The overview and the description of overall pathology of Fragile X Syndrome. Also, explaining the genetic aspect of the mutation.

1. Fragile X Syndrome
By: Leor Surilov
https://upload.wikimedia.org/wikipedia/commons/thumb/a/ab/Fragx-1.jpg/290px-Fragx-1.jpg

2. Table of Contents
Biology Overview
History of disease
Fragile X Syndrome
Research
Famous People
Organizations
Conclusion
References

3. Biology Overview- Genes
Every living organism contains genes
Genes are located in the nucleus of a eukaryotic cell
Genes are a particular DNA sequences that code for our physical and biochemical
characteristics
Genes are passed from parent to offspring through meiosis
Made up of four nucleotides: Adenine, Guanine, Cytosine, and Uracil/Thymine
All genes are organized into a chromosome, with the help of the histone proteins
https://fragilex.org/wp-content/uploads/2012/01/genegraphic.png

4. Biology Overview- Inheritance
Humans possess two copies of each chromosome
Human cells have 23 pairs of chromosomes
 22 pairs of autosomes and 1 pair of sex chromosomes
 Totaling 46 per cell
Males possess one X chromosome and one Y chromosome
Female possess two X chromosomes (carriers)
Each gene has a particular location on a chromosome called locus
Genes are not the same among individuals and alternate forms of genes are called
alleles
http://primaryimmune.org/wp-content/uploads/2013/05/inheritance_figure_1.jpg

5. Biology Overview- Mutation vs Epigenetics
DNA is the “Blueprint” of life and yet, DNA is Fragile
 Environment mutations )radiation, and carcinogens( and Endogenous DNA damage, much more common
Mutations are actively changing the DNA
Protection by DNA Repair mechanisms
Epigenetics (“epi”-on top of) is the switching on or off of a gene through covalent modifications
Epigenetics is important in cellular differentiation and female X inactivation
Unchanged Nucleotide Sequence, but rather affects expression through DNA methylation and histone
modification
 Epigenetics are very stable and are passed on generationally
http://www.frontiersin.org/files/Articles/105911/fcell-02-00049-HTML/image_m/fcell-02-00049-g001.jpg
http://epigeneticsnetwork.ca/wp-content/uploads/2014/12/Histones1.png http://mumtazticloft.com/images/TypesOfMutations.png

6. Fragile X: History
1943, Martin and Bell showed that a particular form of mental retardation was X-
linked, later determined to be Fragile X Syndrome
1969, Herbert Lubs discovered a chromosomal test for Fragile X Syndrome
1991, Discovery of FMR1 gene that causes Fragile X by Drs. Ben Oostra, David
Nelson, and Stephen Warren.
http://www.fraxa.org/fragile-x-syndrome/cause/

7. Fragile X Syndrome (FXS): Epidemiology
 Approx. 1 mill. Americans carry the Fragile X mutation
Prevalence: in males is approximately 1 in 3,600 to 4,000 and in females is approximately 1 in 4,000 to
6,000.
 In males is approx. 1 in 3,600-4,000
 In females is approx. 1 in 4,000-6,000
 frequency of Fragile X permutation (individuals with 50-200 CGG repeats)- 2012 CDC Study
 1 in 151 females (roughly 1 mill. women) in the US
 1 in 468 males (roughly 320,000) in the US
According to Fragile X Research of Canada:
 Most common inherited form of mental impairment
 1 in 4,000 males and 1 in 6,000 females are affected – from all ethnic and socio-economic
backgrounds.
 Female carriers (approx. 20-28%) experience Fragile X-associated primary ovarian insufficiency
(FXPOI)

8. Fragile X Syndrome (FXS): Genetics
Triplet nucleotide repeats mutations of the nucleotide sequence CGG
FMR-1 gene (fragile X mental retardation-1) on the X chromosome (Xq27.3)
 Inheritance as X-linked dominant disease pattern
 More common in males because they possess one X chromosome
FMR1 gene results in the Fragile X mental retardation 1 protein (FMRP1)
Protein helps regulate the production of other proteins and the development of synapses, that are important cell-
cell communication connections between nerve cells
Hypermethylation of the FMR1 gene leads to the inactivation (silencing) of FMRP1 protein
 Normal: 5-40 repeats
 Inactivation: 200+ repeats- phenotypic expression
http://www.fullcirclehealthcareinc.com/uploads/4/1/6/7
/41671693/1436047281.png
http://genetics4medics.com/uploads/3/0/8/0
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9. Fragile X Syndrome (FXS) : Clinical
Presentation
Neurocognitive abnormalities:
Mental retardation- Males: IQs average 30-50; Females: IQs in the 70s
Developmental delays- speech and language by 2 yrs old
Autism
Attention deficit-hyperactivity (ADD)- Associated with poor attention
Speech and language problems
Decline in cognitive level skills- pre-pubertal boys have higher IQs than adolescents and adults
Seizures
Anatomic abnormalities:
Characteristic faces- Long and narrow face, prominent forehead
Macrocephaly- associated with brain abnormality
Macro-orchidism- larger testes with normal testicular function
http://wiki.ggc.edu/images/0/05/Fragile_
x_body_diagram.gif
https://userscontent2.emaze.com/images/684109bd-aecb-4a56-9bec-
78b7c8984875/5d80dec5ae6b4cd9f59b805d9932d85f.jpeg

