1. FRAGILE X SYNDROME
Sayma Zerin
Roll-10,3rd year
Dept. of Genetic Engineering and Biotechnology
University of Dhaka

2. FRAZILE X SYNDROME(FXS)

Most common inherited intellectual disability.

A X-linked disease.

A trinucleotide (CGG) repeat disorder

Cause-a mutation in the fragile X mental retardation
1 (FMR1) gene on the X chromosome.

Can affect both genders.

3. A rare, folic acid-sensitive site at Xq27.3
 Tends to break under stress
 Unstable CGG repeat at the fragile site

WHY IT IS CALLED FRAGILE X SYNDOME?

4. HISTORY
In 1943, J. Purdon Martin and Julia Bell described a
pedigree of X-linked mental disability
 In 1969, Herbert Lubs discovered an unusual
"marker X chromosome" in affected male
 In 1970, Frederick Hecht coined the term "fragile
site".
 In 1991, the FMR1 gene was identified


5. 
Most frequent cause of inherited mental retardation
after down syndrome
WHY WE SHOULD KNOW ABOUT FXS?

Also known as the most common single gene
cause of autism

6. HOW COMMON IS FRAGILE X SYNDROME?
1 in 3600 to 4000 males in the world are born with
the full mutation
 1 in 4000 to 6000 females in the world are born with
the full mutation.
 1 in 800 men in the world are carriers of the Fragile
X premutation.
 1 in 260 women in the world are carriers of the
Fragile X premutation.


7. INHERITENCE PATTERN
Inherited in an X-linked dominant pattern.
 Mothers → premutation or full mutation → passes
to both daughter and son
 Mother → 50% chance of passing mutant X
 father → premutation → passes only to daughters


8. CHANGES IN THE FMR1 GENE
4 forms of FMR1 gene-by the number of CGG
repeat
 Normal range is 5-44 repeats, most commonly
29/30 repeats.
 45-54 repeats → grey zone or intermediate zone
 50-200 repeats→ premutation carrier
 >200 repeats→ full mutation


9. THE FRAGILE X PREMUTATION
55-200 CGG repeat
 Occur in both males and females.
 Expands to full mutation in offspring
 Passing from father-does not expand to a full
mutation.
 Chances of expanding is related to the size of the
mother’s premutation.


10. THE FMR1 FULL MUTATION
>200 CGG repeat
 some degree of methylation
 shut down a methylate region of the FMR-1 gene.
 does not make FMR protein
 Males with a full mutation will have FXS


11. FMRP
Full mutation in FMR1 gene prevents production of
FMRP
 FMRP is a RNA binding protein
 Affects• mGluR pathway
• dopamine pathways
• GABA pathways


12. MOLECULAR BASIS OF FXS
FMRP
Negatively regulate
Protein synthesis by mGluR
activation
mGluR signaling
Increased synthesis of mGluR
dependent protein
FXS

13. SYMPTOMS
Behavioral aspects
 Physical features

• Large, protruding ears
• Long face
• High-arched palate
• Hyperextensible finger joints
• Double-jointed thumbs
• Flat feet
• Soft skin
• Postpubescent macroorchidism
• Hypotonia

Neurological

14. RELATED
Autism
 FXTAS
 FXPOI
 ADHD

DISEASES

15. DIAGNOSIS
PCR
 Southern blot of DNA
 Antibody test
 MS-MCA
 Prenatal tests:
•amniocentesis
•chorionic villus sampling


16. TREATMENT
There is no cure, only treatment.
 Research is actively being conducted.

Educational options
 Therapeutic options
 Medication options


17. EDUCATIONAL OPTIONS
Parents, teachers, and psychologists can develop
an Individualized Education Plan (IEP)
 Placement depends on severity of Fragile X
 Generally three options:

Full inclusion in a regular classroom.
 Inclusion with "pull-out" services
 Full-time, special education classroom


18. THERAPEUTIC OPTIONS

Speech-language therapists


Occupational therapists


Help with tasks, daily activities, and career choice
Physical therapists


Improve pronunciation, slow down speech, etc
Motor control
Behavioral therapists

Identify distressing situations and help to prevent and
cope with them

19. MEDICATION OPTIONS
Treat symptoms
 Examples:

Ritalin for ADD
 Prozac for aggression
 Melatonin for sleep disturbances
 Lithium carbonate for mood instability


Drugs undergoing trials1.mGluR5 antagonist
2.Mavoglurant and diproglurant
3.Fenobam

20. QUESTION???