NORD gratefully acknowledges Jack C. Tarleton, PhD, FACMG, Fullerton Genetics Center, and Robert A. Saul, MD, Medical Director, General Pediatrics, Children's Hospital of Greenville Health System, for assistance in the preparation of this report.
Fragile X syndrome is characterized by moderate intellectual disability in affected males and mild intellectual disability in affected females. Distinctive physical features are sometimes present in affected males including a large head, long face, prominent forehead and chin, protruding ears, loose joints and large testes, but these features develop over time and may not be obvious until puberty. Motor and language delays are usually present but also become more apparent over time. Behavioral abnormalities including autistic behaviors are common.
Fragile X syndrome has been found in all major ethnic groups and races, and is caused by an abnormality (mutation) in the FMR1 gene. FMR1 is a gene located on the X chromosome that produces a protein called FMRP needed for proper cell function. The syndrome became known as the fragile X syndrome because some individuals with the disorder were found to have a segment of their X chromosome that appeared to be broken or fragile (although not completely disconnected). Later it was learned that the FMR1 gene is located precisely where the X chromosome appears to be “fragile” in affected individuals.
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome Xq27.3” refers to band 27.3 on the long arm of the X chromosome where the FMR1 gene is located. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
X-linked dominant disorders such as fragile X syndrome are caused by an abnormal gene located on the X chromosome. Females with the abnormal gene may be affected by this disorder. Males are usually more severely affected than females).
It is the absence or severe reduction of the protein made by the FMR1 gene, FMRP, that causes fragile X syndrome. Mutation of the FMR1 gene causes the loss or reduction of FMRP. Nearly all affected individuals have an instability within the gene leading to an increased number of copies of a portion of the gene called the CGG repeat region (also sometimes called “trinucleotide” or “triplet” repeat region). When greater than 200 repeats are present, abnormal chemical changes occur in FMR1 called methylation. The expansion of the CGG repeat region to greater than 200 repeats accompanied by methylation of the gene, called a “full mutation”, causes the loss of FMRP leading to the fragile X syndrome. Fragile X syndrome occurs more often in males and results in more severe disorder in males.
Mutations in FMR1 are unusual when compared to mutations found in other genes. Some individuals carry between 55 – 200 CGG repeats called a “premutation,” usually without having symptoms associated with fragile X syndrome. These individuals are at risk for having children or grandchildren with fragile X syndrome, however, and also at risk for two adult onset disorders, fragile X tremor-ataxia syndrome (FXTAS) and primary ovarian insufficiency (POI). The conditions have been termed FMR1-Related Disorders. (Please see the Causes and Related Disorders sections of this report for a more detailed explanation regarding premutations and brief summaries of these FMR1-related disorders).
Fragile X syndrome is characterized by moderate intellectual disability in affected males and mild intellectual disability in affected females. The physical features in affected males are variable and may not be obvious until puberty. These symptoms can include a large head, long face, prominent forehead and chin, protruding ears, loose joints and large testes. Other symptoms can include flat feet, frequent ear infections, low muscle tone, a long narrow face, high arched palate, dental problems, crossed eyes (strabismus) and heart problems including mitral valve prolapse. Delayed motor development, hyperactivity, behavior problems, toe walking, and/or occasional seizures can also occur in some patients. Autistic behaviors such as poor eye contact, hand flapping, and/or self-stimulating behaviors are also common. Motor and language delays are usually present but become more apparent over time.
As mentioned above, fragile X syndrome is caused by a mutation in the FMR1 gene located on the X chromosome at Xq27.3. Individuals with fragile X syndrome nearly always have (in greater than 99% of cases) a full mutation of the FMR1 gene which means that they have over 200 CGG repeats and abnormal methylation of the gene. Methylation is a chemical change to the DNA that carries the genetic code of a gene and the abnormal methylation associated with fragile X syndrome causes the gene to be unable to produce FMRP, the protein made by the FMR1 gene, needed for normal development. On rare occasions some patients with fragile X syndrome are partially or completely missing the FMR1 gene due to a deletion of the DNA on the X chromosome where FMR1 is located and have the syndrome because their cells do not produce FMRP. Ultra-rare patients with fragile X syndrome have been found to have a mutation in a single DNA base (called point mutations) resulting in absent or defective FMRP. FMRP is involved in making connections between neurons (nerve cells) in the brain. The absence or severe reduction of this protein leads to the symptoms of fragile X syndrome.
