What is Fragile X?
Symptoms of fragile X syndrome include:
1. Mental impairment, ranging from learning disabilities to mental retardation
2. Attention deficit and hyperactivity
3. Anxiety and unstable mood
4. Autistic-like behaviors
5. Long face, large ears, flat feet, and hyperextensible joints, especially fingers
Boys are typically more severely affected than girls. While most boys have mental retardation, only one-third to one-half of girls have significant intellectual impairment; the rest have either normal IQ or learning disabilities. Emotional and behavioral problems are common in both sexes.
Prevalence of fragile X in the general population
Fragile X syndrome is the single most common inherited cause of mental impairment. Current estimates of its prevalence vary, but some experts believe that fragile X affects at least 1 in 1000 males and females of all races and ethnic groups. More conservative estimates put the frequency at 1 in 1500 males and 1 in 2500 females (Warren, Jama, Feb. 16, 1994 - Vol.271, No.7, p.536). The discrepancy in these numbers is due to the fact that large-scale population studies of the incidence of fragile X have not yet been done. In either case, fragile X is one of the most common genetic diseases in humans. 80-90% of people with fragile X are not yet correctly diagnosed.
What Causes Fragile X?
In 1991, scientists discovered the gene (called FMR1) that causes fragile X. In individuals who have fragile X syndrome, a defect in FMR1 (a full mutation) shuts the gene down. Like a defective factory, the FMR1 gene cannot manufacture the protein that it normally makes. Other individuals are carriers: they have a small defect in the FMR1 gene (called a premutation) but do not show symptoms of fragile X.
Fragile X is inherited. Carrier men (transmitting males) pass the premutation to all their daughters but none of their sons. Each child of a carrier woman has a 50% chance of inheriting the gene. The fragile X premutation can be passed silently down through generations in a family
Testing for fragile X
A DNA based test to diagnose fragile X was developed in 1992. This test is quite accurate, and it can detect both carriers and fully-affected individuals. The blood test that can be ordered by any physician; the blood sample is then sent to one of the labs that offers the test. It usually takes several weeks to get the results.
Because the symptoms of fragile X can be quite subtle, especially in young children, and because fragile X is so frequent in the general populations, many medical specialists recommend that testing for fragile X be considered for any individual with otherwise unexplained developmental delay or mental retardation.
Most major medical centers in the United States now offer the DNA test for fragile X. This test typically costs $200-$300. The older cytogenetic test is more expensive (often about $900) and typically cannot diagnose carriers and can miss some fully-affected individuals as well. For more information about testing, talk to your doctor or genetic counsellor.
Is There Any Treatment?
There is currently no cure for fragile X syndrome, although appropriate education and medications can help maximize the potential of each child. The reference section includes several texts on educational strategies. However, most boys and many girls remain significantly affected throughout their lives. The cost to society for treatment, special education, and lost income is staggering. The need for research aimed at treatment is urgent. Recent significant progress has been made in understanding mechanisms and potential treatments for inherited diseases which are caused by a single gene, such as fragile X. Current medical research focuses on:
1. Gene therapy: studying the gene that causes fragile X in order to determine whether a healthy gene may be inserted into the DNA of affected individuals, thereby replacing the mutated, ineffective gene.
2. Protein replacement therapy: studying the protein product that is lacking due to the mutation, in hopes that the protein may be supplemented from an external source.
3. Psychopharmacology: treating symptoms of the disorder with medications
Many researchers believe that medical treatment, when it becomes available, will be able to help fragile X individuals of all ages. Experts think that the missing FMR protein has a regulatory function in the brain, rather than a structural function, and that this protein is needed throughout a person's life. In other words, the fragile X protein probably affects the "software" of the brain, rather than the "hardware."
Fragile X Syndrome
by Randi Hagerman, M.D., Children's Hospital, Denver, Colorado
What is fragile X syndrome?
Fragile X syndrome is an inherited genetic condition associated with mental retardation. It is identified by a break, or weakness, on the long arm of the X chromosome. Since this is an abnormality of a sex chromosome which can be transmitted from parent to child, the term "sex-linked" or "X-linked" inheritance is used in the medical literature. This means that mothers are carriers and their sons are at risk of being affected, while daughters are at risk of being carriers and sometimes mildly affected. While more boys than girls are affected by fragile X, it is not transmitted from father to son. What are the new DNA findings?
In May of 1991 the gene which is responsible for the fragile X syndrome was sequenced and named FMR-1 (Fragile X Mental Retardation 1 Gene (Verkerk, et al, 1991). This means that the structure of the gene, specifically the DNA components, or nucleotides, were identified where the break or fragile site occurs on the bottom end of the X chromosome. The mutation, or abnormality, which causes the fragile X syndrome is unusual. The mutation consists of a repetitive CGG sequence in the DNA that is much larger than what is seen in the normal population. Carriers have a small amplification of this CGG sequence but affected individuals have a much larger amplification (Warren and Nelson, 1992). DNA testing is now available to identify unaffected carriers and individuals who are affected by the fragile X syndrome. The fragile X syndrome can also be diagnosed by chromosome or cytogenetic testing which shows the break or fragile site on the bottom end of the X chromosome. However, unlike the DNA testing, the cytogenetic testing does not identify carriers. Both the DNA and cytogenetic testing can be done on a small blood sample. How common is fragile X syndrome?
