Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fragile X syndrome is the leading inherited form of mental retardation, and second only to Down's syndrome as a cause of mental retardation attributable to an identifiable genetic abnormality. Fragile X syndrome is caused by a defect in the fragile X mental retardation 1 gene (FMR1), located near the end of the long arm of the X chromosome. FMR1 normally synthesises the fragile X protein (FMRP), but mutations in FMR1 lead to a lack of FMRP synthesis, resulting in fragile X syndrome. While the specific function of FMRP is not yet fully understood, the protein is known to be important for normal brain development. The physical, cognitive and behavioural features of individuals with fragile X syndrome depend on gender (females have two X chromosomes, one active and one inactive) and the molecular status of the mutation (premutation, full mutation or mosaic). Features of the behavioural profile of individuals with fragile X syndrome include hypersensitivity to stimuli, overarousability, inattention, hyperactivity and (mostly in men) explosive and aggressive behaviour to others or self. Social anxiety, other anxiety disorders, depression, impulse control disorder and mood disorders are the most common psychiatric disorders diagnosed in individuals with fragile X syndrome, although no formal studies have been undertaken. There have been very few psychopharmacological studies of the treatment of behaviours associated with fragile X syndrome. These limited studies and surveys of psychotropic drugs used in individuals with fragile X syndrome suggest that stimulants are helpful for hyperactivity, that alpha(2)-adrenoceptor agonists and beta-adrenoceptor antagonists help to control overarousability, impulsivity and aggressiveness, and that SSRIs can control anxiety, impulsivity and irritability, alleviate depressive symptoms and decrease aggressive and self-injurious behaviour. Typical and atypical antipsychotics in combination with other psychotropics have been used for control of psychotic disorders and severe aggressive behaviours. Mood stabilisers have been found to be useful when mood dysregulation or mood disorders are present with or without aggressive behaviour. Folic acid and L-acetylcarnitine (levacecarnine) have not been found to improve deficits or behaviours. As there is no specific psychotropic drug for any of the deficits or behaviours associated with fragile X syndrome, clinicians are advised to diagnose any psychiatric syndromes or disorders present and treat them with the appropriate psychotropic drug. If no psychiatric disorder can be diagnosed and the patient's challenging behaviours cannot be controlled with environmental manipulation or behaviour modification techniques, the most benign psychotropic drug should be used. Antipsychotics should be reserved for psychotic disorders, for impulse control disorders (used in combination with other psychotropics), or when challenging behaviours constitute an emergency. In the future, new medications targeting molecules implicated in the modulation of anxiety, fear and fear responding will be useful for treating the social anxiety and overarousability exhibited by individuals with fragile X syndrome.
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PMID:Neuropsychiatric symptoms of fragile X syndrome: pathophysiology and pharmacotherapy. 1533 Jun 85

MicroRNAs are a class of small endogenous noncoding RNAs which play important regulatory roles mainly by post-transcriptional depression. Finding miRNA target genes will help a lot to understand their biological functions. We developed an ensemble machine learning algorithm which helps to improve the prediction of miRNA targets. The performance was evaluated in the training set and in FMRP associated mRNAs. Moreover, using human mir-9 as a test case, our classification was validated in 9 of 15 transcripts tested. Finally, we applied our algorithm on the whole prediction data set provided by miRanda website. The results are available at http://www.biosino.org/~kanghu/mRTP/mRTP.html.
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PMID:Improving the prediction of human microRNA target genes by using ensemble algorithm. 1737 14

Group I metabotropic glutamate receptors (mGluR) induce long-term depression (LTD) that requires protein synthesis. Here, we demonstrate that Arc/Arg3.1 is translationally induced within 5 min of mGluR activation, and this response is essential for mGluR-dependent LTD. The increase in Arc/Arg3.1 translation requires eEF2K, a Ca(2+)/calmodulin-dependent kinase that binds mGluR and dissociates upon mGluR activation, whereupon it phosphorylates eEF2. Phospho-eEF2 acts to slow the elongation step of translation and inhibits general protein synthesis but simultaneously increases Arc/Arg3.1 translation. Genetic deletion of eEF2K results in a selective deficit of rapid mGluR-dependent Arc/Arg3.1 translation and mGluR-LTD. This rapid translational mechanism is disrupted in the fragile X disease mouse (Fmr1 KO) in which mGluR-LTD does not require de novo protein synthesis but does require Arc/Arg3.1. We propose a model in which eEF2K-eEF2 and FMRP coordinately control the dynamic translation of Arc/Arg3.1 mRNA in dendrites that is critical for synapse-specific LTD.
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PMID:Elongation factor 2 and fragile X mental retardation protein control the dynamic translation of Arc/Arg3.1 essential for mGluR-LTD. 1861 22

