Fragile X Program

Explaining how fragile X happens is not very easy simply because of the way it is inherited. To start, let's talk broadly about genes and chromosomes. Genes are the instructions that tell our bodies how to work and are made up of DNA. We inherit two copies of all of our genes: one copy from our mother and one copy from our father. The DNA is packed into larger structures called chromosomes, and each chromosome contains hundreds to thousands of genes. Most people have 23 pairs of chromosomes, for a total of 46 chromosomes. The first 22 pairs are the same in males and females and are called the autosomes. The 23rd pair, called the sex chromosomes, are different in males and females. Females have two "X" chromosomes, and males have one "X" and one "Y" chromosome.

Fragile X is caused by a change in the FMR1 gene on the X chromosome that causes it to not work properly. Everyone has six to 10 genes that don't work the way they should, but this generally does not cause a problem. However, the change in the FMR1 gene does make a difference. This change (also called a mutation) is complex and occurs over many generations.

The FMR1 gene contains a section of repetitive DNA that in most of the population is only 10 to 40 repeats long. In those with FXS, this repeated region has expanded to more than 200 repeats. When a repeat length is greater than 200, it is referred to as a full mutation or expansion. At this size, the FMR1 gene cannot function and the FMR1 protein cannot be produced. It is the inability of cells to make this protein that is responsible for FXS.

In general, every person gets two copies of every gene. This is a little bit different for the FMR1 gene because it is on the "X" chromosome. Because males have only one "X" chromosome, they have only one copy of the FMR1 gene. If they have a full mutation, their one copy of the FMR1 gene is not working, and one sees the signs of FXS. Because females have two "X" chromosomes and two copies of the FMR1 gene, if a girl inherits a full mutation, the other copy of the gene is usually working, so girls with a full mutation are still able to make FMR1 protein. This is why girls usually have fewer signs of fragile X than boys do.

In general, we expect to see the full mutation in every cell of a person with fragile X syndrome. Sometimes an individual with FXS can have what is called mosaicism. There are two kinds of mosaicism in FXS: repeat-size mosaicism and methylation mosaicism. In repeat-size mosaicism, an individual has some cells that have a full mutation and some cells that have a premutation. In methylation mosaicism, all the cells have a full mutation, but the methylation pattern may not be the same in all cells. Some research studies have shown that individuals with repeat size or methylation mosaicism may be less affected than those who do not have mosaicism.

Methylation is a process in which a chemical group, called a methyl group, gets added to the DNA. When enough methyl groups are added to the DNA, the gene gets turned off. When methyl groups are removed, the gene gets turned on. This is a normal process, and many of our genes are controlled by methylation. However, in FXS, the methylation of the FMR1 gene turns the gene off when it should be turned on. When FMR1 is turned off, its protein is not made, and you see the features of FXS.

When someone with FXS has methylation mosaicism, not all cells will have the FMR1 gene turned off by methylation. Some cells may have it partially turned off, and some cells may have the FMR1 gene turned on.

Girls can also have FXS even though they have two "X" chromosomes. The reason is that they have a full expansion on one chromosome and a normal repeat section (in most cases) on the other chromosome. The copy with the full expansion is not making any FMR1 protein, while the other copy (the normal repeat section) is making protein. Although some protein is being made, it may not be enough, so we can see characteristics of FXS. However, because some protein is being made, girls with FXS are generally less affected than boys.

At this time, there is no cure for FXS. Treatment is provided through therapies such as special education, speech and language therapy, and occupational therapy. Medications may be helpful in managing hyperactivity, short attention span, and other behavioral or emotional problems. In order to determine the best course of action for your child, a comprehensive evaluation is recommended.

Unlike many genetic disorders, being a carrier does put you at an increased risk for certain medical problems.

Females who are premutation carriers are at risk for premature menopause, or loss of menses before the age of 40. Premature menopause occurs at a rate of approximately six percent of females in the general population. With female fragile X premutation carriers, this rate increases to about 20 percent. Even when occurring after age 40, the age of onset for menopause on average can occur six to eight years earlier in women who are fragile X premutation carriers. This can be a serious concern if you are in your 30s and are planning to have another child. If you are currently trying to have a child and are having infertility problems, premature menopause could be a cause. In addition, some of the options for reducing your risk of having another child with fragile X syndrome, such as IVF with PGD, may be a less viable option due to premature menopause. If you are a premutation carrier, you should discuss this risk with your primary care physician and OB/GYN, especially if you are planning on having more children.

Males who are premutation carriers are at risk for a condition known as fragile X tremor ataxia syndrome (FXTAS). FXTAS is characterized by progressively severe intention tremor and difficulty with walking and balance. It can also be associated with dementia characterized by memory loss, trouble formulating plans, difficulty with focusing attention, and difficulty knowing what's appropriate or not. Other neurological findings may also be present. FXTAS appears to affect primarily older premutation carrier males with signs appearing in their 50s to 60s. Recent research has also shown that some premutation carrier females may also develop FXTAS, but not as often as premutation carrier males.

