Fragile X Syndrome History

The History of Fragile X Syndrome. The first appearance the Fragile X syndrome was in 1943 when doctors Martin and Bell discovered that a specific form of mental retardation was X-linked. Both go on to describe a pedigree of X-linked mental disability. (Martin & Bell, 1943). Fragile X Syndrome has not been around for that long, actually less than eighty years. Later in 1969, Herbert Lubs a doctor developed the chromosomal test for Fragile X chromosome. Lubs accomplished this chromosomal test by first noticing an unusual "marker X chromosome" in association with mental disability. The chromosomal test was not used in abundance till the late 1970’s. (Lubs, 1969). Not even a year later though, Frederick Hecht established the term "fragile site". The fragile site is referred to as a non-staining gap at a specific point on a chromosome. Fragile X Syndrome is also known as the Escalante syndrome, which is due to the findings of Peruvian geneticist Julio Anibal Escalante. However, it was not until 1991 that
the FMR1 gene that causes Fragile X Syndrome was identified. The FMRP also known as Fragile X Mental Retardation–1 was discovered by Drs. Ben Oostra, David Nelson, and Stephen Warren. (One Gene Shuts Down, Causing Fragile X Syndrome, 2015). In 1994 only three years later, the discovery of FXPOI, or fragile X-associated primary ovarian insufficiency was established by Schwartz et al. FXPOI is one of three known Fragile X-associated Disorders also referenced as FXD. All three of the FXD are caused by changes in the FMR1 Gene. Next huge milestone for the fragile X community happen on 2001, when Drs. Randi and Paul Hagerman identified FXTAS, another member of the family of Fragile X-Disorder. (Celebrating 30 years of Progress, 2014). FXTAS stands for Fragile X-associated Tremor/Ataxia Syndrome which is a aggressive neurological disease that strikes men over age 52 and causes tremor, ataxia also referred to as (balance problems) and dementia that become increasingly severe with age. Fragile X Syndrome also have made some big recent achievement with creating the First Advocacy Day in 2004 and also forming the FXCRC which is known as the Fragile X Clinical & Research Consortium (FXCRC) with 10 initial clinics around the country. (Fragile X Clinical & Research Consortium (FXCRC), 2008).
The Symptoms and Causes of Fragile X Syndrome. Symptoms of Fragile X Syndrome range from physical to cognitive characteristics. Most common of the symptoms of the Fragile X Syndrome include, mental retardation and autism. Mental retardation is the condition of having an IQ score that is measured to be below 70 to 75 and significant delays or lacks in at least two areas of adaptive skills are present. Whereas Autism on the other hand is, impairments in social interaction and developmental language and communication skills combined with rigid, repetitive behaviors. (What Is Autism?, 2015). Physical characteristics that are sometimes altered due the Fragile X Syndrome include, funnel chest, flat feet, flexible joints and low muscle tone, large body size, ovarian cysts, long ears, enlarged testes, and hand flapping. Cognitive symptoms of Fragile X Syndrome are often to be found cluttered speech, hyperactivity, emotional instability and behavior problems. (Symptoms of Fragile-X Syndrome, 2015). Causes of Fragile X Syndrome consist of a change in a gene called FMR1. A small part of the FMR1 gene code is repeated on a fragile site of the X chromosome. The gene code that is c repeated is known as the CGG segment the more repeats the code segment has, the more likely the condition will occur. The FMR1 gene makes a specific protein that is needed for the human brain to function properly. A defect in the gene makes your body produce too little of the protein, or none at all. (Fragile X Syndrome, 2015).
The Physiological Effects of Fragile X Syndrome.
Fragile X syndrome is actually the most common inherited form of mental retardation currently known to mankind. Fragile X Syndrome is inherited in an X-linked dominate pattern. Referring to X-linked because, if the mutated gene that causes the disorder is located on the X chromosome. (Fragile X syndrome- Genetic Home Reference, 2012). Males will only pass the FXS gene to their daughters (females) and not to their sons (males). (Fragile X Syndrome Diseases and Conditions, 2012). While on the other hand, females will actually have a 50/50 chance to pass the FXS gene along to both their sons (males) and daughters (females). Fragile X Syndrome is known to occur in approximately 1 in 4000 males and in 1 and 8000 females. (Coffee B, et al, 2009). Physiological effects of Fragile X Syndrome begin first at a cellular level and continue to effect tissues and other organ systems.
