FRAGILE X SYNDROME

Content :1. History2. Introduction3. Epidemiology4. Causes5. Signs and Symptoms6. Diagnosis7. Treatment8. Research 9. Conclusion10. References

History

• In 1943, Fragile X syndrome was discovered by James Purdon Martin and Julia Bell.• The disease is also known as Martin-Bell syndrome,

named after their discovery.• 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“• In Brazil and other South American countries ,it is

commonly known as Escalante's syndrome .http://www.ncbi.nlm.nih.gov/pubmed/21611430

Introduction • FXS is a genetic syndrome that is the most

widespread single-gene cause of autism and inherited cause of mental retardation.• It is associated with the expansion of the

CGG trinucleotide repeat affecting the Fragile X mental retardation 1 (FMR1) gene on the X chromosome.• Resulting in a failure to express the fragile X

mental retardation protein (FMRP).• FMRP is required for normal neural development.• Absence of FMRP leads to abnormalities in brain

development and function. http://t3.gstatic.com/images?q=tbn:ANd9GcS7aHl9F1onFAaaZs9eGxp9MMcUr-dDWDQl_A5F0w-lHkw_Qco5

CGG CG CG

CGG CGG CGG CGG CGG ~6-44 Repeats

CGG CGG CGG CGG CGG ~45-54 Repeats

CGG CGG CGG CGG CGG ~ 55-200 Repeats

CGG CGG CGG CGG CGG ~ >200 Repeats

FMR1 gene q27.3

What actually happens??

Mutation

Pre-Mutation

Intermediate

Mild

~55-200 Repeats

>200 Repeats

~6-44 Repeats

~45-54 Repeats

Types:-

MutationPre-Mutation

Epidemiology

• Fragile X syndrome is the most common known inherited cause of mental retardation. • Based on cytogenetic testing, it is thought to affect 1

in 4000 males and 1 in 8000 females. • The condition is underdiagnosed, especially in

females, because craniofacial abnormalities as well as neurobehavioral deficits are often subtle, and the variability in phenotype is tremendous. • The prevalence for the premutation is estimated at 1

in 813 males and 1 in 259 females.

http://270c81.medialib.glogster.com/media/b8/b8c4b3eb2a5b83d3e8c9229b5d687b087aef9676e057123379b7d861f4110166/fx-jpg.jpg

Causes

• In FXS one of the genes on the X chromosome is faulty. • The gene that causes fragile X is

called the FMR1 gene. • Pictures of the X chromosome

show a constriction near the tip of the chromosome, so it looks as though the end of the chromosome is breaking off.• The faulty gene causes this

disruption in the chromosome.http://pcosjournal.com/foray-into-prenatal-genetic-counseling-screening-testing/

Signs & Symptoms :

prominent characteristics of the syndrome • intellectual disability• Large, protruding ears (one or both)• Long face (vertical maxillary excess)• High-arched palate (related to the above)• Hyperextensible finger joints• Hyperextensible ('Double-jointed') thumbs• Flat feet, Soft skin• Postpubescent macroorchidism (Large testes in men after puberty)• Hypotonia (low muscle tone)• single palm crease (crease goes across entire palm)http://qw88nb88.files.wordpress.com/2008/05/finger-hyperextension1.jpg

http://www.mrcophth.com/cataract/higharch.JPG http://t2.gstatic.com/images?q=tbn:ANd9GcTLeL7xqPzymtr5H82lRoLKU-2sogH48qelgTXZHRD2ijqph6N9WQ

Diagnosis :

The diagnosis is based on 3 factors:• Positive carrier testing for the FMR1 premutation,Karyotyping.• A neurological exam that affirms the above characteristics, and• Magnetic Resonance Imaging (MRI) findings that are known to be

related to FXTAS, including white matter changes or decreased size of the brain.• polymerase chain reaction (PCR)• chorionic villus sampling • amniocentesis

• Chorionic villus sampling (CVS) involves taking a sample of cells from the tissue of the placenta of a pregnant woman. These cells are called chorionic villi.

• The procedure is always carried out under the guidance of an ultrasound scan to avoid making a hole in the amniotic sac

• Two different methods can be used during the procedure:• transabdominal CVS• transcervical CVS• Transabdominal CVS• During transabdominal CVS, the stomach is cleaned with antiseptic and a

needle is inserted through the stomach and abdomen wall. The needle is guided towards your womb using the image on the ultrasound scan.

• Attached to the needle is a syringe, which is used to extract a small sample of chorionic villi, after which the needle is removed.

