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Our bodies are made up of about 60 trillion cells. Each one of those cells manufactures proteins. The kinds of proteins any given cell makes determine its particular characteristics, which in turn create the characteristics of the entire body.
The instructions for making these proteins are stored in chemicals or molecules called DNA, which is organized into chromosomes. Chromosomes are found in the center, or nucleus, of all of our cells, including the eggs and sperm.
Chromosomes are passed down from generation to generation through the egg and sperm. Typically, we all have 46 chromosomes in our cells, two of which are sex chromosomes. In females, these are two Xs; in males they are an X and a Y.
Genes are sections of DNA that are passed from generation to generation and perform one function. If we think of DNA as letters in the alphabet, the genes are words and the chromosome is a full sentence. All 46 chromosomes then make up the whole book.
There are many genes on each chromosome; we all have tens of thousands of genes that instruct our bodies on how to develop.
Genes are given names to identify them and the gene responsible for fragile X syndrome is called FMR1. The FMR1 Gene is on the X chromosome.
The FMR1 gene appears in four forms that are defined by the number of repeats of a pattern of DNA called CGG repeats.
Individuals with less than 45 CGG repeats have a normal FMR1 gene. Those with 45-54 CGG repeats have what is called an “intermediate” or “grey zone allele,” which does not cause any of the known fragile X associated disorders.
Individuals with 55-200 CGG repeats have a “premutation,” which means they carry an unstable mutation of the gene that can expand in future generations and thus cause fragile X syndrome in their children or grandchildren. Individuals with a premutation can also develop FXTAS or FXPOI themselves.
Individuals with over 200 CGG repeats have a full mutation of the FMR1 gene, which causes fragile X syndrome.
The full mutation causes the FMR1 gene to shut down or “methylate” in one region. Normally, the FMR1 gene produces an important protein called FMRP. When the gene is turned off, the individual does not make this protein. The lack of this specific protein is what causes fragile X syndrome.
Fragile X-associated Disorders are a group of conditions called trinucleotide repeat disorders. A common feature of these conditions is that the gene can change sizes over generations, becoming more unstable, and thus the conditions may occur more frequently or severely in subsequent generations. These conditions are often caused by a gene change that begins with a premutation and then expands to a full mutation in subsequent generations.
Approximately 1 in 250 females and 1 in 800 males carry the FMR1 premutation. They are thus “carriers” of the premutation.
Premutations are defined as having 55-200 CGG repeats and can occur in both males and females. When a father passes the premutation on to his daughters, it usually does not expand to a full mutation. A man never passes the fragile X gene to his sons, since he passes only his Y chromosome to them, which does not contain a fragile X gene.
A female with the FMR1 premutation will often pass on a larger version of the mutation to her children (more on this point below). She also has a 50 percent chance of passing on her normal X chromosome in each pregnancy, since usually only one of her X chromosomes has the FMR1 mutation.
The chance of the premutation expanding to a full mutation is related to the size of the mother’s premutation. The larger the mother’s CGG repeat number, the higher the chance that it will expand to a full mutation if it is passed on.
Typically, the premutation has no immediate and observable impact on a person’s appearance or health. However, some females with a premutation will experience fragile X-associated primary ovarian insufficiency (FXPOI), which causes infertility, irregular or missed menstrual cycles, and/or early menopause.
Additionally, some older adults with a premutation may develop a neurological condition called FXTAS, (fragile X-associated tremor/ataxia syndrome), an adult onset neurodegenerative disorder.
FXTAS and FXPOI are part of the family of conditions called Fragile X-associated Disorders.
A full mutation is defined as having over 200 CGG repeats and causes that indicate the presence of fragile X syndrome in males and some females. Most full mutation expansions have some degree of Methylation (the process which “turns off” the gene). Males with a full mutation will have Fragile X Syndrome, though with varying degrees of severity
About 65-70 percent of females with a full mutation exhibit some difficulties with cognitive, learning, behavioral, or social functioning, and may also have some of the physical features of FXS (such as large ears or a long face). The remaining 30-35 percent are at risk to develop mental health issues such as anxiety or depression, or they may have no observable effects of the full mutation.
Fragile X in an “X-linked” condition, which means that the gene is on the X chromosome.
Since a woman has two X chromosomes a woman with a premutation or full mutation has a 50% chance of passing on the X with the mutation in each pregnancy, and a 50% chance of passing on her normal X.
If she has a premutation, and it is passed on (to either males or females), it can remain a premutation or it can expand to a full mutation. If she has a full mutation and it is passed on (to either males or females), it will remain a full mutation.
Because males have only one X chromosome, fathers who carry the premutation will pass it on to all their daughters and none of their sons (they pass their Y chromosome on to their sons). There have been no reports of premutations that are passed from a father to his daughter expanding to a full mutation. This appears to only occur when passed from a mother to her children.
In many X-linked conditions only males who inherit the abnormal gene are affected. Fragile X syndrome is one of the X-linked conditions that can also affect females.
Additionally, in other X-linked conditions all males who carry the abnormal form of the gene are affected. In fragile X syndrome, unaffected males can carry the gene in the premutation form while themselves having no symptoms of the condition.