At a cellular level nearly all cases of fragile x syndrome are caused by a mutation in which a DNA segment, known as the CGG Triplet repeats, which is expanded within the FMR1 gene. (Usdin & Kumari, 2015). The FMR1 also referred to as the “fragile x mental retardation” gene provides instructions for making a specific protein called FEMP. The same gene also causes fragile X syndrome when in the full mutation range (200 or greater CGG repeats). FEMP also referred to as the “Fragile X Mental Retardation Protein” which is a protein that helps regulates the production of other proteins. This protein, most commonly found in the brain, is essential for normal cognitive development and female reproductive function. (Berry-Kravis et al., 2007). Mutations of this gene can lead to many serious diseases such as fragile X syndrome, mental retardation, premature ovarian failure, autism, Parkinson's disease, developmental delays and other cognitive deficits. Normally the CGG amino acid Triplet repeats on average thirty to forty times within the DNA segment whereas, someone with Fragile X Syndrome would have the CGG Triplet repeats between 55 to 200 times sometimes even more. The abnormally expanded CGG segment turns off (silences) the FMR1 gene which prevents the gene from producing the production of the protein FEMP. (Liu, 2013). By silencing or becoming methylated the gene there becomes inadequate amounts of FMR1. The mechanism of the abnormal Triplet is what fails at cellular level and disrupts homeostasis.
The amount of FMRP gene in the body is one factor that determines how severe the effects of having Fragile X Syndrome are.
In a gene, the information for making a protein has two parts the introduction and the instructions for making the protein itself. The introduction is also referred to as the Promotor because of how it helps to start the process of building the protein. People who have between the amount of 55 and 200 repeats in the promotor part of the gene may have the zone called, premutation. (Berry-Kravis et al., 2007). Premutation may cause the gene to not work properly, but it does not cause intellectual and development disability. The independent neurological disorder FXTAS arises from what is referred to as a premutation. This disease is thought to stem from increased levels of FMR1 transcript containing an elevated number of repeats. (Toniolo, 2006). Instead, people who have 200 repeats or more in the promotor part of the gene may have full
mutation.
Fragile X Syndrome also affects tissues and specific organs along with the functioning of their systems. FMRP mentioned above also plays a role in the development of synapses, which are specialized connections between nerve cells. These synapses are critical for relaying nerve impulses and creating and maintaining connections between cells in the brain and the nervous system. FMRP is found to be a selective RNA- binding protein that associates with polyribosomes and acts as a negative regulator of translation. Also FMRP is a selective synaptic plasticity encoded by certain mRNA’s, localized in the dendrites. The brain is a major organ that is affected by the FXS gene due to the great amounts of neural synapse and dendrites that are found within the brain. Fragile X Syndrome actually affects the neural pathways of the body. The loss or deficiency of the protein FMRP disrupts the nervous system functions and leads to the signs and symptoms of Fragile X Syndrome.
Physical and cognitive characteristics can begin to be seen by the age of two which display signs and symptoms of Fragile X Syndrome. Fragile X Syndrome causes a range of developmental problems including, learning disabilities and cognitive impairment. These problems include physical features from, large ears, long face, soft skin and large testicles (called “macroorchidism”) in post-pubertal males. (Symptoms of Fragile-X Syndrome, 2015). Not every with the FM1 gene has symptoms of Fragile X Syndrome, because the body may still be able to make FMRP. A few things that affect how much FMRP that can makes includes, the size of the mutation, the number of cells that have can make include the size of mutation, the number of cells that have mutations and lastly whether or not someone is female. These factors determine how much FMRP protein is made and whether or not signs and symptoms of Fragile X Syndrome will be mild or severe.

Treatments Used in Healing Fragile X Syndrome. At this moment in time, there is in no cure for Fragile X Syndrome, but there are still plenty of treatment options that can improve the lives of affected individuals and their families that are involved. Treatments and therapies are used to help patients cope with their disorder. Given the proper education, therapy, and support, all people diagnosed with FXS can make progress in the right direction. Education is one of the first treatments that are used to treat Fragile X Syndrome. Most educational programs vary among patients with FXS depending on the severity of the person's condition. It is mentioned that all children with disabilities (not just Fragile X Syndrome) must receive free and specific education from age three until the end of high school or until the person turns over the age of twenty-one. In today’s society, most professionals believe that children with disabilities, including FXS, should be educated alongside their non-disabled peers. (Fragile X Syndrome (FXS) Prevention And Treatment, 2015). Certain medications that are usually prescribed for behavior disorders, such as attention deficit disorder (ADD) or anxiety, may also be prescribed to treat the symptoms of Fragile X Syndrome. (What Is Fragile X Syndrome, 2013).