Definition of Fragile X syndrome
< b>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.
Common Misspellings: fragile x syndrone
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