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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Both fragile X (FRAXA) syndrome and fragile XE (FRAXE) disorder are caused by an expansion of a polymorphic trinucleotide repeat and are associated with mental impairment. Based on the size and methylation status of the expansion, individuals are classified as having normal, intermediate, premutation or full mutation alleles. Unlike individuals with full mutations, carriers of intermediate and premutated alleles should not exhibit obvious clinical symptoms, since the FMR1 (FRAXA) or FMR2 (FRAXE) genes are not transcriptionally silenced. However, there are data suggesting a phenotype consequence of the FRAXA premutation alleles. We have investigated a population consisted of 276 males with idiopathic mental retardation or learning disability and a control sample of 207 non-affected boys in order to determine if there was a possible phenotype consequence of the expanded unmethylated alleles for FRAXA/FRAXE loci. Direct molecular diagnosis for the FRAXA/FRAXE loci were performed in both populations by using PCR technique and sizing of the amplification products by electrophoresis in denaturing polyacrilamide gels. No FRAXA/FRAXE premutations or FRAXE mutated alleles were observed. The 25 FRAXA full mutations alleles detected were confirmed by Southern blot analysis. We found an excess of intermediate alleles for both FRAXA and FRAXE in the target population, but it did not reach statistically significant difference. This suggests that relatively large unmethylated repeats may not be associated with an abnormal cognitive and/or behavioral phenotype. However, recent evidence that FRAXA premutation alleles in males have increased FMR1 message levels emphasizes the need of more studies using large sample sizes and proper control population to resolve this contradictory observation.
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PMID:The influence of expanded unmethylated alleles for FRAXA/FRAXE loci in the intellectual performance among Brazilian mentally impaired males. 1288 56

Mutations at two fragile sites, FRAXA and FRAXE, loci are caused by an expansion of a CGG/GCC trinucleotide repeat and are characterized by mental retardation. Here we report molecular screening survey of 97 unrelated individuals diagnosed with non-specific mental retardation (MR), which produced positive test for FRAXA in two boys and none positive for the FRAXE mutation. In addition, we studied allelic frequency distribution for the FRAXA locus in this group of mentally retarded patients, as well as in the 99 healthy subjects of Yugoslav population. The distribution of FMR1 CGG repeat size in both groups was similar: the most common allele contained 29 repeats (32.86% in the healthy population and 54.54% in MR population), followed by the allele with 28 CGG repeats (21.43% in the healthy and 12.2% in MR population). Premutation alleles with more than 45 repeats were not found in control nor in the MR group.
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PMID:Prevalence of the fragile X syndrome in Yugoslav patients with non-specific mental retardation. 1466

Fragile X syndrome (FXS) is the commonest cause of inherited mental retardation in males. Even though this affirmation is repeated in virtually all papers referring to FXS, the precise frequency of this syndrome in the general population is unknown. We present a general population screening analyzing an anonymous series of 5,000 consecutive newborn males from the neonatal screening program of the population of Catalonia in Spain. The aim of the study is to determine the incidence of FXS via a simple and economical methodology based on the nonamplification of the fragment containing the CGG repeats of the FRAXA locus in the samples carrying alleles over 52 repeats. From the initial 5,000 samples, 4,920 were in the normal range, 15 gave rise to bands with more than 52 repeats (11 corresponded to intermediate alleles and four premutated alleles). After further studies, two samples were considered to be carriers of full mutations. According to these results, the incidence of FXS affected newborn males is 1 in 2,466, and 1 in 1,233 males is a carrier of the premutation. We can deduce that 1 in 8,333 is an affected female with clinical manifestations and 1 in 411 will be a premutation carrier woman. Upon reviewing the literature, there seems to be variability in the frequencies found by the different groups. Therefore, given that our study is limited to the Catalan population in Spain, these results should be taken as valid for the Catalan region and should only be extrapolated to other populations with caution.
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PMID:Incidence of fragile X in 5,000 consecutive newborn males. 1500 Aug 13

