Diseases

Martin-Bell Syndrome (Fragile X Syndrome) Information

Educational Options

Most children with Fragile X, including those with severe mental retardation, are guaranteed free, appropriate public education under federal law. Public Law 105-17: The Individuals with Disabilities Education Act-IDEA (1997) makes it possible for children with disabilities to get free educational services and educational devices to help them learn as much as they can. Each child is entitled to these services from age three through high school, or until age 21, whichever comes first. Also, every state operates an early intervention program for children from birth to age three; children with Fragile X should qualify for these services. The law also states that children must be taught in the least restrictive environment, appropriate for that individual child. This statement does not mean that each child will be placed in a regular classroom, but instead, that the best combination of one-to-one tutoring, small group work, and regular classroom work will be arranged. Because not all children or adolescents with Fragile X have mental impairment or special needs, a medical diagnosis of Fragile X does not guarantee access to special education services. The child must have certain cognitive or learning deficits. Parents can contact a local school principal or special education coordinator to learn how to have their child examined to see if he or she qualifies for services under the IDEA. If a child qualifies for special services, a team of people, including the child's parents or caregivers, teachers, school psychologist, and other child development specialists, will work together to design an Individualized Education Plan (IEP) for the child. The IEP includes specific learning goals for that child, based on his or her needs and capabilities. The team also decides how best to carry out the IEP, such as making choices about classroom placement for the child, determining any devices or special assistance the child needs, and identifying the developmental specialists who will work with the child. A child with Fragile X should be evaluated and re-evaluated on a regular basis by his or her special services team. In this way, the team can determine how the child is doing and whether any changes are needed in his or her treatment (for instance, changes to the IEP, changes in classroom placement, or changes in other services) to ensure the child is getting the best possible care. In general, there are three classroom placement options for a child with Fragile X, based on his or her specific abilities and needs:

• Full inclusion in a regular classroom. The child spends the full day in the regular classroom rather than just among children with special needs. This situation is sometimes called "mainstreaming." Specialists work with the child in the classroom, with other students present. There may be an aide assigned to help the child with certain kinds of tasks.
• Inclusion with "pull-out" services. In this type of placement, the child spends most of the day in the regular classroom. However, for part of the day, he or she attends small-group classes with one or more developmental specialists, such as a speech-language therapist or a physical therapist. This arrangement gives the child exposure to children who do not have special needs, as well as more individual attention to his or her areas of special needs
• Full-time, special education classroom. Some children with Fragile X may do better in a smaller special education class than in a regular classroom. Special education classrooms usually have fewer children and offer more individualized attention from the teacher. Such programs may be offered at the school or in central locations that serve a larger area. Regional special education centers often have facilities and equipment designed for children with special needs. For some children, a special school for children with similar disabilities may be the best option.

Fragile X syndrome facts*

*Fragile X syndrome facts medically reviewed by Charles Patrick Davis, MD, PhD on 1/15/2015.

• Fragile X syndrome (also called Fragile X) is the most common inherited form of mental problems (mental retardation).
• Fragile X syndrome is caused by changes in a single X chromosome (FMR1).
• FMR1 does not produce enough protein (FMRP) that works cell communication.
• Normal X genes that control FMR1 levels have promoter regions consisting of about 6 to 40 CGG; Fragile X genes have about 55 to 200 (termed premutation) or more than about 200 regions (termed full mutation).
• About 100 trillion cells make up a human body and each should have 46 chromosomes, but males have only one X chromosome; so, if it contains a FMR1 chromosome, the effect of the lack of FMRP is more significant than in females.
• Approximately one in 3,600 to 4,000 males is affected by the full mutation of the FMR1 gene, and about one in 468 males has the premutation form of the FMR1 gene; about one in 151 females in the general population has the premutation while about one in 4,000 to 6,000 females is affected by the full mutation (these are estimates only).
• The Fragile X gene is only carried on an X chromosome; both males and females may transmit a Fragile X (FMR1) gene on their X chromosome so either a man or a woman may be a carrier.
• The signs and symptoms of Fragile X syndrome have five general categories where individuals often show altered or arrested development.
  1. Intelligence and learning (low IQs)
  2. Physical (long face or jaw, short stature, enlarged testicles)
  3. Social and emotional (anxiety)
  4. Speech and language (stuttering and disorganized speech)
  5. Sensory (sensitive to certain stimuli like sounds, balance problems)
• Each individual may exhibit variations in the above five categories.
  • Features of autism and fragile X overlap, but the core deficit in autism is social interaction while the core deficit in fragile X is intellectual function and hyper arousal/anxiety.
  • Angelman syndrome is a genetic disorder that also has features of fragile X with delayed development and severe speech impairment along with seizures, small head size, and hand-flapping movements; but is due to genetic defects or alterations in a gene termed UBE3A.
  • Myotonic dystrophy (muscular degeneration and tissue loss) related to fragile X syndrome as both have similar genetic alterations (repeat expansions of genetic coding)
• Currently, there is no cure for Fragile X syndrome nor are there any definitive treatments other than helping the individual develop to their maximal potential through education; therapies such as speech, language, behavioral, and physical; and other therapies. Fragile X detects FMR1 DNA (PCR or Southern blot methods)
• Medication therapy may only help certain individuals with certain severe problems and should be prescribed only by the patients' doctors; there is no medication that can cure Fragile X syndrome.
• Adults with Fragile X syndrome may benefit from a team approach to help the patient adjust to independent living, if possible.
• IIf a family member has been diagnosed with Fragile X syndrome, other family members may want to be tested to determine if they carry a Fragile X chromosome; there are several accurate DNA tests available for gene testing (see above) and for determining the amount of FMRP produced. Prenatal tests are also available.
• Research is ongoing; gene therapy, gene activation, and FMRP replacement therapy are several areas that may lead to treatments, or possible cure or prevention, in the future.
• Several national organizations may provide additional information on Fragile X syndrome (for example, American Association on Mental Retardation and the National Institute of Child Health and Human Development).

