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Fragile
X in detail:
(from our EXPLAINING FRAGILE X
SYNDROME brochure - download at bottom of this page)
Fragile X Syndrome
Fragile X syndrome is the most common cause worldwide of inherited
intellectual disability. Fragile X is found in all races and at all
socio-economic levels. Latest statistics indicate 1 in 3600 males
and 1 in 4000- 6000 females are affected and that approximately 1 in
260 females are carriers. Characteristics include global
developmental delay, speech and communication problems, anxiety,
poor concentration, hyperactivity (ADHD), autistic-like behaviours
such as an unusual fixed interest in some things and dislike of
change in routine. The name of the syndrome comes from its location
on the X chromosome. Under particular laboratory conditions, the
bottom of the long arm of this chromosome can appear broken or
fragile. It has been estimated that, worldwide, 50% of people
affected by fragile X have not been correctly diagnosed.
Discovery of Fragile X Syndrome
Fragile X syndrome was first identified in 1969, when researchers
discovered the fragile site at the bottom of the (long arm of the) X
chromosome. In 1991 the FMR-1 gene (the fragile X mental retardation
gene 1) was discovered. Everybody has this gene. When functioning
normally, the gene produces a protein called FMRP, which is
essential for normal brain development and function. In people with
fragile X syndrome, the gene may be turned off and the protein may
not be adequately made. The discovery of this gene means accurate
DNA testing for the syndrome is now available.
Inheritance
Inherited characteristics are carried from one generation to the
next by chromosomes. It is usual to have 46 chromosomes (23 pairs).
The sex chromosome pair determines the sex of an individual. Females
have two X chromosomes and males have one X and one Y. These
chromosomes are made up of DNA sequences or genes, which act as
templates for making proteins with specific functions. It has been
estimated that we have between 80,000 – 100,000 genes. A change in a
gene is called a mutation. Some mutations have no effect, but
others, such as in the FMR-1 gene, cause changes in the structure or
function of our bodies. In front of the FMR-1 gene is the DNA
sequence ‘CGG’. This sequence is normally repeated between 6 and 50
times. In some people, this sequence is repeated between 50 to 200
times and is called a premutation, which generally causes few or no
symptoms of fragile X syndrome. In a woman with the premutation, the
size can expand to over 200 repeats when that X chromosome is passed
on in her egg. This is called a full mutation. In the full mutation,
the gene for FMR-1 switches off and no protein is produced. Fragile
X syndrome is the result. The expansion does not occur from males to
their children. Males with the fragile X gene will pass that X
chromosome without a change to all of their daughters.
Appearance
There are some physical features common to many, but not all, people
with fragile X syndrome. The skin is especially smooth and soft. The
ears may be prominent and there can be a high forehead, making the
face look long. In some children, the face does not develop the
narrow look until puberty, if at all. After puberty a big jaw may
develop. These features are more common in males than in females and
are seen in approximately 50% of individuals. Growth patterns
indicate that children with fragile X, especially males, are of
average height or tall while young, but tend to be average once they
are adults.
Developmental Delays
Intellectual disability is the most significant characteristic of
those with fragile X. Most males and approximately two thirds of
females exhibit some intellectual disability. This is usually
accompanied by poor fine and gross motor skills. The range of
learning problems is wide. Some are affected by minor developmental
delays. At the other end of the scale there can be severe
intellectual disability. Most affected males fall somewhere in the
middle. Males typically appear more severely affected than females.
However, parents and educators are often surprised at their
achievements.
Females appear less affected. However, they may experience
difficulty with maths and tend to suffer from a range of anxiety
disorders including social anxiety. Most males and
approximately two thirds of females exhibit some intellectual
disability
Behavioural Effects
It is important to understand the behavioural and emotional effects
of the syndrome, as they can be as significant as developmental
delays. Because people
with fragile X syndrome look much the same as others, their
behaviour problems can be misinterpreted.
Almost all people with the syndrome have trouble self-regulating
their behaviour. This shows up in problems such as attention deficit
disorders and hyperactivity, which can impair learning. Repetitive
behaviours, late toilet training, disturbed sleep and the inability
to control emotions are other behavioural characteristics. Lack of
control of emotional behaviour can result in tantrums or other
emotional outbursts.
Some behaviour, most obvious with males, is similar to autism. For
instance, children can refuse to be touched or held. There can be
difficulty with making eye contact. Hand flapping is often found,
which becomes more vigorous when the personis anxious or excited.
Some people bite their hands or chew their clothing. This can be a
way to calm themselves. Both males and females find
concentrationdifficult. In addition, they may be quite severely
hyperactive and impulsive. They may have fixed interests in objects
and can strongly dislike any change in routine.
Females with fragile X may be shy and moody, lack social skills and
may even avoid social contact. They can suffer from depression and
severe anxiety. Refusing to talk in certain situations (selective
mutism) can be exhibited.
Despite the behavioural challenges outlined, people with fragile X
often enjoy being social, have pleasant personalities and a good
sense of humour.
Medical Issues
People affected by fragile X syndrome have a normal life expectancy.
