FRAGILE X SYNDROME
What Is Fragile X Syndrome?
Fragile X syndrome (FXS) is a rare genetic disorder that may cause intellectual disability, developmental delays, behavioral and learning challenges, and various physical features. It is the most common inherited cause of intellectual disability and monogenic cause of autism spectrum disorder. It’s estimated that approximately 1 in 4,000 to 7,000 males and 1 in 8,000 to 11,000 females have FXS.
Signs and Symptoms of Fragile X Syndrome
Behavioral symptoms
FXS affects both males and females. However, females may experience milder symptoms than males.
Common behavioral symptoms in individuals with FXS include:
- Anxiety
- Autism-like behaviors
such as poor eye contact,
hand flapping, or biting - Attention-deficit
hyperactivity disorder
(ADHD) - Increased risk for
aggression - Sensory processing challenges
(sensitivity to fabrics or clothing,
loud noises, crowds, food
textures, etc.)
Intellectual disabilities and developmental delays
Most individuals with FXS experience intellectual disabilities and developmental delays.
Males with FXS are more likely to have:
- Significant intellectual disability. Most boys with FXS have an average IQ score under 55
- Speech and language delays. Some children with language delays may eventually talk, but some may remain nonverbal throughout their lives
- Motor delays (late crawling, walking, toileting)
Due to having one normal FMR1 (Fragile X Messenger Ribonucleoprotein 1) gene on their second X chromosome, females with FXS often:
- Exhibit less cognitive impairment than males with FXS. Around 25% of females with FXS have an intelligence quotient (IQ) below 70
- Do not usually have as severe challenges with speech or language as compared to males
- Can experience emotional problems, such as social anxiety, social avoidance, shyness, withdrawal, depression, language deficits, and mood swings
Physical Characteristics
Most infants and younger children with FXS may not have any specific physical features of the syndrome. When these children go through puberty, however, they may develop certain physical characteristics associated with connective tissue abnormalities that are typical of those with FXS:
- Narrow or long face
- Large head
- Large ears
- Soft skin
- Hyperflexible
- Low muscle tone
- Flat feet
- Prominent forehead
- High-arched palate
- Large testicles (macroorchidism)
in males
Fragile X Syndrome Causes & Genetics
Fragile X syndrome (FXS) is a single-gene disorder caused by the full mutation of the FMR1 (Fragile X Messenger Ribonucleoprotein 1) gene located on the X chromosome. This gene helps produce Fragile X RNA-binding protein (FMRP), which plays a crucial role in brain development and the biological mechanisms involved in learning and memory.
The FMR1 gene has a “CGG repeat” segment of DNA, representing the combination of the cytosine, guanine and guanine building blocks of the DNA, that are repeated many times. The FMR1 gene normally contains less than 45 trinucleotide repeats. In individuals with FXS, the CGG segment is repeated over 200 times. The expanded CGG segment silences the FMR1 gene, preventing the gene from creating enough FMRP the body requires.
How Is Fragile X Syndrome Inherited?
FXS is a rare hereditary disorder transmitted from parent to child through a gene mutation. FXS is an X-linked dominant disease, meaning a single copy of the mutated gene, located on the X chromosome, is enough for an individual to be affected. Among those affected by FXS, males are at greater genetic risk of developing more severe phenotypes because they possess a single X chromosome as compared to females who possess two X chromosomes. As such, females may show less severe symptoms.
Those born to mothers with the Fragile X mutation:
- Have a one-in-two chance of inheriting the disorder
- Either will inherit the abnormal gene and become Fragile X carriers or experience the effects of the full mutation FXS
- Can expand to the full mutation range with each successive generation
- If males inherit their mother’s fully mutated X chromosome, their only X chromosome is affected
The male premutation carrier’s daughters will:
- Inherit the FMR1 premutation, but none of his sons will
- Be carriers but may not develop FXS themselves
Who Can Be a Fragile X Carrier?
A person with an abnormal gene that increases the risk of having a child or grandchild with a genetic disorder is known as a “carrier.” Anyone can be a carrier of FXS or Fragile X premutations. Fragile X carriers are found among all ethnic backgrounds and racial groups.
The risk of having a Fragile X premutation is higher if you have the following:
- A family history of FXS
- A family history of intellectual
disability, developmental
milestone delays, or autism
spectrum disorders of
unknown cause - Infertility problems
associated with elevated
follicle-stimulating hormone
(FSH) levels or premature
ovarian failure (POF) - A family history of adult-onset
ataxia and/or tremors
Although a carrier of a genetic mutation is traditionally described as a person who inherits an abnormal form of a gene but does not exhibit clinical symptoms, in the instance of Fragile X, some Fragile X premutation carriers are prone to Fragile X-related disorders.
Genetic Testing & Diagnosis
What Is a Fragile X Carrier Genetic Test?
The Fragile X carrier test determines whether an individual is a Fragile X carrier and their risk of having children with Fragile X syndrome (FXS). The test requires a small blood sample. Fragile X carrier testing provides results with over 99% accuracy.
Two main genetic testing methods are utilized to diagnose Fragile X-related disorders.
