Fragile X 101

What is Fragile X Syndrome?

Fragile X syndrome (FXS) is caused by a mutation of a single gene — FMR1 — on the X chromosome and is inherited genetically, often unknowingly. Everyone has the FMR1 gene on their X chromosome, but when a mutation occurs, it can cause intellectual disability, behavioral and learning challenges, and various physical characteristics. There is no cure, but therapies, interventions, and medications are often prescribed to treat behavioral symptoms like anxiety, aggression, and ADHD.

Female carriers have a 50% chance of passing the mutation to each of her children, while males will pass it to all of his daughters (and and none of his sons).

Though Fragile X syndrome occurs in both genders, males are more frequently affected than females, and generally with greater severity. In fact, some females may not experience any of the behavioral, cognitive, or physical features that appear more widely in males.

Exactly why males are more often and more severely affected is unknown. But it’s believed to be due to the fact that females have two X chromosomes and males have only one — can a damaged FMR1 gene on one X chromosome be compensated for by a healthy FMR1 gene on the other? Because males have only one X, if they receive a damaged FMR1 gene, it’s the only one they have.

Life Expectancy

The life span for people with FXS is not affected because there are usually no life-threatening health concerns associated with the condition.

Prevalence

There have been a number of studies aimed at determining the prevalence of FXS in males and females. Studies have been undertaken both in the “special needs” population and the general population. The agreed upon prevalence of FXS:

• Males — approximately 1 in 3,600 to 4,000.
• Females — approximately 1 in 4,000 to 6,000.

Signs & Symptoms

In Males

Physical features

No one individual will have all the features of FXS, and some features, such as a long face and macroorchidism, are more common after puberty. Some of the features are due to poor connective tissue, such as flexible joints, flat feet, and high arched palate.

Physical features may include:

• Large ears
• Long face
• Soft skin
• Flexible joints — particularly fingers, wrists, elbows
• Low muscle tone
• Flat feet
• High arched palate
• Large testicles (called “macroorchidism”) in post-pubertal males

Behavioral characteristics

Behavioral characteristics may include:

• Sensory processing challenges (sensitive fabrics or clothing, loud noises, crowds, food textures, etc.)
• Hand-flapping, hand-biting
• Poor eye contact
• ADHD (attention deficit/hyperactive disorder)
• Anxiety
• Autism spectrum disorders
• Increased risk for aggression
• Sleep disorders

Cognitive Abilities

• Cognitive abilities in FXS include a range from mild learning disabilities to more severe intellectual disabilities. The majority of males with Fragile X syndrome demonstrate moderate intellectual disability.
• Speech and language delay
• Motor delay (late crawling, walking, toileting)

Medical Issues

Medical issues may include:

• Ear infections (also often due to poor connective tissue)
• Strabismus (crossed eyes)
• Seizures

Disposition

Disposition characteristics often include:

• Very social and friendly
• Excellent imitation skills
• Strong visual and long-term memory
• Especially nice, likes to help others
• Wonderful sense of humor

In Females

Behavioral characteristics

Behavioral characteristics seen in males can also be seen in females, though females often have a milder presentation of the syndrome’s behavioral, physical, and connective tissue features.

Cognitive Abilities

About one-third of females with FXS have no to very mild learning disabilities, about a third have mild learning disabilities, and a third have moderate to significant intellectual disabilities.

Additional issues sometimes seen are:

• Emotional and mental health issues
• General anxiety
• Social anxiety

A small percentage of females who have the full mutation of the FMR1 gene that causes FXS will have no apparent signs of the condition — intellectual, behavioral, or physical. These females are often identified only after another family member has been diagnosed.

The 3 Main Fragile X Disorders

Full mutation of the FMR1 gene (> 200 CGG repeats)

1. Fragile X Syndrome

Symptoms include intellectual disability, behavioral and learning challenges, and various physical characteristics. Males are more frequently affected, and generally with greater severity.

Premutation of the FMR1 gene (55–200 CGG repeats)

Traditionally, a carrier of a genetic mutation is defined as a person who inherits an altered form of a gene but shows no effects of that mutation. However, in Fragile X this definition does not exactly fit as carriers of a Fragile X premutation are at risk to develop FXTAS and FXPOI.

2. FXTAS — Fragile X-Associated Tremor/Ataxia Syndrome

Premutation carriers of an FMR1 gene mutation can have no apparent signs of a Fragile X disorder, and may or may not develop FXTAS (pronounced: FAKS-taz), which usually occurs in male premutation carriers after age 50, with symptoms — including balance, tremor, and memory problems — worsening with age.
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3. FXPOI — Fragile X-Associated Primary Ovarian Insufficiency

Premutation carriers of an FMR1 gene mutation can have no apparent signs of a Fragile X disorder, and may or may not develop FXPOI (pronounced: FAKS-poi), which usually occurs in female premutation carriers after age 40, and refers to a spectrum of impaired ovarian functions that can include infertility and early menopause.
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Genetics & Inheritance

Fragile X-associated disorders include a wide range of physical, intellectual, and behavioral symptoms that can affect family members in many different ways. These conditions are passed down in families through expansions of the FMR1 gene. Even for genetics professionals, FMR1 inheritance is complex and confusing, so it’s no surprise that families often have questions about the genetics of Fragile X. We start with some background on genetics and chromosomes …

Testing & Diagnosis

Who should be tested, lab tests for Fragile X including testing costs and reporting time, and other tests for children with developmental delay.

Premutation Carriers

When you or a family member are told you are a “carrier” for a Fragile X mutation, many questions arise.