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 insensitivity to pain is a rare hereditary sensory and autonomic neuropathy (HSAN). This disorder is an autosomal recessive condition: since 1996, mutations attributed to this entity have been found in the neurotrophin tyrosine-kinase gene receptor on chromosome 1. The authors report 3 cases of congenital insensitivity to pain. In these 3 sisters of consanguineous parents, the clinical investigation showed total absence of pain and temperature sensations with preservation of all other sensory modalities, mental retardation, but in contrast to HSAN type IV, there was no anhidrosis. The neurophysiological investigation revealed an isolated axonal sensory polyneuropathy in the 3 patients. The clinical and neurophysiological investigations were normal in both parents and the brother. The physiopathology of this entity is discussed. We suggest a particular form of HSAN type IV with preservation of transpiration or a new entity of congenital insensitivity to pain, which should be analyzed genetically.
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PMID:[Congenital insensitivity to pain: clinical and neurophysiological study in three sisters of a Moroccan family]. 2409 59

Down's syndrome (DS), a major genetic cause of mental retardation, arises from triplication of genes on human chromosome 21. Here we show that DYRK1A (dual-specificity tyrosine-phosphorylated and -regulated kinase 1A) and DSCR1 (DS critical region 1), two genes lying within human chromosome 21 and encoding for a serine/threonine kinase and calcineurin regulator, respectively, are expressed in neural progenitors in the mouse developing neocortex. Increasing the dosage of both proteins in neural progenitors leads to a delay in neuronal differentiation, resulting ultimately in alteration of their laminar fate. This defect is mediated by the cooperative actions of DYRK1A and DSCR1 in suppressing the activity of the transcription factor NFATc. In Ts1Cje mice, a DS mouse model, dysregulation of NFATc in conjunction with increased levels of DYRK1A and DSCR1 was observed. Furthermore, counteracting the dysregulated pathway ameliorates the delayed neuronal differentiation observed in Ts1Cje mice. In sum, our findings suggest that dosage of DYRK1A and DSCR1 is critical for proper neurogenesis through NFATc and provide a potential mechanism to explain the neurodevelopmental defects in DS.
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PMID:Increased dosage of DYRK1A and DSCR1 delays neuronal differentiation in neocortical progenitor cells. 2435 25

Down syndrome is the most common aneuploidy. It is caused by the presence of an extra copy of chromosome 21. Several studies indicate that aberrant expression of the kinase Dyrk1a (dual-specificity tyrosine phosphorylation-regulated kinase 1a) is implicated in Down syndrome, in particular in the onset of mental retardation. Moreover, elevated Dyrk1a activity may also be a risk factor for other neurodegenerative disorders such as Alzheimer's disease. Over the past years, Dyrk1a has appeared as a potential drug target. Availability of sensitive and quantitative enzyme assays is of prime importance to understand the role of Dyrk1a and to develop specific inhibitors. Here, we describe a new method to measure Dyrk1a activity based on the separation and quantification of specific fluorescent peptides (substrate and phosphorylated product) by high-performance liquid chromatography (HPLC). Kinetic and mechanistic analyses using well-known inhibitors of Dyrk1a confirmed the reliability of this approach. In addition, this assay was further validated using brain extracts of mice models expressing different copies of the Dyrk1a gene. Our results indicate that this novel Dyrk1a assay is simple, sensitive, and specific. It avoids the use of radioactivity-based approaches that, until now, have been widely employed to measure Dyrk1a activity.
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PMID:A high-performance liquid chromatography assay for Dyrk1a, a Down syndrome-associated kinase. 2437

Down syndrome (DS) is one of the most common genetic disorders accompanying with mental retardation, cognitive impairment, and deficits in learning and memory. The brains with DS also display many neuropathological features including alteration in neurogenesis and synaptogenesis and early onset of Alzheimer's disease (AD)-like symptoms. Triplication of all or a part of human chromosome 21, especially the 21q22.1~21q22.3 region called 'Down syndrome critical region (DSCR)', has been considered as the main cause of DS. One gene product of DSCR, dual-specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A), has been highlighted as a key contributor to the neural consequences of DS. This minireview summarizes accumulating recent reports about Dyrk1A involvement in the neuritogenesis, synaptogenesis, and AD-like neurofibrillary tangle formation, which is mainly focusing on Dyrk1A-mediated regulation of cytoskeletal proteins, such as tubulin, actin, and microtubule-associated protein tau. Understanding the molecular mechanisms of these phenomena may provide us a rational for new preventive and therapeutic treatment of DS.
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PMID:New Perspectives of Dyrk1A Role in Neurogenesis and Neuropathologic Features of Down Syndrome. 2446 39

Tyrosinemia type II is an inborn error of metabolism caused by a deficiency in hepatic cytosolic aminotransferase. Affected patients usually present a variable degree of mental retardation, which may be related to the level of plasma tyrosine. In the present study we evaluated effect of chronic administration of L-tyrosine on the activities of citrate synthase, malate dehydrogenase, succinate dehydrogenase and complexes I, II, II-III and IV in cerebral cortex, hippocampus and striatum of rats in development. Chronic administration consisted of L-tyrosine (500 mg/kg) or saline injections 12 h apart for 24 days in Wistar rats (7 days old); rats were killed 12 h after last injection. Our results demonstrated that L-tyrosine inhibited the activity of citrate synthase in the hippocampus and striatum, malate dehydrogenase activity was increased in striatum and succinate dehydrogenase, complexes I and II-III activities were inhibited in striatum. However, complex IV activity was increased in hippocampus and inhibited in striatum. By these findings, we suggest that repeated administrations of L-tyrosine cause alterations in energy metabolism, which may be similar to the acute administration in brain of infant rats. Taking together the present findings and evidence from the literature, we hypothesize that energy metabolism impairment could be considered an important pathophysiological mechanism underlying the brain damage observed in patients with tyrosinemia type II.
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PMID:The characterization of neuroenergetic effects of chronic L-tyrosine administration in young rats: evidence for striatal susceptibility. 2525 80

