Fragile X syndrome (FXS)

• Fragile X syndrome (FXS), also called Martin-Bell syndrome, is the most common type of inherited intellectual disability (formerly called mental retardation). Symptoms of FXS are life long, but they range from mild to severe. Symptoms are typically more severe in males than females.
• Individuals with FXS inherit a mutated gene from their parents. This mutated gene is unable to produce enough of a protein (called the familial mental retardation protein) that is needed for the body's cells, especially the brain cells, to develop and function normally. The amount of protein that can be produced varies among patients, and partially determines the severity of the disorder.
• Patients may also experience other symptoms, including social anxiety, attention deficits, speech and language disorders, seizure disorders, and increased sensitivity to sensory stimuli. A patient's life expectancy is largely dependent on the severity of his/her intellectual disability.
• About one out of 4,000 males and one out of 8,000 females are born with FXS each year in the United States.
• Although there is currently no cure for FXS, treatments and therapies have been shown to help FXS patients live healthy and relatively normal lives. No matter how serious a patient's learning disability, he/she is capable of learning new things. Most children with FXS are able to develop basic academic skills, although they may need more time to learn or may require special teaching methods. Many adults are able to live independently and maintain jobs. Early intervention and proper care has been shown to increase a patient's long-term prognosis.

• Fragile X syndrome (FXS) is an inherited condition that is passed down from parents to their children. In order to develop the condition, a person only has to inherit one copy of a mutated, or abnormal, FMR1 gene. In healthy individuals, this gene provides instructions on how to make a protein (called familial mental retardation protein or FMRP) that is needed for the brain to grow and develop. When the gene is mutated, the body makes too little or none of the protein and FXS occurs.
• The amount of FMRP in the body is one factor that determines how severe the symptoms of FXS will be. For instance, individuals with relatively normal amounts of FMRP typically experience few, if any, symptoms. In contrast, individuals who have almost no FMRP typically experience very severe symptoms of FXS. The amount of FMRP that can be produced depends on whether the person's abnormal gene is partially or completely mutated. It also depends on the person's gender.
• This abnormal gene is located on the X-chromosome, which is a sex chromosome. The gene is inherited as an X-linked dominant trait. Because females have two X-chromosomes, they usually experience less severe symptoms than males, who have only one X-chromosome. This is because the female's second, healthy copy of the X-chromosome may lessen some of the effects of the mutated chromosome.
• A father with FXS will pass the mutated gene to each of his daughters. However, if he has a son, the father provides a copy of his Y-chromosome, not his X-chromosome. Therefore, a father with FXS can never pass the disorder onto his sons. A mother with FXS has a 50% chance of passing the mutated X-chromosome to each of her daughters or sons.

