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At least 19 recordsLinked to original sources

PubMed1990

Ocular anomalies in fragile X syndrome.

Fragile X (fra[X]) syndrome is a newly discovered, but relatively common, genetic disorder with an estimated frequency of 1:1000. Several ocular dysfunctions may be associated with this syndrome, but there are few articles that fully report on these. A review of this genetic disorder is provided, as well as a discussion of a case review of a family with three siblings with fragile X syndrome. Since this disorder is the most common familial cause of mental retardation, is second only to Down's syndrome as a genetic cause for mental retardation, and may play a significant role in learning disabilities, the eye care practitioner should be aware of its importance.

Adult↗

PubMed2001

[Experimental therapeutic models for fragile X syndrome].

Fragile X syndrome is the most frequent form of familial mental retardation. The disease is caused by the absence of the function of the FMR1 gene product (FMRP). FMRP is a mRNA binding protein but the mechanism by which FMRP inactivation leads to the cognitive deficits in fragile X patients is still unknown. There is no effective specific treatment for the disease. The genetics of the fragile X syndrome suggest that gene therapy may eventually be able to provide a cure for the disease. However several different approaches are also being investigated by many different research laboratories. The search for an effective therapy for fragile X patients will be facilitated by a better understanding of the pathophysiology of the disease. This requires research into many different areas of biology including protein replacement therapy, gene reactivation, transcriptional regulation, neuronal activity enhancement and neuroprotection, nutritional intervention, regulation of neurotransmission and synapse regeneration. All these approaches can be investigated using animal models of the fragile X syndrome, before being used to develop effective treatment for fragile X patients. Although there is still no cure for the fragile X syndrome, the symptoms of the disease can be treated using an integrated approach where the different interventions are supported by a specific team. All of these approaches are providing new insights into both the treatment of fragile X patients and our understanding of the pathophysiology of the disease. Until a cure is found, an integrated approach to intervention is the best way to minimise or avoid some of the manifestations associated with the fragile X syndrome.

Animals↗

PubMed2006

ACOG committee opinion. No. 338: Screening for fragile X syndrome.

Fragile X syndrome is the most common inherited form of mental retardation, affecting approximately 1 in 4,000 males and 1 in 8,000 females. DNA-based molecular analysis is the preferred method of diagnosis for fragile X syndrome and its premutations. Prenatal testing for fragile X syndrome should be offered to known carriers of the premutation or mutation. Testing for fragile X syndrome should be considered for any child with developmental delay of uncertain etiology, autism, or autistic behavior or for any individual with mental retardation of uncertain etiology. Women with ovarian failure or an elevated follicle-stimulating hormone level before 40 years of age without a known cause should be screened to determine whether they have the fragile X premutation.

DNA Methylation↗

PubMed2001

[Experimental therapy: reactivation of the FMR1 gene involved in fragile X syndrome].

Fragile X syndrome represents the most common inherited cause of mental retardation worldwide. Fragile X belongs to a large group of more than 200 mental retardation conditions caused by mutations in X-linked genes (XLMR), that have a collective frequency of up to 1 in 1000 males. Fragile X syndrome is also unique because it was the first genetic condition caused--in the overwhelming majority of cases--by the expansion of an unstable CGG repeat, becoming the prototype of a growing list of inherited disorders due to the instability of trinucleotide repeats. Ten years after the cloning of the FMR1 gene involved in fragile X syndrome, we still don't know all the molecular players that allow the destabilization of the CGG repeat located close to the gene's CpG island. However, the finding of a founder effect in fragile X syndrome indicates that only few of the unstable repeats eventually reached the pathological range. The line of research was aimed at understanding what happens after the fragile X mutation has reached a pathological size. What we showed with our 'reactivation' experiments is that the size of the CGG expansion per se does not cause the silencing of the FMR1 gene: it's the methylation that is added to the expansion that leads to the transcriptional block. Thus, by studying the 'reactivation' of fragile X full mutations, we try to learn more about their 'inactivation' and--hopefully--about possible ways of preventing or 'reverting' their inactivation in fragile X children.

Child↗

PubMed2002

Alterations in the auditory startle response in Fmr1 targeted mutant mouse models of fragile X syndrome.

