FMR1 Gene Disorders Research Program

two family members on a walk
 

Fragile X Syndrome is a genetic disorder that affects approximately 1 in 3,000 to 1 in 4,000 males and approximately 1 in 4,000 to 1 in 6,000 females. It is caused by a specific mutation on the FMR1 gene. People with Fragile X have a full mutation of the FMR1 gene. Some people have what is called a premutation, or less than a full mutation of the FMR1 gene.


What are Fragile X and FMR1 Gene Premutations?

Proteins are important for human development and the healthy function of our bodies. If the gene has a mutation, the instructions for building the protein will not make sense. It may be built incorrectly, or it may not get built at all. 

Fragile X is caused by extra ‘words’ in the genetic code of the FMR1 gene. On part of the gene, there is a repetition of a specific word. These repeated words are called CGG repeats because the 3-letter genetic code combination of CGG is repeated many times. In healthy people, the CGG word is repeated between 6 and 54 times. People with Fragile X have more than 200 CGG-repeats. These extra words prevent the messenger RNA from making the amino acids that are needed for building the FMR1 protein. These extra words also make it look like part of the X chromosome is going to break off, which is how Fragile X got its name. People who have between 55 and 200 repeats are called premutation carriers. They are able to produce more of the FMR1 protein than people with the ‘full’ mutation but less than people who don’t have the mutation.

The FMR1 gene is located on the X chromosome. The X chromosome is one of the two chromosomes that determine biological sex in humans; a biological female has two Xs and a biological male has one X and one Y. Each parent contributes one chromosome to the child. The female contributes one X and dad contributes either an X (child will be biologically female,) or a Y, in which case the offspring will be biologically male. 

So, if a biological female inherits the Fragile X mutation from one parent, she may inherit a healthy X chromosome from the other parent. This means that she will either be protected from developing symptoms, or her symptoms won’t be as severe, because the healthy X chromosome provides protection from the unhealthy chromosome. A male only inherits one X chromosome, so if that X chromosome has the mutation, he does not have another X chromosome to protect him. This means that boys are more likely to have Fragile X syndrome than girls, and boys with Fragile X usually have more severe symptoms than girls with Fragile X.


Fragile X Syndrome

The mutation of the FMR1 gene prevents the body from making enough protein. The FMR1 protein is important for brain development and the health of reproductive systems. Scientists also believe that the FMR1 protein helps translate the genetic code to make other important proteins. Because of the importance of FMR1 protein the body, people with the full FMR1 mutation – known as Fragile X Syndrome – may have many of the following characteristics:

  • Intellectual deficits that can range from mild learning difficulties to severe intellectual disability
  • Behaviors including poor attention, hyperactivity, social anxiety, repetitive hand biting/flapping, poor eye contact, unusual reactions to sensory stimuli, aggression. Many people with Fragile X syndrome may also have ADHD or autism spectrum disorder.
  • Areas of strength that include social and friendly temperament and strong memory and imitation skills.
  • Unusual physical features that include large ears, soft skin, ear infections, flat feet, high arched palate, double-joined fingers, and hyperflexible joints. Soft skin and large testicles (males) may also occur, but they are more likely to appear after puberty.
  • Females with Fragile X often have milder symptoms than males, and a small percentage of females with the full mutation do not have symptoms.


Fragile X Premutation Carriers and Health

Fragile X premutation carriers are people who are likely to have a child with Fragile X Syndrome, but they do not have Fragile X Syndrome themselves. Premutation carriers have between 55 and 200 CGG repeats, which is less than people with Fragile X Syndrome but more repeats than are found in healthy people. Approximately 1 in 468 males and 1 in 151 females are premutation carriers. While premutation carriers do not have Fragile X syndrome, they are at higher risk for other health issues. These include:

Fragile X Tremor Ataxia Syndrome (FXTAS)

FXTAS is a condition that affects movement in people who have the Fragile X premutation. Symptoms are similar to Parkinson’s disease and usually appear later in life and worsen over time. Male premutation carriers over the age of 50 are most commonly affected, but female premutation carriers may also develop symptoms. The risk of developing FXTAS increases with age.  

The main symptoms include shaking of the hands when using tools or reaching for something (intention tremor) and balance or stability problems when walking or using stairs (gait ataxia). People with FXTAS also have damage to the brain's white matter in a region called the medial cerebellar peduncles (MCP), which can be observed using Magnetic Resonance Imaging (MRI). This brain pathology is one of the primary signs that doctors use to diagnose FXTAS.

Other symptoms that clinicians use to help diagnose FXTAS include resting tremor (Parkinsonism), problems with short-term memory, problems with decision making and “executive function” (initiating and completing activities, changing behavior as needed, anticipating and planning for new tasks and situations, and problem solving). MRI findings include damage to the brain’s white matter that is outside of the cerebellum (lesions of cerebral white matter) and shrinking of the brain (brain atrophy). 

Additionally, symptoms that may occur but are not used for diagnosis include numbness or tingling in the extremities (neuropathy), mood instability (irritability, personality changes), cognitive decline (loss of skill in reading, math, etc.), problems with autonomic control (impotence, loss of bladder control, low of bowel control), high blood pressure, thyroid disorders, and fibromyalgia.

Fragile X Premature Ovarian Insufficiency (FXPOI)

Because of the importance of the FMR1 gene in reproductive health, premutation carriers are at risk for disorders of the reproductive system. FXPOI is a condition where the ovaries do not function properly in women with the Fragile X premutation. About 20-25% of adult women with the FMR1 premutation have FXPOI. It can also occur in teenagers with the premutation, though it is less common.

Ovaries have many important functions in female reproductive health. They store and maintain a woman’s eggs throughout her lifetime. The ovaries also control when eggs are released for potential fertilization during a woman’s menstrual cycle (usually one egg per cycle). 

In women with FXPOI, the ovaries do not function properly, and they act like the ovaries of an older woman. They do not keep the eggs healthy, and they do not release eggs as often.

Symptoms of FXPOI are similar to symptoms of menopause. They include absent or irregular menstrual cycles, infertility or poor fertility, hot flashes and vaginal dryness. Women with severe cases of FXPOI may experience premature ovarian failure, where a woman’s menstrual periods stop occurring before the age of 40. Women with the FMR1 premutation may have normal ovarian function, but they may go through early menopause (at around 40-45 years instead of 45-55 years of age).

Women who do not have the Fragile X premutation can also have premature ovarian insufficiency (POI) and may experience similar symptoms to women with FXPOI. Doctors can diagnose FXPOI using genetic testing to confirm FMR1 premutation status and tests of hormone levels, specifically follicle stimulating hormone (FSH), which is an indicator of ovarian function.

Fragile X-Associated Neuropsychiatric Disorders (FXAND)

According to recent research findings by Dr. Randi Hagerman and her team at University of California-Davis MIND Institute, FMR1 premutation carriers may be at increased risk for a variety of mental and other health conditions. These conditions may include anxiety, depression, attention deficit hyperactive disorder (ADHD), chronic pain, fibromyalgia, chronic fatigue, sleep problems, and autoimmune disorders. Though it is not known why premutation carriers are more likely to develop these health problems, Dr. Hagerman believes that it may be due to the toxic effect of the premutation on the brain in addition to other environmental factors, such as stress. Diagnosis and treatment of these conditions in premutation carriers is the same as it is for non-carriers. Treatments may include counseling and prescription medication such as an antidepressant or antianxiety medication.

Additional information

National Fragile X Foundation 

FRAXA Research Foundation 

Centers for Disease Control and Prevention 

National Institutes of Health