Genetic: Fragile X
Genetic: Fragile X
Fragile X syndrome is a genetic disorder caused by a mutation in the FMR1 gene on the X chromosome. This gene makes a protein called fragile X mental retardation 1 protein, whose function is not fully understood but is thought to be related to the development of synapses, which are specialized junctions between nerve cells. The mutation in the gene blocks production of the needed protein, leading to mental retardation and other developmental problems in affected children. The disorder is called fragile X because the mutated gene causes part of the chromosome to look unusually slender or fragile under a microscope.
Fragile X syndrome is a genetic disorder caused by a mutation in the FMR1 gene on the X chromosome. The disorder was first described in 1943 by two psychiatrists named Martin and Bell, who determined that the syndrome is sex-linked. The specific gene involved, however, was not identified until 1991.
The mutation consists of the expansion of a section of the gene that ordinarily consists of six to fifty-five repeats of a specific trinucleotide (triplet-nucleotide; nucleotides are one of the building blocks of DNA). In some people, this portion of the FMR1 gene contains more than fifty-five repeats of the triplet. People with sixty to 200 repeats have what is called a premutation; they do not have the typical symptoms of fragile X syndrome but they can carry the defective gene and pass it on to their children. The repeated portion of the FMR1 gene is likely to have more repetitions added when it is passed from a woman with the premutation to her children. When the number of repetitions grows to about 230, the gene is switched off and does not produce the protein that it normally makes. This gene change is then considered a full mutation. Some people with fragile X syndrome have as many as 1,000 repetitions of the crucial triplet in the FMR1 gene.
Because the X chromosome is a sex-linked chromosome, fragile X syndrome affects boys more severely than girls. Girls have two X chromosomes, whereas boys have one X chromosome and one Y chromosome. A boy who inherits a full mutation of the FMR1 gene will develop fragile X
syndrome because his only X chromosome contains the mutated gene. A girl who inherits a full mutation may not be as severely affected because each cell of her body needs to make use of only one of its two X chromosomes; it can inactivate the other X chromosome.
People with a fragile X premutation are usually of normal intelligence but may suffer from other health problems. About 20 percent of women with the premutation stop having menstrual periods unusually early, often by age forty. Men and some women with the premutation are at increased risk of developing a movement disorder accompanied by memory loss, tremor, and loss of sensation in the lower legs.
Fragile X syndrome is the most common genetic cause of mental retardation in boys, affecting one in 4,000 males and one in 8,000 females. A screening study that was done of children in special education programs in the United States found that approximately one in 400 males receiving special education services have fragile X syndrome. According to the Centers for Disease Control and Prevention (CDC), about one in 259 women carry the fragile X mutation and could pass it to their children. About one in 800 men carry fragile X changes; their daughters will also be carriers. As far as is known, fragile X syndrome is equally common in all races and ethnic groups; it appears to be one of the most common genetic disorders in humans. No large-scale population screening in any country in the world has been carried out, however.
The cause of fragile X syndrome is a mutation in the FMR1 gene on the X chromosome. Not all children are affected to the same extent by the mutation, however. Girls who inherit the fragile X may appear normal or they may have some degree of mental retardation, but usually to a
lesser degree than boys with the syndrome. Between 33 and 50 percent of girls with fragile X syndrome have significant intellectual impairment; the rest have either normal intelligence or specific learning disabilities, such as mathematics. Emotional and behavioral problems occur in children of either sex. Children with fragile X syndrome have characteristic physical features as well as developmental and behavioral difficulties:
- Elongated face with large ears
- Flat feet
- Double-jointed fingers and easily dislocated joints
- Poor muscle tone
- Excessive curvature of the spine
- In males, unusually large testicles
- Mental retardation (IQ between 20 and 70)
- Difficulty with speech and language development
- Some autistic behaviors (poor eye contact, extreme shyness, and hand flapping)
- Problems paying attention
- About 20 percent of boys with fragile X meet all the diagnostic criteria for autism. Most boys and some girls with fragile X have some symptoms of autism; however, many are socially outgoing and can form relationships with other people.
- Rapidly changing moods
- Seizures (about 25 percent)
The diagnosis of fragile X syndrome is based on a combination of family history, early signs of mental retardation in the child, and specific genetic
testing. Patients who have several mentally retarded male relatives or a mother with mental retardation or learning disabilities are sometimes screened on the basis of this family history. In other cases the child may not be diagnosed until he or she has started school and his or her learning disabilities become apparent. The standard diagnostic test for fragile X syndrome is a DNA test that was developed in 1992. It counts the number of repetitions in the FMR1 gene and can detect carriers of the mutation as well as fully affected persons. The doctor takes a sample of the patient's blood and sends it to a laboratory for analysis. The test is expensive but is often covered by health insurance.
There is no cure for fragile X syndrome. Treatment usually involves a combination of approaches. The syndrome can be treated through cognitive behavioral therapy, special education programs, speech and language therapy, medications for anxiety and depression, and treatment of physical abnormalities if needed. Because fragile X syndrome is not a rare condition, specific educational approaches for these children have been developed and tested. Most children affected by the syndrome, however, will need some form of treatment throughout their lives.
The prognosis for a child with fragile X syndrome depends on sex and on the number of repeated triplets in the FMR1 gene. Girls usually have a better prognosis for intellectual development than boys; children with fewer repeats in the gene have a better prognosis than those with several hundred. People with fragile X syndrome do, however, have a normal life expectancy.
There is no way to prevent the genetic mutation that causes fragile X syndrome. Parents who have a child with the condition should consult a genetic counselor, however, to determine the risk of having another child with the syndrome or a child who is a carrier of the mutation. Accurate diagnosis is important because of the possibility of other family members inheriting either the syndrome itself or other problems related to an increased number of repeats in FMR1.
Research is focused on learning more about the FMR protein. It is known that the lack of the protein does not destroy nerve cells but rather delays their development. It is possible that a treatment can be found that will help the nerve cells and the synapses that join them to develop normally.
SEE ALSO Attention-deficit hyperactivity disorder; Autism; Depression; Down syndrome
WORDS TO KNOW
Nucleotides: The basic structural units of DNA and RNA.
Premutation: An abnormally large number of repeated triplets in certain genes that does not cause obvious symptoms of a genetic disorder but can expand into a full mutation when transmitted to offspring.
Synapse: The medical term for specialized connections between nerve cells.
Triplet: In genetics, a unit of three nucleotides that starts or stops the production of a specific protein. Triplets are also called codons.
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