Premutations have 55-200 CGG repeats and are potentially unstable. Individuals having a premutation do not have the fragile X syndrome but are at risk for having the adult onset FMR1 disorders FXTAS and POI.
When passed from generation to generation premutations may be unstable and become full mutations, but the risk for instability is different depending upon whether a female or male premutation carrier is transmitting the premutation. Females with a premutation of the FMR1 gene are at risk to have children with fragile X syndrome because the number of CGG repeats can increase when the gene is passed into the next generation. The greater the number of copies of CGG in a premutation, the more likely these will increase to become a full mutation causing the fragile X syndrome in offspring.
When males with a premutation reproduce, their male offspring have no risk to inherit the premutation because fathers do not contribute an X chromosome to their sons. In contrast, female offspring whose fathers have a premutation always inherit it and thus grandchildren of males with the premutation are at risk to have fragile X syndrome. Because the premutation is relatively stable when transmitted from father to daughter, the daughters almost never are affected with fragile X syndrome. However, their children are at increased risk because the premutation may be unstable when transmitted to the next generation.
Normal FMR1 genes have approximately 5-44 CGG repeats and this number remains stable from generation to generation. Occasionally, in some individuals with 45-54 repeats there will be some minor instability such that these individuals will have several more (or less) repeats than their parents. A FMR1 repeat number between 45 and 54 is called “intermediate” or “gray zone”, but this minor instability does not lead to any symptoms of fragile X syndrome or the FMR1-related disorders. Having an intermediate number of CGG repeats is still considered as being in the normal range of repeat number.
The fragile X syndrome affects about 1 in 4,000 males and 1 in 6,000 to 8,000 females in the USA; that is, it affects about twice as many males as it does females. However, about four times as many females appear to be carriers of the altered gene as do males (1:250 females and 1:1000 males). Fragile X syndrome has been found in all major ethnic groups and races.
Over 99% of individuals with fragile X syndrome have a full mutation (over 200 CGG repeats and abnormal methylation) in the FMR1 gene. Molecular genetic testing is used to determine the number of CGG repeats in the FMR1 gene and testing to determine methylation status of the FMR1 gene is often used to follow up a finding of an expanded CGG region.
Chromosome analysis using special techniques to induce fragile sites in chromosomes was once used to diagnose fragile X syndrome, but is no longer used for this purpose. Fragile X syndrome is the name given to this condition because some affected individuals have an X chromosome that looked as if it had “broken” or was “fragile” and was held together by the slightest of ties. This technique is no longer used in the diagnosis of this syndrome because it is both less accurate and costlier than are molecular techniques.
There are many treatments for fragile X syndrome that can improve the lives of affected individuals and their families. These include special education, speech, occupational, and sensory integration training, and behavior modification programs. With educational efforts, therapy, and support, all individuals with fragile X syndrome can make progress. Other treatment may depend on an affected individual’s specific symptoms. Genetic counseling is recommended for affected individuals and their families.
There are numerous Fragile X Clinics in the US and throughout the world. These clinics specialize in treatments, therapies, and support for individuals with fragile X syndrome and can guide parents to medication options to address specific symptoms. New medications are likely to become available to treat affected individual and the specialty clinics can assist parents with current information. For a detailed discussion of Treatments and Interventions please go to the National Fragile X Foundation website (https://fragilex.org/learn/treatment-and-intervention/).
The development of animal models for fragile X syndrome studies over the last two decades resulted in great anticipation that effective drug treatments could be discovered. Some drugs, originally developed to treat other disorders, were shown to be effective in treating symptoms of fragile X syndrome in the animal models but when used on human subjects appeared to be less effective. However, there are many researchers who are actively working on treatments for fragile X syndrome. FRAXA, an organization actively searching for a fragile X syndrome cure, raises funds and supports extensive efforts for fragile X research. The FRAXA website (www.fraxa.org) is an excellent source of current information about their research projects and clinical trials.
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