• General: Symptoms of fragile X syndrome (FXS) range from mild to severe. In general, patients with FXS experience some combination of symptoms that affect their mental, physical, social, and sensory characteristics. Females with FXS often experience milder symptoms than males.
• Intellectual disabilities: Patients with FXS may have mild to severe intellectual disabilities (formerly called mental retardation). Researchers typically use intelligence quotient (IQ) tests to measure the severity of a person's intellectual disabilities. Individuals with IQ scores between 85 and 115 are considered to have average intelligence.
• About 80% of males with FXS have IQs that are less than 75 (below average). Most males with full mutations have IQs that range between 40 and 85, which are considered mild to moderate mental impairments.
• Females tend to experience less severe intellectual disabilities than males. Females are more likely than males to have relatively normal mental development or mild to moderate learning disabilities. For instance, a female with FXS may have a learning disability that affects her ability to understand math, even though she has a normal IQ. Only about 30% of females who have full mutations are considered intellectually disabled.
• Patients with FXS have intellectual strengths and weaknesses. For instance, patients typically have good aptitudes for visual patterns and images. This skill helps them learn and recognize words. Many patients are also good at following instructions that are given in the form of pictures or images. In contrast, FXS patients typically have difficulty organizing information, solving problems, planning ahead, and thinking abstractly.
• Most children with FXS are able to develop basic academic skills, although they may need more time to learn or may require special teaching methods. Many adults are able to live independently and maintain jobs.
• Physical characteristics: Many infants and young children with FXS do not have physical traits that are characteristic of the syndrome. However, some individuals may have very soft or velvety skin, broad foreheads, or slightly larger heads than other children of the same age. This is because the mutated gene is unable to produce a protein that is needed for the body's cells to develop and function normally.
• Distinct physical characteristics typically develop during puberty, when the child is about 11 years old. Common physical characteristics include an elongated face or jaw, larger ears, and short stature. Patients may have flat feet, scoliosis (curved spine), and loose, flexible joints. Males may develop enlarged testicles (a condition called macro-orchidism), that may be twice as big as normal. Macro-orchidism does not affect sexual development.
• Social and emotional problems: Children with FXS, particularly males, experience social anxiety. This occurs when individuals feel extremely worried and nervous in social situations, especially when they meet new people. Feelings of intense anxiety may lead to avoidance behavior. For instance, individuals may avoid eye contact with others or avoid certain social settings. Physical symptoms associated with anxiety include heart palpitations, faintness, blushing, and profuse sweating.
• Patients with FXS may also become easily upset, angered, or irritable. This is because some patients may feel overwhelmed by certain sounds or sights. It may also occur if there are unexpected changes in the patient's routine. For instance, entering a busy store may cause a patient to whine, cry, or become extremely tense. Some may throw tantrums or perform repetitive movements, such as rocking back and forth. These outbursts are generally the worst during adolescence because this is when individuals experience changes in hormone levels. Some individuals, particularly teenage males, may exhibit aggressive or hostile behavior.
• Patients may also experience attention deficits. They may have difficulty concentrating or staying focused for extended periods of time.
• Increased sensitivity to stimuli: Patients with FXS may be more sensitive than normal to certain sensory stimuli, such as loud noises, or bright lights. Some individuals may not like the texture of certain fabrics or feel uncomfortable or overwhelmed when they are touched by others.
• Poor balance: Patients with FXS may have poor balance and coordination. As a result, it may take patients longer to learn how to sit up, stand, walk, or ride a bike than the average person.
• Seizures: About 20% of patients with FXS have a seizure disorder.
• Speech and language disorders: Patients with FXS may have difficulty communicating through speech. They may have difficulty pronouncing sounds, talking in a fluent rhythm, or have abnormalities in the pitch, quality, or volume of speech. Individuals may also have problems understanding social cues, such as body language, tone of voice, or facial expressions. As a result, individuals may speak out of turn or have difficulty understanding others. Speech and language problems can range from mild to severe. Some communication problems may be the result of social anxiety.
• Speech and language problems are more likely to affect males with FXS because they typically experience more serious intellectual disabilities than females. In fact, most females have speech, language, vocabulary, and grammar skills that are appropriate for their ages. However, some females may speak in a rambling or disorganized fashion.
• In some cases of FXS, speech and language disorders may be severe. Some children may begin talking later in life, while others may remain nonverbal throughout their lives. Nonverbal individuals are often able to use computer-based and picture-based devices, as well as sign language and body language, to communicate with others.

• A DNA blood test can be performed to diagnose fragile X syndrome (FXS). A sample of the patient's blood is analyzed for the presence of the mutated gene. If it is present, a positive diagnosis is made.
• Genetic counseling is available to all individuals who undergo DNA testing. The counselor helps the individual understand the test results, as well as the potential risk of passing the condition on to his/her children.

• Hernia: Individuals with Fragile X syndrome (FXS) may have weak connective tissue. As a result, patients have an increased risk of developing hernias. This happens when an organ pushes through a weak spot or abnormal opening in tissue. This condition can be corrected with surgery.
• Middle ear infections (otitis media): Patients with FXS have an increased risk of experiencing middle ear infections.
• Heart defects: Patients with weak connective tissue may also have heart defects, such as a mitral valve prolapse. This happens when a valve inside the heart does not form properly. As a result, blood in the heart does not flow smoothly, and it may cause a heart murmur. This condition is usually not life threatening. However, individuals with mitral valve prolapses should visit their healthcare providers regularly to monitor their conditions.

