FRAGILE X SYNDROME

WHAT IS FRAGILE X SYNDROME? 

Fragile X (named for the "fragile" site on the X chromosome 
that is exhibited by most people having this syndrome) is 
estimated to affect about 5% of the mentally impaired population. 
Effects range from very mild to quite severe. Problems may include 
learning disabilities, short attention span, hyperactivity, speech 
abnormalities and autistic-like behavior. Some of the physical 
features sometimes associated with fragile X syndrome are large or 
prominent ears, a long face with a protruding chin, and very 
extensible finger joints. Fragile X males usually also have 
enlarged testes after birth. Males with this disorder have
a mental retardation rate of 100 percent, while females with
Fragile X syndrome have a 50 percent rate of mental retardation.

*Fragile X syndrome is considered the most common inherited cause 
of mental retardation in the general population. Fragile X 
syndrome affects males and females. 

* The number of people carrying the fragile X gene may be as high as 1
in 625. The prevalence: 1:1,250 males and 1:2,500 females have this
disorder.

* As a rule, the mother of an affected child is a carrier of the
fragile gene. 

* Age of onset: toddler -> adolescence

* Risk factors: familial - fits neither dominant or recessive X-linked
inheritance patterns (carrier frequency for females: 1:500)

HOW FRAGILE X SYNDROME IS INHERITED

Genes are made up of DNA, which is the chemical substance 
that tells the body's cells what to do. Genes usually come in 
pairs, one from the mother and the other from the father, and are 
packaged into microscopically-visible chromosomes. Women have two 
X chromosomes in each body cell and men have one X chromosome and 
one Y chromosome. This may account for the fact that males with this 
disorder are much more likely to have mental retardation, since they 
inherit only one defective X chomosome, which has a very heavy 
genetic loading for intelligence. The male inherits only one
(which in this case is defective) X chomosome from his mother, and 
a Y chromosome from his father. The female, on the other hand
inherits one X chromosome from the mother, and one from the father.
In 1991, scientists identified "FMR-1"("Fragile X Mental 
Retardation" gene) , the gene that when abnormal causes fragile X 
syndrome. In fragile X, it is turned "off" because it's DNA on the 
X chromosome has a large change in length called a "full 
mutation". If the change in length is short and the gene is still 
"on", it is called a "premutation". Individuals with a premutation 
of the fragile X gene are called "carriers"; they are not usually 
affected with the disease. Boys who have a full mutation are 
affected with fragile X syndrome. On the other hand, girls who 
have a full mutation may not be affected. This is because their 
second X chromosome is usually working properly. While a number of 
females with a full mutation have learning disabilities, mental 
retardation and/or psychiatric disorders, many have no symptoms at 
all. The fragile X mutation is located on the X chromosome and its 
pattern of inheritance can be predicted. A woman who carries a 
fragile X mutation has a 50-50 chance of passing it to each of her 
children. However, a man with a fragile X mutation will always 
pass it to his daughters, but cannot pass it to his sons. Fragile 
X premutations can be passed on in families by men or women, even 
if they have no outward signs of the syndrome. A premutation can 
enlarge to a full mutation only if it is inherited from the 
mother. It is important to remember that parents have no control 
over which genes are passed on to their children. 

CLINICAL FEATURES:

FOR MALES:

1. Neurological Manifestations
Mental Retardation (100%). Ranges from profound to normal 
IQ with learning disabilities mental impairment is low for 
premutation carriers.

3. Developmental Delays

A. Gross Motor

B. Speech/Language, generalized language disability
more jargon, perseveration, echolalia, cluttering

4. Behavior: variable but tends to improve around puberty
A. Hyperactivity
B. Short attention span
C. Emotional instability
D. Autistic-like behaviour (in 5-10%)
E. Hand biting, tactile defensiveness

5. Genitourinary Manifestations
A. Macro-orchidism. Found in 80-90% of affected males after 
puberty testes usually not enlarged prior to puberty. One 
or both testes may be of normal size. normal testicular function

6. Dysmorphic Features
A. Craniofacial:
large head - prominent mandible
long, thin face - prominent forehead
large ears +/- low set, posteriorly rotated, poorly formed

B. Connective Tissue Manifestations
hyperextension of fingers
mild-to-moderate pectus excavatum
floppy mitral valve (in 80% over the age of 18)

FOR FEMALES

1. Neurological Manifestations
Mental Retardation (50%)
50% impaired due to unfavourable X chromosome inactivation

2. Developmental Delays

3. Behavioral Manifestations:
A. Shyness
B. Emotional Liability. Difficulty controlling emotions.
These females will cry very easily, also become aggitated
and emotional with very little provocation.

