Fragile X Program Frequently Asked Questions (FAQ)

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Background Information on FXS

1. Did I do anything to cause fragile X syndrome?
No. There is nothing you did before or during the pregnancy or after your child was born to cause fragile X syndrome. Fragile X syndrome is genetic which means it is caused by a change in a gene, in this case, the FMR1 gene. The change causes the gene not to work the way it should, leading to the problems seen in fragile X syndrome.

Because fragile X syndrome is genetic, it can be passed on and you are at risk for having another child with fragile X syndrome. It is important to know that you have no control over whether this change gets passed on to your child or not. In addition, other family members may also be at risk of having children with fragile X syndrome, so it is important to inform them of your child's diagnosis.

2. What does cause fragile X syndrome?
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 not to work properly. Everyone has 6-10 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) in the FMR1 gene is complex and occurs over many generations.

The FMR1 gene contains a section of repetitive DNA that in most of the population is only 10-40 repeats long. In those with fragile X syndrome, this repeated region has expanded to over 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 fragile X syndrome.

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 fragile X syndrome. Because females have two "X" chromosomes and 2 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, however, an individual with fragile X syndrome can have what is called mosaicism. There are two kinds of mosaicism in fragile X syndrome: 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.

3. What is methylation?
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 fragile X syndrome, 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 fragile X syndrome.

When someone with fragile X syndrome 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.

4. I heard only boys have fragile X syndrome. Why does my daughter have it also?
Girls can also have fragile X syndrome 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 fragile X syndrome. However, because some protein is being made, girls with fragile X syndrome are generally less affected than boys.

5. Is there a cure?
At this time, there is no cure for fragile X syndrome. Treatment for fragile X syndrome 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.

Family Members and Family Planning

6. Could my brothers and sisters have children with fragile X syndrome?
For moms, yes, your siblings and also your cousins are at risk for having children with fragile X syndrome. For dads, it is possible but unlikely. Why is this the case? To begin with, the repetitive region in the FMR1 gene expands through generations. There is an intermediate expansion, called the fragile X premutation, that is about 60-200 repeats in length. Individuals with a repeat length of this size are called premutation carriers and do not have symptoms associated with fragile X syndrome. However, the premutation is unstable and can expand to the full mutation in future generations. For reasons that are not well understood, expansion typically only occurs when the premutation is inherited from the mother.

When a couple has a child with fragile X syndrome, we know that the mother is a premutation carrier as the premutation typically only expands to the full mutation when inherited from the mother. Because mom inherited the premutation from one of her parents, her siblings and cousins are also at risk for being premutation carriers and having children with fragile X syndrome. Testing mom's parents to determine who she inherited the premutation from can tell us which side of her family is at risk for having children with fragile X syndrome.

With dads, it's a little trickier. Dads can have either the normal repeat length (10-40 repeats) or be premutation carriers themselves. The only way to determine this is through DNA testing. In general, testing is not performed unless there is a history of fragile X in his family. If testing is performed and dad is found to be a premutation carrier, his siblings and cousins are at risk for having children with fragile X syndrome.

7. If I am a premutation carrier, am I at risk for anything?
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 6% of females in the general population. With female fragile X premutation carriers, this rate increases to about 20%. Even when occurring after age 40, the age of onset for menopause on average can occur 6-8 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.

8. I want more children. Is there any way to tell whether I will have another child with fragile X syndrome?
By having a child with fragile X syndrome, you are at an increased risk of having a 2nd child with the condition. However, prenatal diagnosis is available. Either chorionic villus sampling (CVS) at 10-12 weeks gestation or amniocentesis at 14-18 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 approximately 4 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.

Potential Medical Problems

9. My child has/had feeding problems. Is this going to be a lifelong problem?
Usually, feeding problems and vomiting improve with age. If feeding problems are severe, a study called an esophageal pH probe study may be done to look for reflux. A barium swallow study may be performed to assess reflux treatment. Treatment for reflux generally involves thickening feedings and placing your child in an upright position after meals. Medication may also be needed.

10. I've heard that children and adults with fragile X syndrome may have significant behavior issues. What can be done to manage behaviors?
It's true that many individuals with fragile X syndrome 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 with fragile X syndrome. 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.

11. My child suffers from seizures. Is this common in fragile X syndrome?
Seizures occur in approximately 20% of individuals with fragile X syndrome and usually present early in childhood. The types of seizures generally seen in individuals with fragile X syndrome 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.

12. My child has been referred to an ophthalmologist, but he doesn't seem to have any vision problems.
In about 25-55% of individuals with fragile X syndrome 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.

13. I finally got my daughter potty trained, but she is still wetting herself at night. She gets upset when she wakes up. What can I do?
This along with delays in potty training are frequent problems in children with fragile X syndrome. 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.

14. I read that people with fragile X syndrome have connective tissue problems. What does this mean?
Connective tissue connects and supports other tissues and includes cartilage, blood, and bone. We're not entirely sure why individuals with fragile X syndrome have connective tissue problems. Many of these problems are minor, such as loose, flexible (or hyperextensible) joints. Flat feet are also common in children with fragile X syndrome. 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.

15. My son with fragile X syndrome is 12 years old. Some of the boys his age at school are starting to go through puberty. Will he go through puberty normally?
Your son should go through puberty normally. One thing to be aware of is that in 80-90% of males with fragile X syndrome 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.

16. My daughter appears to be starting puberty. What should I expect?
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 fragile X syndrome 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. Girls who present with features of precocious puberty should see an endocrinologist who may use hormone treatment to stop the progression.

17. Will my child be able to have children?
Yes. Both males and females with fragile X syndrome are fertile. Girls with fragile X syndrome are at risk for having children who also have fragile X syndrome. Boys with fragile X syndrome are premutation carriers, even though they themselves have the full mutation. Therefore, all of their daughters will be premutation carriers.

18. Our oldest son was recently diagnosed with fragile X syndrome. At the time, the doctor said something could be wrong with his heart. Is this something serious?
About 50% of adults with fragile X syndrome, including females, 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 fragile X syndrome have high blood pressure. This can be treated using blood pressure medications.

19. I'm only 38 years old and I'm already starting menopause. My gynecologist says it may be because I'm a fragile X premutation carrier. Is she right?
It is true that being a premutation carrier puts you at higher risk for premature menopause. Approximately 20% of females who are fragile X premutation carriers experience premature menopause (loss of menses before age 40), as opposed to 6% 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 6-8 years earlier than in women in the general population.

20. My father is starting to develop a tremor which the doctors think could be Parkinson's disease. I read somewhere that male fragile X premutation carriers are at risk for neurological problems. Is Parkinson's one of them?
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% of premutation carrier men will show signs of FXTAS by their 80s.

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