Human cells 101

More than 100 trillion cells make up the human body. Most of these cells contain all the genes and other information needed to "build" a human being. Much of this genetic information is found in the nucleus of the cell, a "control center" that keeps all the material together in one place. The nucleus stores its genetic material in packages called chromosomes. Most people have 46 chromosomes in each cell-23 from their mother and 23 from their father. After fertilization, the two sets of chromosomes match up to form 23 pairs. The chromosomes in the 23rd pair are called the sex chromosomes, X and Y; they determine a person's sex. Males usually have one Y chromosome and one X chromosome; females usually have two X chromosomes. Each chromosome is made up of genes. Genes contain the information used by other parts of the cell to make proteins, the body's building blocks. Proteins make up the structure of your organs and tissues; they are also needed for your body's chemical functions. Each protein performs a specific job in different types of cells, and the information for making at least one protein is contained in a single gene. Genes are made up of various lengths of DNA, which contains four chemicals: adenine (A), guanine (G), cytosine (C), and thymine (T). These chemicals line up like beads on a necklace to form strands of code. They also pair up with each other to form the double strands that are characteristic of DNA. The gene's chemical code for a protein has two parts: the introduction area (promoter), and the instructions for creating the protein. The instructions for making the protein are inside the cell's nucleus, but the parts that actually make the protein are outside the nucleus. To send the instructions to the protein-producing areas of the cell, the gene "reads" the chemical code and rewrites it into a new form (called messenger RNA). The new form is then sent out of the cell's nucleus to make proteins. But, if either the original code or the new form of the code is incorrect or has missing parts, the cell can't make the correct protein. Without the protein, the body may not develop or function normally. This is what happens in Fragile X. The FMR1 gene contains too many repeats of one specific sequence, CGG, which is an important part of the promoter region for making FMRP (see the figure below). Illustration of the promoter region on a FMR1 mutated gene. The number of CGG repeats affects how the code is read and rewritten into its new form. So when the new form of the code gets to the protein-making areas of the cell, the cell has trouble using it to make FMRP, the protein that is abnormal, missing, or in low amounts in people with Fragile X. The cell either can't use the code, and so makes no FMRP, or tries to use the code and makes abnormal or unusable FMRP.

Intelligence and learning

Many people with Fragile X have impaired intellectual functioning, which affects their ability to think, reason, and learn. In most cases, researchers use an intelligence test to measure intellectual functioning, resulting in an IQ (intelligence quotient) score. But this score reflects many things besides the ability to think. Attention disorders, hyperactivity, anxiety, and language processing problems can interfere with test-taking skills and learning. Because many people with Fragile X have these problems, a person with Fragile X may have more capabilities than his or her IQ score suggests. Researchers consider people who score between 85 and 115 on an IQ test to have "average" intelligence.7 On the whole, less than 20 percent of males with Fragile X have an IQ in this range.2 At the same time, few people with Fragile X are severely or profoundly impaired, with IQs below 40 or 25, respectively.8 In general, those with a full mutation tend to have an IQ somewhere in between 40 and 85, which is considered mild to moderate mental impairment. Suggestions for working with individuals with Fragile X

• Know the learning style of the individual.
• Develop a consistent daily schedule or routine.
• Use visual signs (pictures, sign language, logos, words) and concrete examples or materials to present ideas, concepts, steps, etc.
• Prepare the individual for any changes in routine by explaining them ahead of time, possibly using visual signs.
• Include functional goals with academic goals; for instance, teaching the individual the names of different pieces of clothing as well as how to dress him/herself.
• Provide opportunities for the child to be active and move around.
• Use computers and interactive educational software.
• Provide a quiet place where the child can retreat and regroup.