Fragile X syndrome (FRAXA) is the most common form of inherited mental retardation (MR). The mutational mechanism leading to the disease involves an expansion of a trinucleotide repeat located at the 5' UTR region of the gene FMR-1. Four types of alleles can be identified in the population, based on the number of repeats: normal (6-40), gray-zone (41-60), premutated (61-200), and fully mutated (>200). Despite only full mutations being associated with the development of the disorder, some authors propose a correlation between FRAXA premutation and the occurrence of premature ovarian failure (POF). We have undertaken a study in 58 women from 24 fragile X syndrome families ascertained for FRAXA testing. Using Southern blotting for direct DNA analysis we have identified 19 normal, 33 premutation carriers, and 6 fully mutated individuals (including 4 somatic mosaics showing premutated and fully mutated alleles). Among the premutated women, 11 experienced menopause before the age of 40 (POF), including one somatic mosaic, which was different from the ones with normal pattern who did not experience POF. Our data corroborate the notion that females carrying alleles in the premutation range are at high risk of experiencing POF.
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PMID:Premature ovarian failure and FRAXA premutation: Positive correlation in a Brazilian survey. 1505 35

Mental retardation is a frequent cause of intellectual and physical impairment. Several genes associated with mental retardation have been mapped to the X chromosome, among them, there is FMR1. The absence of or mutation in the Fragile Mental Retardation Protein, FMRP, is responsible for the Fragile X syndrome. FMRP is an RNA binding protein that shuttles between the nucleus and the cytoplasm. FMRP binds to several mRNAs including its own mRNA at a sequence region containing a G quartet structure. Some of the candidate downstream genes recently identified encode for synaptic proteins. Neuronal studies indicate that FMRP is located at synapses and loss of FMRP affects synaptic plasticity. At the synapses, FMRP acts as a translational repressor and in particular regulates translation of specific dendritic mRNAs, some of which encode cytoskeletal proteins and signal transduction molecules. This action occurs via a ribonucleoprotein complex that includes a small dendritic non-coding neuronal RNA that determines the specificity of FMRP function via a novel mechanism of translational repression. Since local protein synthesis is required for synaptic development and function, this role of FMRP likely underlies some of the behavioural and developmental symptoms of FRAXA patients. Finally we review recent work on the Drosophila system that connects cytoskeleton remodelling and FMRP function.
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PMID:Molecular insights into mental retardation: multiple functions for the Fragile X mental retardation protein? 1511 19

The Fragile X (FRAXA) syndrome is the most common cause of familial (monogenic) mental retardation and is widespread in human populations. This syndrome is characterised by an unusual mode of transmission for an X-linked disease. In affected families, one frequently finds clinically normal transmitting males, whose daughters - also clinically normal - have a high risk of having affected children. The risk of developing the disease (penetrance) thus appears to increase in successive generations of the same family through maternal transmission. As shown by molecular cloning of the fragile X locus, Fragile X mutations are unstable expansions of a CGG trinucleotide repeat, located in the first exon (non-protein-coding) of the FMR1 gene (for Fragile X Mental Retardation). Two main types of mutation are observed in affected families. A full mutation is found in patients with mental retardation and corresponds to large expansions of the repeat. Premutations are moderate expansions and are found in normal transmitting males and in the majority of clinically normal carrier females. About 15% of patients show a mosaic pattern consisting of both full mutations and premutations. Although analysis of the CGG expansion has led to the establishment of reliable tests for diagnosis and genetic counseling of Fragile X syndrome, care must be exercised to use these tools to answer the concerns of the families and avoid doing harm. In our opinion, testing in children should be restricted to those who show a developmental delay, cognitive deficits and/or abnormal behavior evocative of the syndrome. A carrier diagnosis in a girl who is clinically normal should probably only be performed at an age where she can understand the consequences for family planning and the options of prenatal diagnosis. When testing children with borderline cognitive deficits, a positive diagnosis should be used to improve educational strategies for the children - and not to stigmatise them.
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PMID:Fragile X mental retardation syndrome: from pathogenesis to diagnostic issues. 1513 1

Fragile X syndrome is a frequent genetic disease associated to developmental disorders, including learning disability, mental retardation, behavioral problems and pervasive developmental disorders (autism and related conditions). We studied a sample of 82 individuals (69 males and 13 females) presenting with pervasive developmental disorders using three techniques for the diagnosis of fragile X syndrome (FXS). Cytogenetic analysis detected the fragile site in four males, but only one showed a consistent positive rate. Molecular study based on the PCR technique was inconclusive for most females (92.3%), which where latter submitted to Southern blotting analysis, and for one male (1.4%), excluding the FRAXA mutation in the remaining male individuals (98.6%). Molecular tests using the Southern blotting technique confirmed only one positive case (1.2%) in a male subject. These results showed that Southern blotting analysis of the FRAXA mutation has the best sensitivity and specificity for the diagnosis of FXS but also validated the PCR technique as a confinable screening test.
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PMID:Laboratorial diagnosis of fragile-X syndrome: experience in a sample of individuals with pervasive developmental disorders. 1617 1

