Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Congenital ornithine transcarbamylase (OTC) deficiency is the most common inborn error of urea cycle enzymes in humans. A large percentage of survivors of neonatal OTC deficiency suffer severe developmental disorders, including seizures, mental retardation and cerebral palsy. Neuropathological studies reveal ventricular enlargement, cerebral atrophy and delayed myelination, as well as Alzheimer type II astrocytosis. Using the sparse-fur (spf) mouse model of congenital OTC deficiency, studies of central cholinergic integrity revealed a developmental delay in choline acetyltransferase activity and of high-affinity [3H]-choline uptake in several brain structures. Subsequent studies of muscarinic cholinergic binding site distribution showed a widespread loss of M1 sites, consistent with cholinergic cell loss. These alterations are similar to those reported in Alzheimer's disease, suggesting that the severe cognitive dysfunction in congenital OTC deficiency may at least partly result from a muscarinic cholinergic lesion. Possible mechanisms involved in the pathogenesis of cholinergic cell loss in congenital OTC deficiency include ammonia-induced inhibition of pyruvate and alpha-oxoglutarate oxidation, resulting in decreased synthesis of acetyl CoA and a cerebral energy deficit, as well as NMDA receptor-mediated excitotoxicity. Treatment of spf mice with acetyl-L-carnitine (ALCAR) results in partial recovery of the developmental choline acetyltransferase deficit, suggesting a potential therapeutic benefit of ALCAR in congenital OTC deficiency. Other therapies currently used include ammonia-lowering strategies (using sodium benzoate or sodium phenylacetate) and, in severe cases, liver transplantation.
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PMID:Evidence for a central cholinergic deficit in congenital ornithine transcarbamylase deficiency. 977 87

Phenylketonuria (PKU), with its associated hyperphenylalaninemia (HPA) and mental retardation, is a classic genetic disease and the first to have an identified chemical cause of impaired cognitive development. Treatment from birth with a low phenylalanine diet largely prevents the deviant cognitive phenotype by ameliorating HPA and is recognized as one of the first effective treatments of a genetic disease. However, compliance with dietary treatment is difficult and when it is for life, as now recommended by an internationally used set of guidelines, is probably unrealistic. Herein we describe experiments on a mouse model using another modality for treatment of PKU compatible with better compliance using ancillary phenylalanine ammonia lyase (PAL, EC 4.3.1.5) to degrade phenylalanine, the harmful nutrient in PKU; in this treatment, PAL acts as a substitute for the enzyme phenylalanine monooxygenase (EC 1.14.16.1), which is deficient in PKU. PAL, a robust enzyme without need for a cofactor, converts phenylalanine to trans-cinnamic acid, a harmless metabolite. We describe (i) an efficient recombinant approach to produce PAL enzyme, (ii) testing of PAL in orthologous N-ethyl-N'-nitrosourea (ENU) mutant mouse strains with HPA, and (iii) proofs of principle (PAL reduces HPA)-both pharmacologic (with a clear dose-response effect vs. HPA after PAL injection) and physiologic (protected enteral PAL is significantly effective vs. HPA). These findings open another way to facilitate treatment of this classic genetic disease.
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PMID:A different approach to treatment of phenylketonuria: phenylalanine degradation with recombinant phenylalanine ammonia lyase. 1005 48

Hyperammonemia is mainly found in hepatic encephalopathy and in genetic defects of the urea cycle or other pathways of the intermediary metabolism. Clinically a difference has to be made between chronic moderate hyperammonemia and acutely increased concentrations. Pathogenetic mechanisms of ammonia toxicity to the brain are partly unraveled. In some animal models confounding variables, such as the reduced intake of food and amino acid imbalance due to liver insufficiency, do not allow to establish unequivocal causal relationships between the ammonia concentration and measured effects. In chronic moderate hyperammonemia an increased flux through the serotonin pathway is a key factor. It is caused by an increased transport of large neutral amino acids (including tryptophan) through the blood-brain barrier, accentuated by the imbalance of plasma amino acids in hepatic insufficiency. It is stimulated by D- or L-glutamine. Evidence is presented showing that a functioning gamma-glutamyl cycle (glutathione formation) is a prerequisite. In acute hyperammonemia involvement of NMDA receptors, glutamate, NO and cGMP plays an additional role. In hyperammonemic crises the increased cerebral blood flow leads to brain edema; factors discussed here are increased osmolytes in astrocytes and serotoninergic activity. Recent data indicate that axonal development is affected by ammonia and can be normalized in vitro by creatine supplementation in developing mixed brain cell aggregate cultures, thus reviving the old hypothesis of the impact of hyperammonemia on energy metabolism in the developing brain that could cause mental retardation.
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PMID:Mechanisms of hyperammonemia. 1224 Oct 9

