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)

Neurobehavioral correlates of CGG amplification were studied in 17 nonretarded adult female carriers of fragile X syndrome. The results revealed a significant relationship between IQ and the number of CGG repeats in the 5' untranslated region of the FMR1 gene. Women with a full mutation (> 200 CGG repeats) scored below average in IQ, visual-spatial perception, visual-spatial organization, and executive function. There were no differences in fine motor dexterity or memory as a function of CGG amplification status. A history of major depressive disorder was identified in 71% of the sample, but incidence of depression was not associated with the degree of CGG amplification. Schizotypal features were noted in 18%. No intellectual or neuropsychological deficit was found in women with a premutation (< 200 CGG repeats). Decrements in IQ, visual-spatial perception, and executive function appear to arise as a consequence of the CGG amplification.
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PMID:Neurobehavioral characteristics of CGG amplification status in fragile X females. 772 12

Fragile X syndrome (FXS), a form of human mental retardation, is caused by loss of function mutations in the fragile X mental retardation gene (FMR1). The protein product of FMR1, fragile X mental retardation protein (FMRP) is an RNA-binding protein and may function as a translational suppressor. Metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) in hippocampal area CA1 is a form of synaptic plasticity that relies on dendritic protein synthesis. mGluR-LTD is enhanced in the mouse model of FXS, Fmr1 knockout (KO) mice, suggesting that FMRP negatively regulates translation of proteins required for LTD. Here we examine the synaptic and cellular mechanisms of mGluR-LTD in KO mice and find that mGluR-LTD no longer requires new protein synthesis, in contrast to wild-type (WT) mice. We further show that mGluR-LTD in KO and WT mice is associated with decreases in AMPA receptor (AMPAR) surface expression, indicating a similar postsynaptic expression mechanism. However, like LTD, mGluR-induced decreases in AMPAR surface expression in KO mice persist in protein synthesis inhibitors. These results are consistent with recent findings of elevated protein synthesis rates and synaptic protein levels in Fmr1 KO mice and suggest that these elevated levels of synaptic proteins are available to increase the persistence of LTD without de novo protein synthesis.
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PMID:Metabotropic receptor-dependent long-term depression persists in the absence of protein synthesis in the mouse model of fragile X syndrome. 1645 52

Fragile X mental retardation protein (FMRP), the lack of which causes fragile X syndrome, is an RNA-binding protein encoded by the FMR1 gene. FMRP accompanies mRNAs from the nucleus to dendritic regions and is thought to regulate their translation at synapses. It has been shown that FMRP moves into nontranslating stress granules (SGs) during heat stress of cultured fibroblasts (Mazroui et al., 2002). We used a novel method to isolate SGs from neurons by virtue of their TIA-1 (T-cell intracellular antigen 1) protein component, and found that FMRP moved out of polyribosomes and into SGs subsequent to oxidative stress. We then examined FMRP changes in subcellular localization resulting from mechanically induced neuronal injury by placement of electrodes into the dentate gyrus and the perforant path of the hippocampus in vivo. During the first 10 min after electrode insertion into one hippocampus, FMRP shifted into SGs and away from polyribosomes, in both hippocampi. Although the injury discharge subsided beyond 10 s, FMRP levels in polyribosomes and stress granules did not return to basal levels until 30 min after electrode penetration. Our findings suggest that procedures for in vivo induction of long-term potentiation or long-term depression should incorporate a 30 min rest period after electrode insertion, and indicate that the contralateral hippocampus cannot be considered an unstimulated control tissue.
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PMID:Fragile X mental retardation protein shifts between polyribosomes and stress granules after neuronal injury by arsenite stress or in vivo hippocampal electrode insertion. 1651 Jul 18

Fragile X syndrome (FraX) is the most common known cause of inherited mental impairment. FMR1 gene mutations, the cause of FraX, lead to reduced expression of FMR1 protein and an increased risk for a particular profile of cognitive, behavioral, and emotional dysfunction. The study of individuals with FraX provides a unique window of understanding into important disorders such as autism, social phobia, cognitive disability, and depression. This review highlights the typical phenotypic features of individuals with FraX, discussing the apparent strengths and weaknesses in intellectual functioning, as evidenced from longitudinal follow-up studies. It also discusses recent neuroanatomic findings that may pave the way for more focused disease-specific pharmacologic and behavioral interventions. This article describes the results of recent medication trials designed to target symptoms associated with FraX. It also describes some recent behavioral interventions that were conducted in our laboratory.
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PMID:Fragile X syndrome: assessment and treatment implications. 1756 85

The fragile X disorder spectrum, due to a CGG expansion in FMR1, includes fragile X syndrome (>200 repeats) and the premutation-associated disorders of ovarian insufficiency and tremor/ataxia syndrome (approximately 55-199 repeats). Altered neurobehavioral profiles including variation of phenotypes associated with mood and anxiety may be expected among younger premutation carriers given this spectrum of disorders. However, previous studies have produced conflicting findings, providing the motivation to examine these phenotypes further. We investigated measures of mood and anxiety in 119 males and 446 females age 18-50 ascertained from families with a history of fragile X syndrome and from the general population. Scores were analyzed using a linear model with repeat length as the main predictor, adjusting for potential confounders. Repeat length was not associated with anxiety, but was marginally associated with depression and negative affect in males and negative affect only in females. These results suggest that premutation carriers may be at risk for emotional morbidity; however, phenotypic differences were subtle and of small effect size.
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PMID:Investigation of phenotypes associated with mood and anxiety among male and female fragile X premutation carriers. 1853 97

