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Dept. of Genetic Engineering and Biotechnology

Course-307

Fragile
Sayma Zerin
Roll-10, 3rd year

Syndrome
Fragile X Syndrome
Fragile X syndrome (FXS) is the most common known cause of inherited intellectual disability.
Fragile X...
INCIDENCE
Based on the best available evidence:
Approximately one-million Americans carry the Fragile X mutation, includin...
This means that women with the premutation have an increased risk of having a child with fragile X syndrome. Chances of ex...
region of the FMR-1 gene. Premuations display few or no symptoms of FXS while the full mutation significantly magnifies sy...
thesis of those proteins which are responsible for causing long term depression (LTD). The absence of FMRP in dopamine and...
DIAGNOSIS

 PCR
Determine the number of CGG repeat but can’t detect methylation pattern. Both
premutation and full mutati...
speech therapy, occupational therapy, and physical therapy. The expertise of psychologists,
special education teachers, an...
OUTLINE
Pg. 1……………………. A. Introduction
B. Name and Brief History
Pg. 2-3…………………. A. Incidence
B. Inheritance pattern
C. Ch...
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Fragile x syndrome

  1. 1. Dept. of Genetic Engineering and Biotechnology Course-307 Fragile Sayma Zerin Roll-10, 3rd year Syndrome
  2. 2. Fragile X Syndrome Fragile X syndrome (FXS) is the most common known cause of inherited intellectual disability. Fragile X syndrome is a genetic condition that causes a range of developmental problems including learning disabilities and cognitive impairment. Usually, males are more severely affected by this disorder than females. It is also called Martin–Bell syndrome, Marker X syndrome & in South American countries it is most commonly known as Escalante's syndrome. FXS is an X-linked disorder. It is a single gene disorder carried by either a mother or a father. Impairmentin this disease canrange from learning disabilities to more severe cognitive or intellectual disabilities (sometimes referred to as mental retardation). FXS is the most common known cause of autism or "autistic-like" behaviors. Symptoms also can include characteristic physical and behavioral features and delays in speech and language development. It is the first known disease of trinucleotide repeat disorder. Fragile X syndrome 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), which is required for normal neural development. WHY IT IS CALLED FRAGILE X SYNDROME A fragile site is a heritable point in a chromosome that tends to constrict and thus may tends to break under replication stress. In FXS, there is a rare, folic acid-sensitive site at Xq27.3. Unstable CGG repeat in the tip of the long arm of X chromosome may cause constriction which gives the impression that the tip is ready to detach from the rest of the chromosome. Thus it the name Fragile X Syndrome comes. TIMELINE OF FXS 1943- J. Purdon Martin and Julia Bell discovered that a kind of mental retardation was linked to X chromosome from a pedigree analysis. Later this disease was named as FXS. 1969- Herbert Lubs discovered an unusual "marker X chromosome" in affected male. He also developed a chromosomal test for Fragile X in order to accurately identify affected patients. 1970- Herbert Lubs’s test was used worldwide.Frederick Hecht coined the term "fragile site". 1991- Scientists discovered the FMR1 (fragile X mental retardation 1) gene that causes Fragile X Syndrome.
  3. 3. INCIDENCE Based on the best available evidence: Approximately one-million Americans carry the Fragile X mutation, including approximately 100,000 with fragile X syndrome, and are at risk for developing a Fragile Xassociated Disorder. Approximately 1 in 3600 to 4000 male in the world is born with the full mutation for Fragile X. Approximately 1 in 4000 to 6000 females in the world is born with the full mutation for Fragile X. Approximately 1 in 800 men in the world is carriers of the Fragile X premutation. Approximately 1 in 260 women in the world are carriers of the Fragile X premutation. The vast majority of males with the full mutation will have fragile X syndrome. Approximately 50% of females with the full mutation will have some features of fragile X syndrome. The reason it is lower in females is that, while all males with an FMR1 full mutation will have fragile X syndrome, some females with an FMR1 full mutation will not have behavioral, cognitive or physical features of FXS. FXS is also known as the most common single gene cause of autism. Between 2-6 percent of all children diagnosed with autism are reportedly linked with the Fragile X gene mutation. Concurrently, approximately one-third of all children diagnosed with fragile X syndrome also have autism. INHERITANCE PATTERN Fragile X Syndrome is an X-linked dominant condition with reduced penetration (referring to its partially recessive nature). FXS is an "X-linked" condition, meaning that the gene is on the X chromosome. It is inherited in dominant pattern meaning that only one copy of mutated gene is sufficient to cause the condition. Since a woman has two