Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
 ...
PMID:[The metabolic basis of the hyperphenylalaninemias and tyrosinemia]. 135 1

The tetrahydrobiopterin (BH4) cofactor is essential for the aromatic amino acid hydroxylases that are involved in phenylalanine degradation and catecholamine and serotonin biosynthesis. Furthermore, BH4 is an essential and limiting cofactor for all types of nitric oxide synthases. BH4 deficiency results in hyperphenylalaninemia and monoamine neurotransmitter depletion associated with progressive mental retardation and is most commonly due to autosomal recessive mutations in 6-pyruvoyltetrahydropterin synthase (PTPS), the second enzyme for cofactor biosynthesis. Due to the relatively poor blood-brain barrier penetration of the cofactor, conventional therapy requires, besides oral doses of synthetic BH4, administration of neurotransmitter precursors and an aromatic amino acid decarboxylase inhibitor. The outcome of this therapy is not always beneficial. In this study we transduced into primary patient fibroblasts the human cDNAs for the BH4 biosynthetic enzymes GTP cyclohydrolase I and PTPS, expressed from different retroviral vectors. This allowed BH4 biosynthesis in originally PTPS-deficient cells. Moreover, the double-transduced fibroblasts released between 200 and 800 pmol of BH4/10(6) cells/day. Such engineered fibroblasts may be grafted into the central nervous system and used as depository cells for constitutive delivery of BH4.
 ...
PMID:Retrovirus-mediated double transduction of the GTPCH and PTPS genes allows 6-pyruvoyltetrahydropterin synthase-deficient human fibroblasts to synthesize and release tetrahydrobiopterin. 964 48

Fragile X syndrome is the most common form of inherited mental retardation, associated with both cognitive and behavioral anomalies. The disease is caused by silencing of the fragile X mental retardation 1 (fmr1) gene, which encodes the mRNA-binding, translational regulator FMRP. Previously we established a disease model through mutation of Drosophila fmr1 (dfmr1) and showed that loss of dFMRP causes defects in neuronal structure, function, and behavioral output similar to the human disease state. To uncover molecular targets of dFMRP in the brain, we use here a proteomic approach involving two-dimensional difference gel electrophoresis analyses followed by mass spectrometry identification of proteins with significantly altered expression in dfmr1 null mutants. We then focus on two misregulated enzymes, phenylalanine hydroxylase (Henna) and GTP cyclohydrolase (Punch), both of which mediate in concert the synthetic pathways of two key monoamine neuromodulators, dopamine and serotonin. Brain enzymatic assays show a nearly 2-fold elevation of Punch activity in dfmr1 null mutants. Consistently brain neurochemical assays show that both dopamine and serotonin are significantly increased in dfmr1 null mutants. At a cellular level, dfmr1 null mutant neurons display a highly significant elevation of the dense core vesicles that package these monoamine neuromodulators for secretion. Taken together, these data indicate that dFMRP normally down-regulates the monoamine pathway, which is consequently up-regulated in the mutant condition. Elevated brain levels of dopamine and serotonin provide a plausible mechanistic explanation for aspects of cognitive and behavioral deficits in human patients.
 ...
PMID:Protein expression profiling of the drosophila fragile X mutant brain reveals up-regulation of monoamine synthesis. 1563 90