• General: Currently, there is no cure for fragile X syndrome (FXS). However, many treatments and therapies may help patients cope with the disorder. With proper therapy and education, most children with FXS are able to develop basic academic skills, and many adults are able to live independently and maintain jobs. However, patients may need more time to learn new things or may require special teaching methods. Early intervention and proper care helps ensure the best possible prognosis, in terms of intellectual, social, and emotional development.
• Although the U.S. Food and Drug Administration (FDA) has not approved any drugs for the treatment of Fragile X, many medications, including anticonvulsants, antidepressants, antipsychotics, and stimulants, have been used to treat the symptoms of the disorder.
• Education: Most children and adolescents with FXS syndrome must have access to education that is tailored to their specific strengths and weaknesses. According to the Individuals with Disabilities Education Act, all children with disabilities must receive free and appropriate education from age three until the end of high school or until the person is 21 years old (whichever occurs first). However, since not all individuals with FXS have intellectual disabilities, not all individuals need to have access to special education programs. Parents can contact special education coordinators to find out how their children can be examined to determine if they qualify for these services.
• If a child has intellectual disabilities, members of the patient's school should consult with the patient's parents or caregivers to design and write an individualized education plan. Once all parties agree with the plan, the educational program should be started. The school faculty should document the child's progress in order to ensure that the child's needs are being met.
• Educational programs vary among patients depending on the severity of the person's condition. In general, most experts believe that children with disabilities, including FXS, should be educated alongside their non-disabled peers. The idea is that non-disabled students will help the patient learn appropriate behavioral, social, and language skills. Therefore, some FXS patients are educated in mainstream classrooms. Other patients attend public schools but take special education classes. Others attend specialized schools that are designed to teach children with disabilities.
• Behavioral therapy: Behavioral therapy may also be beneficial. Several different types of behavioral therapy are available to help FXS patients improve their communication and social skills, as well as their learning abilities and adaptive behaviors. Behavioral therapy has been shown to reduce inappropriate behavior, including aggressive behavior, in FXS patients. Therapy may also help patients cope with distressing situations and control their emotions. For instance, behavioral therapists may help patients learn how to calm down when they feel anxious or nervous in new social settings. Evidence suggests that behavioral therapy is most effective if it is started early in life, when the patient is three to four years old or younger.
• Speech-language therapy: Some patients with FXS syndrome may benefit from speech-language therapy. During speech-language therapy, a qualified speech-language professional (SLP) works with the patient on a one-to-one basis, in a small group, or in a classroom, to overcome speech disorders. Programs are tailored to the patient's individual needs. On average, patients receive five or more hours of therapy per week for three months to several years.
• Speech pathologists use a variety of exercises to improve the patient's communication skills. Exercises typically start off simple and become more complex as therapy continues. For instance, the therapist may ask the patient to name objects, tell stories, or explain the purpose of an object.
• Occupational therapy: Patients may benefit from occupational therapy. During sessions, a therapist helps the child learn skills to help him/her perform basic daily tasks, such as feeding, dressing, and communicating with others. There are therapists who specialize in patients with specific disorders, including intellectual disabilities. Parents and caregivers can ask their children's pediatricians for recommended therapists.
• Physical therapy: Physical therapy may help patients improve their physical strength, balance, posture, and motor coordination. A variety of techniques, including exercises, stretches, traction, electrical stimulation, and massage, are used during physical therapy sessions. A therapist may also teach parents or caregivers how to exercise a baby's muscles. Therapy should be used cautiously because FXS patients may have weak connective tissue, which puts them at risk of developing hernias. Straining or lifting heavy objects increases the risk of experiencing a hernia.
• Anticonvulsants: Patients who experience seizures and/or have unstable moods or emotions may benefit from medications called anticonvulsants. Phenobarbital (Luminal® Sodium) is one of the oldest and safest anticonvulsants for children. Valproic acid (Depakene® or Depakote®) has also been shown to be a safe and effective medication for children.
• Antidepressants: Patients who experience depression, obsessive-compulsive behaviors, aggressive behaviors, and/or anxiety may benefit from antidepressants. They may reduce repetitive behaviors, tantrums, aggression, and irritability in patients. Drugs called selective serotonin reuptake inhibitors (SSRIs) are the most common type of antidepressants used. Commonly prescribed SSRIs include fluoxetine (Prozac®), fluvoxamine (Luvox®), sertraline (Zoloft®), and paroxetine (Paxil®). Less commonly prescribed antidepressants include clomipramine (Anafranil®), mirtazapine (Remeron®), amitriptyline (Elavil®), and bupropion (Wellbutrin®).
• Antipsychotic drugs: Antipsychotic drugs have been used to help treat aggressive and repetitive behaviors, as well as hyperactivity in FXS patients. Commonly prescribed drugs include risperidone (Risperdal®), olanzapine (Zyprexa®), and quetiapine (Seroquel®).
• Stimulants: Stimulants, such as methylphenidate (Ritalin®) and amphetamines (Adderall® or Dexedrine®), may help treat hyperactivity and/or attention-deficit/hyperactivity disorder (ADHD), which are often associated with FXS. These drugs help increase the patient's ability to concentrate and reduce the person's overactivity.

C

Unclear or conflicting scientific evidence

• L-carnitine
  : The human body produces L-carnitine in the liver, kidney, and brain. There is not enough evidence to support the use of carnitine supplements to treat hyperactive behavior in children with fragile X syndrome (FXS).
• Avoid if allergic to L-carnitine. Use cautiously with peripheral vascular disease, high blood pressure, alcohol-induced liver cirrhosis, or diabetes. Use cautiously in low birth weight infants and individuals on hemodialysis. Use cautiously if taking anticoagulants (blood thinners), beta-blockers, or calcium channel blockers. Avoid if pregnant or breastfeeding.
• Strong negative scientific evidence
  :
• Folate (folic acid)
  : Folate and folic acid are forms of a water-soluble B vitamin. Folate occurs naturally in food, and folic acid is the man-made form of this vitamin. Folic acid supplementation has not been shown to improve symptoms of fragile X syndrome.
• Avoid if allergic to folate or any folate product ingredients. Avoid with coronary stents. Use cautiously with seizure disorders. It is recommended that pregnant women consume 400 micrograms daily in order to reduce the risk of birth defects. Folate is likely safe if breastfeeding.

• Currently, there is no known method of prevention of fragile X syndrome (FXS). Individuals who have FXS can meet with genetic counselors to learn about the risks of having a child with the disorder.