20th century. As the incidence of diseases with major extrinsic causes declined, the heritability of disease as a whole increased. Accordingly, the genetic (intrinsic) causes of disease have become important. The genome project is an international venture out of which will come new knowledge about the biological basis of health and disease, and technologies to apply that knowledge in medicine and other disciplines. Phenylketonuria (PKU) at one time was seen only as a rare inborn error of metabolism causing severe mental retardation. Yet, the gene frequency is about 1% in Caucasian and Oriental populations, higher still in some populations with particular histories that have enhanced gene frequency. These genetic facts make PKU a paradigm in human genetics. This genetic disease, for which it was thought there was nothing to be done, has yielded to inquiries at clinical, metabolic, protein (enzyme) and DNA (PAH gene) levels. Results have shown that, early diagnosis (by population screening) and treatment (by low phenylalanine diet) largely prevents mental retardation. DNA analysis reveals particular associations between PKU mutations, RFLP haplotypes and populations; these associations are relevant for counseling. PKU illustrates well how medical science, molecular biology and gene mapping can improve knowledge and contribute to child health.
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PMID:Child health, the genome project and phenylketonuria. 751 3

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 is no longer associated with mental retardation and other devastating neurological effects. Nonetheless, learning disabilities and IQ loss are common, even in early-treated individuals. Until recently, IQ was used as the sole measure of mental functioning in this population. As specific academic deficits were recognized and as a greater variety of tests became available, evaluation of children with phenylketonuria has included neuropsychological testing. A review of the 21 published reports highlights the areas of consensus and the need for additional well designed studies in the future. Problem solving, particularly abstract reasoning and executive functions, appears to be impaired in children with phenylketonuria. Reaction time, or speed of mental processing, appears to be the other important area affected in PKU. An information processing model is presented as a paradigm for further research and development of remedial strategies for children with phenylketonuria.
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PMID:Review of neuropsychological functioning in treated phenylketonuria: an information processing approach. 776 71

The objective of neonatal screening for phenylketonuria and congenital hypothyroidism is early diagnosis and initiation of treatment to prevent brain damage and mental retardation. We present the results of the Norwegian national neonatal screening programme for phenylketonuria and congenital hypothyroidism. Screening for phenylketonuria based on serum phenylalanine determinations started in 1967 and covered the whole country in 1978. National screening for congenital hypothyroidism started in 1979. One hundred children with phenylketonuria and 280 children with a strong indication of congenital hypothyroidism have been detected up to 1 October 1994. Screening-related challenges and principles of treatment are discussed.
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PMID:[Screening of newborn infants in Norway for severe metabolic disease]. 790 Jan 9

We report our experience with the deficiency of 6-pyruvoyltetrahydropterin synthase, the most common form of tetrahydrobiopterin deficiency. We investigated 5200 patients suspected of having some inborn error of metabolism in a 10-year period, and detected 30 cases (from 28 sibships) of hyperphenylalaninaemias, HPA. From these, 4 sibships (5 patients) were affected by deficiency of 6-pyruvoyltetrahydropterin synthase. All of them were ethnically mixed, with some European ancestry detected in all. The age of diagnosis ranged from 2 to 9 years, and all were initially referred for investigation by having mental retardation and seizures. All of them showed low urinary biopterin levels and a marked elevation of neopterin. Although we detected only a few cases of HPA (30), 5 cases of 6-pyruvoyltetrahydropterin account for almost 20% of this total. The literature, however, reports a proportion of around 0.5%. As the frequency of classical phenylketonuria in our region is similar to that found in Caucasians (1/12,500), we believe that the frequency of this disease in South Brazil may be higher than expected (of the order of 1/400,000). We speculate that this finding could be related to a genetic drift (or founder effect).
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PMID:Possible high frequency of tetrahydrobiopterin deficiency in south Brazil. 796 77