-
Polymerase chain reaction (PCR) – This identifies the extent of the repetitive section of the FMR1 (Fragile X Messenger Ribonucleoprotein 1) gene, including CGG repeats in the normal, intermediate, premutation, and full mutation ranges
-
Southern blot analysis – In instances of full mutations, labs usually follow up with a southern blot analysis to determine the gene’s methylation status. Abnormal methylation associated with FXS can prevent the FMR1 gene from producing FMRP
Laboratories generally report the number of CGG repeats in the FMR1 gene. If there is a full mutation in the FMR1 gene (ie >200 CG repeats), methylation status and the presence of mosaicism (if detected) will also be reported. Genetic mosaicism is when two or more cell populations from the same individual have different genetic results. This can result in variability in severity of symptoms.
In FXS, there are two types of mosaicism: size and methylation. Size mosaicism is the presence of different-size CGG repeats and methylation mosaicism is when the DNA methylation status may vary.
The results of a Fragile X carrier test usually fall into one of the following:
- Negative – Individual is not a
Fragile X carrier, and individual’s
children are not at increased risk for FXS - Intermediate – Individual’s results
fall within the range between
negative and premutation.
Although an individual’s children
are not at an increased risk of FXS,
future generations may be at risk
for the condition -
Premutation – Individual is a
carrier of the altered FMR1
gene. They may be at risk for
FXPOI, FXTAS, and females
have a 50% chance of having
children with FXS or a
premutation - Full mutation – An individual
with a full mutation of Fragile
X is diagnosed with FXS
Symptoms of Adults Living With Fragile X Syndrome
The signs and symptoms of Fragile X syndrome (FXS) and their challenges can vary widely.
Individuals with FXS often take longer to reach developmental milestones and struggle to master the adaptive skills necessary for everyday life. The way in which the disorder manifests in a person may vary throughout different stages of their lives, including, as discussed below, adulthood.
Intellectual Disability in Adults With Fragile X Syndrome
Adults with FXS may face unique challenges, such as problems with memory, abstract thinking, problem-solving, learning disabilities, and planning.
Functional Challenges in Adults With Fragile X Syndrome
Well-rounded interpersonal skills are crucial for adult life. Since FXS is associated with deficits in social communication and interaction, increased social anxiety, and autistic mannerisms (such as poor social awareness and restricted and repetitive behavior), the degree to which adults with FXS can interact with others may correspond to their independence in various dimensions of adult life.
Some adult females with the full FMR1 (Fragile X Messenger Ribonucleoprotein 1) gene mutation may lead more typical adult lives, including living independently, pursuing higher education, working full-time, and having friends. Adult males with FXS, on the other hand, are more likely to have limited independence regarding their employment, residence, ability to perform everyday activities, and form friendships.
Functional skills, such as eating, dressing, toileting, and communicating, are often impaired in adults with FXS. These impairments in daily living skills have been shown repeatedly to have a strong correlation with various outcomes for adults with intellectual disabilities, including employment success and the ability to form friendships.
Co-occurring Mental Health Conditions in Adults With Fragile X Syndrome
Individuals with FXS have an increased risk of co-occurring mental health conditions.
- Depression and anxiety have reportedly been found to occur in about one-half to more than two-thirds of males and females with FXS (between the ages of 4 and 59)
- Attention problems and/or hyperactivity have also been reported in about 80% of children and adults with FXS
- Aggression and self-injurious behavior occur in adults but are more common in males than females, with more than 40% of males being diagnosed with or treated for problems with aggression (~43%) and self-injury (~47%) as compared to ~13% and ~17% respectively in females
Level of Independence in Adults With Fragile X Syndrome
Adults with Fragile X syndrome (FXS) have varying levels of independence. About four in 10 females with FXS and about one in 10 males with FXS are able to reach a high or very high level of independence in adult life, according to a national family survey of 328 adults with FXS, while others may have considerably more limited independence in these areas and others, such as housing, employment, and daily living activities. During adolescence and early adulthood, individuals with FXS may be able to do more on their own and have fewer behavioral issues, but this trend may level off or even reverse by the time they hit their early thirties.
Adult Premutation Carriers
Individuals with 55-200 CGG repeats in their FMR1 gene are known as Fragile X premutation carriers. Premutation carriers do not have FXS but may have or later develop other Fragile X-associated disorders, such as Fragile X-Associated Tremor/Ataxia syndrome (FXTAS) or Fragile X-Associated Primary Ovarian Insufficiency (FXPOI).
Fragile X-Associated Tremor/Ataxia Syndrome
- Symptoms: Characterized by unsteadiness (ataxia), memory problems, and intention tremors
- Affected Population: Adult-onset neurodegenerative disorder usually affecting males over 40 years of age. Females account for a rather small proportion of the FXTAS population and tend to have less severe symptoms
- Prevalence: Among premutation carriers, about 45% of males over 40 years of age and 16% of females over 40 years of age develop FXTA
- Prognosis: The condition progresses at varying levels in different individuals
Fragile X-Associated Primary Ovarian Insufficiency
- Affected Population: Approximately 10-30% of female premutation carriers develop FXPOI
- Symptoms: Ovarian dysfunction, including irregular menstrual cycles, increased follicle-stimulating hormone, fertility problems, and menopause before the age of 40. For some premutation carriers, menopause can begin in their early 20s
It’s important to remember that not everyone with an FMR1 premutation goes on to develop a Fragile X-associated condition and how someone experiences a condition might vary widely. Researchers are still studying to understand why this is the case.
