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Definition of «Fragile X syndrome»

Fragile X syndromeFragile X syndromeFragile X syndromeFragile X syndrome

Fragile X syndrome: One of the most common causes of inherited mental retardation and neuropsychiatric disease in human beings, affects as many as one in 2000 males and one in 4000 females. The syndrome is also known as FRAXA (the fragile X chromosome itself) and as the Martin-Bell syndrome. However, the preferred name is fragile X syndrome.

The characteristic features of the fragile X syndrome in boys include prominent or long ears, a long face, delayed speech, large testes (macroorchidism), hyperactivity, tactile defensiveness, gross motor delays, and autistic-like behaviors.

Much less is known about girls with fragile X syndrome. Only about half of all females who carry the genetic mutation have symptoms themselves. Of those, half are of normal intelligence, and only one-fourth have an IQ under seventy. Few fragile X girls have autistic symptoms, although they tend to be shy and quiet.

Fragile X syndrome is due to a dynamic mutation (a trinucleotide repeat) at an inherited fragile site on the X chromosome, and so is an X-linked disorder. Because the mutation is dynamic, it can change in length and hence in severity from generation to generation, from person to person, and even within a given person.

The diagnosis of the fragile X syndrome is confirmed by the detection of an increased number of CGG trinucleotide repeats (over 230) in the FMR1 gene, usually with aberrant methylation of the FMR1 gene. The increased trinucleotide repeats and methylation changes in FMR1 can be detected by molecular genetic testing.

Trinucleotide repeat expansion of at least three genes located on the X chromosome has now been associated with the formation of "fragile sites." Trinucleotide expansions within two of these genes, FRAXA (within the FMR1 gene) and FRAXE (within the FMR2 gene), are associated with mental retardation, while that at a third, FRAXF (not yet associated with a specific gene) is not. Mutations in the FMR1 gene, for example, produce expansion of CGG repeats in the 5' untranslated region of the gene and lead to a severely disabling neurodevelopmental disorder. Such expansion leads to physical, neurocognitive, and emotional characteristics linked to, but not exclusively determined by, alterations in the FMR1 gene or the level of its protein, FMRP.

Approximately 15-25% of individuals with fragile X syndrome also are diagnosed with mild to moderate autism and autism spectrum disorders. Expression of the protein FMRP and autistic status appear to be associated with developmental outcome. Other clinical abnormalities associated with fragile X syndrome include attention deficit hyperactivity disorder (ADHD) and anxiety disorders.

The laboratory methods for the prenatal diagnosis of gene expansion of FRAXA, associated with FMR1 and its encoded protein, FMRP, are accurate, sensitive, and relatively inexpensive. For such methods to be applied as general screening techniques, however, more knowledge (about prevalence, risk factors, and nature of high repeat alleles) needs to be obtained. Because different human populations may not be equivalent with respect to fragile X expansion, consideration of ethical issues related to variability of phenotype, the possibility of mislabeling, and the value of screening if there is no definitive therapy, is required.

Although FMR1 is subject to X inactivation, abnormal methylation appears to contribute to the phenotype observed in mosaic patients. These individuals experience upregulation of the FMR1 gene. Further, expanded repeats appear to be abnormally methylated from the start, although the mechanism by which such abnormal methylation occurs remains unknown. Expanded FMR1 genes are also "silenced" through a process of deacetylation.

FMRP is found in both nucleus and cytoplasm, where it binds with mRNAs associated with ribonucleoproteins (RNPs) specifically associated with polyribosomes. In neurons, FMRP-associated RNPs are located in the cell body, as well as in the dendrites, at the base of dendritic spines. Thus, FMRP may play a role in synaptic function and plasticity.

Individuals with fragile X syndrome also exhibit neuroendocrinologic and reproductive disorders. Macroorchidism occurs in males with overt fragile X syndrome. Premature ovarian failure occurs in females who do not have the number of CGG repeats to produce overt fragile X syndrome, but have an expanded number of repeats with few or no apparent neurological symptoms (premutation carriers).

Variation in the cognitive and behavioral phenotype of the fragile X syndrome has been demonstrated in intellectual functioning, learning disability, executive function, attention, hyperactivity, depression, anxiety, and autistic behaviors. The explanation for this variation in phenotypic expression may depend on understanding the role of genetics and brain development in cognition and behavior.

For treatment modalities to be instituted for the fragile X syndrome, suppression of expansion, restoration of expression, small molecule agents, and gene replacement will need to be considered. As of now, these are tasks for the future.

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