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 way it is inherited. It is the most common form of inherited 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, defined as an IQ below 70. About one-third of women with fragile X syndrome have a mild intellectual disability.

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 percent of males and 5 percent 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. While they are intellectually normal, they are thought to be more vulnerable to anxiety and depression.

The main risks for carriers of a premutation are fragile X-associated tremor/ataxia syndrome (FXTAS) and premature ovarian failure (POF).

Approximately 40 percent of men over the age of 50 with a fragile X premutation will develop FXTAS. (The exact percentage of women premutation carriers affected by FXTAS is unknown but is thought to be lower.) 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.

About 20 percent of women with a premutation experience premature ovarian failure (POF), in which their menstrual periods stop by age 40. Only 5 to 10 percent of women with POF will be able to have children. One study found that 21 percent of women with a premutation experienced POF, compared to 1 percent in the general population. In general, women with premutations larger than 80 repeats were at lower risk for POF when compared to women with smaller premutations. Women with full mutations are not at increased risk for POF.

How Is Fragile X Syndrome Inherited?

Fragile X syndrome is inherited in a complex way that is different from 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," in which a particular section of DNA is repeated a certain number of times in a row. By counting the number of CGG repeats for each parent, one can determine the likelihood that his or her child will have fragile X syndrome.

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

Category FMR1 CGG repeat size
Normal 5 to 44 repeats
Intermediate 45 to 54 repeats
Premutation 55 to 200 repeats
Full mutation More than 200 repeats

Normal

An FMR1 gene with 5 to 44 CGG repeats is considered normal. An individual with this number of FMR1 CGG repeats is very unlikely to pass fragile X syndrome on to his or her children. These genes 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 15 CGG repeats, his or her child is also very likely to have a gene with 15 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. 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.

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 and POF. 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.

If a Parent Has a Mutation or Premutation, 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 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 are unstable and may expand to become full mutations in the child.

Premutations pass more or less identically from father to child; the CGG repeats do not expand in number. Therefore, men with premutations are not at risk of having children with fragile X syndrome.

Will the Child Inherit the Premutation?

If the father has a premutation on his X chromosome, all of his daughters will have that same premutation. 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 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 that premutation and a 50% chance that they will not. Only children who inherit the premutation would be at risk for fragile X syndrome.

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 FXTAS (male) or POF (female) as adults.
  2. The premutation expands into a full mutation, causing fragile X syndrome in males and risk for fragile X syndrome in females.

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.

Number of Maternal Premutation CGG Repeats Percentage (Total Women) Which Expanded to Full Mutations
55-59 <1% (0/66)
60-69 2% (1/63)
70-79 11% (2/18)
80-89 33% (4/12)
90-99 80% (89/111)
>100 100% (2/2)

Adapted from Nolin et al. (2003) and Nolin et al. (2011). These percentages typically exclude families with a family history of fragile X syndrome.

Nolin SL, Brown WT, Glicksman A, Houck GE Jr, Gargano AD, Sullivan A, et al. (2003). Expansion of the fragile X CGG repeat in females with premutation or intermediate alleles. American Journal of Human Genetics, 72(2):454-64. PMID: 12529854.

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.