Parents enrolling in a national survey of families of children with fragile X (FX) reported whether each of their children had been diagnosed or treated for developmental delay or eight conditions frequently associated with FX: attention problems, hyperactivity, aggressiveness, self-injury, autism, seizures, anxiety, or depression. This article reports results for 976 full mutation males, 259 full mutation females, 57 premutation males, and 199 premutation females. Co-occurring conditions were frequently reported for all FMR1 gene variations. The number of co-occurring conditions experienced was strongly associated with parent reports of their child's ability to learn, adaptability, and quality of life. Most individuals with the full mutation experienced multiple co-occurring conditions, with a modal number of 4 for males and 2 for females. Most (>80%) full mutation males and females had been diagnosed or treated for attention problems. Premutation males, when compared with a matched group of non-FX males, were more likely to have been diagnosed or treated for developmental delay, attention problems, aggression, seizures, autism, and anxiety. Premutation females were more likely to have been diagnosed or treated for attention problems, anxiety, depression, and developmental delay. Clusters of conditions were identified, seeming to occur in an additive fashion. Self-injury, autism, and seizures rarely occurred in isolation, but were more likely in individuals who also had problems with attention, anxiety, and hyperactivity. The findings provide a reference point for future studies on the prevalence and nature of co-occurring conditions in FX; suggest the possibility that certain conditions cluster together; provide evidence that male and female carriers experience elevated rates of co-occurring conditions compared with matched groups of non-carrier children; and emphasize the importance of including an assessment of co-occurring conditions in any clinical evaluation of individuals with abnormal variation in the FMR1 gene.
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PMID:Co-occurring conditions associated with FMR1 gene variations: findings from a national parent survey. 1857 Feb 92

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive neurological disorder that affects older adult carriers, predominantly males, of premutation alleles (55 to 200 CGG repeats) of the fragile X (FMR1) gene. Principal features of FXTAS are intention tremor, ataxia, parkinsonism, cognitive decline, and peripheral neuropathy; ancillary features include, autonomic dysfunction, and psychiatric symptoms of anxiety, depression, and disinhibition. Although controlled trials have not been carried out in individuals with FXTAS, there is a significant amount of anecdotal information regarding various treatment modalities. Moreover, there exists a great deal of evidence regarding the efficacy of various medications for treatment of other disorders (eg, Alzheimer disease) that have substantial phenotypic overlap with FXTAS. The current review summarizes what is currently known regarding the symptomatic treatment, or potential for treatment, of FXTAS.
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PMID:Treatment of fragile X-associated tremor ataxia syndrome (FXTAS) and related neurological problems. 1868 48

Fragile X syndrome (FXS) is caused by a mutation that silences the fragile X mental retardation gene (FMR1), which encodes the fragile X mental retardation protein (FMRP). To determine whether FMRP replacement can rescue phenotypic deficits in a fmr1-knockout (KO) mouse model of FXS, we constructed an adeno-associated virus-based viral vector that expresses the major central nervous system (CNS) isoform of FMRP. Using this vector, we tested whether FMRP replacement could rescue the fmr1-KO phenotype of enhanced long-term depression (LTD), a form of synaptic plasticity that may be linked to cognitive impairments associated with FXS. Extracellular excitatory postsynaptic field potentials were recorded from CA3-CA1 synaptic contacts in hippocampal slices from wild-type (WT) and fmr1-KO mice in the presence of AP-5 and anisomycin. Paired-pulse low-frequency stimulation (PP-LFS)-induced LTD is enhanced in slices obtained from fmr1 KO compared with WT mice. Analyses of hippocampal synaptic function in fmr1-KO mice that received hippocampal injections of vector showed that the PP-LFS-induced LTD was restored to WT levels. These results indicate that expression of the major CNS isoform of FMRP alone is sufficient to rescue this phenotype and suggest that post-developmental protein replacement may have the potential to improve cognitive function in FXS.
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PMID:Fragile X mental retardation protein replacement restores hippocampal synaptic function in a mouse model of fragile X syndrome. 1957 88

Women with fragile X mental retardation (FMR1) gene premutations (55-200 CGG repeats) were until recently believed to be unaffected. It is now known that up to 8% of older female FMR1 premutation carriers develop fragile X-associated tremor/ataxia syndrome (FXTAS). Female carriers may also develop primary ovarian insufficiency, thyroid disease, hypertension, seizures, peripheral neuropathy, and fibromyalgia. We present a 60-year-old woman with FMR1 premutation who had depression, anxiety, and conversion disorder with seizures. The FMR1 premutation with its associated mRNA toxicity is postulated as an underlying neurobiological mechanism of conversion symptoms, through functional and structural neural dysconnectivity.
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PMID:Conversion disorder in women with the FMR1 premutation. 1984 97

The mutations in the FMR1 gene have been described as a family of disorders called fragile X-associated disorders including fragile X syndrome, fragile X-associated tremor/ataxia syndrome, primary ovarian insufficiency, and other problems associated with the premutation, such as hypothyroidism, hypertension, neuropathy, anxiety, depression, attention-deficit hyperactivity disorders, and autism spectrum disorders. The premutation is relatively common in the general population affecting 1 of 130 to 250 female individuals and 1 of 250 to 800 male individuals. Therefore, to provide appropriate treatment and genetic counseling for all of the carriers and affected individuals in a family, a detailed family history that reviews many of the disorders that are related to both the premutation and the full mutation should be carried out as exemplified in these cases. To facilitate the integration of this knowledge into clinical practice, this is the first case report that demonstrates only premutation involvement across 3 generations.
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PMID:Broad clinical involvement in a family affected by the fragile X premutation. 1999


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