Fragile X syndrome results from inadequate production of the fragile X mental retardation protein (FMRP). Mice with a mutation targeted to the Fmr1 gene lack FMRP and thus are a valuable animal model for studying the behavioral and neural phenotype of this human disorder. Mice of two genetic backgrounds containing the Fmr1 mutation, C57BL/6J (C57-KO) and an F1 hybrid (C57BL/6J mutant x FVB/NJ; F1-KO) did not differ from control mice in behavior in the elevated plus maze or the open field. Both the C57-KO and F1-KO mice exhibited greater startle responses than normal mice to low intensity (80 dB) white noise bursts and decreased responses to high intensity (120 dB) white noise bursts. These behavioral alterations appear to be specific to the Fmr1 mutation since they are present on both genetic backgrounds. Furthermore, the mice lacking FMRP resemble individuals with fragile X syndrome in their increased sensitivity to low intensity auditory stimuli. These findings should prove useful in determining how the absence of FMRP alters the brain and behavior, and in testing potential treatments for fragile X syndrome.

Acoustic Stimulation↗

PubMed1993

Molecular pathology of the fragile X syndrome.

Fragile X syndrome is the most common form of familial mental retardation (one in 1250 males and one in 2500 females, characterized by prominent dysmorphic features, macro-orchidism, and varying degrees of mental retardation. Diagnosis of this syndrome has relied on cytogenetic demonstration of the fragile site at position Xq27.3. A gene associated with the fragile X syndrome, FMR-1, has been isolated and mapped to the region of the X chromosome that corresponds to the region of the fragile site. Expansion of a trinucleotide repeat, CGG, and abnormal methylation of a CpG island account for the majority of mutations identified in FMR-1. These molecular characteristics have greatly enhanced the identification of affected individuals and carriers of the premutation who were not detected cytogenetically.

Blotting, Southern↗

PubMed1990

Fragile X syndrome.

Fragile X syndrome is the most important X-linked etiology of mental retardation and developmental disability currently known. Accumulating evidence also indicates that male and female carriers of the fragile X genetic abnormality demonstrate a relatively specific pattern of psychiatric disturbance. Fragile X males frequently manifest behaviors from the autistic spectrum whereas females show dysfunction in social interaction, thought processes, and affective regulation. In this review, an overview of the fragile X syndrome is presented with a focus on the occurrence of particular neuropsychiatric characteristics in males and females. Relevant data from recent genetic and neurobiological research is also described. The ability to study individuals with a specific genetic cause of psychopathology such as fragile X syndrome makes this condition of particular interest to biological psychiatry.

Autistic Disorder↗

PubMed1998

[Molecular biologic screening test (PCR) for fragile X syndrome].

Fragile X syndrome is the most common inherited from of familial mental retardation. It is caused by an expanded CGG repeat in the first exon of the fragile X mental retardation gene. A polymerase chain reaction based technique was used for the identification of full mutations among men. According to our conditions full mutations failed to amplify. An internal control was used at a CG rich region 147 bp upstream of the polymorphic region. The bands were visualised on silver stained polyacrylamide gels. From the 57 individuals studied molecular analysis was performed on 38 males and 16 females. From the 26 males with suspected fragile X syndrome 9 males resulted in no amplification of the 500 kb product, all having a positive cytogenetic result for fragile X syndrome. One cytogeneticly positive male had normal results by molecular studies suggesting a different mutation. All control males had normal results. The results on the 16 females studied were inconclusive. We suggest that our method is highly sensitive and specific for screening males for fragile X syndrome.

Female↗

PubMedDate not supplied

Fragile X syndrome.

Fragile X syndrome is the most common form of inherited mental retardation. It is seen in people of all nationalities and in all areas of the world. Fragile X syndrome can be a devastating condition, as many boys are severely retarded and require multiple services. Treatment involves behaviour management techniques, appropriate school placement, community support for the family, and careful medical follow-up often including psychopharmacology. The genetics of fragile X syndrome is now understood, prenatal testing is available, and the disorder is preventable through appropriate genetic counselling. This review focuses on the neurobiology of fragile X syndrome, its clinical features and treatment.