4. Dysmorphic Features: 
A. Mild craniofacial and connective tissue manifestations

WHO SHOULD BE TESTED FOR FRAGILE X?

Fragile X testing should be considered for any individual with 
unexplained mental retardation or developmental delay, especially 
when there is more than one such person in the extended family. 
Testing to detect carriers is also indicated for females with 
appropriate family history of one or more retarded autistic 
members, whether or not fragile X has been confirmed in the 
family. Any person, with our without a family history, can choose 
to be tested for fragile X for these or other reasons. For 
example, all GIVF egg donors are prescreened to exclude the 
possibility that they are fragile X carriers. 

CAN A BABY BE TESTED BEFORE BIRTH FOR FRAGILE X?
Testing can be done early in pregnancy (at about 10-11 weeks) by 
chorionic villus sampling (CVS), or by amniocentesis, which is 
usually performed between weeks 15-17. Because carrier testing of 
mothers is definitive, fetal testing is not usually performed 
unless the mother is a proven carrier. 

HOW CAN I GET FRAGILE X TESTING?
A small amount (about two teaspoons) of blood is needed for testing to
be performed. The blood sample will be sent to the specialized 
GIVF laboratory for testing, and your doctor will have results in 
about two weeks. As with all laboratory procedures, a physician 
must order the specimen collection and testing. 

GENETIC COUNSELING
If fragile X syndrome is identified in your family, comprehensive 
genetic counseling will be very important. Your doctor can make a 
referral for you to have the testing and counseling. The counselor 
will take a complete family history and help explain the 
diagnosis, testing and treatment options that are appropriate for 
the individuals involved. 

WHAT CAN BE DONE FOR CHILDREN WITH FRAGILE X SYNDROME 

There is no known treatment for this disorder, although 
symptoms, such as coordination, and speech problems can usually be 
treated with appropriate physical and speech therapy. 
Hyperactivity, and emotional symptoms can usually be treated with 
a variety of medications. The degree of intellectual impairment 
will determine the extent of educational intervention. These 
children usually live a normal life span. Integration into 
society depends upon the degree of intellectual impairment. 

1. Many Fragile X children, especially boys, have deficits
such as poor motor coordination, hypotonea, poor motor
planning and tactile defensiveness. These problems
sometimes trigger tantrums or out-of-control behavior
when the child becomes overwhelmed by multiple sensory
stimuli or confusion in the environment. If these
problems are apparent, teachers, parents or others may
assist by using calming or relaxation techniques at home
and school.

2. Parents may want to consult with their family physician
to explore the appropriateness of any medical
intervention. Hyperactivity and attentional problems are
often present in Fragile X males and occasionally in
female carriers. Stimulants in low dosage have been
found to be helpful with many Fragile X males. Higher
doses may cause significant mood lability or an increase
in tantrums.

3. References suggest the importance of parents receiving
genetic counseling when Fragile X Syndrome is diagnosed.
This is considered essential in developing a better
understanding of the syndrome and providing appropriate
parenting in light of the academic, developmental and
behavioral difficulties often present. It is also
important that relatives be informed of the presence of
this disorder in the family genes so that other affected
family members might be possibly identified and assisted
accordingly. Family planning issues might also be a
topic that the parents may want to discuss.

4. Although there is no cure for the Fragile X Syndrome, a
team approach involving the teacher, psychologist, speech
and language pathologist and parents can lead to
improvements in behavior and significant developmental
and academic progress.

5. Language delays, particularly in auditory processing,
topic maintenance, attention sequencing, pragmatics and
abstract reasoning, are often noted. Assessments in
these areas may pinpoint significant delays which may
qualify these students for speech and language therapy to
address these needs. Once these children are better able
to communicate their needs and wants with others, many
behavioral and social difficulties may also improve.