Maternal phenylketonuria (PKU) has adverse effects on the offspring including microcephaly, mental retardation, congenital heart disease, and intrauterine growth retardation. Maternal non-PKU mild hyperphenylalaninaemia (MHP) is believed to be benign, but whether there may be long-term consequences to offspring is unclear. In an international survey we have obtained information about 86 mothers with MHP (blood phenylalanine 167-715 mumol/L), their 219 untreated pregnancies, and 173 offspring. Spontaneous fetal loss (13% of pregnancies), congenital heart disease (2.3% of offspring), and severe non-cardiac anomalies (2.9% of offspring) occurred at frequencies within expected limits for the general population. For weight and length at birth the median percentile was the 50th but that for birth head circumference was the 25th. Median z-scores for birth length and head circumference were significantly lower for offspring of mothers with phenylalanine concentrations above 400 mumol/L than for those whose mothers had lower values (p = 0.05 and p = 0.005, respectively). The median intelligence quotient (IQ) of the offspring (3-27 years) was 100 for those whose mothers had higher phenylalanine concentrations and 108 for those of the lower phenylalaninaemia group. However, offspring IQ correlated slightly more closely with maternal IQ (r = 0.53, p < 0.001) than with maternal phenylalanine concentration (r = 0.45, p = 0.02). Maternal MHP does not seem to have serious consequences for the fetus. A maternal phenylalanine concentration of less than 400 mumol/L does not warrant intervention. Nevertheless, maternal blood phenylalanine above this value is associated with slightly lower birth measurements and offspring IQ than lower maternal blood phenylalanine concentrations.
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PMID:Maternal mild hyperphenylalaninaemia: an international survey of offspring outcome. 784 32

We performed a retrospective study of all patients with methylmalonic acidemia diagnosed during the past 20 years. Only those patients who were nonresponsive to vitamin B12 in vivo and in vitro were included. The final study group consisted of 26 patients, of whom 16 had a neonatal (early) onset; in 10 patients the diagnosis was made after 2 months to 2.2 years (late onset). Of the early-onset patients, 14 (87%) died, with a mean survival time of 1.5 years (range, 10 days to 2.5 years), whereas four of the late-onset patients (40%) died (range, 1.2 to 15 years). At present, eight patients are alive; their mean age is 4.6 years (range, 1 to 10 years). In the early 1970s, treatment was based on the principles of treating patients with phenylketonuria: restricting natural protein intake and supplementing essential amino acids, vitamins, and trace elements. After about 1980, nasogastric tube feeding became a mainstay of the therapy, natural protein restriction became stricter, and the use of essential amino acid mixtures diminished. Carnitine was added to the therapy and, in later years, metronidazole. Since these changes were implemented, the number of episodes of metabolic decompensation and hospitalizations has decreased. Mean survival time of the patients, in particular those with early onset, has only slightly improved, partly because of psychosocial problems in many of these families. Almost all the patients, especially those with early onset, had some degree of neurologic impairment and mental retardation, and many patients were at less than 2 SD for weight or height or both. In contrast, the neurologic and mental status of the late-onset patients was frequently normal, and their weight and height were more often within normal limits. Our results show that the treatment of methylmalonic acidemia still poses considerable problems; despite intense medical efforts and familial stress, the prognosis for the early-onset patients is disappointing. The patients with late-onset disease, however, appear to have a fairly good prognosis with the present therapeutic approach. Liver transplantation or possibly genetic therapy might improve our results in the future.
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PMID:Clinical outcome of long-term management of patients with vitamin B12-unresponsive methylmalonic acidemia. 799 62

In Japan, a nationwide mass screening system for neonatal metabolic diseases was established in 1977. This system consisted of screening programs for five main congenital metabolic diseases, including phenylketonuria (PKU). To evaluate the efficiency of the mass screening system, a cost-benefit analysis of the screening program for PKU (as a typical case in Japan) was carried out. The costs of the detection and the treatment program were compared with the projected benefit (avoided costs) that results from prevention of the mental retardation associated with the disorders due to PKU. Costs and benefits were discounted at an annual rate of 7%. Assuming that the incidence of PKU was 1/80,500 and the total number of infants screened was 1.2 million, net benefits for the screening program were $283,000, and the cost-benefit ratio was 1:2.5. The sensitivity analysis for the incidence of PKU showed that the cost-benefit ratios exceeded one.
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PMID:Health economic analysis of the neonatal screening program in Japan. 807 Oct 1

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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