The ARX gene mutations have been demonstrated to cause different forms of mental retardation (MR). Beside FMR1, in families with X-linked mental retardation (XLMR), the ARX dysfunction was demonstrated to be among the most frequent causes of this heterogeneous group of disorders. Nevertheless, in sporadic cases of MR, ARX mutations are extremely rare. In order to evaluate the frequency of ARX mutation in XLMR, we performed mutational analysis of ARX in 165 mentally retarded probands negative for FRAXA and belonging to families in which the condition segregates as an X-linked condition. The same recurrent mutation, an in frame 24 bp insertion (c.428-451 dup (24 bp)), was identified in five patients. In one family, the mother of two affected boys was found not to carry the mutation detected in her sons. These data suggest the presence of germline mosaicism for the mutation in the mother. Our results confirm the significant contribution of ARX mutations in the etiology of MR, especially in this group of patients selected for XLMR (3%). These data, together with those reported in the literature, imply that screening for c.428-451 dup (24 bp) mutation should be recommended in all patients with suspected XLMR.
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PMID:The ARX mutations: a frequent cause of X-linked mental retardation. 1652 16

In contrast to the numerous well-known microdeletion syndromes, only a few microduplications have been described, and this discrepancy may be due in part to methodological bias. In order to facilitate the detection of genomic microdeletions and microduplications, we developed a new assay based on QMPSF (Quantitative Multiplex PCR of Short fluorescent Fragments) able to explore simultaneously 12 candidate loci involved in mental retardation (MR) and known to be the target of genomic rearrangements. We first screened 153 patients with MR and facial dysmorphism associated with malformations, or growth anomalies, or familial history, with cytogenetically normal chromosomes, and the absence of FRAXA mutation and subtelomeric rearrangements. In this series, we found a 5q35 deletion removing the NSD1 gene in a patient with severe epilepsy, profound MR and, retrospectively, craniofacial features of Sotos syndrome. In a second series, we screened 140 patients with MR and behaviour disturbance who did not fulfil the de Vries criteria for subtelomeric rearrangements and who had a normal karyotype and no detectable FRAXA mutation. We detected a 22q11 deletion in a patient with moderate MR, obesity, and facial dysmorphism and a 4 Mb 17p11 duplication in a patient with moderate MR, behaviour disturbance, strabismus, and aspecific facial features. This new QMPSF assay can be gradually upgraded to include additional loci involved in newly recognised microduplication/microdeletion syndromes, and should facilitate wide screenings of patients with idiopathic MR and provide better estimates of the microduplication frequency in the MR population.
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PMID:Simple detection of genomic microdeletions and microduplications using QMPSF in patients with idiopathic mental retardation. 1677 31

Hyper-expansion of a CGG repeat in the 5' untranslated region of the FMR1 gene followed by methylation and silencing is the predominant cause of Fragile X syndrome, the most common inherited mental retardation disorder. Most detailed studies of the FMR1 gene have focused on Caucasian populations and patients. We performed a detailed haplotype and linkage disequilibrium analysis of the FMR1 gene in a total of 454 unselected normal X chromosomes from three Asian populations, Chinese, Malay and Indian. Compared to Caucasians and African Americans, the diversity of normal FMR1 CGG repeat lengths, patterns and flanking haplotypes were lower in Asians. Strong linkage disequilibrium was observed between the CGG repeat and flanking FMR1 markers in all three Asian populations, with strong association between specific CGG repeat alleles and flanking marker alleles observed only in the Chinese and Malays. A test for randomness of distribution between FRAXA CGG repeat patterns and flanking FMR1 marker haplotypes also revealed a highly significant non-random distribution between CGG repeat patterns and flanking haplotypes in all three ethnic groups (P < 0.001). Extending previous findings in Caucasians and African Americans we present a novel statistical approach, using data from unselected population samples alone, to show an association between absence of at least one AGG interruption in any position (5', 3', or middle) and increased CGG repeat instability.
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PMID:FMR1 CGG repeat patterns and flanking haplotypes in three Asian populations and their relationship with repeat instability. 1704 53


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