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)

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 classification of genetic disease into chromosomal, monogenic and multifactorial categories is an oversimplification. Phenylketonuria (PKU) is a classic 'monogenic' autosomal recessive disease in which mutation at the human PAH locus was deemed sufficient to explain the impaired function of the enzyme phenylalanine hydroxylase (enzymic phenotype), the attendant hyperphenylalaninemia (metabolic phenotype) and the resultant mental retardation (cognitive phenotype). In the era of molecular genetics, expectations for a consistently close correlation between the mutant genotype and variant phenotype have been somewhat disappointed, and PKU is used here to illustrate how and why this might be the case. So-called monogenic traits do, indeed, conform to long-accepted ideas about the expression of 'major' loci and their importance in determining parameters of phenotype, but the associated features are as complex, in their own ways, as those in so-called complex traits.
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PMID:Monogenic traits are not simple: lessons from phenylketonuria. 1039 Jun 25

Phenylketonuria (PKU) is one of the most common inborn errors of metabolic disorders. Although PKU induced mental retardation can be prevented after neonatal screening by following treatment with low phenylalanine diet, some parents are seeking prenatal diagnosis. We screened for mutations in exon 3 and 7 of the PAH gene using the DGGE and restriction enzyme method, in combination with STR linkage analysis. Prenatal diagnosis was carried out in 8 PKU families. With this strategy, we are able to make prenatal diagnosis in about 65-70% PKU families. All diagnosis was confirmed in the newborn.
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PMID:Molecular studies and prenatal diagnosis of phenylketonuria in Chinese patients. 1140 Jul 88

Phenylketonuria (PKU) is a metabolic disorder due primarily to mutations in the PAH gene that impair both phenylalanine hydroxylase activity and disposal of l-phenylalanine from the normal diet. Excess phenylalanine is toxic to cognitive development and a low-phenylalanine diet prevents mental retardation, but it is a difficult therapeutic option. Previous studies with recombinant phenylalanine ammonia-lyase, PAL, demonstrated pharmacologic and physiologic proofs of principle for PAL as an alternative therapy for PKU but its immunogenicity was problematic. From a series of formulations of linear and branched polyethylene glycols chemically conjugated to PAL, we have created a parenteral therapeutic agent for PKU treatment. All the pegylated molecules were fully characterized in vitro and the most promising formulations were then tested in vivo in the PKU mouse model. The linear 20-kDa PEG-PAL combination abolished in vivo immunogenicity after repeated challenge while retaining full catabolic activity against phenylalanine, suggesting potential as a novel PKU therapeutic.
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PMID:Development of pegylated forms of recombinant Rhodosporidium toruloides phenylalanine ammonia-lyase for the treatment of classical phenylketonuria. 1592 70

Maternal PKU Syndrome (MPKU) is an embryopathy resulting from in utero phenylalanine (PHE) toxicity secondary to maternal phenylalanine hydroxylase deficient phenylketonuria (PKU). Clinical phenotypes in MPKU include mental retardation, microcephaly, in utero growth restriction, and congenital heart defects. Numerous in utero toxic exposures alter DNA methylation in the fetus. The PAH(enu2) mouse is a model of classical PKU while offspring born of hyperphenylalaninemic dams model MPKU. We investigated offspring of PAH(enu2) dams to determine if altered patterns of DNA methylation occurred in response to in utero PHE exposure. As neurologic deficit is the most prominent MPKU phenotype, methylome patterns were assessed in brain tissue using methylated DNA immunoprecipitation and paired-end sequencing. Brain tissues were assessed in E18.5-19 fetuses of PHE unrestricted PAH(enu2) dams, PHE restricted PAH(enu2) dams, and heterozygous(wt/enu2) control dams. Extensive methylome repatterning was observed in offspring of hyperphenylalaninemic dams while the offspring of PHE restricted dams displayed attenuated methylome repatterning. Methylation within coding regions was dominated by noncoding RNA genes. Differential methylation of promoters targeted protein coding genes. To assess the impact of methylome repatterning on gene expression, brain tissue in experimental and control animals were queried with microarrays assessing expression of microRNAs and protein coding genes. Altered expression of methylome-modified microRNAs and protein coding genes was extensive in offspring of hyperphenylalaninemic dams while minimal changes were observed in offspring of PHE restricted dams. Several genes displaying significantly reduced expression have roles in neurological function or genetic disease with neurological phenotypes. These data indicate in utero PHE toxicity alters DNA methylation in the brain which has downstream impact upon gene expression. Altered gene expression may contribute to pathophysiology of neurologic presentation in MPKU.
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PMID:Methylome repatterning in a mouse model of Maternal PKU Syndrome. 2521 79

Phenylketonuria is a hereditary metabolic disorder due to the deficiency of tetrahydrobiopterin or phenylalanine hydroxylase. Delayed diagnoses of it manifest a progressive irreversible neurological impairment in the early years of the disease. Guthrie test and tandem mass spectrometry aided in early detection and intervention of phenylketonuria, which significantly decreased the disability of patients as well as reducing the need for diagnosis in adults. This is a case report of a 60-year-old Asian man, characterized by severe visual-spatial disorders and bilateral diffuse symmetric white matter lesions on magnetic resonance imaging, who was diagnosed as phenylketonuria with his congenital mental retardation sibling. Heterozygous mutations exist in gene encoding PAH c.1068C>A and c.740G>T. During the diagnosis, we looked up at other late-onset genetic diseases considered to occur rarely but gradually revealed similar clinical manifestations and significant white matter lesions gaining importance in guiding to correct diagnosis and treatment. We made a comprehensive review of phenylketonuria and other inherited diseases with major prevalence in adulthood with prominent white matter involvement. Our study aims to help neurologists to improve recognition of metabolism-related leukoencephalopathies without neglect of the role of congenital genetic factors.
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PMID:Effect of Delayed Diagnosis of Phenylketonuria With Imaging Findings of Bilateral Diffuse Symmetric White Matter Lesions: A Case Report and Literature Review. 3163 99