Fragile X syndrome (FXS) is the most common form of inherited mental retardation. The syndrome results from the absence of the fragile X mental retardation protein (FMRP), which is encoded by the fragile X mental retardation 1 (FMR1) gene. FMR1 and its two paralogs, fragile X-related genes 1 and 2 (FXR1 and -2), form the Fmr1 gene family. Here, we examined long-lasting synaptic plasticity in Fmr1 knockout, Fxr2 knockout, and Fmr1/Fxr2 double knockout mice. We found that metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) in the hippocampus was affected in Fmr1 knockout, Fxr2 knockout, and Fmr1/Fxr2 double knockout mice at young ages (4-6 wk old). In addition, Fmr1/Fxr2 double knockout mice showed significant deficiencies relative to either Fmr1 or Fxr2 knockout mice in baseline synaptic transmission and short-term presynaptic plasticity, suggesting FMRP and FXR2P may contribute in a cooperative manner to pathways regulating presynaptic plasticity. However, compared with wild-type littermates, late-phase long-term potentiation (L-LTP) was unaltered in all knockout mice at 4-6 mo of age. Interestingly, although Fmr1/Fxr2 double knockout mice exhibited a more robust enhancement in mGluR-LTD compared with that in Fmr1 knockout mice, Fxr2 knockout mice exhibited reduced mGluR-LTD. Furthermore, unlike Fmr1 knockout mice, mGluR-LTD in Fxr2 knockout mice required new protein synthesis, whereas mGluR-LTD in Fmr1/Fxr2 double knockout mice was partially dependent on protein synthesis. These results indicated that both FMRP and FXR2P function in synaptic plasticity and that they likely operate in related but independent pathways.
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PMID:Altered hippocampal synaptic plasticity in the FMR1 gene family knockout mouse models. 1924 59

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by a CGG repeat expansion in the premutation range (55-200) in the fragile X mental retardation 1 gene. Onset is typically in the early seventh decade, and men are principally affected. The major signs are cerebellar gait ataxia, intention tremor, frontal executive dysfunction, and global brain atrophy. Other frequent findings are parkinsonism (mild), peripheral neuropathy, psychiatric symptoms (depression, anxiety, and agitation), and autonomic dysfunction. The clinical presentation is heterogeneous, with individuals presenting with varied dominating signs, such as tremor, dementia, or neuropathy. Magnetic resonance imaging shows atrophy and patchy white matter lesions in the cerebral hemispheres and middle cerebellar peduncles. The latter has been designated the middle cerebellar peduncle sign, which occurs in about 60% of affected men, and is relatively specific for FXTAS. Affected females generally have less severe disease, less cognitive decline, and some symptoms different from that of men, for example, muscle pain. Management of FXTAS is complex and includes assessment of the patient's neurological and medical deficits, treatment of symptoms, and provision of relevant referrals, especially genetic counseling. Treatment is empirical, based on anecdotal experience and on knowledge of what works for symptoms of other disorders that also exist in FXTAS. Presently, the disorder is underrecognized because the first published report was only in 2001 and because the presentation is variable and mainly consists of a combination of signs common in the elderly. However, accurate diagnosis is critical for the patient and for the family because they need education regarding their genetic and health risks.
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PMID:Fragile X-associated tremor/ataxia syndrome: clinical phenotype, diagnosis, and treatment. 1957 29

Research during the past 20 years on families of children with developmental disabilities has yielded a rich body of knowledge about the stress of parenting a child with DD, and the risk and protective factors that result in profiles of family resilience vs. vulnerability at various stages of the family life course. Virtually all of this research has been based on data collected from self-report measures, and has focused on family interactions and relationships, and the psychosocial well-being of individual family members. The present chapter focuses on different sources of data, namely biomarkers, which have the potential to extend our understanding of the biological mechanisms by which the stress of parenting a child with developmental disabilities can take its toll on parents' physical and mental health. We focus on two examples: (1) variations in the FMR1 gene, FMRP, and FMR1 messenger RNA in mothers of children with fragile X syndrome and the association of these measures with maternal depression and anxiety; and (2) profiles of cortisol expression in mothers of children with disabilities and the association of cortisol with daily measures of caregiving stress.
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PMID:Biomarkers in the Study of Families of Individuals with Developmental Disabilities. 2041 57