Chorionic villus sampling (CVS)

http://t1.gstatic.com/images?q=tbn:ANd9GcSbW-PNGfSUuiyBZru1S3fMPIr3Sb2wjDtJ1xLLDlR-Nqn8ykhj

Treatment

Pharmacological

antidepressants such as selective serotonin reuptake inhibitors

(SSRIs)

antipsychotics such as Risperdal and Seroquel

Anticonvulsants used to control seizures as well as

mood swings

Non-pharmacological

speech therapy,

behavioural therapy,

Sensoryntegration occupational therapy,

special education

genetic counseling

Address:Aurinko Academy,#82, Tropical Paradise,Kudlu, Bangalore 560068,Karnataka, India.

Non-Pharmacological treatment

http://www.news-medical.net/image.axd?picture=2012%2f11%2fFragile+X.jpg

Research• The increased understanding of the molecular mechanisms of

disease in FXS has led to the development of therapies targeting the affected pathways.

• Evidence from mouse models shows that mGluR5 antagonists (blockers) can rescue dendritic spine abnormalities and seizures, as well as cognitive and behavioral problems, and may show promise in the treatment of FXS. Gül Dölen et al.(2008)

• Two new drugs, AFQ-056 (mavoglurant) and dipraglurant, as well as fenobam are currently undergoing human trials for the treatment of FXS. P. Cole (2012).

• In addition, there is evidence from mouse models that minocycline, an antibiotic used for the treatment of acne, rescues abnormalities of the dendrites. An open trial in humans has shown promising results, although there is currently no evidence from controlled trials to support its use. McLennan Y et al.(2011)

http://t2.gstatic.com/images?q=tbn:ANd9GcROwwIZBh3j_vilpPyOv0wyBtx0dTZzQgw6jGk6QUF60_XmHcxnFg

Lovastatin for Fragile X? • High-profile publication by FRAXA-funded team at MIT, led by Dr. Mark Bear, suggests

an available medication may treat Fragile X.• It has been known for some time that lovastatin can indirectly decrease the activity of

these ras-ERK signaling pathways (an action only remotely related to its primary cholesterol-lowering function). This effect is relatively weak, but more potent ERK inhibitors are usually quite toxic. Lovastatin and related “statins” have a long track record of safe administration to millions of patients around the world, including children. The experiments described in this paper show convincingly that lovastatin inhibits ras-ERK signaling enough to have significant therapeutic effects in Fragile X animal models.

• The trial is well underway, as the graphic shows. So far, 13 patients have been screened for the trial, 8 have completed the first treatment phase (a low dose of Lovastatin for one month) and 4 have gone into the second phase (a higher dose of Lovastatin for two months). No one has withdrawn from the trial after starting treatment.

http://drugline.org/img/drug/mevacor-14891_2.jpg

http://www.fraxa.org/images/lovax.jpg

Conclusion

• There is no specific treatment available for fragile X syndrome. Supportive therapy for children who have fragile X syndrome includes:• Special education and anticipatory management including avoidance of

excessive stimulation to decrease behavioral problems.• Medication to manage behavioral issues, although no specific medication has

been shown to be beneficial.• Early intervention, special education and vocational training.• Some children cope in mainstream schools, sometimes with some extra help,

while others need to go to a school which can provide for their special educational needs.

References • Bassell GJ, Warren ST (2008). "Fragile X syndrome: loss of local mRNA regulation alters synaptic

development and function". Neuron 60 (2): 201–14.doi:10.1016/j.neuron.2008.10.004. PMID 18957214.

• Dölen G, Carpenter RL, Ocain TD, Bear MF (2010). "Mechanism-based approaches to treating fragile X". Pharmacol Ther 127 (1): 7893.doi:10.1016/j.pharmthera.2010.02.008. PMID 20303363

• Holsen, Laura M.; Dalton, Kim M.; Johnstone, Tom; Davidson, Richard J. (2008)."Prefrontal social cognition network dysfunction underlying face encoding and social anxiety in fragile X syndrome". NeuroImage 43 (3): 592–604.doi:10.1016/j.neuroimage.2008.08.009. PMC 2598775. PMID 18778781

• P. Cole (2012). "Mavoglurant". Drugs of the Future 37 (1): 7–12.doi:10.1358/dof.2012.37.1.1772147.• Sherman, S. (2002). "Epidemiology". In Hagerman, R. J.; Hagerman, P. J. Fragile X Syndrome, Diagnosis

Treatment and Research (3rd ed.). Baltimore: Johns Hopkins University Press. ISBN 0-8018-6843-2.• http://discovery.yukozimo.com/who-discovered-fragile-x-syndrome/• http://www.medmerits.com/index.php/article/fragile_x_syndrome/P6• http://www.bbc.co.uk/health/physical_health/conditions/fragilex1.shtml• http://www.sciencedirect.com/science/article/pii/S0092867408009513