Child↗

PubMed1995

Rapid antibody test for fragile X syndrome.

Fragile X syndrome is the most common known cause of inherited mental retardation. Identification of patients and carriers of fragile X syndrome is usually done with a DNA test system but we have developed a rapid antibody to identify fragile X patients. This non-invasive test requires only 1 or 2 drops of blood and can be used for screening large groups of mentally retarded people and neonates for fragile X syndrome.

Antibodies, Monoclonal↗

PubMed1990

Amyotrophic lateral sclerosis in a patient with fragile X syndrome.

Fragile X syndrome is a common cause of mental retardation. We report the clinical and pathologic features of a patient with fragile X syndrome who developed amyotrophic lateral sclerosis (ALS) at a relatively young age. Although the occurrence of these 2 diseases could be a mere coincidence, the development of ALS in this patient might be related to the chromosomal aberration of fragile X syndrome.

Adult↗

PubMed1994

Advances in molecular analysis of fragile X syndrome.

Fragile X syndrome is a common cause of mental retardation that is inherited as an X-linked dominant disorder with reduced penetrance. Fragile X syndrome has been shown to be caused by an unstable CGG repeat within the fragile X mental retardation-1 (FMR1) gene. The repeat is normally polymorphic with six to 52 repeats, while affected males and females exhibit a massive expansion resulting in 230 to more than 1000 repeats. Such expansions, called "full mutations," are associated with abnormal methylation of the FMR1 gene leading to transcriptional suppression. The resulting absence of the encoded protein, FMRP, a cytosolic RNA-binding protein, is believed to result in the phenotype. Nonpenetrant male carriers and many female carriers exhibit premutation alleles of intermediate length (50 to 230 repeats), which are normally expressed. Male carriers transmit only unstable premutations while female premutation carriers can have carrier offspring with premutations or affected children with full mutations. The risk of having an affected child is directly related to the number of maternal repeats, with sequentially increasing probabilities of these alleles converting to full mutations as they are transmitted to subsequent generations. Advances have led to highly accurate laboratory diagnoses of both carrier and affected individuals as well as markedly improved prenatal diagnosis. In addition, a previously unrecognized class of mutation, later found responsible for several other important genetic diseases, has emerged.

DNA↗

PubMed1999

[Molecular cytogenetics of fragile X syndrome].

Fragile X syndrome is the most common heritable form of mental retardation, and affects 1 in 1500(male)-2500(female), with minor dysmorphic manifestations such as long face with large protruding ears and macro-orchidism in mentally retarded male patients. The syndrome is caused by dynamic mutation(trinucleotide repeat expansion) at FRAXA located on the long arm of X chromosome. Molecular diagnosis enables carrier identification as well as prenatal diagnosis, in which the cytogenetic method was not feasible. Premutation in phenotypically normal carriers and full mutation in mentally retarded patients explain the characteristic inheritance of the disease called anticipation. This article describes the recent advancements in molecular cytogenetics of fragile X syndrome.

Anticipation, Genetic↗

PubMed2002

Gene expression profiles in a transgenic animal model of fragile X syndrome.

Fragile X syndrome is the most common inherited form of mental retardation. Although this syndrome originates from the absence of the RNA-binding protein FMRP, the molecular mechanisms underlying the cognitive deficits are unknown. The expression pattern of 6789 genes was studied in the brains of wild-type and FMR1 knockout mice, a fragile X syndrome animal model that has been associated with cognitive deficits. Differential expression of more than two-fold was observed for the brain mRNA levels of 73 genes. Differential expression of nine of these genes was confirmed by real-time quantitative reverse transcription-polymerase chain reaction and by in situ hybridization. In addition to corroborating the microarray data, the in situ hybridization analysis showed distinct spatial distribution patterns of microtubule-associated protein 2 and amyloid beta precursor protein. A number of differentially expressed genes associated with the fragile X syndrome phenotype have been previously involved in other memory or cognitive disorders.

Amyloid beta-Protein Precursor↗

PubMed2000

FMRP detection assay for the diagnosis of the fragile X syndrome.

