Fragile X Syndrome By: Leor Surilov

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Table of ContentsBiology OverviewHistory of disease Fragile X SyndromeResearch Famous People OrganizationsConclusion References

Biology Overview- Genes

Every living organism contains genesGenes are located in the nucleus of a eukaryotic cellGenes 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/ThymineAll genes are organized into a chromosome, with the help of the histone proteins

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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

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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

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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 Syndrome1991, 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/

Fragile X Syndrome (FXS): Epidemiology Approx. 1 mill. Americans carry the Fragile X mutationPrevalence: 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)

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 chromosomeFMR1 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 cellsHypermethylation of the FMR1 gene leads to the inactivation (silencing) of FMRP1 protein Normal: 5-40 repeats Inactivation: 200+ repeats- phenotypic expression

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Fragile X Syndrome (FXS) : Clinical PresentationNeurocognitive abnormalities:Mental retardation- Males: IQs average 30-50; Females: IQs in the 70sDevelopmental delays- speech and language by 2 yrs oldAutismAttention 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 adultsSeizures

Anatomic abnormalities:Characteristic faces- Long and narrow face, prominent forehead Macrocephaly- associated with brain abnormality Macro-orchidism- larger testes with normal testicular function

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Fragile X Syndrome (FXS): Diagnosis

DNA Probe analysis Gold standard is either PCR or Southern blot analysisPre-natal Testing (During Pregnancy) for pregnant women who have an FMR1 permutation or full mutation- risky and not very commonTest Types: Amniocentesis (sample of amniotic fluid) Chorionic villus (sample of cells from the placenta)

Fragile X Syndrome: Treatment

Symptomatic treatment in order to maximize potential and minimize symptoms Special educational servicesIndividualized 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

Fragile X: Prevention

Genetic counselling Epigenetic mutations is still not really understood and therefore no real prevention is present

Fragile X: ResearchPilot 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 patientsNNZ-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)

Fragile X: Famous People Mary Jane Clark, mystery writer, son has Fragile X syndromeChris Benoit, WWE Wrestler, son had Fragile X Syndrome

Organizations

ConclusionFragile 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

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