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.

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fragile X syndrome -'eks- n an X-linked inherited disorder that is caused by repeats of a trinucleotide sequence on the X chromosome which are abnormal in number and degree of methylation, that is characterized by moderate to severe mental retardation, by large ears, chin, and forehead, and by enlarged testes in males, and that often has limited or no effect in heterozygous females called also fragile X

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an X-linked syndrome associated with a fragile site on the X chromosome at q27.3, associated with mental retardation, enlarged testes, high forehead, and enlarged jaw and ears in most males and mild mental retardation in many heterozygous females. It is a triplet repeat disorder, associated with expansion of CGG triplet repeat sequences in the promoter region of a gene expressed in human brain cells, the FMR1 (fragile X mental retardation 1) gene, with triplet repeats expanding from the normal 50 to as many as several thousand in the full syndrome. Between 50 and 200 copies, the sequence is unstable and prone to expansion; individuals appear normal, but are said to carry a (heritable) premutation, and when over 200 copies are present, abnormalities of methylation occur in the promoter region and prevent expression of the gene, and clinical symptoms are apparent. The expansion and methylation abnormalities also appear to interfere with chromosome replication, producing the characteristic fragile site.