Hyperammonemia is a common finding in children with methylmalonic acidemia, an inherited metabolic disease characterized by mental retardation, convulsions, and accumulation of methylmalonic acid (MMA). Although it has been suggested that MMA induces convulsions through succinate dehydrogenase (SDH) inhibition, very little is known about the contribution of hyperammonemia to the development of convulsions in these patients. In the present study we investigated the effects of ammonium ions on the convulsant action of MMA, MMA-induced inhibition of striatal succinate dehydrogenase, and the striatal content of thiobarbituric acid-reactive substances (TBARS). Adult rats were injected with ammonium acetate (1.5 mmol/kg, sc) or sodium acetate (1.5 mmol/kg, sc), followed 5 min later by buffered MMA (3 micromol/microl) or NaCl (4.5 micromol/microl) injected into the striatum. The animals were observed in an open field for the appearance of convulsive episodes. After 30 min of behavioral evaluation, the animals were sacrificed and had their striatal TBARS content measured. Ammonium acetate pretreatment caused no behavioral effects per se, but potentiated MMA-induced convulsions and increased basal TBARS content and MMA-induced TBARS production in the striatum. Ammonium chloride had no effect on basal succinate dehydrogenase activity and did not alter MMA-induced inhibition of SDH in vitro. These results suggest that ammonia potentiates MMA-induced behavioral effects through a mechanism that does not involve further succinate dehydrogenase inhibition, but may involve facilitation of MMA-induced oxidative damage and provide evidence that ammonia and MMA may have mutually additive toxicity.
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PMID:Ammonia potentiates methylmalonic acid-induced convulsions and TBARS production. 1289 56

A de novo deletion of the long arm of chromosome 2 at 2q31-33 was observed in the fetal amniocyte G-banded karyotype performed because of possible multiple malformations identified by ultrasound at 23 weeks gestation. Two days after the uneventful term delivery of a 2.45 kg male, the neonate experienced cardiopulmonary decompensation and biochemical changes compatible with carbamoyl phosphate synthetase I (CPS I) deficiency (elevated ammonia with a peak of 948 micromol/L, deficiency of citrulline, and no increase in orotic acid). The child died on day 3 of life. Physical anomalies confirmed at autopsy included double superior vena cava, ectopic adrenal tissue, and metatarsus adductus. The autopsy also revealed histologic evidence consistent with CPS deficiency, most notably microvesicular steatosis of the liver and Alzheimer's Type II changes with hypertrophic astrocytes in the basal ganglia. A postnatal lymphocyte karyotype confirmed the chromosome 2q31-33 deletion. Enzyme analysis on postmortem liver tissue confirmed the diagnosis of CPS deficiency. CPS I is reported to be mapped to 2q35 by NCBI (http://www.ncbi.nlm.nih.gov/mapview/) and 2q34 by ENSEMBL (http://www.ensembl.org/). The UCSC Human Genome Browser July 2003 assembly also places the gene at 2q34 (http://genome.UCSC.edu/). Fluorescence in situ hybridization (FISH) analysis with a BAC clone (RP11-349G4) of CPS I demonstrated that one copy of the gene was deleted in this infant. Using additional probes corresponding to the bands in the region of deletion, we identified the deleted region as 2q32-2q34. Our observations support the CPS I map position (ENSEMBL, UCSC) at 2q34. Additionally, potential conditions associated with deletions narrowly defined by standard cytogenetic techniques merit consideration in prenatal counseling. As demonstrated here, deletions may not only result in malformations and mental retardation but also increase the likelihood of revealing mutated genes located in the undeleted region of the homologous chromosome.
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PMID:Interstitial deletion of chromosome 2q32-34 associated with multiple congenital anomalies and a urea cycle defect (CPS I deficiency). 1521 54