Fragile X syndrome (FXS) is the most common identifiable genetic cause of intellectual disability and autistic spectrum disorders (ASD), with up to 50% of males and some females with FXS meeting criteria for ASD. Autistic features are present in a very high percent of individuals with FXS, even those who do not meet full criteria for ASD. Recent major advances have been made in the understanding of the neurobiology and functions of FMRP, the FMR1 (fragile X mental retardation 1) gene product, which is absent or reduced in FXS, largely based on work in the fmr1 knockout mouse model. FXS has emerged as a disorder of synaptic plasticity associated with abnormalities of long-term depression and long-term potentiation and immature dendritic spine architecture, related to the dysregulation of dendritic translation typically activated by group I mGluR and other receptors. This work has led to efforts to develop treatments for FXS with neuroactive molecules targeted to the dysregulated translational pathway. These agents have been shown to rescue molecular, spine, and behavioral phenotypes in the FXS mouse model at multiple stages of development. Clinical trials are underway to translate findings in animal models of FXS to humans, raising complex issues about trial design and outcome measures to assess cognitive change that might be associated with treatment. Genes known to be causes of ASD interact with the translational pathway defective in FXS, and it has been hypothesized that there will be substantial overlap in molecular pathways and mechanisms of synaptic dysfunction between FXS and ASD. Therefore, targeted treatments developed for FXS may also target subgroups of ASD, and clinical trials in FXS may serve as a model for the development of clinical trial strategies for ASD and other cognitive disorders.
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PMID:Targeted treatments for fragile X syndrome. 2148

The salient neuropathological defect in fragile X syndrome is the overabundance of immature dendritic spines in cortical pyramidal neurons. This review examines this anatomical synaptic defect in the context of other alterations in synaptic and circuit plasticity in fragile X mice. In theory, abnormal spines could lead to dysfunctional circuits and vice versa, so it is still not clear which problem comes first. Because of the tight structure-function relationships at the synapse, and given the significant overlap between signaling pathways that regulate spine shape/dynamics and long-term synaptic plasticity (both of which involve proteins regulated by fragile X mental retardation protein [FMRP]), it is argued that the two defects cannot be separated. It will be critical to determine whether neurons that lack FMRP and demonstrate alterations in long-term potentiation/depression also fail to undergo the expected enlargement/shrinkage of dendritic spines associated with those forms of synaptic plasticity or to establish clear links from FMRP signaling to either spine instability or defective synaptic plasticity, especially during critical periods of brain development. The resulting data will be vital in guiding translational research that can identify novel molecular targets for therapy in this devastating disorder.
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PMID:Which comes first in fragile X syndrome, dendritic spine dysgenesis or defects in circuit plasticity? 2155 Oct 76

Fragile X syndrome (FXS) is a common form of inherited intellectual disability and is one of the leading known causes of autism. The mutation responsible for FXS is a large expansion of the trinucleotide CGG repeat in the 5' untranslated region of the X-linked gene FMR1. This expansion leads to DNA methylation of FMR1 and to transcriptional silencing, which results in the absence of the gene product, FMRP, a selective messenger RNA (mRNA)-binding protein that regulates the translation of a subset of dendritic mRNAs. FMRP is critical for mGluR (metabotropic glutamate receptor)-dependent long-term depression, as well as for other forms of synaptic plasticity; its absence causes excessive and persistent protein synthesis in postsynaptic dendrites and dysregulated synaptic function. Studies continue to refine our understanding of FMRP's role in synaptic plasticity and to uncover new functions of this protein, which have illuminated therapeutic approaches for FXS.
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PMID:Molecular mechanisms of fragile X syndrome: a twenty-year perspective. 2201 84

The fragile X mental retardation 1 gene (Fmr1) is polymorphic for CGG trinucleotide repeat number in the 5'-untranslated region, with repeat lengths <45 associated with typical development and repeat lengths >200 resulting in hypermethylation and transcriptional silencing of the gene and mental retardation in the fragile X Syndrome (FXS). Individuals with CGG repeat expansions between 55 and 200 are carriers of the fragile X premutation (PM). PM carriers show a phenotype that can include anxiety, depression, social phobia, and memory deficits. They are also at risk for developing fragile X-associated tremor/ataxia syndrome (FXTAS), a late onset neurodegenerative disorder characterized by tremor, ataxia, cognitive impairment, and neuropathologic features including intranuclear inclusions in neurons and astrocytes, loss of Purkinje cells, and white matter disease. However, very little is known about dendritic morphology in PM or in FXTAS. Therefore, we carried out a Golgi study of dendritic complexity and dendritic spine morphology in layer II/III pyramidal neurons in primary visual cortex in a knock-in (KI) mouse model of the PM. These CGG KI mice carry an expanded CGG trinucleotide repeat on Fmr1, and model many features of the PM and FXTAS. Compared to wild-type (WT) mice, CGG KI mice showed fewer dendritic branches proximal to the soma, reduced total dendritic length, and a higher frequency of longer dendritic spines. The distribution of morphologic spine types (e.g., stubby, mushroom, filopodial) did not differ between WT and KI mice. These findings demonstrate that synaptic circuitry is abnormal in visual cortex of mice used to model the PM, and suggest that such changes may underlie neurologic features found in individuals carrying the PM as well as in individuals with FXTAS.
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PMID:Abnormal dendrite and spine morphology in primary visual cortex in the CGG knock-in mouse model of the fragile X premutation. 2261 20


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