Fragile X- Associated Disorders (FXD)

Fragile X- Associated Disorders (FXD)

If you have just found out through prenatal testing that your baby has a Fragile X-Associated Disorder (FXD) or may have a FXD, or if you have just learned that you are a carrier of Fragile X and are looking for more information, the Genetic Support Foundation is a good starting point.

There are other important resources out there, including your doctor and genetic counselor. We have also compiled a list of resources below that can provide you with additional information and support.

After reviewing the information below, if you have a question that you are having difficulty finding an answer for, please feel free to contact us

 

Overview of Fragile X-Associated Disorders

There are 3 distinct conditions that are caused by changes or mutations in this gene including, Fragile X syndrome (FXS), Fragile X-associated primary ovarian insufficiency (FXPOI) and  Fragile X-associated tremor/ataxia syndrome (FXTAS).  FXDs are X-linked conditions meaning that the gene or instruction involved is found on the X chromosome.  Since this gene (called fragile X mental retardation 1 or FMR1) is found on the X chromosome (one of the sex chromosomes) and men have one X and women have two X chromosomes, these conditions affect males and females differently, with males (boys) usually having more symptoms than females (girls).  There is nothing that mom or dad can do to cause or prevent FXDs.



Types of Fragile X-Associated Disorders

Fragile X Syndrome

FXS is the most common inherited cause of intellectual disabilities and occurs in both genders, however, girls generally have less severe symptoms. Individuals with FXS may also have characteristic facial features, developmental and language delays, learning impairment, and behavioral and mental health issues.

Individuals with FXS have a form of the Fragile X gene called a “full mutation.”

Fragile X-associated primary ovarian insufficiency (FXPOI)

FXPOI is associated with infertility, early menopause and other ovarian problems in women of reproductive age who are Fragile X carriers (one of their X chromosomes has a change in the Fragile X gene and the other one doesn’t). Carriers have a form of the Fragile X gene called a “premutation.”

Fragile X-associated tremor/ataxia syndrome (FXTAS)

FXTAS is an adult onset (over age 50) neurological condition that can cause balance and memory problems, tremors and other neurological and psychiatric symptoms in Fragile X carriers. It is more common in males than females. FXTAS is also caused by a Fragile X “premutation”.



How does someone get Fragile X?

The genetic aspects of Fragile X-associated disorders can be very confusing.  This video may help you get some basic understanding:

Fragile X-associated disorders are X-linked conditions, meaning the gene involved is found on the X chromosome.  FXDs are caused by changes or mutations in the fragile X mental retardation 1 gene (FMR1).  As explained in genetics 101, the basis of a gene is the underlying structure called DNA, which is made of four chemical bases or letters, adenine (A), guanine (G), cytosine (C), and thymine (T).  Part of the FMR1 gene has a stretch of DNA with CGG letters repeated over and over again, which is normal for this gene (e.g. CGGCGGCGGCGG). Six-40 CGG repeats is normal, with 30 being the average number of repeats. When there are more than 40 CGG repeats, it may cause the gene to not work as usual and lead to FXDs. FXDs can also be caused by a different type of mutation besides the CGG repeat, but this is rare.

Individuals who do not carry or have Fragile X-associated disorders typically have less than 40 CGG repeats in their FMR1 gene.

If a person has approximately 55-200 repeats, they are considered to have a “premutation”. The vast majority of individuals with the premutation do not show fragile X syndrome–related symptoms or features; however, there have been some rare reports of individuals with premutations who have with learning and behavioral disabilities1. Individuals with a premutation are at increased risk for Fragile X-associated primary ovarian insufficiency (FXPOI) and Fragile X-associated tremor/ataxia syndrome (FXTAS). Women who have a premutation also have an increased chance of having a baby with a full mutation, which causes fragile X syndrome. The reason for this is that this gene can change when passed on to the next generation and, especially in mom, is prone to “expanding” or adding more CGG repeats. The chances of a premutation expanding to a full mutation (causing Fragile X syndrome) are based on repeat length and estimates can be discussed with your doctor or genetic counselor.

Individuals with CGG repeats greater than 200 have fragile X syndrome. Again, boys typically have more symptoms than girls due to the fact that the gene involved is on the X-chromosome and boys have 1 X-chromosome and girls have 2 X chromosome

The number of CGG repeats, also called the “size of the mutation,” affects the type of symptoms and how serious the symptoms of Fragile X syndrome will be.

Status of IndividualNumber of CGG repeats
Unaffected/Not a carrier
Less than 45
Intermediate/Gray zone 45-54
Premutation (at risk for FXPOI and FXAS and mom at risk of having a child with full mutation)55-200
Full Mutation (Fragile X syndrome in males and some females)More than 200

 

 

 



If I am a carrier of a Fragile X mutation, what are the chances that my child will inherit Fragile X Syndrome?

Fragile X Associated Disorders follow the X-linked pattern of inheritance.  If you are a female and carry the fragile X mutation (full or premutation), you have a 50% chance of passing it on to each of your children.  Again, when mom passes on a full or premutation, it may expand and the baby may end up having more CGG repeats than mom.  If this happens with a premutation, it can expand to a mutation that is full which causes fragile X syndrome.  If dad is a carrier of a FXD premutation, it does not have a risk of expanding when passed on to his children, but his daughters would have a risk of passing on an expanded mutation to their children.  When dad is a carrier of FXD, he will pass on this change or mutation to ALL of his daughters and NONE of his sons. For more detailed information on X-linked inheritance click here.



I have been offered carrier testing for Fragile X. Can you tell me more about this option?

Fragile X syndrome occurs in approximately 1 in 4000 males (boys). Approximately 1 out of every 260 women is a carrier of Fragile X.

 

Many providers offer carrier screening for various genetic conditions to women who are pregnant or considering pregnancy. Unlike some of the other carrier screening options such as cystic fibrosis, Fragile X is a carrier screening option that only some providers offer to ALL of their women who are pregnant/considering pregnancy and some only offer if there is a family history that makes them suspicious of Fragile X. The American Congress of Obstetricians and Gynecologists and the American College of Genetics and Genomics do NOT advocate carrier screening for all patients. These professional societies recommend testing only in cases where the family history indicates or upon patient request.

Since the genetic aspects of Fragile X-Associated disorders (FXDs) are fairly complex and confusing, it is very important that you talk to your provider or genetic counselor prior to having carrier screening for FXDs. It is also important to keep in mind that there is a chance that you could be found to be a carrier and if so, you may be at risk for developing symptoms of Fragile X- Associated Primary Ovarian Insufficiency (FXPOI) or Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS).

For more information on prenatal carrier testing, click HERE.




Resources

Fragile X- Associated Disorders handbook from the National Fragile X Foundation  

National Institutes of Health/National Institute of Child Health & Human Development information on Fragile X-associated disorders

References

1. Tassone F, Hagerman RJ, Taylor AK, et al. Clinical involvement and protein expression in individuals with the FMR1 premutation. Am J Med Genet 2000;91:144–152.


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