10. Fragile X Syndrome (FXS): Diagnosis
DNA Probe analysis
Gold standard is either PCR or Southern blot analysis
Pre-natal Testing (During Pregnancy) for pregnant women who have an FMR1
permutation or full mutation- risky and not very common
Test Types:
 Amniocentesis (sample of amniotic fluid)
 Chorionic villus (sample of cells from the placenta)

11. Fragile X Syndrome: Treatment
Symptomatic treatment in order to maximize potential and minimize symptoms
Special educational services
Individualized Educational Plan (IEP)
Therapy Treatment: Speech-language pathologist, occupational therapist, physical
therapists, and behavioural therapists
No medication treatment has been approved by the Food and Drug Administration
(FDA) specifically for the treatment of Fragile X or its symptoms, but certain
medication are used to treat certain symptoms

12. Fragile X: Prevention
Genetic counselling
Epigenetic mutations is still not really understood and therefore no real prevention is
present

13. Fragile X: Research
Pilot Studies showing promising results in
mGluR5 antagonists, Lithium, and GABA
agonists
MG01CI- Teva Pharmaceutical drug, is a
extended release formulation of metadoxine
used mostly for ADHD patients
NNZ-2566- Neuren Pharmaceutical drug
used previously for Rett Syndrome. The drug
is synthetic analog of a naturally present
neurotrophic peptide derived from insulin-
like growth factor-1 (IGF-1)

14. Fragile X: Famous People
Mary Jane Clark, mystery writer, son has Fragile X syndrome
Chris Benoit, WWE Wrestler, son had Fragile X Syndrome

15. Organizations

16. Conclusion
Fragile X syndrome is a result of triplet nucleotide repeat mutation of CGG nucleotide
sequence
Mutation is hereditary
FMR-1 gene mutation on the X chromosome is a result of methylation of 200+ CGG
repeats that inactivates FMRP1 protein
Causes a variety of intellectual disabilities that mainly affects males
 Diagnosis occurs by PCR or Southern blot analysis
Psychologically it is important to diagnosis Fragile X syndrome to assist the individual and
the parents
Symptomatic treatment present through educational and therapeutic approaches
No FDA approved medication to treat Fragile X syndrome

17. References
Barone, J., & Castro, M. A. (2016). USMLE Step 1 Lecture Notes 2016| Pathology. New York, NY:
Kaplan Publishing.
Dew-Hughes, D. (2004). Educating children with fragile X syndrome: A multi-professional view.
London: RoutledgeFalmer.
Fragile X Syndrome. (n.d.). Retrieved October 21, 2016, from
http://my.clevelandclinic.org/health/diseases_conditions/hic_Fragile_X_Syndrome
Fragile X syndrome. (n.d.). Retrieved October 27, 2016, from
https://en.wikipedia.org/wiki/Fragile_X_syndrome
Fragile X Syndrome. (2016, October 18). Retrieved October 21, 2016, from
https://ghr.nlm.nih.gov/condition/fragile-x-syndrome
Pediatrics Clerkship| Fragile X Syndrome. (n.d.). Retrieved October 21, 2016, from
https://pedclerk.bsd.uchicago.edu/page/fragile-x-syndrome
Prevalence. (n.d.). Retrieved October 21, 2016, from https://fragilex.org/fragile-x/prevalence/
Simmons, D. (2008). Epigenetic Influences and Disease. Retrieved October 21, 2016, from
http://www.nature.com/scitable/topicpage/Epigenetic-Influences-and-Disease-895
What is Fragile X syndrome? (n.d.). Retrieved October 21, 2016, from
http://www.fragilexcanada.ca/index.php?id=11,0,0,1,0,0