By having a child with FXS, you are at an increased risk of having a second child with the condition. However, prenatal diagnosis is available. Either chorionic villus sampling (CVS) at 10 to 12 weeks gestation or amniocentesis at 14 to 18 weeks gestation can be performed. With CVS, there is a preliminary result available in the first trimester, although the confirmatory testing for a final result is often not available until the second trimester. In addition, certain results from CVS analysis can sometimes be difficult to interpret. For further details about why these issues can occur, talk to your genetic counselor. With amniocentesis, results are generally available about four weeks after the procedure is performed. Even with diagnosis of a full mutation in either a male or female, it is not possible to determine what difficulties he or she may have.

Other risk reducing options are available, including in vitro fertilization (IVF) with preimplantation genetic diagnosis (PGD), IVF with egg donor, and adoption. As with CVS, results from PGD can sometimes be difficult to interpret and may require confirmatory testing. The decision to follow through with one of these options is a very personal one, and what may be right for one couple is not right for another. There is no right answer. These options can be further discussed with your doctor or genetic counselor.

It's true that many individuals with FXS have behavior issues. Hyperactivity is common in childhood, but does tend to improve in adolescence and adulthood. Social anxiety is also common, and may be particularly severe in females. Anxiety may lead to outbursts of aggression, particularly in males. Another concern of parents is their child's obsessive and compulsive behavior. This may manifest itself in repetitive behavior.

Usually, medications can be used to treat these behaviors. This combined with other treatment modalities, including counseling and sensory integration therapy, can be very helpful for those who have significant behavior problems. In addition, treatments specific for behaviors can be helpful. For example, limiting excessive sensory stimulation whenever possible may prevent aggressive outbursts and social anxiety. Working with a psychologist can help children who have tantrums, oppositional behavior, or severe hyperactivity.

Seizures occur in approximately up to 15 percent of boys and six to eight percent of girls with FXS and usually present early in childhood. The types of seizures generally seen in individuals with FXS generally respond well to anti-seizure medication. The seizures tend to resolve by adolescence, but may continue into adulthood.

If you believe your child is having seizures, an appointment with a neurologist should be scheduled as soon as possible. The neurologist may perform an EEG to determine what kind of seizures your child is having and will discuss a treatment plan with you.

About 25 to 55 percent of individuals with FXS have eye problems, including strabismus (the inability to focus both eyes on an object because of muscle weakness in one eye), hyperopia (far-sightedness), and astigmatism. Corrective lenses are generally used to treat far-sightedness and astigmatism. Treatment for strabismus often involves patching, eye exercises, or lenses to strengthen the weak eye. If none of these work, surgery may be required.

Delays in potty training are frequent problems in children with FXS. Some behavioral tactics, such as decreasing fluids after dinner, going to the bathroom before bedtime, and waking your child to go to the bathroom when you go to bed, may help to decrease the frequency of bed-wetting. Your doctor may also be able to prescribe medications that help.

Connective tissue connects and supports other tissues and includes cartilage, blood, and bone. We're not entirely sure why individuals with FXS have connective tissue problems. Many of these problems are minor, such as loose, flexible (or hyperextensible) joints. Flat feet are also common. Joint hyperextensibility tends to improve with age. Most of the time, having loose, flexible joints does not cause a problem and requires no treatment. Occasionally, however, a joint may be dislocated and will require treatment.

Your son should go through puberty normally. One thing to be aware of is that 80 to 90 percent of males with FXS have what is called macroorchidism, or large testicles. This generally does not cause any complications and does not require any intervention. However, because males with fragile X may have connective tissue problems, having large testicles may predispose them to inguinal hernias. Inguinal hernias can occur during childhood, adolescence, and adulthood.

As with boys, girls seem to go through puberty normally. It is important to address your daughter's emotional status before and during her period as girls with FXS are prone to mood swings and anxiety, particularly during times of hormonal change (such as puberty and her period).

There have been a number of reports about girls having precocious puberty (starting puberty early). Girls who have features of precocious puberty should see an endocrinologist.

Yes. Both males and females with FXS are fertile. Girls are at risk for having children who also have FXS. Boys with FXS are premutation carriers, even though they themselves have the full mutation. Therefore, all of their daughters will be premutation carriers.

About 50 percent of adults with FXS, male or female, have something called mitral valve prolapse (MVP). This means that one of the heart valves, the mitral valve, is leaky. If MVP is severe or associated with mitral regurgitation (meaning the blood goes back to the chamber where it came from), prophylactic antibiotics for surgical or dental procedures may be recommended.

In addition to MVP, many adults with FXS have high blood pressure. This can be treated using blood pressure medications.

It is true that being a premutation carrier puts you at higher risk for premature menopause. About 20 percent of females who are fragile X premutation carriers experience premature menopause (loss of menses before age 40), as opposed to six percent in the general population. Interestingly enough, full mutation carriers (or girls with fragile X syndrome) are not at a higher risk for fragile X syndrome. Even when occurring after age 40, the age of onset for menopause in premutation carriers can occur six to eight years earlier than in women in the general population.

Older males who are fragile X premutation carriers are indeed at risk for a combination of neurological problems called fragile X-associated tremor/ataxia syndrome (FXTAS). FXTAS is characterized by progressively severe intention tremor and difficulty with walking and balance. It can also be associated with dementia characterized by memory loss, trouble formulating plans, difficulty with focusing attention, and difficulty knowing what's appropriate or not. Signs of FXTAS start appearing when male premutation carriers are in their 50s and 60s. About 75 percent of premutation carrier men will show signs of FXTAS by their 80s.