Fragile X Syndrome

Fragile X Syndrome or FXS is a genetic condition which is caused by mutation on the X sex chromosome. It is known to cause a range of developmental problems including learning and cognitive disabilities. FXS is one of leading causes of academic and behavioral disability and can be diagnosed by genetic testing. While there is no current cure; scientists are hopeful that soon there will be.

FXS is inherited in an X-linked dominance; meaning that the gene associated with it is located on the X chromosome. The inheritance is considered dominant if having only one mutated copy of the gene is enough to cause symptoms of FXS.

The specific gene locus on the X chromosome related to FXS is in the FMR1 gene on the band Xq27.3. The full form of the FMR1 gene is Fragile X Mental Retardation 1; this gene makes a protein called Fragile X Mental Retardation protein (FMRP) (Fragile X Syndrome. Genetic and Rare Diseases Information Center). FMRP is needed for normal brain development and people with the mutation for Fragile X don’t make this protein. Some with disorders related to FXS have changes in the FMR1 gene, but do supply some of the protein; so, they don’t have FXS.

The FMR1 gene contains a section of DNA called a Cytosine-Guanine-Guanine (CGG) triplet repeat, which typically repeats from 5 to about 40 times. In most cases of Fragile X, this section is repeated more than 200 times (Fragile X Syndrome. Genetic and Rare Diseases Information Center). This essentially “turns off” the FMR1 gene, causing it to disrupt the function of the nervous system. In very little cases, mutation in the FMR1 gene. These changes include complete deletion of some or even all of the gene, or a mutation in the amino acid used to make the protein necessary for the gene’s function.

People that have only 55 to 200 repeats of the CGG segment have a FMR1 premutation. Those who have a premutation have a relatively normal intellect. In some cases, many with a premutation can have lower levels of gene’s protein and could even have a mild form of FXS. Some might even have an increased risk of developing fragile X-associated Tremor/Ataxia syndrome (FXTAS). In addition, roughly 20% of the women with a premutation have a premature ovarian failure.

Women who carry an FMR1 gene premutation with about 55 to 200 CGG repeats can expand to more than 200 repeats in their cells that develop eggs. This means that a woman with a premutation or even a full mutation has a higher chance to have a child with FXS; but the size of the risk depends in the number of CGG repeated passed on to them (Fragile X Syndrome. Genetic and Rare Diseases Information Center).  

Men with permutations aren’t at risk for the repeats expanding over 200 when passing this specific gene to their children (Fragile X Syndrome. Genetic and Rare Diseases Information Center). Men with an FXS premutation pass the mutation to female offspring, but no male offspring. This is because a female offspring gets an X chromosome from her mother and an X from her father, but a male offspring gets an X from their mother and a Y from their father. Since FXS is a mutation in the X chromosome, the gene mutation cannot be passed from father to son.

Fragile X Syndrome is characterized in many ways, the most identifiable categories include developmental problems and intellectual disability. FXS being the leading cause of inherited intellectual disability in males, they have a degree of intellectual disability that ranges from mild to severe. Females with fragile X have a normal intelligence or some degree of intellectual disability. Other symptoms associated with fragile X are delayed speech and language. For example, not sitting, not walking, or not talking at the same time as other children of the same age. Social and behavioral problems like not making eye contact, hand flapping, and acting and speaking without thinking are also often signs linked with FXS. Connected with fragile X are additional disorders like anxiety, Attention Deficit Disorder (ADD), symptoms of Autism Spectrum Disorder (ASD), and seizures. As mentioned, males are far more severely affected than females causing most males have characteristic physical features that become more prominent with age (Fragile X Syndrome. Genetic and Rare Diseases Information Center). Although symptoms vary from person to person; a long, narrow face, large ears, projecting jaw and forehead, flexible fingers, and flat feet are some examples.

Human Phenotype Ontology (HPO) collects information on symptoms describes in medical resources. The HPO is regularly updated; it states that the following symptoms occur in 80% to 99% of people with fragile X (Fragile X Syndrome – Genetics Home Reference – NIH). Chronic Otitis Media- which is a chronic infection of the middle part of the ear, folate-dependent fragile site at Xq28, having an IQ between 34 and 49, joint laxity, and specifically in males Macroorchidism- which are large testis that are inherited after puberty. Macroorchidism is the second most common genetic cause of an intellectual disability (Fragile X Syndrome – Genetics Home Reference – NIH).

