Fragile X syndrome

M. K. Tadjudin
Fakultas Kedokteran dan Ilmu Kesehatan
Universitas Islam Negeri Syarif Hidayatullah
Jakarta
 Fragile X syndrome (1)
FXS, or Martin-Bell syndrome, is a genetic
syndrome which results in a spectrum of
characteristic physical and intellectual
limitations and emotional and behavioral
features which range from severe to mild in
manifestation
Associated with the expansion of a single
trinucleotide gene sequence (CGG) on the X
chromosome, and results in a failure to
express the protein coded by the FMR1 gene,
which is required for normal neural
development
 Fragile X syndrome (2)
Four generally accepted states of the
chromosome region involved in Fragile X
syndrome which relate to the length of the
repeated CGG sequence; Normal (29-31 CGG
repeats) (not affected by the syndrome),
Premutation (55-200 CGG repeats)(not
affected by the syndrome), Full Mutation
(more than 200 CGG repeats)(affected), and
Intermediate or Gray Zone Alleles (40 - 60
repeats)
 Fragile X syndrome (3)
Martin and Bell in 1943, described a
pedigree of X-linked mental disability,
without considering the
macroorchidism (larger testicles)
In 1969 Herbert Lubs first sighted an
unusual "marker X chromosome" in
association with mental disability
In 1970 Frederick Hecht coined the term
"fragile site
 Fragile X syndrome (4)
Escalante's syndrome is synonymous
with the fragile X syndrome. This term
has been used in South American
countries
Fragile X is the most common known
single gene cause of autism and the
most common inherited cause of
intellectual disability
 Causes (1)
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 2000 males and 1 out of about every 259
females.
Incidence of the disorder itself is about 1 in
every 3600 males and 1 in 4000-6000 females.)
Normally, the FMR1 gene contains between 6-55
repeats of the CGG codon (trinucleotide
repeats)
 Causes (2)
In people with the fragile X syndrome, the FMR1
allele has over 230-4000 repeats of this codon
Expansion of the CGG repeating codon to such
a degree results in a methylation of that portion
of the DNA, effectively silencing the expression
of the FMR1 protein
This methylation of the FMR1 locus in
chromosome band Xq27.3 is believed to result
in constriction of the X chromosome which
appears 'fragile' under the microscope at that
point, a phenomenon that gave the syndrome
its name
 Causes (3)
Mutation of the FMR1 gene leads to the
transcriptional silencing of the fragile X-
mental retardation protein, FMRP
In normal individuals, FMRP is believed to
regulate a substantial population of
mRNA: FMRP plays important roles in
learning and memory, and also appears to
be involved in development of axons,
formation of synapses, and the wiring and
development of neural circuits
 Causes (4)
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
One hypothesis is that many symptoms are
caused by unchecked activation of mGluR5, a
metabotropic glutamate receptor, which was
found in a 2007 study to contribute significantly
to the pathogenesis of the disease mGluR5
blockers could be used to treat fragile X
syndrome
Prominent
characteristics of the
syndrome include an
elongated face, large
or protruding ears,
and low muscle tone.
 Characteristics (1)
Elongated face,
Large or protruding ears,
Low muscle tone.
Flat feet,
Soft skin
Larger testes (macroorchidism), and
Cluttered speech or nervous speech
Stereotypic movements (e.g., hand-flapping)
Atypical social development, particularly shyness,
limited eye contact, memory problems, and difficulty
with face encoding.
Autism.
 Characteristics (2)
Females who have the syndrome experience
symptoms to a lesser degree because of their
second X-chromosome, however, they can
develop symptoms just as severe as their male
counterparts
While full mutation males tend to present with
severe intellectual disability, the symptoms of
full mutation females run the gamut of
minimally affected to severe intellectual
disability, which may explain why females are
underdiagnosed relative to males
 Similarities between X-linked
recessive inheritance and fragile X
Males are predominantly affected;
Females (mothers) are obligatory carriers
(i.e., are conclusively proven to be carriers) if
a male child is affected, but not necessarily if
female children are affected, as a female
child with one fragile and one normal X
chromosome may have inherited the fragile
chromosome from the father without
symptoms
A difference is that females may also have
clinical symptoms.
 Diagnosis
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.