X chromosomes a female with a premutation or full mutation has a 50% chance of passing on the X with the mutation in each pregnancy. If she has a premutation, and it is passed on to offspring, it can remain a premutation or it can expand to a full mutation. If she has a full mutation and it is passed on, it will remain a full mutation. Additionally, in other X-linked conditions all males who carry the gene are affected, however in Fragile X Syndrome, unaffected males can carry the gene in the premutation form and have no symptoms of Fragile X Syndrome. Males with the premutation will pass it on to all of their daughters and none of their sons. In women, the FMR1 gene premutation on the X chromosome can expand to more than 200 CGG repeats in cells that develop into eggs.
  4. 4. This means that women with the premutation have an increased risk of having a child with fragile X syndrome. Chances of expanding are related to the size of the mother’s premutation. By contrast, the premutation in men does not expand to more than 200 repeats during meiosis as it is passed to the next generation. Men pass the premutation only to their daughters as full mutation is lost during spermatogenesis. Their sons receive a Y chromosome, which does not include the FMR1 gene. This is the display of a punnet square involving the gene that causes Fragile X Syndrome. The simulation illustrates what could potentially happen if either a mother or a father were carrying the FMR1 gene and then passed it on to their offspring. In Diagram A, the father has the FMR1 gene which he then passes on to 50% of his offspring, two daughters. In Diagram B, the mother has the FMR1 gene which she passes on to 50% of her offspring, one girl and one boy. CHANGES IN THE FMR1 GENE Fragile X syndrome is a genetic disorder which occurs as a result of a mutation of the fragile X mental retardation 1 (FMR1) gene on the X chromosome, most commonly an increase in the number of CGG trinucleotide repeats in the 5' untranslated region of FMR1. In a small percentage of cases, other types of mutations cause fragile X syndrome. These mutations delete part or all of the FMR1 gene, or change one of the building blocks (amino acids) used to make the fragile X mental retardation 1 protein.FMR1 gene has four allelic forms which aredistinguished by the number of CGG repeat present in the gene. In unaffected individuals, the FMR1 gene contains 5-44 repeats of the CGG codon, most commonly 29 or 30 repeats. 45 to 54 repeats are considered as "grey zone", with a premutation allele generally considered to be between 50 and 200 repeats in length. Fragile X syndrome patient have a full mutation of the FMR1 allele, with over 200 repeats of the CGG. Premutation individual carry an unstable mutation which can expand in future generations. The full mutation causes the gene to shut down a methylated
  5. 5. region of the FMR-1 gene. Premuations display few or no symptoms of FXS while the full mutation significantly magnifies symptoms. Normally, the FMR-1 gene produces an important protein called FMRP. When the gene is turned off, the individual does not make fragile X mental retardation protein (FMRP). The lack of this specific protein is believed to cause Fragile X Syndrome. In some cases, however, individuals with a premutation have lower than normal amounts of the fragile X mental retardation 1 protein. As a result, they may have mild versions of the physical features seen in fragile X syndrome. FMRP-MOLECULAR BASIS OF FXS Full mutation in FMR1 gene prevents production of FMRP. FMRP is found in highest concentrations in the brain and testes. It is a translational regulator and regulates local protein synthesis in dendrites and synapses. It appears to bind selectively to around 4% of mRNA that function at many synapses in mammals. These mRNA targets have been found to be located in the neuronal dendrites and brain tissue from FXS patients shows abnormal dendritic spines. Also FMRP has been found to regulate many signaling pathway such as mGluR pathway, dopamine pathway, GABA pathway. Recent research on mGluR pathway shows that lack of FMRP is partially responsible for the symptoms caused in FXS. FMRP negatively regulate protein synthesis stimulated by mGluR activation. When FMRP is not produced, mGluR signaling causes increased syn-
  6. 6. thesis of those proteins which are responsible for causing long term depression (LTD). The absence of FMRP in dopamine and GABA pathways causes attention deficit, hyperactivity problems and anxiety symptoms found in FXS. SIGNS AND SYMPTOMS  Behavioral aspects Behavior problems associated with fragile X syndrome includes: o Delay in crawling, walking, or twisting o Hand clapping or hand biting o Hyperactive or impulsive behavior o Mental retardation o Speech and language delay o Tendency to avoid eye contact o Learning disability (Low IQ in male)  Physical features o Large, protruding ears o Long face o High-arched palate o Hyper extensible finger joints o Double-jointed thumbs o Flat feet o Soft skin o Post-pubescent macroorchidism (Larger testes in men after puberty) o Hypotonia (low muscle tone)  Neurological o Higher risk of developing partial seizures(14% male and 6% female have seizure) o A key neurological feature found in FXS patients is, in certain areas of their brain neurons have immature and dense dendritic spines. The dendrites are sites at which the majority of excitatory synapses occur. Similar abnormalities are found in other mental retardation.  Related diseases o Autism o Fragile X associated tremor/ataxia syndrome (FXTAS)- in premutation individual o Fragile X related primary ovarian insufficiency (FXPOI)- 20% of premutation female individual o Attention deficit hyperactivity disorder (ADHD)- majority of males with FXS and 30% females
