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)

Three people applied for genetic counselling, but during the consultations the clinical geneticist discovered other problems for which advice could have been given but was not asked. This caused a serious dilemma. The first person was a woman who wanted to know the risks of epilepsy for her potential offspring, but then it became clear that she appeared to have Huntington's disease in the family. The second person was a man who wanted to know about the genetic risks for his offspring of a borderline psychiatric disorder, but the geneticist, seeing that the partner had severe limb defects, wondered whether these were caused by a genetic disorder. The third patient was a pregnant woman who came asking about the risks caused by mental retardation in one of her ancestors, but who appeared to be a heavy drinker and user of cocaine and ecstasy. In dealing with such 'secondary' problems, it should be kept in mind that persons seeking advice must decide for themselves whether or not they want to be informed regarding these problems or not.
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PMID:[Genetic counseling: should side issues become main issues?]. 954 32

Dynamic mutations are a new type of genetic alteration identified in recent years. They are due to an increased number of repetitions of a particular trinucleotide and are associated with a particular group of neurological and/or neuromuscular disorders. They are characterized by intergenerational and intragenerational instability. There is an inversely proportional relationship between the number of repetitions and the age at which the first symptoms are seen (genetic anticipation). To date 13 disorders, due to this type of mutation, have been described. Some, such as sex-linked mental retardation (fragile X), myotonic dystrophy or Friedreich's ataxia involve an anomalous number of repetitions, reaching over a thousand of a given trinucleotide. Another group known as the polyglutamine disorders, since the CAG trinucleotide is repeated in all cases (dominant and familial ataxias, Huntington's disease) have an increased number of repetitions but there are less than a hundred of them. Finally, recently a third group has been described, oculo-pharyngeal dystrophy with less than a dozen repetitions. Why an increased number of repetitions of a trinucleotide found in or out of a gene is associated with a particular disorder is one of the questions raised by these mutations and which is starting to be discovered.
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PMID:[Clinical and genetic implications of dynamic mutations in neuropediatric practice]. 1010 67

In patients with neurodegenerative disorders, namely Alzheimer's disease and Huntington's disease, we compared serum concentrations of tryptophan, kynurenine and the kynurenine per tryptophan ratio with concentrations of soluble immune activation markers. Significantly lower tryptophan concentrations were observed in the patients, and lower tryptophan levels as well as higher kynurenine levels and higher kynurenine per tryptophan ratios correlated with higher concentrations of neopterin, and soluble receptors for TNF and interleukin-2. In both groups of patients tryptophan concentrations correlated inversely with the degree of mental retardation. No such association existed for the duration of the disease. The data show that systemic chronic immune activation in patients with Alzheimer's disease and Huntington's disease is associated with significant degradation of tryptophan, which is most likely due to activation of indoleamine (2,3)-dioxygenase by immunologic stimuli. Further studies will be necessary to investigate a potential role of tryptophan degradation in the pathogenesis of neurodegenerative disorders.
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PMID:Degradation of tryptophan in neurodegenerative disorders. 1072 Oct 50