They do not suffer from major medical problems because of the
syndrome and thus are
generally healthy. However, there are some medical factors which may
be more common in those with fragile X syndrome.
Problems with connective tissue can lead to flat feet and low muscle
tone. Eyelids that tend to puffiness and chests with a ‘hollow’ look
are features which probably also relate to this problem. The joints
are often extremely flexible and may be subject to dislocation.
Hernias are sometimes present.
Children, especially boys, are particularly prone to ear infections
(otitis media). It is very important that every occurrence of ear
infection is treated quickly, as problems in speech and language can
be increased if there is even a slight temporary hearing loss. Eye
problems can include squint (strabismus), long sightedness and
visual perceptual problems.
About one in four people with fragile X have epilepsy which can be
generalised or focal (grand mal, petit mal or absences, or complex
partial seizures). Seizures usually begin in childhood or
adolescence and are not frequent, often being outgrown before
adulthood. A few people have heart valve problems (mitral valve
prolapse), which may show up in late adolescence to early adulthood.
Hence annual medical review is recommended.
Many boys develop enlarged testicles(macroorchidism) after puberty,
but this does not seem to pose any medical problems. Women with the
premutation can have premature menopause. In extreme cases this can
occur in the early twenties.
A progressive, neurological condition affecting some male carriers
of fragile X over the age of 50 has recently been identified. It is
called Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) and is
characterised by tremors, balance problems and dementia that become
worse with age. The men are generally healthy until they reach their
middle years, and have normal to above average intelligence.
Research suggests that as many as 30 percent of male carriers may
develop
FXTAS later in life. Initial signs of the disorder may include
difficulty writing, using utensils, pouring water and walking. The
symptoms progress over years or
decades, until many daily tasks become extremely difficult. There
may also be short-term memory loss, anxiety, decreased sensation to
touch in the lower
extremities and rigidity in movement. It is common to find these
males misdiagnosed as having Parkinson’s disease, senile dementia or
Alzheimer’s disease. Studies are underway to determine the best
methods of treatment for the condition.
Speech
Most males exhibit delayed speech as children and poor command of
spoken language.
Some are inhibited when they do begin to speak. The rhythm of their
speech may be uneven or be fixed in a chant-like pattern. The
automatic use of known phrases is common. Speech can be very fast
and others may find it difficult to understand.
Males with fragile X often continually repeat words and phrases
(perseveration). This may be because they are anxious, or be an
example of repetitive behaviour, which some people with fragile X
find hard to control. Echoing the words of others (echolalia) is
another problem. Males can speak constantly and inappropriately
about a single topic. There are often problems in the use of
expressive language, that is, in conveying thoughts to others.
Speech and language problems tend to be less severe in affected
girls.
On the positive side, vocabulary can be within the normal range.
Some children verbally imitate others extremely well; this can
become a helpful learning tool. Comprehension by the person with
fragile X can be greater than the observer believes.
Speech and language pathologists can assist in encouraging people to
communicate, and in improving the speech of older children and
adults. For non-verbal individuals, augmentative communication
systems, such as visual aids and signing, may be introduced. As with
all helping techniques,
the earlier the therapy begins the better.
Sensory Integration
People with fragile X have difficulty in sorting out and screening
all the messages that come through their senses. They are extremely
hypersensitive to their
environment. The problems they have in sorting sensory information
are called ‘sensory integration deficits’. These characteristics can
increase learning and
behavioural problems, as all sensations are received in an extreme
form. They may have a negative response to situations that seem
normal to others. Such situations include reactions to unfamiliar or
strong smells, refusing to wear tight clothing, or clothing made of
a rough fabric and being extra sensitive to bright or flashing
lights. They are often disturbed in areas of high ambient noise,
such as shopping centres and other crowded locations. People with
fragile X may not be able to communicate what is upsetting them. It
is important for carers to know about this sensory integration
problem.
This response to sensory overstimulation has been called ‘sensory
defensiveness’. Individual programs, usually involving commonsense
ways of organising and reducing environmental stimulation, can be
planned to lessen the reaction. For instance, noise which is sensed
as too loud, lighting which seems too bright and hypersensitivity to
certain types of clothing can all be changed. Occupational therapy
with a sensory integration focus can lessen a person’s sensory
defensiveness.
Treatment
There is currently no cure for fragile X syndrome. However, a
variety of treatment and management strategies have been found to be
very helpful. A combination of educational, medical and behavioural
management techniques have been demonstrated to improve the outcomes
for affected individuals and their families. The child’s educational
program should include occupational, physical and speech therapies,
introduced as early as possible. These therapies can be very
effective when designed to meet the needs of an individual in an
early intervention and school program.
There are medications that can assist
people with fragile X and these should be controlled through
clinical administration and continual testing to monitor progress.
Medications have to be monitored to ensure that the right dosage is
prescribed, side effects are minimised and that negative behaviours
are not experienced.
Education
Education is available for people with fragile X at all stages of
their development, from pre-school to the end of high school.
Post-secondary education is an option for some.