  7. 7. DIAGNOSIS  PCR Determine the number of CGG repeat but can’t detect methylation pattern. Both premutation and full mutation can be detected.  Southern blot of DNA Determine both number of CGG repeat and methylation pattern using a methylase enzyme. Both premutation and full mutation can be detected.  Antibody test Willemsen et al developed a diagnostic test based on the use of Antibody to FMRP to detect presence or absence of FMR protein in lymphocyte or hair root. This method can develop full mutation in male but is not useful in mosaic males or female as some FMRP is produced.  MS-MCA Methylation specific melting curve analysis is a recently developed method.it is based on the fact transcription error seen on the FMR1 gene results in hypermethylation (Dahl et al-2007). It can be used in males only but allows rapid identification  Prenatal tests: FXS can be identified in babies before birth byo amniocentesis o chorionic villus sampling FXS due to missense mutations or deletions involving FMR1 requires sequencing of the FMR1 gene for identification TREATMENT At this point of time there is currently no cure available to prevent FXS. However, there are alternatives towards helping patients improve their lives by assisting them come to terms with their disability and overcome various obstacles. Management includes such approaches as
  8. 8. speech therapy, occupational therapy, and physical therapy. The expertise of psychologists, special education teachers, and genetic counselors may also be beneficial. Drugs may be used to treat hyperactivity, seizures, and other problems. Folic acid has been found to improve hyperactivity and attention deficits in some pre-adolescent males with fragile X syndrome. Ritalin for ADD, Prozac for aggression, Melatonin for sleep disturbances, and Lithium carbonate for mood instability can be used. Though these medicines help to prevent some of the symptoms, however there are side effects. Establishing a regular routine, avoiding over stimulation, and using calming techniques may also help in the management of behavioral problems. Mainstreaming of children with fragile X syndrome into regular classrooms is encouraged because they do well imitating behavior. Peer tutoring and positive reinforcement are also encouraged. Doctors must first evaluate the different characteristics of the patients before administrating a long term treatment plan. Recent studies have focused on a number of critical areas. The role of FMRP's RNA partners, many of which have now been validated through in vitro assays, is of primary importance. Also being examined is the function the various domains of FMRP and its translation of polyribosome on the mRNA as a messenger ribonucleoprotein, basically an RNA-binding protein, which is still relatively unknown. Evidence from mouse models shows that mGluR5 antagonists can rescue dendritic spine abnormalities and seizures, as well as cognitive and behavioral problems, and may show promise in the treatment of FXS. Two new drugs, AFQ-056 (mavoglurant) and dipraglurant, as well as the repurposed drug fenobam are currently undergoing human trials for the treatment of FXS. There is also early evidence for the efficacy of arbaclofen, a GABAB agonist, in improving social withdrawal in individuals with FXS and ASD.Fragile X is also known as the most prominent cause of autism; hopefully when FXS has been uncovered there could be more scientific advances that could help to lessen or even possibly get rid of the effects of autism. Although Fragile X Syndrome might appear to be a very rare genetic it is not too distant as one might think. Nevertheless, it is more common than people think and misunderstood Syndrome. Even if there is no cure it does not mean that people suffering from its affects can’t get better. With better research, medication, and individual therapy being provided, scientists have been able to assist patients in improving their standard of living by developing their motor skills and mental capacity. Maybe in future gene therapy and protein supplement will finally be able to cure this disease
  9. 9. OUTLINE Pg. 1……………………. A. Introduction B. Name and Brief History Pg. 2-3…………………. A. Incidence B. Inheritance pattern C. Changes in FMR1 gene Pg. 3-4………………….. A. Changes in FMR1 gene B. FMR protein Pg. 5…………………….A. Signs and symptoms Pg. 6…………………….. A. Diagnosis Pg. 7…………………….. A. Treatment
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