Histidinemia (MIM235800) is characterized by elevated histidine in body fluids and decreased urocanic acid in blood and skin and results from histidase (histidine ammonia lyase, EC 4.3.1.3) deficiency. It is the most frequent inborn metabolic error in Japan. Although the original description included mental retardation and speech impairment, neonatal screening programs have identified the majority of histidinemic patients with normal intelligence. Molecular characteristics of histidase in histidinemia have not been determined, and cytogenetically visible deletions of 12q22-24.1 in which histidase gene resides have not been identified in histidinemic patients. In order to investigate whether individuals with this disorder have small deletions, additions, or point mutations in the histidase gene, we screened genomic DNA isolated from 50 histidinemic individuals who were discovered by the neonatal screening program. The methods employed included polymerase chain reaction (PCR) amplification of exons 1-21 of the histidase gene, followed by mutation detection enhancement gel electrophoresis and sequencing of the PCR products displaying heteroduplex bands. Four missense mutations (R322P, P259L, R206T, and R208L), two exonic polymorphisms (T141T c.423A-->T and P259P c.777A-->G), and two intronic polymorphisms (IVS6-5T-->C and IVS9+25A-->G) were identified. The frequencies of each polymorphism estimated either by dot blot allele-specific oligonucleotide hybridization, restriction enzyme digestion, or direct sequencing of the PCR products amplified from 50 unrelated normal individuals were 0.28, 0.30, 0.40, and less than 0.01, respectively. Mutation analysis of one family demonstrated that the patient inherited R322P from the mother and P259L from the father. This report describes the first mutations occurring in the coding region of the histidase structural gene in patients with histidinemia.
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PMID:Molecular characterization of histidinemia: identification of four missense mutations in the histidase gene. 1580 99

Structure-based protein engineering coupled with chemical modifications (e.g., pegylation) is a powerful combination to significantly improve the development of proteins as therapeutic agents. As a test case, phenylalanine ammonia-lyase (PAL, EC 4.3.1.5) was selected for enzyme replacement therapy in phenylketonuria [C.R. Scriver, S. Kaufman, Hyperphenylalaninemia:phenylalanine Hydroxylase Deficiency. The Metabolic and Molecular Bases of Inherited Disease, McGraw-Hill, New York, 2001, Chapter 77], an inherited metabolic disorder (OMIM 261600) causing mental retardation due to deficiency of the enzyme l-phenylalanine hydroxylase (EC 1.14.16.1). Previous in vivo studies of recombinant PAL demonstrated a lowering of blood l-phenylalanine levels; yet, the metabolic effect was not sustained due to protein degradation and immunogenicity [C.N. Sarkissian, Z. Shao, F. Blain, R. Peevers, H. Su, R. Heft, T.M. Chang, C.R. Scriver, A different approach to treatment of phenylketonuria:phenylalanine degradation with recombinant phenylalanine ammonia lyase, Proc. Natl. Acad. Sci. USA 96 (1999) 2339; J.A. Hoskins, G. Jack, H.E. Wade, R.J. Peiris, E.C. Wright, D.J. Starr, J. Stern, Enzymatic control of phenylalanine intake in phenylketonuria, Lancet 1 (1980) 392; C.M. Ambrus, S. Anthone, C. Horvath, K. Kalghatgi, A.S. Lele, G. Eapen, J.L. Ambrus, A.J. Ryan, P. Li, Extracorporeal enzyme reactors for depletion of phenylalanine in phenylketonuria, Ann. Intern. Med. 106 (1987) 531]. Here, we report the 1.6A three-dimensional structure of Rhodosporidium toruloides PAL, structure-based molecular engineering, pegylation of PAL, as well as in vitro and in vivo PKU mouse model studies on pegylated PAL formulations. Our results show that pegylation of R. toruloides PAL leads to promising therapeutic efficacy after subcutaneous injection by enhancing the in vivo activity, lowering plasma phenylalanine, and leading to reduced immunogenicity. The three-dimensional structure of PAL provides a basis for understanding the properties of pegylated forms of PAL and strategies for structure-based re-engineering of PAL for PKU treatment.
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PMID:Structure-based chemical modification strategy for enzyme replacement treatment of phenylketonuria. 1600 65

