What Causes FXTAS?

FXTAS is a late onset (over age 50) neurological condition. It occurs in individuals who have a specific change in the “Fragile X” gene, which is on the X chromosome. This gene is called the FMR1 gene.  The specific change is called a Fragile X or FMR1 premutation. Individuals who have an FMR1 premutation are Fragile X “carriers,” meaning they may not experience any of the symptoms of Fragile X syndrome but “carry” the potential to pass the premutation on to their offspring (more on this below). Not all carriers will develop FXTAS, but all individuals with FXTAS have an FMR1 premutation. Researchers are investigating what other factors might contribute to FXTAS in FMR1 premutation carriers.

The FMR1 gene can undergo changes that cause FXTAS and other Fragile X-associated Disorders (conditions caused by genetic changes on the "X" chromosome, which often affect males more than females). These changes affect a pattern of DNA called CGG repeats. Typically, the FMR1 gene has up to 54 of these CGG repeats. A premutation in the FMR1 gene results in 55-200 CGG repeats, and a full mutation results in more than 200 CGG repeats. Individuals with a full mutation are not at risk for FXTAS, but often have fragile X syndrome.

The following section describes this gene change in detail.

Cells, Chromosomes, Genes, and DNA

The Fragile X gene can be passed on in families by and to people of either gender who have no obvious signs of any of the Fragile X-associated Disorders. To understand how this happens, we will review basic hereditary information.

Every person’s body is made up of many millions of tiny structures called cells. Within each cell is the genetic information we inherit from our parents. The genetic information is contained in “genes,” and the genes are found lined up on structures called chromosomes. The genes are made from long strands of DNA (deoxyribonucleic acid). DNA is often called the “genetic code.” The DNA molecules are symbolized by letters C, G, T and A.

Each gene is made from a specific sequence of DNA molecules.

Chromosomes and genes are like strings of plastic beads. The whole strand of beads represents the chromosome, each bead might represent a gene, and the plastic from which the beads are made would be the DNA molecules.

Genes, which usually occur in pairs, are the instructions that determine our growth, development, and many other characteristics. For example, certain genes determine eye and hair color, while others determine blood type.

Genes are often called the “units of heredity” because the information they contain is passed from one generation to the next. We all inherit one gene of each pair from our mother and the other gene in a pair from our father. In this way, our bodies work with a combination of instructions inherited from both our parents. Parents have no control over which genes they pass on to their children.

A given gene can occur in many alternative forms called alleles. For example, the gene for eye color has an allele for blue eyes, an allele for brown eyes, green eyes, etc. This is similar to the various types of apples that occur: each type, such as Delicious, Pippin or Fuji, might be called an allele in the apple family. This concept of each allele as one form of a gene is important in understanding the genetics of FXTAS, because we all have different size Fragile X alleles.

Thousands of genes are packed together to form chromosomes. Most people have 46 chromosomes (23 pairs). There are 44 “non-sex” chromosomes, numbered in pairs from 1-22, that are the same in males and females. We call the 23rd pair the “sex” chromosomes because they determine a person’s sex (male or female). In females, both sex chromosomes are similar and are called “X” chromosomes. Males have one “X” and one “Y” chromosome. The Fragile X gene is on the “X” chromosome. The following diagrams illustrate chromosomes from a female and a male.

The Fragile X Gene—FMR1

Fragile X got its name because under a microscope, a portion of the X chromosome from an individual with fragile X syndrome appears “broken” or “fragile.” As researchers studied this area of the X chromosome in individuals with fragile X syndrome, they found it contained more than the normal amounts of DNA. Specifically, it turned out to have a large number of repetitions of DNA called a CGG repeat. This expansion of DNA is what gives the Fragile X chromosome its unique appearance.

In May 1991, researchers identified the gene responsible for Fragile X. This gene, which is on the X chromosome, is called FMR1, which stands for “Fragile X Mental Retardation 1.” (Note that most of the disability community no longer uses the term “mental retardation,” instead referring to it as “intellectual disability,” but that is what the gene was originally named in the scientific literature.) Every person has at least one copy of the FMR1 gene. Women have two X chromosomes, so they have two copies of the gene. Men have only one X chromosome, so they have just one copy of FMR1. The gene varies in length from one person to another. The variation occurs because there is a range of CGG repeat numbers from person to person. What distinguishes people who have a fragile X mutation from those who don’t is the number of times this CGG pattern is repeated. 

Most of our genes either make a protein or regulate proteins made by other genes. The FMR1 gene is responsible for producing a protein that is important in brain development. This protein is called FMRP (Fragile X Mental Retardation Protein). Individuals with fragile X syndrome have a deficiency of this protein.

Definition of Carriers

Unlike other X-linked genetic disorders, both males and females can be carriers of a Fragile X mutation.  A carrier is an individual who “carries” an altered form of a gene that can lead to having a child or offspring in future generations with a genetic disorder. We are all carriers of three to five gene mutations, many of which are "silent." It is only through genetic testing that we know which ones we carry. Some genes are on the non-sex chromosomes, which are the same in males and females, while some are on the sex chromosomes, namely the X or Y chromosome. 

The gene for Fragile X (the FMR1 gene) is on the X chromosome, which is why fragile X syndrome is called an X-linked genetic disorder. Often in X-linked disorders, only females are carriers and only males are affected. However, in Fragile X both males and females can be carriers (and both males and females can be affected with fragile X syndrome). This occurs because this gene can go through change as it is passed down in a family. These changes lead to what is called a premutation and a full mutation. The difference between a premutation and a full mutation is defined by the number of CGG repeats (repeats of a DNA pattern).

A premutation carrier is defined as an individual, male or female, who has between 55-200 CGG repeats and has a normal methylation pattern. (Methylation is a process that shuts down the gene in individuals with Fragile X syndrome.) Typically methylation only occurs in individuals with a full (over 200 CGG repeats) mutation. In rare cases, individuals with fewer than 200 repeats (usually over 150) can exhibit some methylation on lab testing. The full mutation is defined as having over 200 CGG repeats with some degree of methylation.

A female can be a “carrier” of a premutation or a full mutation.  In other words a female can have either a premutation or full mutation and not have any known cognitive, behavioral or intellectual affects of it (though many females with a full mutation will have some affects of it).Women with either one are at risk to have a child, whether male or female, with Fragile X syndrome. The magnitude of this risk is related to their number of CGG repeats.

A male can be a “carrier” of a premutation, however, the vast majority of males with a full mutation have fragile X syndrome.  A male premutation carrier will pass this premutation (as a premutation, not a full mutation) on to all of his daughters and none of his sons, and therefore, is at negligible risk to have a child with Fragile X syndrome. However, there is a risk for Fragile X syndrome in his grandchildren through his daughters.

The specific number of CGG repeats and methylation status of each person’s gene is identified as the individual's "allele." An allele is defined as the various forms a given gene can take (like the various types of potatoes that exist).  For example, individuals with,  lets say,  88 CGG repeats will often be told they have an “88”  or “premutation size” allele.

Traditionally, a carrier of a genetic mutation was defined as an individual who inherited an altered form of a gene but suffered no effects or symptoms of that gene change or mutation. However, in Fragile X  (and some other genetic conditions) this definition does not exactly fit, as carriers of a premutation are at risk to develop Fragile X-associated tremor ataxia syndrome (FXTAS), and Fragile X-related primary ovarian insufficiency (FXPOI) (a cause of early menopause or infertility).