Medication Options

Currently, there is no medication that can cure Fragile X. Further, the Food and Drug Administration (FDA) has not approved any drugs specifically for the treatment of Fragile X or its causes. But, in many cases, medications18 have been used to treat many of the symptoms associated with Fragile X, as shown in the table on the next page. Please note that the NICHD does not endorse or support the use of any of these medications in treating symptoms of Fragile X syndrome, or for other conditions for which the medications are not FDA approved. Medication is most effective when paired with therapy designed to teach new coping skills or behavior. Not every medication helps every child with behavioral symptoms related to Fragile X. Doctors usually prescribe these kinds of medications on a trial basis, to see if they help. If so, the doctor may need to adjust the dose to meet the needs of each child. This chart is meant for reference ONLY and should not take the place of your health care provider's advice. You should discuss any questions you may have about medication with your health care provider directly. Some of these medications have serious risks involved with their use; others may make symptoms worse at first or may take several weeks to become effective. Doctors may have to try different dosages or different combinations of medications to find the most effective plan. Families, caregivers, and doctors need to work together to ensure that a medication is working, and that a medication plan is safe. Symptoms Generic Medications (brand name in parentheses) Seizures Mood instability

• Methylphenidate (Ritalin, Concerta) and dexamethamphetamine (Adderall, Dexedrine)
• L-acetylcarnitine
• Venlafaxine (Effexor) and nefazodone (Serzone)
• Amantadine (Symmetrel)
• Folic acid

• Clonidine (Catapres TTS patches)
• Guanfacine (Tenex)

Physical

Many infants and young children with Fragile X have no distinctive physical features. Some children have very soft, velvety skin, a broad forehead, or a slightly larger head than other children their age. However, when these children enter puberty, usually around age 11, they may begin to develop certain features that are typical of teens and adults with Fragile X, such as a longer face or jaw and larger, more noticeable ears. Most do not grow as tall as their peers, or as tall as one might expect them to grow, based on the height of their family members. Other physical changes also come with puberty for those who have Fragile X. Many males develop enlarged testicles, a condition called macro-orchidism (pronounced mack-roe-ORK-id-izm). With this condition, the testicles may grow to twice their normal size. This condition is not due to hormonal imbalance and does not affect sexual development. One job of FMRP may be to help the body maintain its connective tissues. Connective tissues support the body, inside and out. Many people with Fragile X have loose, flexible joints. They may have flat feet and be able to extend joints like the thumb, knee, and elbow further than normal. Weak connective tissue can predispose a person to certain medical conditions, such as hernia and frequent middle ear infections. Weak connective tissue can also affect the valves and vessels of the heart, so that blood in the heart may not flow smoothly, which creates a heart murmur (called mitral valve prolapse, pronounced my-trell valv proh lapss). Although it involves the heart, this condition is usually not life threatening, but it is a good idea for a person with a heart murmur to be monitored by a health care professional on a regular basis. Late in life, some males who have a premutation may develop hand tremors10 and problems with walking. How does Fragile X affect the brain? Understanding how Fragile X affects the brain and learning what role FMRP plays in normal brain development and function are areas of active research. For instance, some evidence suggests that FMRP is involved in forming pathways in the brain. Normally, brain cells called neurons have special areas that grow toward each other to form connections. These connections, called "synapses," are arranged in neural pathways. Thoughts, sounds, and memories are recorded and stored in these pathways. However, not every experience recorded in these neural pathways is useful or needs to be kept throughout life. So, as part of normal development, the brain "prunes" itself. Like pruning the branches of a tree, removing unneeded or ineffective pathways in the brain strengthens other pathways and makes room for new growth and new learning. FMRP may somehow influence the pruning process in the brain. People without enough FMRP may have may have too many neural pathways or many connections that don't work well. This situation would explain some of the symptoms of Fragile X, such as an extreme sensitivity to new sights, sounds, smells, and touches. Using mice and fruit flies that no longer have a working gene to make FMRP, scientists are working to understand how the absence of this protein affects the brain. Recent research is trying to determine whether a certain process that runs out of control in mice with little or no FMRP leads to the behavioral and learning problems typical in people with Fragile X. Such animal studies may reveal exactly how FMRP functions in the brain and suggest ways to correct situations caused by a lack of the protein. Fragile X affects females in some different ways. About 16 percent11 to 19 percent12 of females who have a premutation gene experience premature ovarian failure (POF), meaning their ovarian function stops before normal menopause, sometimes well before the age of 40. Some may experience POF as early as their mid-twenties. POF affects a woman's ability to get pregnant. It is important, then, for women to know whether or not they have a premutation gene, and to have this knowledge early enough, so that they can consider their options for having a family. In contrast, POF occurs in only 1 percent of women who have two normal FMR1 genes,13 and the average age of menopause for women who are not affected by Fragile X is 51. Women who have a full mutation gene do not lose ovarian function as early as women with a premutation gene, but they still tend to begin menopause earlier than women who are not affected by Fragile X. Scientists do not know why the effect is milder in women who have a full mutation form of the gene than in women with a premutation form of the gene.

