What is Fragile X syndrome?
FXS is the most common form of inherited intellectual disability, with impairments varying broadly across mild learning disabilities to autism. In addition, there may be behavioural and emotional concerns such as hyperactivity, anxiety and mood disorders.
Diagnosis in children often leads to identification of family members with premutations and associated conditions.
Causes
Fragile X occurs when a mutation in the FMR1 gene stops the body from making FMRP proteins.
FMRP
The Fragile X Mental Retardation Protein (FMRP) is found in all cells. However, it is most plentiful in the nerve cells - particularly the part that “talks” to other nerve cells - the dendrites. FMRP in the brain regulates levels of another protein called MGluR5, which tells neurons to grow dendrites and attach to other neurons to pass information along.
When the dendrites are the right size and shape, FMRP makes MGluR5 tell the neurons to stop. When FMRP is missing, the dendrites grow uncontrolled and allow signals to get lost on their way from one neuron to another. This makes it hard to learn and respond to stimuli in the same way as people whose neurons can communicate easily.
A person with nearly normal levels of FMRP usually has mild FXS symptoms, while a person with very little or no normal FMRP has more severe symptoms.
FMR-1 Gene
The FMRI gene has a job to do - creating FMRP.
The information for making FMRP involves two parts: the introduction or promoter and the instructions for the protein itself.
The promoter region of the FMR-1 gene contains repeats of a specific sequence (cytosine-guanine-guanine or CGG) that - when normal - controls the activity level of building FMRP.
The FMR-1 gene is found on the X chromosome, which means that girls (with two X chromosomes) have two copies of the FMR-1 gene, and boys (who have one X chromosome) have only one. Girls may be able to compensate for genetic errors if their second copy of FMR-1 is normal, meaning that their fragile X symptoms are generally less severe.
Mutations
A mutation is any change in a gene.
In the FMR-1 gene, the area of the promoter that is rich in CGG repeats may have a mutation which creates an abnormal expansion of the DNA located there.
In a normal FMR1 gene, the CGG pattern appears between 10 - 40 times in a row.
In a full mutation of an FMR-1 gene, the CGG pattern can appear more than 200 times causing methylation. This methylation “turns off” the FMR-1 gene so that no FMRP is made.
Premutations
Sometimes, the CGG pattern repeats itself more times than normal, but not enough for the full mutation, and not enough to stop the gene from making some FMRP.
When this happens, the individual is said to be a “premutation carrier.” The premutation gene can grow into the full mutation in the carrier’s children, grandchildren or descendants - especially when the carrier is female.
Being Mosaic
Not every cell in the body is the same. In Fragile X, this means that some cells may have 200 or more CGG repeats in the FMR-1 gene, while other premutation cells may have fewer than 200 repeats.
This is called being "mosaic," meaning that the mutation is in some of the cells, but not all of them (or not to the same degree). These premutation cells may be able to make some FMRP resulting in milder symptoms of Fragile X for mosaic individuals.
Fragile X Testing
Fragile X Testing should be considered for:
- any individual with otherwise unexplained developmental delays, mental impairments or autis
- older males experiencing tremors/ ataxia
- younger females experiencing infertility or early menopause
Related Conditions
Premutations
A premutation carrier is an individual, male or female, who has between 55-200 CGG repeats in the Fragile X (FMR1) gene. The full mutation is defined as over 200 CGG repeats. People who have other fragile X-related conditions (not FXS) have changes in their FMR1 gene but usually still make some FMRP.
Carriers of a premutation are at risk to develop the following FXS related conditions:
FXPOI is a condition in which the ovaries are not functioning at full capacity in an FMR1 female premutation carrier. Common symptoms include absent or irregular periods, symptoms of menopause such as hot flashes, etc, early menopause and infertility. Women who have a premutation in their FMR1 gene are at higher risk for having children who have FXS.
FXTAS is an “adult onset” neurodegenerative disorder, occurring more commonly in males than females. It is a disorder that can cause tremors and problems with walking, balance (also called ataxia), memory, mood disorders and eventual congnitive decline among older adults.
Some people with a premutation may have noticeable symptoms, and others may not.
Symptoms and Therapy
People with Fragile X do not all have the same symptoms, but they do have some things in common.
Intelligence and Learning:
Problems can range from the mild, such as learning disorders, to the severe, such as an intellectual or developmental disability. FXS may affect the ability to think, reason, and learn.
Because many people with Fragile X also have attention disorders, hyperactivity, anxiety, and language-processing problems, a person with Fragile X may have more capabilities than his or her IQ score suggests.
Physical:
As children with Fragile X begin to develop, they may grow into certain features that are typical of the syndrome including:
- narrow face
- large head
- large ears
- flexible joints
- flat feet
- prominent forehead
These physical signs become more obvious with age.
Behavioral, Social, and Emotional:
- afraid or anxious in new situations
- trouble making eye contact with other people
- trouble paying attention or be aggressive (boys especially),
- be shy around new people (girls especially)
- attention disorders
- problems with hyperactivity
Speech and language:
Most boys with FXS have problems with speech and language including:
- trouble speaking clearly
- stuttering, or leaving out parts of words
- problems understanding social cues, tone of voice, or specific types of body language.
Girls do not usually have severe problems with speech or language.
Most children with FXS begin talking later, however a few might stay nonverbal throughout their lives.
Sensory:
Many children with FXS can be bothered by:
- bright light
- loud noises
- certain ways clothing feels on their body
These sensory issues might cause them to act out. Symptoms are often milder in females than in males.
