Fragile X syndrome is a genetic disease affecting various organ systems.
The name refers to the X chromosome, where the disease gene is located.
Under a microscope, the X chromosome appears fragile or broken at the site of the mutation due to chromatin condensation.
FMR1 Gene
The gene responsible for fragile X syndrome is called FMR1 (fragile X mental retardation 1).
"Mental retardation" is an outdated term for intellectual disability.
Triplet Repeat
The FMR1 gene contains a triplet repeat (or trinucleotide repeat), where a sequence of three DNA nucleotides is repeated.
In FMR1, the repeating sequence is CGG (cytosine, guanine, guanine).
These CGG repeats are located in the 5' untranslated region of FMR1.
The 5' untranslated region is the part of the DNA at the beginning of the gene that is transcribed into mRNA but not translated into protein and modulates gene expression.
Promoter Region
Upstream from the 5' untranslated region is the promoter, which initiates transcription of the gene into mRNA.
Normally, the promoter is turned on, allowing the FMR1 gene to be expressed.
FMRP Protein
Expressed FMR1 mRNA is translated into fragile X mental retardation protein (FMRP).
FMRP aids in the development of the brain and other tissues.
Mechanism of Fragile X Syndrome
Repeat Expansion
Fragile X syndrome is caused by a repeat expansion, where the number of CGG repeats increases significantly.
This expansion occurs due to slipped mispairing during DNA replication.
DNA polymerase, the enzyme responsible for copying DNA, gets confused by the repetitive sequence.
It loses its place and re-copies the same section, leading to an increase in the number of repeats.
Number of CGG Repeats
Normal number of CGG repeats: 5 to 44.
Intermediate expansion alleles: 45 to 54 CGG repeats; do not cause symptoms.
Premutation alleles: 55 to 200 CGG repeats; may cause mild symptoms.
Full fragile X syndrome mutation: over 200 CGG repeats; leads to the distinctive fragile X chromosome appearance.
Allele Expansion
Alleles tend to become longer as DNA polymerase becomes more unstable.
Intermediate alleles can become premutation alleles, and premutation alleles can expand into full fragile X syndrome mutations.
DNA Methylation
The repeat expansion attracts a DNA methylase enzyme, which methylates the cytosines in the CGG repeats.
These methyl groups cause the chromatin (DNA wrapped around histones) to condense.
Gene Silencing
When chromatin is condensed, transcription factors cannot bind to the FMR1 gene.
The promoter of the FMR1 gene is locked in the "off" state.
As a result, FMRP is not produced in adequate amounts, leading to fragile X syndrome.
Symptoms of Fragile X Syndrome
Intellectual disability
Delayed speech
Delayed motor development (e.g., walking at 18 months instead of 12 months)
Autism
ADHD
Seizure disorders
Physical Features
Long and narrow face
Prominent jaw and forehead
Large ears that stick out
Larger than normal testes after puberty (in males)
Severity in Females
Fragile X is typically milder in females than males.
Many females with the fragile X mutation have no symptoms due to reduced penetrance.
This is because females have a normal backup copy of FMR1 on their other X chromosome.
Skewing of X chromosome inactivation can influence the severity of symptoms in females.
Inheritance
FMR1 expansions are almost always inherited from the mother.
Premutation Carriers
Premutation carriers have too few repeats to develop fragile X syndrome but can have other symptoms.
FXTAS
Fragile X associated tremor ataxia syndrome (FXTAS) is an adult-onset progressive neurological disease.
Symptoms include:
Intention tremor (shaking when movement is initiated)
Ataxia (difficulty walking)
Memory and cognitive problems
White matter changes detected by brain MRI
Primary Ovarian Insufficiency
Female premutation carriers can develop FMR1-related primary ovarian insufficiency.
The ovaries shut down early, leading to menopause before age 40.
Diagnosis
Fragile X, FXTAS, and FMR1-related primary ovarian insufficiency are diagnosed by a DNA test that counts the number of CGG repeats.
Diagnosis is important for counseling individuals about the risks to themselves and family members.
FMR1 testing is often done for individuals with intellectual disability, developmental delay, or autism.
Carrier testing can be done for pregnant women.
Treatment
Treatment is directed at individual symptoms.
Special education for intellectual disability
Stimulants for ADHD
Evaluation by a reproductive endocrinologist for premature ovarian insufficiency
Summary
Fragile X syndrome is caused by the expansion of over 200 CGG triplet repeats in the FMR1 gene on the X chromosome.
Symptoms are more likely in males and include:
Intellectual disability and autism
Long, narrow face, prominent jaw and forehead, large ears
Large testes in adolescent males
Premutation carriers can have fragile X tremor ataxia syndrome and premature ovarian failure.