fragile X syndrome

What is fragile X syndrome?

Fragile X syndrome (FXS), caused by extra CGG repeats in the FMR1 gene, is a condition that causes a variety of developmental and behavioral problems. Fragile X syndrome is an X-linked disease. This means that the FMR1 gene is on the X-chromosome. Males have one copy of the X-chromosome, while females have two copies. Because males only have one copy, a harmful change in the FMR1 gene typically causes more severe symptoms in males. Carrier females may be asymptomatic or may exhibit symptoms. Fragile X syndrome is the most common inherited form of intellectual disability. It is the leading single-gene cause of autism spectrum disorders.

Fragile X syndrome typically causes moderate intellectual disability (defined as an IQ below 70) in males. However, the severity of intellectual impairment varies from individual to individual. A few male patients do not have an intellectual disability. About one-third of females with fragile X syndrome have a mild intellectual disability.

As infants, children with fragile X syndrome may have weak muscles (hypotonia), stomach acid that comes up into the mouth (gastric reflux), and frequent ear infections. Their motor, mental, and speech milestones tend to be delayed. Children with fragile X syndrome often have behavioral problems such as anxiety, hyperactivity, hand flapping, biting, and temper tantrums. About one-third of males with fragile X syndrome have autism or autism-like behavior. Symptomatic females usually have milder symptoms than males. Behavioral problems in females may appear as depression, shyness, and avoidance of social situations. Some individuals with the condition have attention deficit disorder and cannot sustain focused attention on a specific task. Individuals with fragile X syndrome, particularly males, may lack impulse control, make poor eye contact, and be easily distracted.

Males with fragile X syndrome often share characteristic physical features such as a long, narrow face with a prominent jaw and forehead, a large head, flexible joints, and large ears. These features become more apparent with age. These characteristics tend to be milder or absent in females with the condition. After puberty, males with fragile X syndrome typically have enlarged testicles.

Roughly 15% of males and 5% of females with fragile X syndrome will experience seizures. While some experience heart murmurs (known as mitral valve prolapse), it is usually harmless and may not require treatment.

Effects of a premutation

Males and females with a premutation do not have fragile X syndrome but may experience specific physical symptoms. The main risks for carriers of a premutation are fragile X-associated tremor/ataxia syndrome (FXTAS), fragile X-associated premature ovarian insufficiency (FXPOI), and fragile X-associated neuropsychiatric disorders (FXAND).

Fragile X-associated tremor/ataxia syndrome (FXTAS): FXTAS causes an inability to coordinate muscle movements that worsens over time (ataxia), tremors, memory loss, impaired ability to think or remember information (dementia), a loss of feeling and weakness in the lower legs, and some mental and behavioral changes. Approximately 40% of males over 50 years of age with a fragile X premutation will develop FXTAS. Between 8-16% of females with a fragile X premutation are affected by FXTAS. Typically, symptoms of FXTAS begin around age 60 with a tremor, followed several years later by the inability to coordinate muscle movements.

Fragile X-associated primary ovarian insufficiency (FXPOI): About 20% of females with a premutation experience FXPOI. This condition causes their menstrual periods to stop before age 40. Females with FXPOI will often have difficulty getting pregnant, and many will not be able to have children. Females with a full mutation are not at increased risk for POI.

Fragile X-associated neuropsychiatric disorders (FXAND): There is an increased rate of neuropsychiatric conditions among premutation carriers. These include depression, generalized and social anxiety, and attention deficit disorder.

How is fragile X syndrome inherited?

Fragile X syndrome is inherited in an X-linked manner. The inheritance is much more complex than many other genetic diseases. A healthcare professional, such as a genetic counselor, can help answer questions about this condition and the risk of transmitting it to the next generation.

Fragile X syndrome is caused by changes in the FMR1 gene, which is located on the X-chromosome. This gene contains a segment of DNA called the "CGG repeat." The CGG repeat in the FMR1 gene is a pattern of DNA that repeats itself many times. By counting the number of CGG repeats in the parents, one can determine the likelihood that a child will have fragile X syndrome.

The CGG repeat in the FMR1 gene falls into one of the following four categories:

Normal

An FMR1 gene with 5 to 44 CGG repeats is considered normal. Individuals with this number of FMR1 CGG repeats do not have an increased chance of having a child with fragile X syndrome. CGG repeats in this range are considered stable because they usually pass from parent to child with the same number of repeats. For example, if a parent's gene has 30 CGG repeats, their child will likely have a gene with 30 CGG repeats.

Intermediate

An individual with 45 to 54 repeats is not expected to have an increased chance of passing on fragile X syndrome to their child, but the number of repeats transmitted to the next generation may increase slightly.

Premutation

Individuals with 55 to 200 CGG repeats have a premutation. They do not have symptoms of fragile X syndrome. However, they are at increased risk for FXTAS, FXPOI, and FXAND. Depending on which parent has the premutation, future children may be at risk of having fragile X syndrome.

