fragile X syndrome

What Is Fragile X Syndrome?

Fragile X syndrome (FXS), caused by repeats in the FMR1 gene, is a condition that causes a spectrum of developmental and behavioral problems which tend to be more severe in males because of the X-linked inheritance of this disease. It is the most common inherited form of intellectual disability and it is the leading single-gene cause of autism spectrum disorders.

Fragile X syndrome typically causes moderate intellectual disability in males, although the severity of intellectual impairment varies from individual to individual. A small number of male patients do not have an intellectual disability, generally defined as an IQ below 70. Approximately 50% of females with fragile X syndrome will have intellectual disability which is typically less severe compared to affected males.

As infants, children with fragile X syndrome may display poor muscle tone, 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. In symptomatic females, who usually have milder symptoms than males, behavioral problems may appear as depression, shyness, and avoidance of social situations. Some individuals with the condition have attention deficit disorder, with an inability to sustain focused attention on a specific task. As they become adolescents and young adults, individuals with fragile X syndrome, particularly males, may lack impulse control, make poor eye contact, and/or 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 symptoms 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 from a condition called mitral valve prolapse, it is usually harmless and may not require treatment.

Effects of a Premutation

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

FXTAS: Approximately 40% of men over the age of 50 with a fragile X premutation will develop FXTAS. Between 8-16% of women with a fragile X premutation are affected by FXTAS. FXTAS causes an inability to coordinate muscle movements (ataxia) that worsens over time, tremors, memory loss, dementia, a loss of feeling and weakness in the lower legs, and some mental and behavioral changes. Often symptoms of FXTAS begin around age 60 with a tremor, followed several years later by ataxia. One study of 55 men with FXTAS found that from the time symptoms begin, additional life expectancy ranged from 5 to 25 years.

FXPOI: About 20% of women with a premutation experience premature ovarian insufficiency (FXPOI), in which their menstrual periods stop prior to age 40. Only 5-10% of women with POI will be able to have children. One study found that 21% of women with a premutation experienced POI, compared to 1% in the general population. Women with full mutations are not at increased risk for POI.

FXAND: Several neuropsychiatric disorders which are common in the general population may have increased incidence among premutation carriers. Approximately 50% of premutation carriers will be affected by a neuropsychiatric disorder, most commonly anxiety and depression in adults. Attention and social deficits are also more common. These neuropsychiatric disorders as a feature of the fragile X premutation have recently been named FXAND.

How Is Fragile X Syndrome Inherited?

Fragile X syndrome is inherited in an X-linked manner. The inheritance is much more complex compared to many other genetic diseases. A healthcare professional can help explain any 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 mother, 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. An individual with this number of FMR1 CGG repeats is not at an increased risk to have a child with fragile X syndrome. CGG repeats in this range may be thought of as stable, in that they usually pass from parent to child with the same number of repeats. For example, if the parent's gene has 30 CGG repeats, his or her child is also very likely to have a gene with 30 CGG repeats.

Intermediate

An individual with 45 to 54 repeats is not at substantial risk for passing on fragile X syndrome to his or her child, but the number of repeats transmitted to the next generation may increase slightly.

Premutation

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

Full Mutation

An individual with more than 200 repeats is considered to have a full mutation. Full mutations cause the FMR1 gene to malfunction, shutting down its ability to produce a functional protein.

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 are not at increased risk to have a child with fragile X syndrome. Most intermediate alleles appear to be stable and do not expand significantly when passed on. However, in some cases repeats in the intermediate range may expand slightly when passed on to the next generation. For example, a parent with 45 CGG repeats could have a child with 50 CGG repeats. If the number of repeats continues to increase in subsequent generations, future generations (i.e., grandchildren or great-grandchildren) may be at risk for inheriting fragile X. However, expansion to a full mutation in one generation from a maternal allele with fewer than 56 repeats has not been reported. Older children may wish to 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 are NOT at increased risk for the physical symptoms that can affect premutation carriers such as FXTAS, FXPOI, and FXAND.

What Does it Mean to Have a Premutation or Full Mutation? What Is the Risk That His or Her Child Will Develop Fragile X Syndrome?

If a mother has a full mutation, 50% of her children will also inherit the full mutation and be at risk for symptoms of fragile X syndrome. Men 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?

If a woman is a premutation carrier, then she is at risk of having children with fragile X syndrome. Premutations inherited from the mother can be unstable and may expand to become full mutations in the child.

Premutations are typically stable when passed from father to daughter. While there can be a change in CGG repeat number, premutations do not expand to full mutations when passed from father to daughter. Therefore, men 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 father to daughter. However, there can be a change in the number of CGG repeats between father and daughter. These daughters 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. Fathers generally pass a Y chromosome to their sons instead of an X, so fragile X premutations cannot be passed from father to son.

If the mother has a premutation on one of her X chromosomes, there is a 50% chance in each pregnancy that her 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 mother has a gene with a premutation that gets passed to her children, there are two possibilities:

1. The premutation does not expand beyond 200 repeats and remains as 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 woman has, the more unstable the gene is and the more likely it will expand to a full mutation in her children. The smallest premutation observed to expand to a full mutation in a single generation is 56 repeats.

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

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

Nolin SL, Glicksman A, Ersalesi N, Dobkin C, Brown WT, Cao R, et al. (2015). Fragile X full mutation expansions are inhibited by one or more AGG interruptions in premutation carriers. Genet. Med. 17 358–364. PMID: 25210937

Nolin SL, Glicksman A, Ding X, Ersalesi N, Brown WT, Sherman SL, Dobkin C. (2011). Fragile X analysis of 1112 prenatal samples from 1991 to 2010. Prenatal Diagnosis, 31(10):925-31. PMID: 21717484.

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 also 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 experience heart murmurs from a condition called mitral valve prolapse, 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.