Estimates vary on the prevalence of the fragile X syndrome, but an evaluation of school children in England found a prevalence rate of approximately 1 in 1,000 males with fragile X mental retardation (Webb, 1986). The prevalence of carriers in the general population is approximately 1 in 600 (Sherman, 1992). If a 3 percent prevalence of mental retardation in the general population is used, fragile X syndrome may account for up to 10 percent of mental retardation. It is the most common inherited cause of mental retardation known to exist. The gene prevalence shows that it is the most common mutation in the human genome that causes intellectual difficulties. Why aren't girls affected as much as boys?
The X chromosome is unique among the 23 pairs of chromosomes found in each human cell. It is one-half of the chromosome pair that determines sex. If, at conception, an embryo receives an X chromosome from the mother and a second one from the father, it will be a female. But if it gets a Y-shaped chromosome from the father, the embryo will be male. Thus, males can only inherit a fragile X from their mothers. Disorders which are carried on the X chromosome usually demonstrate less involvement in females because a second X chromosome can compensate for a defective gene on the other X chromosome. In fragile X, approximately 30 percent of females who inherit the fragile X gene will be affected intellectually by this syndrome. Females, however, more commonly demonstrate learning disabilities including math deficits and problems with attention span even though their IQ may be within the normal range. What are the physical characteristics of fragile X syndrome?
The physical features associated with fragile X syndrome include a long narrow face, prominent ears, jaw and forehead. Enlarged testicles, known as macroorchidism, is another physical characteristic. Many young children with fragile X syndrome may not show these features although prominent ears are seen in approximately two-thirds of children. Loose joints, particularly in the finger joints, are also quite common in childhood. After puberty these features are more common, particularly the long face and macoorchidism. Physical features are often more subtle in females, but approximately 50 percent of females who are affected intellectually also demonstrate prominent ears and/or loose and hyperextensible finger joints. What degree of mental retardation is associated with fragile X syndrome?
About 80 percent of boys who inherit the fragile X have mental impairment, ranging from severe retardation to low-normal intelligence. The majority are mildly to moderately retarded. Girls are much less affected, with estimates that about 30 percent with the genetic condition have some degree of mental retardation (Sherman, et al, 1985). Recent research suggests that IQs of males with the fragile X syndrome appear to decline throughout childhood. While young boys may be only mildly impaired, adults with the fragile X syndrome are usually moderately or severely retarded. This is because their rate of learning does not keep pace with their initial IQs as they grow older (Lachiewicz, et al, 1987). What behavioral symptoms are associated with fragile X?
Men and boys with the fragile X syndrome are usually socially engaging, but they have an unusual style of interacting with other people (Meryash, 1985). They tend to avoid direct eye contact during conversation, and hand-flapping or hand-biting is common. They may have an unusual speech pattern characterized by a fast and fluctuating rate and repetitions of sounds, words or phrases. They also may have a problem in their attention span, hyperactivity, and motor delays. Some males demonstrate autistic-like behaviors, including perseverative speech, unusual hand mannerisms and problems in relating to others (Hagerman, 1991). Can fragile X be treated?
There is no cure for fragile X syndrome, but medical intervention can improve the problems in attention and hyperactivity of many young boys (Hagerman, 1991; Hagerman and McKenzie, 1992). A variety of medications can improve attention span, concentration, hyperactivity, aggressive behavior and other problems (Hagerman, 1991). Treatment for children with fragile X syndrome is determined by an individualized program of special education including such components as speech therapy, physical therapy and vocational preparation. A child less than age 3 can benefit from an early intervention program. In general, children who are living at home and enrolled in special education will function at a higher level as adults than do men who were institutionalized years ago and never received special education (Meryash, 1985). The research suggesting that IQs of males decline as they grow older has implications for special education programs. Early intervention and preschool education become especially important, for evidence indicates that while the rate of learning slows with age, males with fragile X syndrome do not lose previously acquired skills or deteriorate in functioning (Lachiewicz et al, 1987). When was fragile X syndrome identified?
Although it was well-known for years that more males than females are affected by mental retardation, it was the 1960s before scientists perfected ways to look at chromosomes and detect abnormalities. The fragile site on the long arm of the X chromosome was first noted in 1969 by Dr. Herbert Lubs who discovered these chromosomes in a family having two brothers with mental retardation. By the late 1970s this condition was named fragile X by Dr. Grant Sutherland who was studying the occurrence of fragile sites. While the announcement about the fragile X chromosome was first published in the medical press in the late 1970s, it has only come to the attention of the public in the last ten years. Because of its recent discovery, most individuals with this syndrome are undiagnosed. Since the identification of the FMR-1 gene, DNA testing is now available for identifying both carriers and individuals affected by the fragile X syndrome (Verkerk, et al, 1991). What are the chances of having a child with fragile X?
The DNA testing has demonstrated that all individuals who demonstrate the fragile X syndrome have a parent who is a carrier. If the person affected by fragile X is a male, the carrier is always his mother. Since the carrier mother has two X chromosomes the chance of passing on the fragile X chromosome is 50 percent. The DNA testing can document the degree of amplification of the CGG repeat in the carrier. A higher level of amplification in a carrier female will increase the risk that the gene will amplify further in an affected child. Amplification only occurs from the carrier status when the gene passes through a female. Carrier males who are unaffected by the syndrome will pass the gene to all of their daughters but to none of their sons. The gene, however, will not amplify when passed on by a father so that daughters of carrier males are almost always unaffected carriers. Since the inheritance pattern in fragile X is complex, it is important for family members to receive genetic counseling concerning their risks of carrying the fragile X gene and passing it on to their children. 