New hopes for cloning susceptibility genes for schizophrenia and bipolar affective disorder followed the discovery of a novel type of DNA mutation, namely unstable DNA. One class of unstable DNA, trinucleotide repeat expansion, is the causal mutation in myotonic dystrophy, fragile X mental retardation, Huntington disease and a number of other rare Mendelian neurological disorders. This finding has led researchers in psychiatric genetics to search for unstable DNA sites as susceptibility factors for schizophrenia and bipolar affective disorder. Increased severity and decreased age at onset of disease in successive generations, known as genetic anticipation, was reported for undifferentiated psychiatric diseases and for myotonic dystrophy early in the twentieth century, but was initially dismissed as the consequence of ascertainment bias. Because unstable DNA was demonstrated to be a molecular substrate for genetic anticipation in the majority of trinucleotide repeat diseases including myotonic dystrophy, many recent studies looking for genetic anticipation have been performed for schizophrenia and bipolar affective disorder with surprisingly consistent positive results. These studies are reviewed, with particular emphasis placed on relevant sampling and statistical considerations, and concerns are raised regarding the interpretation of such studies. In parallel, molecular genetic investigations looking for evidence of trinucleotide repeat expansion in both schizophrenia and bipolar disorder are reviewed. Initial studies of genome-wide trinucleotide repeats using the repeat expansion detection technique suggested possible association of large CAG/CTG repeat tracts with schizophrenia and bipolar affective disorder. More recently, three loci have been identified that contain large, unstable CAG/CTG repeats that occur frequently in the population and seem to account for the majority of large products identified using the repeat expansion detection method. These repeats localize to an intron in transcription factor gene SEF2-1B at 18q21, a site named ERDA1 on 17q21 with no associated coding region, and the 3' end of a gene on 13q21, SCA8, that is believed to be responsible for a form of spinocerebellar ataxia. At present no strong evidence exists that large repeat alleles at either SEF2-1B or ERDA1 are involved in the etiology of schizophrenia or bipolar disorder. Preliminary evidence suggests that large repeat alleles at SCA8 that are non-penetrant for ataxia may be a susceptibility factor for major psychosis. A fourth, but much more infrequently unstable CAG/CTG repeat has been identified within the 5' untranslated region of the gene, MAB21L1, on 13q13. A fifth CAG/CTG repeat locus has been identified within the coding region of an ion transporter, KCNN3 (hSKCa3), on 1q21. Although neither large alleles nor instability have been observed at KCNN3, this repeat locus has been extensively analyzed in association and family studies of major psychosis, with conflicting findings. Studies of polyglutamine containing genes in major psychosis have also shown some intriguing results. These findings, reviewed here, suggest that, although a major role for unstable trinucleotides in psychosis is unlikely, involvement at a more modest level in a minority of cases cannot be excluded, and warrants further investigation.
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PMID:The unstable trinucleotide repeat story of major psychosis. 1081 8

Wolf-Hirschhorn syndrome (WHS) is a deletion syndrome caused by segmental haploidy of chromosome 4p16.3. Its hallmark features include a 'Greek warrior helmet' facial appearance, mental retardation, various midline defects and seizures. The WHS critical region (WHSCR) lies between the Huntington's disease gene, HD, and FGFR3. In mice, the homologs of these genes map to chromosome 5 in a region of conserved synteny with human 4p16.3. To derive mouse models of WHS and map genes responsible for subphenotypes of the syndrome, five mouse lines bearing radiation-induced deletions spanning the WHSCR syntenic region were generated and characterized. Similar to WHS patients, these animals were growth-retarded, were susceptible to seizures and showed midline (palate closure, tail kinks), craniofacial and ocular anomalies (colobomas, corneal opacities). Other phenotypes included cerebellar hypoplasia and a shortened cerebral cortex. Expression of WHS-like traits was variable and influenced by strain background and deletion size. These mice represent the first animal models for WHS. This collection of nested chromosomal deletions will be useful for mapping and identifying loci responsible for the various subphenotypes of WHS, and provides a paradigm for the dissection of other deletion syndromes using the mouse.
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PMID:Mouse models for the Wolf-Hirschhorn deletion syndrome. 1115 56

Neurological and psychiatric illnesses are among the most common and most serious health problems in developed societies. The most promising advances in neurological and psychiatric diseases will require advances in neuroscience for their elucidation, prevention, and treatment. Technical advances have improved methods for identifying brain regions involved during various types of cognitive activity, for tracing connections between parts of the brain, for visualizing individual neurons in living brain preparations, for recording the activities of neurons, and for studying the activity of single-ion channels and the receptors for various neurotransmitters. The most significant advances in the past 20 years have come from the application to the nervous system of molecular genetics and molecular cell biology. Discovery of the monogenic disorder responsible for Huntington disease and understanding its pathogenesis can serve as a paradigm for unraveling the much more complex, polygenic disorders responsible for such psychiatric diseases as schizophrenia, manic depressive illness, and borderline personality disorder. Thus, a new degree of cooperation between neurology and psychiatry is likely to result, especially for the treatment of patients with illnesses such as autism, mental retardation, cognitive disorders associated with Alzheimer and Parkinson disease that overlap between the 2 disciplines.
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PMID:Prospects for neurology and psychiatry. 1117 65

Aggressive behavior has been associated with numerous neurologic conditions including traumatic brain injury, mental retardation, developmental disorders, Huntington disease, and several dementias. Preclinical and human studies suggest that dysfunction of neural systems involving the brainstem, hypothalamus, amygdala, or prefrontal cortex can give rise to aggression. Several neurochemicals are felt to be relevant to modulation of aggression, including serotonin, dopamine, norepinephrine, GABA, acetylcholine, and androgens. Pharmacologic intervention studies have targeted these systems but have been limited by inconsistent definitions of aggression and a relative paucity of controlled trials. This article briefly reviews studies of neural systems and medication trials relevant to aggression and propose a clinical approach to treatment of patients manifesting aggressive behavior.
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PMID:Pharmacologic approach to aggression in neuropsychiatric disorders. 1129 Oct 20