Full mutation

Individuals with more than 200 CGG repeats have a non-functioning FMR1 gene (also known as a full mutation). Males with more than 200 CGG repeats usually have symptoms of fragile X syndrome. Females with more than 200 CGG repeats may also have symptoms of fragile X syndrome and are at risk of passing the condition on to their children.

What does it mean to have an intermediate result?

An FMR1 gene that has 45-54 repeats is considered intermediate. The number of CGG repeats is higher than normal but not large enough to be considered a premutation. Sometimes CGG repeats in the intermediate range are referred to as "gray zone" results. Individuals with an intermediate repeat do not have an increased chance of having a child with fragile X syndrome. Most intermediate genes are stable and do not significantly expand when passed on. However, repeats in the intermediate range may slightly expand when passed on to the next generation in some cases. For example, a parent with 45 CGG repeats could have a child with 50 CGG repeats. If the number of repeats continues to increase, future generations (i.e., grandchildren or great-grandchildren) may have a chance of inheriting fragile X. Expansion to a full mutation in one generation from a maternal gene with fewer than 56 repeats has not been reported. Children of individuals with an intermediate result may consider fragile X testing to determine their CGG repeat sizes once they are adults for reproductive planning purposes.

Approximately 3% of patients undergoing fragile X carrier screening will have an intermediate result. Individuals with an intermediate repeat do NOT have an increased chance of having the physical symptoms affecting premutation carriers such as FXTAS, FXPOI, and FXAND.

What does it mean to have a premutation or full mutation? What is the chance that a child will have fragile X syndrome?

For females with a full mutation, 50% of their children will also inherit the full mutation and be at risk for symptoms of fragile X syndrome. Males who have full mutations typically do not reproduce.

Premutations are more complicated. When the parent has a premutation, the risk of a child developing fragile X syndrome depends on the answers to the following questions:

1. Which parent has the premutation?
2. Will the child inherit the premutation?
3. Will the premutation expand to a full mutation?

Which parent has the premutation?

Females that are premutation carriers are at risk of having children with fragile X syndrome. Premutations inherited from a female can be unstable and may expand to become full mutations in the child. This risk can be modified by AGG interruptions, which reduce the likelihood of expansion.

Premutations passed from a male parent may change the CGG repeat number. However, premutations do not expand to full mutations when passed from a male parent. Therefore, males with premutations are not at risk of having children with fragile X syndrome.

Will the child inherit the premutation?

Premutations are not thought to expand to full mutations when passed from a male parent to a female child. However, there can be a change in the number of CGG repeats. These female children are generally not at risk of having fragile X syndrome, but their future children (the grandchildren of the original premutation carrier) will be at risk. Male parents pass a Y chromosome to their male children instead of an X, so fragile X premutations are not passed from a male parent to a male child.

If a female parent has a premutation on one of their X chromosomes, there is a 50% chance in each pregnancy that their child will inherit the X chromosome with the premutation and a 50% chance that they will not. Only children who inherit the X chromosome with the premutation would be at risk for fragile X syndrome if it expands.

Will the premutation expand to a full mutation?

If a female parent has a gene with a premutation that gets passed to their children, there are two possibilities:

1. The premutation does not expand beyond 200 repeats and remains a premutation in the child. That child has no symptoms of fragile X syndrome but may experience FXAND and FXTAS or FXPOI as adults.
2. The premutation expands into a full mutation, causing fragile X syndrome in males and risk for fragile X syndrome in females.

Rarely, a CGG repeat may contract (or reduce in number). Therefore, there is a small possibility that a premutation could be passed on as an intermediate or normal repeat to the child.

The greater the number of CGG repeats a female has, the more unstable the gene is and the more likely it will expand to a full mutation in their children. The smallest premutation observed to expand to a full mutation in a single generation is 56 repeats.

More than 94% of genes with >90 CGGs expand to a full mutation.

Adapted from Nolin et al. (2015) and Nolin et al. (2011). These percentages typically exclude families with a family history of fragile X syndrome.

How Common Is Fragile X Syndrome?

The incidence of fragile X syndrome is estimated to be 1 in 4,000 males and 1 in 8,000 females.

How Is Fragile X Syndrome Treated?

There is no cure for fragile X syndrome, but children with the condition can be treated and supported in many ways depending on their particular symptoms and the severity of those symptoms. They may benefit from educational support like early developmental intervention, special education classes in school, speech therapy, occupational therapy, and behavioral therapies. A physician may prescribe medication for behavioral issues such as aggression, anxiety, or hyperactivity.

A small number of these children experience seizures which can be controlled with medication. While some have a heart murmur, it is usually harmless and may not require treatment.

What Is the Prognosis for an Individual with Fragile X Syndrome?

While many of the children with fragile X syndrome have learning and behavioral problems, they generally do not have major medical problems and can live a normal lifespan.