ConditionChildren's health
Fragile X Syndrome
Fragile X syndrome (FXS) is a genetic condition caused by a change in the FMR1 gene on the X chromosome. It is the most common inherited cause of intellectual disability and the most common single-gene cause of autism. Boys are usually more affected than girls. Signs include developmental and speech delay, learning difficulties, anxiety, attention problems, autism features and some physical traits. There is no cure, but early intervention, therapies and medicines for specific symptoms make a real difference.
Also called: FXS, Fragile X, Martin-Bell syndrome, FMR1-related disorder
At a glance
- Cause
- Expansion of a CGG repeat in the FMR1 gene, switching off production of FMRP protein.
- How common
- About 1 in 4,000 males and 1 in 8,000 females.
- Main features
- Developmental delay, intellectual disability, speech delay, anxiety, ADHD, autism features.
- Inheritance
- X-linked; carried by mothers (and passed by carrier fathers to all daughters).
- Diagnosis
- FMR1 DNA test.
- Carriers (premutation)
- Risk of early menopause (FXPOI) and a late-life tremor and balance disorder (FXTAS).
When to get help
Call 911 or go to the ER
- A seizure lasting more than 5 minutes, or repeated seizures without recovery between them
See a doctor within a day or two
- A first seizure or staring spells
- Self-injury or aggressive behavior that puts the child or others at risk
Book a routine appointment
- A child with speech or motor delay, learning difficulty, or autism features, especially with a family history of intellectual disability
- Irregular or stopped periods before age 40 in a woman with a family history of fragile X
- Tremor and balance problems after 50 in a grandparent of a child with fragile X
- Planning a pregnancy when there is a family history of fragile X
What causes fragile X syndrome
The FMR1 gene contains a stretch of repeating DNA letters, CGG. The number of repeats determines what happens:
| CGG repeats | Category | Effect |
|---|---|---|
| Under 45 | Normal | No effect |
| 45 to 54 | Intermediate | Usually no effect; may expand slightly in future generations |
| 55 to 200 | Premutation (carrier) | No fragile X syndrome, but risk of FXPOI and FXTAS; can expand in children |
| Over 200 | Full mutation | Gene switched off; fragile X syndrome |
Without the FMRP protein made by FMR1, nerve connections in the brain do not develop normally.
Inheritance
Fragile X is X-linked. A mother who carries a premutation or full mutation has a 50% chance of passing the altered gene to each child, and a premutation can expand to a full mutation when passed from mother to child. Fathers with a premutation pass it to all daughters (usually without expansion) and to none of their sons. Many families discover they carry it only after a child is diagnosed.
Signs and symptoms
Development and learning
- developmental delay: late sitting, walking and talking
- intellectual disability, usually moderate in boys; girls often have milder learning difficulties or normal intelligence
- speech that is rapid, repetitive or hard to follow
Behavior and emotions
- anxiety, particularly social anxiety, and shyness
- ADHD features: hyperactivity, impulsivity, short attention span
- autism features in many boys, such as poor eye contact, hand flapping, hand biting and sensitivity to noise or touch
- temper outbursts and aggression in some
Physical features
Often subtle, especially in young children:
- long, narrow face and large or prominent ears
- prominent forehead and jaw (after puberty)
- flexible joints, flat feet, soft skin
- enlarged testicles after puberty in boys
- low muscle tone
Medical problems
- seizures in roughly 1 in 10 to 1 in 5 boys
- frequent ear infections
- strabismus (crossed eyes)
- mitral valve prolapse
- reflux and sleep problems
Fragile X in girls
Because girls have two X chromosomes, one working copy partly compensates. Girls with a full mutation are often affected more mildly, with learning difficulties (especially math), anxiety, shyness and attention problems.
Conditions in premutation carriers
- Fragile X-associated primary ovarian insufficiency (FXPOI): affects about 1 in 5 female carriers, causing irregular periods, reduced fertility and menopause before 40. See primary ovarian insufficiency.
- Fragile X-associated tremor/ataxia syndrome (FXTAS): a late-onset tremor, balance problems, memory decline and neuropathy, mainly in male carriers over 50.
- Fragile X-associated neuropsychiatric disorders: anxiety and depression are more common in carriers.
Diagnosis
The FMR1 DNA test (PCR and Southern blot or related methods) measures the number of CGG repeats. It is recommended for:
- children with developmental delay, intellectual disability or autism
- people with a family history of fragile X or unexplained intellectual disability
- women with early menopause or ovarian insufficiency
- adults over 50 with unexplained tremor and balance problems
Testing during pregnancy (chorionic villus sampling or amniocentesis) is available for known carriers.
Treatment and support
There is no cure, but many supports help:
- Early intervention from infancy: speech, occupational and physical therapy
- Special education with individualized education plans, visual supports and small-group learning
- Behavioral therapy for anxiety, social skills and behavior
- Medicines for symptoms: stimulants for ADHD, SSRIs for anxiety, and others for aggression or sleep
- Anti-seizure medicines when needed
- Regular checks: eyes, ears, heart and growth
- Genetic counseling for the whole family, since many relatives may be carriers
Research into targeted treatments is ongoing.
Outlook
Fragile X is lifelong, but life expectancy is normal. With support, many people with fragile X learn, work, form relationships and live semi-independently. Early diagnosis allows early intervention and gives families information about carrier risks.
Frequently asked questions
What are the signs of fragile X syndrome?
Common signs include delayed speech and motor development, learning difficulties or intellectual disability, anxiety, hyperactivity, autism features such as hand flapping and poor eye contact, and physical features like a long face and large ears.
How is fragile X inherited?
It is X-linked. Carrier mothers have a 50% chance of passing the altered gene to each child, and a premutation can expand to a full mutation. Carrier fathers pass the premutation to all their daughters but none of their sons.
Can girls have fragile X syndrome?
Yes. Girls can have the full mutation, but they are usually more mildly affected than boys because their second X chromosome partly compensates. Learning difficulties, anxiety and shyness are common.
What is a fragile X carrier?
A carrier has a premutation, 55 to 200 CGG repeats. Carriers do not have fragile X syndrome, but they can pass on an expanded gene, and they have higher risks of early menopause (women) and a tremor and balance disorder later in life (mostly men).
Sources
This guide was written from current patient and clinical guidance, including:
- CDC: Fragile X syndrome (FXS)
- National Fragile X Foundation: What is Fragile X
- MedlinePlus Genetics: Fragile X syndrome
- American College of Medical Genetics and Genomics: Technical standards for fragile X testing
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): Fragile X syndrome