Fragile X syndrome is almost always caused by the absence or deficit of the FMR1 protein (FMRP). Diagnostic methods include polymerase chain reaction and Southern blotting, which are performed on DNA isolated from peripheral leukocytes. Recently, different immunocytochemical tests have been described to identify patients with fragile X syndrome, based on the detection of FMRP in cells by a monoclonal antibody. This review aims to provide an update on the different antibody methods for prenatal and postnatal diagnosis of the fragile X syndrome.

Fragile X Messenger Ribonucleoprotein 1↗

PubMed1999

A methylation PCR approach for detection of fragile X syndrome.

Fragile X syndrome is associated with the expansion of the number of CGG trinucleotide tandem repeats at the 5' untranslated region of the FMR1 gene. The number of CGG trinucleotide repeats in normal individuals ranges between 5 and 50, in asymptomatic carrier individuals it ranges between 50 and 200, and in affected individuals it is more than 200 CGG repeats. In addition, in affected individuals the cytosine residues in the CGG repeats and the adjacent CpG island are methylated and the FMR1 gene is transcriptionally inactive. The most common diagnostic method for the detection of the syndrome is Southern blot analysis. Methods based on the polymerase chain reaction (PCR) could facilitate the rapid screening of large numbers of individuals by accurately determining the number of CGG repeats. Current PCR techniques for amplification of CGG repeats are, however, inefficient and unreliable because of their 100% C+G composition. Thus, most of the described PCR protocols require subsequent Southern blot analysis and autoradiography. We present a novel PCR approach for the diagnosis of fragile X syndrome based on the methylation-sensitive conversion of C residues to U by bisulfite on single-strand DNA and subsequent amplification of the antisense strand with specific primers. A PCR with primers for methylated C residues will amplify the CpG dinucleotide region upstream to CGG repeats exclusively in affected males. As a result of extensive mismatch between primers and bisulfite-treated DNA, no PCR fragments will be obtained in normal and transmitting males. Moreover, the bisulfite treatment dramatically reduces the C+G component of the region; thus, the high Tm and the strong secondary structures are no longer obstacles for PCR amplification. In normal and carrier individuals, UUG repeats (previously 3'-CCG-5') in the antisense strand can easily be amplified and visualized on a gel by ethidium bromide staining. We applied our method on 25 males previously diagnosed by Southern blot analysis. All the samples were easily and accurately diagnosed. The method has considerable advantages compared with other diagnostic tests for fragile X syndrome.

Base Sequence↗

PubMed1991

Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome.

Fragile X syndrome is the most frequent form of inherited mental retardation and is associated with a fragile site at Xq27.3. We identified human YAC clones that span fragile X site-induced translocation breakpoints coincident with the fragile X site. A gene (FMR-1) was identified within a four cosmid contig of YAC DNA that expresses a 4.8 kb message in human brain. Within a 7.4 kb EcoRI genomic fragment, containing FMR-1 exonic sequences distal to a CpG island previously shown to be hypermethylated in fragile X patients, is a fragile X site-induced breakpoint cluster region that exhibits length variation in fragile X chromosomes. This fragment contains a lengthy CGG repeat that is 250 bp distal of the CpG island and maps within a FMR-1 exon. Localization of the brain-expressed FMR-1 gene to this EcoRI fragment suggests the involvement of this gene in the phenotypic expression of the fragile X syndrome.

Alleles↗

PubMed1992

[Pathology of unstable sequence of genome: fragile-X-syndrome].

Fragile X syndrome is the most frequent form of inherited mental retardation and is associated with a fragile site at Xq27-3. This fragile site is an unstable microsatellite repeat, p(CCG). In fragile X syndrome families, this sequence exhibits variable amplification, the length of which correlates with phenotype. Affected persons have both a "full mutation" and abnormal DNA methylation. Subjects with smaller increase of this sequence, called "premutation", have little or no risk retardation, but are at high risk of having affected children or grandchildren. The passage from "premutation" to "full mutation" status occurs only with transmission from the mother. The unusual segregation patterns in fragile X pedigrees is referred to as the Sherman paradox, now elucidated by genotypic analysis. We present here a brief review of this pathology and illustrate the use of this new diagnostic test in our laboratory.

DNA↗