Sensory

Many children with Fragile X are sensitive to certain sensations. Disorders commonly associated or sharing features with Fragile X Autism. Most males and about one-third of females with Fragile X show some autism-like behaviors, such as flapping hands, biting themselves, repetitious actions, and walking on toes.14 About 33% of children with Fragile X show enough of these behaviors to receive a formal diagnosis of autism.15 However, among people diagnosed with autism first, only about 4 percent are found to have an X chromosome with the FMR1 gene mutation. Attention Deficit Disorder (ADD)/Attention Deficit Hyperactivity Disorder (ADHD). Between 80 and 90 percent of males, and 35 to 47 percent of females with Fragile X have an attention disorder.16,17 They are unable to focus their attention and stay with a task. They may be disorganized. Some are hyperactive and seem to be constantly in motion. Connective Tissue Problems. Due to weak connective tissue, people with Fragile X have a higher risk of dislocating their joints and developing hernias and ear infections than those who aren't affected by Fragile X. About half of adults with Fragile X have a heart murmur caused by mitral valve prolapse,17 which is usually not life threatening. Seizures. About 20%6 of children with Fragile X also experience seizures. In most cases, seizures are successfully treated with medication and disappear by adolescence. Premature Ovarian Failure (POF). POF occurs when a woman's ovaries stop working properly and she is under the age of 40. As mentioned earlier in this article, about 16 to 19 percent of females who carry a premutation gene for Fragile X experience POF, some as early as age 20.10,11 Women with a full mutation gene for Fragile X are less likely to have POF, but do tend to go through menopause earlier than women who do not carry a mutated gene. They may become frantic at the sound of a loud noise or may be easily distracted by slight sounds in the room. They may be bothered by the texture of their clothes against their skin, or they may be unable to focus on the parts of their environment that are important, such as the sound of the teacher's voice. Infants with Fragile X may have problems drinking from a bottle, perhaps because the feel of the nipple upsets them. Some children try to avoid being touched, and even a brief tickle or hug may be overwhelming. Even though many of these symptoms are often life-long, most people affected by Fragile X, with the proper intervention, can find ways to handle or avoid the discomfort. (See the Are there treatments for Fragile X syndrome? section for more information.) Children with Fragile X may also have problems with balance. A sense of balance helps keep the body upright and stable. Problems with balance, coordination, and connective tissue can cause difficulties for children with Fragile X as they learn to sit, stand, and walk, or later, to ride a bike. Even so, most children with Fragile X learn to do these tasks.

Social and emotional

Most children with Fragile X-especially boys-feel a great deal of social anxiety; that is, they aren't completely comfortable in new situations, meeting new people, or doing new things. Their level of anxiety can be so high that they may avoid social situations. When these children do seek contact with others, they are often extremely nervous or uncomfortable. Their anxiety may show up as a lack of eye contact and/or fast, choppy speech. Although all children feel some degree of social anxiety, this discomfort usually doesn't keep them from being social, as it may for children with Fragile X. In addition to being anxious, males with Fragile X tend to be easily upset. They are easily overwhelmed with sights and sounds (see the What are the signs and symptoms of Fragile X?-Sensory section of this article for more information), and can become very distressed in a busy store or restaurant. Unexpected changes in routine, like entering a new class or classroom, can also upset them. Some children respond by becoming extremely rigid or tense, while others whine or cry. At times, their reactions can spill over into tantrums or repetitive actions, such as rocking back and forth and biting themselves. In adolescence, changes, such as rising hormone levels, may make these outbursts more extreme. In one study of teenage males with Fragile X, about one-third showed angry, aggressive behavior.8 Such behavior can get them into trouble at school. Providing medication and a calm environment can help keep such behaviors from getting worse. (See the Are there treatments for Fragile X? section for more information.) In addition, males with Fragile X tend to experience much longer periods of anxiety than their peers. Like other males, their heart rate and other signs of nervousness increase when they do challenging tasks, but many males with Fragile X stay highly anxious for much longer time frame. So, in addition to having a level of anxiety that is often higher than their peers, males with Fragile X also take longer to calm down than other males do. Females with Fragile X may have social problems, too, but theirs tend to be milder. A female with Fragile X may feel uneasy around strangers or have trouble making friends, but these females don't tend to be aggressive as adolescents.