Children with developmental delay can be helped with early
intervention even before a diagnosis is made. The earlier that this
intervention can be included into the child’s learning pattern, the
better the results later on.
Depending on the age, abilities and needs of the child with fragile
X, the facilities
provided by the education systems and the wishes of the family,
schooling may take place in mainstream classes, special classes in
mainstream schools or classes in schools geared specifically for
those with special needs.
Pre-school and school teachers should be encouraged to work with the
particular strengths of those with fragile X. For example, they
generally have very good long-term memories, and they tend to learn
visually. Use of pictures can be very helpful, and illustrated
social stories can assist with behaviour. A particular strength of
many students with fragile X is their computer skills. There is a
wide range of software available which can assist in all aspects of
learning.
Individuals can be helped in the classroom with structured routines,
careful preparation for changes, the use of calming techniques and
the elimination of distractions. They benefit greatly from being
able to see ‘the whole picture’ of what is going to happen, for
example knowing in advance the full schedule for the day’s
schooling. They are excellent imitators, which makes it desirable
for them to be placed with good role models in the classroom
wherever possible. To assist in their child’s learning, parents
should give teachers as much information as they can.
Post secondary education, if appropriate, can be undertaken through
some community and Department of Technical and Further Education (TAFE)
colleges, or through specialised courses run by some charitable
institutions. At the upper end of the spectrum, university education
is available to those who qualify
through normal competitive entrance procedures.
Many educators find that children and adults with fragile X are now
being educated to a level that may be higher than originally thought
possible. People with fragile X often hold jobs in which they can
achieve satisfactorily and are regarded well by their colleagues.
They can become useful, productive and valued members of their
communities.
Testing
Accurate DNA testing for fragile X is now available. The test is
called ‘DNA Studies for fragile X syndrome’. Any medical
practitioner can now refer a patient to a geneticist or a
developmental paediatrician to arrange the test. Cytogenetic studies
(chromosome tests)should be carried out at the same time to
eliminate the possibility of other genetic disorders.
Testing is recommended for several groups. It should be carried out
on any male or female who has an intellectual
disability of unknown cause, or is developmentally delayed along
with other characteristics of fragile X syndrome. It should also be
carried out when a person
shows autistic-type behaviour which is associated with learning
problems. People who show any of the characteristic symptoms of
fragile X syndrome should be tested, whatever their family history,
as should any person who has a family member diagnosed with fragile
X.
If there is a history of intellectual disability in a family,
individuals who show no symptoms of fragile X should be tested to
find out whether or not they are carriers. This is important for
those who are thinking about becoming parents. Knowing their carrier
status can help a couple to make decisions about family planning.
Tests for fragile X carried out before 1991 may not be correct. The
results of cytogenetic tests since then may be inaccurate. People
who were tested before 1991 or who have only had a cytogenetic test
should have a DNA test.
Women who experience premature menopause (before the age of 40) or
who have a family history of premature menopause should also be
tested for fragile X.
Accurate prenatal testing is available for female carriers of the
disorder. Two pre-natal tests detect the presence of fragile X in
the foetus. Chorionic villus sampling (CVS) is used when the foetus
is between 10 and 12 weeks. A small amount of placenta is taken from
the uterus for testing. Results are usually available within two
weeks.
In the second method, amniocentesis, a small amount of amniotic
fluid which contains foetal cells is removed. The test is usually
done between the 14th and the 18th week of pregnancy. Growing and
testing of the cells can take two to four weeks. Using this test a
woman wishing to find out if her baby is free from fragile X might
have to wait until she is 22 weeks pregnant for a result.
A new test has recently become available, called preimplantation
genetic diagnosis (PGD). This involves taking a single cell from an
embryo before it implants in the uterus. The cell can be tested to
see if the fragile X chromosome has been inherited. An IVF cycle is
needed to produce the embryos for testing. There are only a few
specialized centres in the world performing PGD. This test
isavailable in Australia. Current official indications for testing
for fragile X syndrome are available on the website of the Human
Genetics Society of Australasia,www.hgsa.com.au, under ‘Policies’.
The first three of these indications are covered by Medicare.
Counselling
People should have genetic counselling whenever there is a positive
result from a DNA test for fragile X. Very often the diagnosis takes
people by surprise. The general lack of knowledge of the syndrome in
most communities adds to the feelings of distress and worry which
can accompany the diagnosis of a genetic condition. Genetic
counselling makes clear the opportunities open to couples for family
planning and helps to explain the effect the diagnosis may have for
the immediate and extended family. Often families need further
counselling of a different type. The shock of the diagnosis is often
great and the family as a whole, and individual members of it, often
need supportive counselling. It is important that those affected by
a diagnosis are able to talk about their concerns.
Further Information
Fragile X is a challenging condition for families to learn about,
adjust to and live with. Fortunately there is an increasing amount
of research being undertaken into its many facets, aimed at
increasing our knowledge and improving treatments. There is also an
increasing range of published materials and websites related to
fragile X, all of which can provide useful insights. This website
lists much of this material and provides
links to useful websites.
To download our "Explaining Fragile X
Syndrome" brochure, please click on the image of the brochure below:
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