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# 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

Tap one to see what it is and open it in 3D.

- [Frontal lobe](https://durgical.com/en/anatomy/superior-frontal-gyrus/)
- [Testes](https://durgical.com/en/anatomy/testis/)
- [Auricle](https://durgical.com/en/anatomy/auricle/)
- [Hippocampus](https://durgical.com/en/anatomy/hippocampus/)
- [Mandible](https://durgical.com/en/anatomy/mandible/)
- [Ovaries](https://durgical.com/en/anatomy/ovary/)

## In biochemistry

- [Epigenetics: DNA and histone methylation](https://durgical.com/en/biochemistry/topics/epigenetics-dna-and-histone-methylation/)
- [Types of mutations](https://durgical.com/en/biochemistry/topics/types-of-mutations/)
- [Trinucleotide repeat expansion disorders](https://durgical.com/en/biochemistry/topics/trinucleotide-repeat-expansion-disorders/)
- [Southern, Northern and Western blots](https://durgical.com/en/biochemistry/topics/southern-northern-and-western-blots/)
- [5-Methylcytosine](https://durgical.com/en/biochemistry/molecules/5-methylcytosine/)

## Why it happens

- [Nonclassic inheritance: repeat expansions, mitochondrial genes, imprinting, mosaicism](https://durgical.com/en/general-pathology/nonclassic-inheritance-repeat-expansions-mitochondrial-genes-imprinting-mosaicis/)

## 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](https://durgical.com/en/anatomy/skin/)

## Red flags

- Seizures
- Loss of language or acquired skills
- Severe self-injury or aggression

## 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.

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Educational information, not medical advice. For any symptom, see a health professional.

Sources: [Fragile X syndrome: MedlinePlus Genetics](https://medlineplus.gov/genetics/condition/fragile-x-syndrome/) (MedlinePlus, US National Library of Medicine, 2026); [FMR1 gene: MedlinePlus Genetics](https://medlineplus.gov/genetics/gene/fmr1/) (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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Source: https://durgical.com/en/conditions/fragile-x-syndrome/
License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/conditions/fragile-x-syndrome/