Phenylketonuria and hyperphenylalanemia are inborn errors in metabolism of phenylalanine arising from defects in steps to convert phenylalanine to tyrosine. Phe accumulation causes severe mental retardation that can be prevented by timely identification of affected individuals and their placement on a Phe-restricted diet. In spite of many studies in patients and animal models, the basis for acquisition of mental retardation during the critical period of brain development is not adequately understood. All animal models for human disease have advantages and limitations, and characteristics common to different models are most likely to correspond to the disorder. This study established similar levels of Phe exposure in developing rats between 3 and 16 days of age using three models to produce chronic hyperphenylalanemia, and identified changes in brain amino acid levels common to all models that persist for ~16 h of each day. In a representative model, local rates of glucose utilization (CMRglc) were determined at 25-27 days of age, and only selective changes that appeared to depend on Phe exposure were observed. CMRglc was reduced in frontal cortex and thalamus and increased in hippocampus and globus pallidus. Behavioral testing to evaluate neuromuscular competence revealed poor performance in chronically-hyperphenylalanemic rats that persisted for at least 3 weeks after cessation of Phe injections and did not occur with mild or acute hyperphenylalanemia. Thus, the abnormal amino acid environment, including hyperglycinemia, in developing rat brain is associated with selective regional changes in glucose utilization and behavioral abnormalities that are not readily reversed after they are acquired.
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PMID:Biochemical, Metabolic, and Behavioral Characteristics of Immature Chronic Hyperphenylalanemic Rats. 2622 89

Introduction. Congenital insensitivity to pain and anhidrosis (CIPA) or hereditary sensory and autonomic neuropathy type IV is an extremely rare syndrome. Three clinical findings define the syndrome: insensitivity to pain, impossibility to sweat, and mental retardation. This pathology is caused by a genetic mutation in the NTRK1 gene, which encodes a tyrosine receptor (TrkA) for nerve growth factor (NGF). Methods. The consultation of a child female in our center with CIPA and a tibia fracture in pseudoarthrosis encouraged us to carefully review literature and examine the therapeutic possibilities. A thorough review of literature published in Pubmed was done about CIPA and other connected medical issues mentioned in the paper. Conclusions. The therapeutic approach of CIPA remains unclear. The preventive approach remains the only possible treatment of CIPA. We propose two new important concepts in the therapeutic approach for these patients: (1) early surgical treatment for long bone fractures to prevent pseudoarthrosis and to allow early weight bearing, decreasing the risk of further osteopenia, and (2) bisphosphonates to avoid the progression of osteopenia and to reduce the number of consecutive fractures.
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PMID:Update Review and Clinical Presentation in Congenital Insensitivity to Pain and Anhidrosis. 2657 24

Hyperphenylalaninemia/phenylketonuria (PKU) is one of the most common inborn errors of amino acid metabolism affecting about 1:15,000 infants in the United States. PKU is an autosomal recessive disorder that if untreated results in mental retardation. The most common cause of PKU is deficiency of the enzyme phenylalanine hydroxylase that converts phenylalanine to tyrosine. Tyrosine deficiency results in impaired synthesis of catecholamines and thyroxine. Less commonly, it can result from defects in the synthesis or regeneration of tetrahydrobiopterin (BH4), an essential cofactor for the enzyme phenylalanine hydroxylase. Increased phenylalanine and decreased tyrosine in blood are used in the diagnosis and follow-up of patients with PKU. LC/MS/MS method is described for the quantification of phenylalanine and tyrosine.
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PMID:Determination of Phenylalanine and Tyrosine by High Performance Liquid Chromatography-Tandem Mass Spectrometry. 2660 33

Richner-Hanhart syndrome (RHS, tyrosinemia type II) is a rare, autosomal recessive inborn error of tyrosine metabolism caused by tyrosine aminotransferase deficiency. It is characterized by photophobia due to keratitis, painful palmoplantar hyperkeratosis, variable mental retardation, and elevated serum tyrosine levels. Patients are often misdiagnosed with herpes simplex keratitis. We report on a a boy from Brazil who presented with bilateral keratitis secondary to RHS, which had earlier been misdiagnosed as herpes simplex keratitis.
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PMID:Herpetiform keratitis and palmoplantar hyperkeratosis: warning signs for Richner-Hanhart syndrome. 2783 14

Phenylketonuria and tyrosinemia type II, the two metabolic disorders, are originated due to the complications in metabolism of phenylalanine (Phe) and tyrosine (Tyr), respectively. Several neurological injuries, involving microcephaly, mental retardation, epilepsy, motor disease, and skin problems etc., are the symptoms of these two diseases. It has been reported that toxic amyloid fibrils are formed at high concentrations of Phe and Tyr. Our study indicates that the fibril forming mechanisms of Phe and Tyr are completely different. In the case of Phe, -NH3+ and -COO- groups of neighboring molecules interact via hydrogen bonding and polar interactions. On the other hand, there is no role of - NH3+ group in the fibril forming mechanism of Tyr. In Tyr fibril, the two hydrogen bonding partners are -OH and -COO- groups. In addition, we have also investigated the effect of three lanthanide cations on the fibrillar assemblies of Phe. It has been observed that the efficiencies of three lanthanides to inhibit the fibrillar assemblies of Phe follow the order Tb3+< Sm3+< Eu3+.
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PMID:Investigation of Fibril Forming Mechanisms of l-Phenylalanine and l-Tyrosine: Microscopic Insight toward Phenylketonuria and Tyrosinemia Type II. 2812 42


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