Phenylketonuria (PKU) is an autosomal recessive genetic disorder in which mutations in the phenylalanine-4-hydroxylase (PAH) gene result in an inactive enzyme (PAH, EC 1.14.16.1). The effect is an inability to metabolize phenylalanine (Phe), translating into elevated levels of Phe in the bloodstream (hyperphenylalaninemia). If therapy is not implemented at birth, mental retardation can occur. PKU patients respond to treatment with a low-phenylalanine diet, but compliance with the diet is difficult, therefore the development of alternative treatments is desirable. Enzyme substitution therapy with a recombinant phenylalanine ammonia lyase (PAL) is currently being explored. This enzyme converts Phe to the harmless metabolites, trans-cinnamic acid and trace ammonia. Taken orally and when non-absorbable and protected, PAL lowers plasma Phe in mutant hyperphenylalaninemic mouse models. Subcutaneous administration of PAL results in more substantial lowering of plasma and significant reduction in brain Phe levels, however the metabolic effect is not sustained following repeated injections due to an immune response. We have chemically modified PAL by pegylation to produce a protected form of PAL that possesses better specific activity, prolonged half-life, and reduced immunogenicity in vivo. Subcutaneous administration of pegylated molecules to PKU mice has the desired metabolic response (prolonged reduction in blood Phe levels) with greatly attenuated immunogenicity.
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PMID:Phenylalanine ammonia lyase, enzyme substitution therapy for phenylketonuria, where are we now? 1616 90

Acute hyperammonemia (HA) causes cerebral edema and brain damage in children with urea cycle disorders (UCDs) and in patients in acute liver failure. Chronic HA is associated with developmental delay and mental retardation in children with UCDs, and with neuropsychiatric symptoms in patients with chronic liver failure. Astrocytes are a major cellular target of hyperammonemic encephalopathy, and changes occurring in these cells are thought to be causally related to the brain edema of acute HA. To study the effect of HA on astrocytes in vivo, we crossed the Otc(spf) mouse, a mouse with the X-linked UCD ornithine transcarbamylase (OTC) deficiency, with the hGFAP-EGFP mouse, a mouse selectively expressing green fluorescent protein in astrocytes. We used FACS to purify astrocytes from the brains of hyperammonemic and healthy Otcspf/GFAP-EGFP mice. RNA isolated from these astrocytes was used in microarray expression analyses and qRT-PCR. When compared with healthy littermates, we observed a significant downregulation of the gap-junction channel connexin 43 (Cx43) the water channel aquaporin 4 (Aqp4) genes, and the astrocytic inward-rectifying potassium channel (Kir) genes Kir4.1 and Kir5.1 in hyperammonemic mice. Aqp4, Cx43, and Kir4.1/Kir5.1 are co-localized to astrocytic end-feet at the brain vasculature, where they regulate potassium and water transport. Since, NH4+ ions can permeate water and K+-channels, downregulation of these three channels may be a direct effect of elevated blood ammonia levels. Our results suggest that alterations in astrocyte-mediated water and potassium homeostasis in brain may be key to the development of the brain edema.
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PMID:Gene expression profiling of astrocytes from hyperammonemic mice reveals altered pathways for water and potassium homeostasis in vivo. 1818 79

Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder characterized by rod-cone dystrophy, polydactyly, central obesity, mental retardation, and hypogonadism. Although many organs are involved in BBS, hyperammonemia caused by portal hypertension has been reported previously in only a single patient. We describe the second such patient with BBS and hyperammonemia, associated with fluctuating mental impairment. The patient was a 17-year-old boy with BBS. Esophageal, gastric, and rectal varices and mild hepatic dysfunction started to develop at 5 years of age. A liver biopsy showed dilated portal veins with mild fibrosis in portal tract. From the age of 17 years, he often had forced laughter with apparently normal consciousness. Laboratory examinations revealed hyperammonemia (112.2mg/ml). Oral medication lowered the blood ammonia level to 69.9 mg/ml, reduced the frequency of forced laughter, and improved his IQ. Patients with BBS may have additional diseases or conditions that affect mental status, such as hyperammonemia. Physicians should explore the underlying causes of these conditions and treat such patients, who already have a compromised quality of life.
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PMID:Treatable fluctuating mental impairment in a patient with Bardet-Biedl syndrome. 1893 27


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