Conditions · Metabolism (biochemistry)
Fragile X syndrome !
The most common inherited cause of intellectual disability and of genetic autism; a CGG repeat switches off the FMR1 gene.
Updated 2026-11-01
Structures involved
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In biochemistry
- Epigenetics: DNA and histone methylation
- Types of mutations
- Trinucleotide repeat expansion disorders
- Southern, Northern and Western blots
- 5-Methylcytosine
Why it happens
What it is
An X-linked disorder caused by an expansion of more than 200 CGG repeats in the 5' region of FMR1, which becomes methylated and stops making the FMRP protein.
Who gets it
It affects about 1 in 4,000 males and 1 in 8,000 females. Women usually have milder forms because of X inactivation. In Colombia a cluster of cases has been described in Ricaurte (Valle del Cauca); a national figure is lacking.
Causes
- Expansion of the FMR1 CGG repeat (Xq27.3) to more than 200 copies (full mutation)
- Inherited from a mother with a premutation (55–200), which expands when passed on
- Rare: FMR1 deletions or point mutations
Risk factors
- Mother carrying a premutation or full mutation
- Maternal relatives with intellectual disability, early ovarian insufficiency or tremor-ataxia in grandparents
Pathophysiology
The CGG expansion leads to methylation of the FMR1 promoter CpG island and chromatin compaction; the gene stops being transcribed. Without FMRP, a protein that restrains translation of hundreds of mRNAs at synapses, local protein synthesis driven by mGluR5 glutamate receptors rises: dendritic spines stay long and immature and synaptic plasticity is disturbed. In the premutation the gene is over-transcribed and the CGG RNA is toxic (FXTAS tremor-ataxia, FXPOI ovarian insufficiency).
Classification
- Full mutation (> 200 CGG): fragile X syndrome
- Premutation (55–200): FXTAS in older adults, primary ovarian insufficiency in women
- Intermediate zone (45–54): no disease, may become unstable
Symptoms and signs
- Developmental and language delay; moderate intellectual disability in males
- Autistic features, attention deficit, hyperactivity and social anxiety
- Long face, large ears and prominent jaw (clearer after puberty)
- Macroorchidism after puberty
- Joint hypermobility, flat feet and soft skin
Diagnosis
- Clinical
- A child with developmental delay or autism, especially with a maternal family history.
- Tests
- PCR to count FMR1 CGG repeats and Southern blot (or PCR with methylation analysis) for large expansions; the old fragile-site karyotype is no longer used.
- Imaging
- Imaging is not needed for diagnosis; brain MRI is usually normal.
Treatment
- Rehabilitation
- Early intervention, speech, occupational and behavioural therapy; individualised educational support.
- Medical
- Medicines for associated symptoms (attention deficit and hyperactivity, anxiety, aggression, seizures), case by case.
- Follow-up
- Heart (mitral valve prolapse), eye and recurrent ear infection follow-up.
- Follow-up
- Genetic counselling for the family: testing the mother and maternal aunts and cousins (premutation).
Complications
- Seizures (about one in ten males)
- Mitral valve prolapse
- Recurrent otitis media and strabismus
- In premutation carriers: early menopause; in older carriers: tremor and ataxia
Prognosis
Life expectancy is normal; independence depends on the degree of disability and the support received.
Prevention
- Genetic counselling and carrier testing in affected families
- Prenatal or preimplantation diagnosis when the family asks for it
Test yourself
Think of the answer, then tap the question to see it.
What mechanism silences FMR1 in fragile X?
An expansion of more than 200 CGG repeats causes promoter methylation and the gene stops being transcribed.
Why is the disease usually passed through the mother?
The premutation expands to a full mutation mainly when it passes through the female germline.
What does an FMR1 premutation cause?
Primary ovarian insufficiency in women and fragile X tremor-ataxia syndrome (FXTAS) in older adults, mainly men.
Which physical finding appears in males after puberty?
Macroorchidism (large testes), along with a long face and large ears.
Educational information, not medical advice. For any symptom, see a health professional.
Sources: Fragile X syndrome: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); FMR1 gene: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); Textbook of Biochemistry for Medical Students, 6th ed. (Jaypee Brothers Medical Publishers (Vasudevan DM, Sreekumari S, Vaidyanathan K), 2011).
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