Fragile x SYNDROME (FXS) is the most common inherited cause of mental disability. Although the precise number of people with this disorder is unknown, the Centers for Disease Control and Prevention has estimated that 1 in 4,000 males and 1 in 6,000 females have FXS. FXS is caused by the absence or dysfunction of a protein called the Fragile X mental retardation protein (FMRP). FMRP is essential to the nervous system because it is necessary for proper nerve maturation and for forming efficient nerve connections in developing embryos. The absence of FMRP in FXS patients is caused by a change, or mutation, in the Fragile X Mental Retardation 1 gene, FMR1. The FMR1 gene is responsible for producing the FMRP protein at the correct time during embryonic development. Currently, no cure exists for FXS. However, research on stem cells from humans, mice, and flies has helped us understand how the disease develops and may lead to improved treatment options.
The symptoms of FXS can vary widely, with boys often more affected than girls. FXS most commonly affects intelligence, learning, physical appearance, social interactions, speech, and the senses. The intellectual disabilities in FXS patients range from mild learning disabilities to severe mental retardation. The physical symptoms of FXS are often undetectable in children; however, some teens and adults with FXS have long ears, faces, and jaws. Some patients have connective tissue defects, which cause flat feet, extendable joints, balance problems, and non-life-threatening heart murmurs.
About 20 percent of FXS patients are prone to seizures. Furthermore, autism-like behaviors (i.e., flapping hands, self-biting, repetitive actions, and walking on the toes) are also frequently observed in FXS children. Children with FXS may also have behavioral challenges that cause them to be extremely anxious in new social situations. Attention deficit disorder (ADD)/attention deficit hyperactivity disorder (ADHD) as well as autism are both common in FXS patients. Boys with FXS usually have some speech language problems. Most begin using words later in childhood than their unaffected peers. Speech problems may range from enunciation, stuttering, omitting parts of words, and misunderstanding tone of voice. FXS patients may also have difficulty comprehending body language. Finally, FXS patients can be extremely sensitive to sensory stimulation (e.g., bright light, loud noises, or skin sensitivity). Some children with FXS avoid being touched and have trouble making eye contact.
The symptoms of FXS can be reduced and/or eliminated with treatment. Because developmental defects cause many of the symptoms, physicians believe that the earlier FXS is diagnosed, the more the patient can learn, and the better the outcome. Since FXS affects so many aspects of personal development, many types of treatment are used. Despite their mental disabilities, FXS patients are capable of learning. Through special educational programs FXS children can progress in school, learn independence, and become employed as adults. Heart murmurs can be monitored by a physician, seizures treated with medication, and balance problems addressed with physical therapy.
Speech therapy can improve speech impediments and help patients communicate, while behavioral therapy can help children cope with stress induced by social situations and sensory sensitivity.
INHERITANCE
The FMR1 gene is located on the X chromosome, one of the chromosomes that determine an individual’s sex. For this reason, FXS is a sex-linked disease that affects boys more than girls. All genetic material (DNA) in humans is located in two pairs of 23 chromosomes. An individual inherits half of their DNA from their mother (23 chromosomes) and half from their father (another 23 chromosomes). Twenty-two out of the 23 pairs of chromosomes are identical. The nonidentical pair of chromosomes determines the sex of the individual: these are the X and the Y-chromosomes.
A woman has two X chromosomes, one that was passed from her mother and the other from her father. A man has one X chromosome and one Y chromosome; the X was inherited from his mother and the Y from his father. A male who inherits a defective FMR1 gene will have FXS, because his only X chromosome will have the mutated gene. A woman who inherits one defective FMR1 gene may not be as severely affected by FXS because she has a second X chromosome that contains a normal FMR1 gene.
The defect in the FMR1 gene that causes FXS is caused by an abnormally long stretch of DNA at the beginning of the FMR1 gene. DNA is made up of four types of molecular building blocks, or nucleotides, called adenine (A), guanine (G), cytosine (C), and thymine. The beginning of a normal FMR1 gene typically has between 6 and 45 repeats of the nucleotides CGG. In contrast, people with FXS have over 200 CGG repeats. This large number of repeats causes the gene to be turned off during the development of a fetus, ultimately causing a deficiency in the FMRP protein. Without FMRP, the nervous system in the fetus fails to develop properly.
Some people have a higher than normal number of CGG repeats in their FMR1 gene (55-200 repeats), but do not have FXS. People with this in-between number of repeats have the Fragile X premutation, but do not have FXS because their FMR1 gene still works. However, people with FMR1 premutations are considered to be carriers of FXS because they can have children with FXS. Carrier men will pass the premutation to all of their daughters and none of their sons. Carrier women with one FMR1 premutation have a 50 percent chance of passing the permutation to her children. The FMR1 premutation is unstable and is prone to further, albeit inconsistent, expansion when passed from one generation to the next. Thus, the FMR1 premutation can be passed down within families for generations before any child inherits a full mutation and is affected by FXS.
STEM CELL RESEARCH
Since FMR1 mutations affect the early development of neurons during fetal formation, scientists studying FXS need to understand how the FMR1 gene works in the pre-nerve cells of a fetus. These pre-nerve cells are called neuronal stem cells or embryonic stem cells. By studying the embryonic stem cells derived from mice, flies, and humans, scientists have begun to understand how the FMR1 gene is important for nerve maturation. Furthermore, studies have found that a decrease in FMRP protein ultimately alters nerve cell signaling and may affect how nerves work together in the brain to learn and create memories. Drugs could possibly block these aberrant signaling events and improve the learning capability of FXS patients.
Stem cells derived from animals have limited research potential because they lack the repeat sequences at the beginning of the FMR1 gene. As a result, these models are inadequate for scientists who want to study how and why the extended repeats turn off the FMR1 gene. Recently, scientists have developed human embryonic stem cells with the FMR1 gene defect. Studies of these cells have shown that the FMR1 gene is still functional in the earliest stages of the embryo and is shut off later during development. By understanding how and why the FMR1 gene gets turned off, scientist may be able to reverse this event in embryos with the FXS mutation.