FXS affects both males and females and is found in all ethnic groups and races. A review of research estimated that about 1 in 4,000 males and about 1 in 8,000 females have been diagnosed with FXS (Fragile X Syndrome – Genetics Home Reference – NIH). According to a 2012 study done by the CDC, 1 in 151 females, or about 1 million women and 1 in 468 males, or about 320,000 men are carriers of the FMR1 premutation in the US. This means that 1 million women and 320,000 men are carriers of the genetic mutation, not that 1 million women and 320,000 men have FXS. In the US an overall of 1.5 million people carry the Fragile X mutation, but 100,000 people actually have FXS (What Is Fragile X Syndrome (FXS)?).

Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the diagnosis of an FMR1 related disorder (including FXS too) has been confirmed; so genetic testing for FXS is available for diagnosis.

There generally is no treatment to “cure” FXS, but management of this condition is often very helpful. Knowing the need for special education and avoiding excessive stimulation of the body can help with controlling behavioral problems. Early intervention in education can help as it is tailored to fit specific learning challenges with small class sizes for individual attention. Medications can help manage behavioral issues that affect social interactions (Fragile X Syndrome. NORD). Strabismus, ear infections, reflux, seizures or epilepsy disorder, mitral valve prolapses, and a high blood pressure are all health-related problems associated with FXS that different medications can control and even stop. Some may even use therapy to help learn to talk and to walk and interact with others (Fragile X Syndrome. NORD).

A theory that mutations in the FMR1 gene lead to overexpression of a specific receptor in the brain has led to an amazing revelation. Mark Bear, a neuroscientist at MIT engineered mice with a similar mutation to produce less of that receptor. The engineered animals suffered fewer seizures, which is one hallmark of FXS, and had that of a normal brain structure compared to other mice living with the disease (Singer, Emily). The receptor, mGluR5 or Metabotropic glutamate receptor subtype 5 has been associated with mood, behavioral, and anxiety disorders. “Whilst we know that many proteins are regulated by the fragile X protein, and are therefore disrupted in fragile X individuals, mGluR5 seems to be one of the most important” (Singer, Emily ). Mark Bear said. He emphasized that the mice in the study profited from lowered levels of mGluR5 and he believes that many humans living with FXS can benefit from it too.

Another potential cure in progress is using the CRISPR/Cas9 system. Dr. Rudolf Jaenisch and his team at MIT’s institute for biomedical research announced, “rescue of Fragile X syndrome neurons by DNA methylation editing of the FMR1 gene” (Can CRISPR Cure Fragile X Syndrome?). The researchers used CRISPR/Cas9 technology to remove the molecular tags that make the mutated gene shut off in Fragile X neurons. As a result, some neurons started to make the protein (FMRP) normally. The cells were then transferred into mice. The mice continued to produce the FMRP for three months.

Adults and adolescents with FXS have a generally normal life expectancy. Although some people are more prone to a number of medical problems; many that are affected have an active lifestyle and good health. Regular medical checkups and raising awareness of increased risks can in the long run improve the quality of life and the outlook for affected people. New technologies in the rise has led many to believe that soon researchers many be able to create a lasting cure to Fragile X Syndrome.

Bibliography

Fragile X Syndrome – Genetics Home Reference – NIH. U.S. National Library of Medicine, National Institutes of Health, ghr.nlm.nih.gov/condition/fragile-x-syndrome.

Fragile X Syndrome. Genetic and Rare Diseases Information Center, U.S. Department of Health and Human Services, rarediseases.info.nih.gov/diseases/6464/fragile-x-syndrome.

Fragile X Syndrome. NORD (National Organization for Rare Disorders), 18 Sept. 2017, rarediseases.org/rare-diseases/fragile-x-syndrome/#:~:text=Fragile%20X%20syndrome%20has%20been,needed%20for%20proper%20cell%20function.

Can CRISPR Cure Fragile X Syndrome? • Fragile X Research – FRAXA Research Foundation. Fragile X Research – FRAXA Research Foundation, 4 June 2018, http://www.fraxa.org/can-crispr-cure-fragile-x-syndrome/.

Singer, Emily. “Scientists Cure Fragile X in Mice.” MIT Technology Review, MIT Technology Review, 2 Apr. 2020, http://www.technologyreview.com/2007/12/20/35512/scientists-cure-fragile-x-in-mice/.

What Is Fragile X Syndrome (FXS)? Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 15 July 2020, http://www.cdc.gov/ncbddd/fxs/facts.html.