Speech and language

Language difficulties in children who have Fragile X range from mild stuttering to more severe problems with basic language skills. Basic language skills include the ability to pronounce words clearly, to speak and write using words and grammar correctly, and to communicate in meaningful ways. Females with Fragile X rarely have severe problems with speech or language. In fact, many have vocabulary and grammar skills that are appropriate for their age, which can help them learn to read and write. However, their social anxiety and shyness may get in the way of communication. Some females with Fragile X speak in a rambling, disorganized way or often get off the subject. Most males with Fragile X have more serious problems expressing themselves. These difficulties typically include problems speaking clearly and other problems with language that can be moderate to severe. In terms of speech, males with Fragile X often have problems coordinating the structures, vocal processes (such as pitch, loudness, and tone), and movements needed for clear speech. They often have difficulty receiving and processing spoken information, such as following spoken directions, storing words and concepts for future use, and creating their own meaningful responses to questions or comments. Males with Fragile X may stutter or leave sounds out of their words. Many repeat themselves, restart the same sentence many times, or ask the same question again and again. Some may talk too fast, mumble, or speak in a loud, high voice. Some of these difficulties may be due to sensory overload or social anxiety, rather than a problem with the parts of the brain that control speech and language. Perhaps most importantly, males with Fragile X usually have difficulty using speech and language in social contexts. They often seem unaware of conversational "clues," such as facial expressions, tone of voice, and body language. As a result, they may speak out of turn, fail to answer a question, or turn away because they aren't sure what to do. Unlike males with other developmental disorders, like autism, males with Fragile X seem to be very interested in communicating, but may experience sensory overload or social overload when they try to hold a conversation. For some children, language problems are more severe. Many children with Fragile X begin talking later than expected. Most begin using words around age four, but some may not talk until age of six or eight.6 Most talk eventually, but some may remain nonverbal throughout life. For these nonverbal children, a wide variety of picture-based and computer-based devices may help them to communicate, which could also reduce behavior difficulties that result from not being able to talk. Pictures, sign language, and generic gestures can also be helpful for all children with Fragile X, before they start talking.

Therapeutic Options

A variety of professionals can help individuals with Fragile X and their families deal with symptoms of the disorder. Such assistance is usually most effective when provided by health care professionals experienced with Fragile X.

• Speech-language therapists can help people with Fragile X to improve their pronunciation of words and sentences, slow down speech, and use language more effectively. They may set up social or problem-solving situations to help a child practice using language in meaningful ways. For the minority of children who fail to develop functional speech, this type of specialist may work with other specialists to design and teach nonverbal ways of communication. For example, some children may prefer to use small picture cards arranged on a key ring to express themselves; or they may learn to use a hand-held computer that is programmed to "say" words and phrases when a single key is pressed.
• Occupational therapists help find ways to adjust tasks and conditions to match a person's needs and abilities. For example, this type of therapist might teach parents to swaddle or massage their baby who has Fragile X to calm him or her. Or the therapist might find a specially designed computer mouse and keyboard or a pencil that is easier for a child with poor motor control to grip. At the high school level, an occupational therapist can help a teenager with Fragile X identify a job, career, or skill that matches his or her interests and individual capabilities.17
• Physical therapists design activities and exercises to build motor control and to improve posture and balance. They can teach parents ways to exercise their baby's muscles. At school, a physical therapist may help a child who is easily over-stimulated or who avoids body contact to participate in sports and games with other children.
• Behavioral therapists try to identify why a child acts in negative ways and then seek ways to prevent these distressing situations, and to teach the child to cope with the distress. This type of specialist also works with parents and teachers to find useful responses to desirable and undesirable behavior. During puberty, rising and changing hormone levels can cause adolescents to become more aggressive. A behavioral therapist can help a teenager recognize his or her intense emotions and teach healthy ways to calm down.