FRAGILE X SYNDROME
Fragile X syndrome, also known as the Martin-Bell
syndrome, is a syndrome of X-linked intellectual
disability. Boys with the syndrome may have large testes (macroorchidism),
prognathism, hypotonia and autism,
and a characteristic but variable face with large ears, long face,
high-arched palate, and malocclusion. Additional abnormalities may
include lordosis, heart defect, pectus excavatum, flat feet, shortening
of the tubular bones of the hands, and joint laxity. Females who
have one fragile chromosome and one normal X chromosome may range
from normal to mild manifestations of the fragile X syndrome. The
fragile X syndrome has an estimated incidence of 1 in 4,000-9,000
males and 1 in 7,000-15,000 females.
causes of Fragile X syndrome
The fragile X syndrome is a genetic disorder caused
by mutation of the FMR1 gene on the X chromosome. Mutation at that
site is found in 1 out of about every 1250 males and 1 out of about
every 2500 females.
Because males normally have only one copy of the
X chromosome, those males with significant trinucleotide expansion
at the FMR1 locus are symptomatic. They are intellectually disabled
and may show various physical features of the fragile X syndrome.
Females have two X chromosomes and thus have double
the chance of having a working FMR1 allele. Females carrying one
X chromosome with an expanded FMR1 gene can have some signs and
symptoms of the disorder or be normal.
Males with the fragile X cannot transmit it to
any of their sons (since males contribute a Y chromosome, not an
X, to their male offspring), but will transmit it to all of their
daughters, as males contribute their X to all of their daughters.
Females carrying one copy of the fragile X can
transmit it to their sons or daughters. Sons who receive the fragile
X are at high risk of intellectual
disability. Daughters who receive
the fragile X may appear normal or they may be intellectually disabled,
usually to a lesser degree than boys with the syndrome.
Symptoms of Fragile X syndrome
Prominent characteristics of the syndrome include
an elongated face, large or protruding ears, large testicles (macroorchidism),
and low muscle tone.
intellectual disability (mental retardation), prominent characteristics
of the syndrome include an elongated face, large or protruding ears,
flat feet, large testicles (macroorchidism), and low muscle tone.
Behavioral characteristics may include stereotypic
movements (e.g., hand-flapping) and atypical social development,
particularly shyness and limited eye contact. Some individuals with
the fragile X syndrome also meet the diagnostic
criteria for autism. While full mutation males tend to present
with severe intellectual disability, the symptomology of full mutation
females runs the gamut of minimally affected to severe intellectual
disability, which may explain why females are underdiagnosed relative
Diagnosis of Fragile X syndrome
Fragile X syndrome was originally diagnosed by
culturing cells in a folate deficient medium and then assessing
the cultures for X-chromosome breakage by cytogenetic analysis of
the long arm of the X chromosome. This technique proved unreliable
for both diagnosis and carrier testing.
The fragile X abnormality is now directly determined
by analysis of the number of CGG repeats and their methylation status
using restriction endonuclease digestion and Southern blot analysis.
Treatment and current research
Recent studies have focused on a number of critical
areas. The role of FMRP's RNA partners, many of which have now been
validated through in vitro assays, is of primary importance. Also
being examined is the function the various domains of FMRP, an RNA-binding
protein, which is still relatively unknown.
While there is no current cure for the syndrome,
there is hope that further understanding of its underlying causes
would lead to new therapies. Currently, the syndrome can be treated
through behavioral therapy, special education, medication, and when
necessary, treatment of physical abnormalities. Persons with the
fragile X syndrome in their family histories are advised to seek
genetic counseling to assess the likelihood of having children who
are affected, and how severe any impairments may be in affected
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