The present review on the pharmacological reactivation of inactive genes focuses on our experience with the fragile X syndrome. The fragile X syndrome of mental retardation is the prototype of a series of inherited neurological disorders caused by abnormal expansion of repeated trinucleotide sequences embedded in various genes. In a number of these disorders, such as Huntington disease and several forms of spinocerebellar ataxias, the expanded CAG repeat is translated, resulting in a polyglutamine-containing protein that indirectly causes neurodegeneration. On the contrary, in the fragile X syndrome, the expanded CGG repeat is contained in the regulatory region of the FMR1 gene and causes transcriptional inactivation. The mutation spares the coding region of the FMR1 gene, which potentially would allow synthesis of a normal protein if transcription could be restored. This prompted us to try and reactivate the gene function with different pharmacological regimens. We discuss our successful results with DNA demethylating and histone hyperacetylating drugs and their implications for future treatments of the fragile X syndrome.
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PMID:Pharmacological reactivation of inactive genes: the fragile X experience. 1171 76

Dentatorubral-pallidoluysian atrophy is a rare autosomal-dominant neurodegenerative disorder caused by an expansion of a CAG repeat in the atrophin-1 gene on chromosome 12. Dentatorubral-pallidoluysian atrophy is characterized clinically by prominent anticipation and a wide variety of symptoms that depend on age of onset and number of trinucleotide repeats. The juvenile type of dentatorubral-pallidoluysian atrophy, like Huntington's disease, is most commonly inherited via paternal transmission of the gene and most frequently presents with early-onset progressive myoclonus epilepsy with mental retardation and ataxia. We present six affected individuals with dentatorubral-pallidoluysian atrophy from a black family living in North America. This pedigree includes two severe juvenile-onset cases, one of maternal transmission and the other of paternal transmission. Both cases of juvenile-onset disease presented with autistic features and seizures. Interestingly, cranial magnetic resonance imaging performed on the more affected child revealed only mild cerebellar atrophy. The present family expands the clinical description of juvenile-onset dentatorubral-pallidoluysian atrophy and emphasizes the importance of considering dentatorubral-pallidoluysian atrophy in children with progressive myoclonus epilepsy.
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PMID:Juvenile dentatorubral-pallidoluysian atrophy: new clinical features. 1181 36

Major achievements made over the last several years have highlighted the important roles of creatine and the creatine kinase reaction in health and disease. Inborn errors of metabolism have been identified in the three main steps involved in creatine metabolism: arginine:glycine amidinotransferase (AGAT), S-adenosyl-L-methionine:N-guanidinoacetate methyltransferase (GAMT), and the creatine transporter. All these diseases are characterized by a lack of creatine and phosphorylcreatine in the brain, and by (severe) mental retardation. Similarly, knockout mice lacking the brain cytosolic and mitochondrial isoenzymes of creatine kinase displayed a slightly increased creatine concentration, but no phosphorylcreatine in the brain. These mice revealed decreased weight gain and reduced life expectancy, disturbed fat metabolism, behavioral abnormalities and impaired learning capacity. Oral creatine supplementation improved the clinical symptoms in both AGAT and GAMT deficiency, but not in creatine transporter deficiency. In addition, creatine supplementation displayed neuroprotective effects in several animal models of neurological disease, such as Huntington's disease, Parkinson's disease, or amyotrophic lateral sclerosis. All these findings pinpoint to a close correlation between the functional capacity of the creatine kinase/phosphorylcreatine/creatine system and proper brain function. They also offer a starting-point for novel means of delaying neurodegenerative disease, and/or for strengthening memory function and intellectual capabilities.Finally, creatine biosynthesis has been postulated as a major effector of homocysteine concentration in the plasma, which has been identified as an independent graded risk factor for atherosclerotic disease. By decreasing homocysteine production, oral creatine supplementation may, thus, also lower the risk for developing, e.g., coronary heart disease or cerebrovascular disease. Although compelling, these results require further confirmation in clinical studies in humans, together with a thorough evaluation of the safety of oral creatine supplementation.
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PMID:Health implications of creatine: can oral creatine supplementation protect against neurological and atherosclerotic disease? 1204 43


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