Fragile X syndrome

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With Fragile X syndrome, sometimes just called Fragile X, the “X” refers to the X chromosome, where the disease gene is located.
The “fragile” refers to the fact that under a microscope, the X chromosome looks fragile or broken at the site of the mutation.
That’s because the chromatin which makes up the chromosome gets really condensed at that point. Fragile X is a genetic disease that affects various organ systems.
Now, the gene for Fragile X is called FMR1, which stands for Fragile X mental retardation 1. Mental retardation is the old term for intellectual disability, which is one of the key features of Fragile X syndrome.
The FMR1 gene has a triplet repeat, or trinucleotide repeat, which means that a group of three DNA nucleotides is repeated multiple times in a row.
In FMR1, it’s the nucleotides cytosine, guanine, and guanine, or CGG. These CGGs are found in the 5’ untranslated region of FMR1.
A 5’ untranslated region is the part of DNA at the beginning of the gene that’s made into mRNA but not protein, and helps modulate gene expression.
Just upstream from the 5’ untranslated region is FMR1‘s promoter, the region that causes the gene to be transcribed to mRNA, which is usually turned on.
Expressed FMR1 mRNA gets translated into Fragile X mental retardation protein, or FMRP, and it helps in development of the brain and other tissues.
In Fragile X syndrome, there is a repeat expansion, meaning there’s an increased number of CGG repeats in the gene. This repeat expansion is caused by slipped mispairing, which is where the enzyme DNA polymerase gets confused when copying a repetitive sequence.
DNA polymerase loses its place among the FMR1 triplet repeats and goes back to recopy what it already just copied. This is like getting lost in a video and watch the same part over and over.
But since DNA polymerase is making copies, the effect is an increase, or expansion, of the number of repeats. The normal number of CGG triplets is 5-44.
Alleles with 45 to 54 CGG repeats are called intermediate expansion alleles and they don’t cause any symptoms. Alleles with 55 to 200 CGGs are called premutation alleles, and they can cause some mild symptoms.
Finally if an allele has over 200 CGGs, then it’s considered a full fragile X syndrome mutation and can make the chromosome take on its distinctive look.
Alleles can tend to get longer and longer as DNA polymerase becomes more and more unstable copying the longer stretches of repeats, so an intermediate expansion allele can become a premutation allele, and a premutation allele can expand to become a full fragile X syndrome mutation.
The repeat expansion attracts a DNA methylase enzyme to the site and causes the cytosines in the CGG repeats to become methylated.
These bulky methyl groups cause the chromatin - which is DNA wrapped around histones - to condense. When it’s in a condensed form, regions of the FMR1 gene can’t be bound by transcription factors.
As a result, the promoter of the FMR1 gene is locked in the “off” state, so its product FMRP can’t be made in adequate amounts, and that leads to Fragile X syndrome.
Fragile X can cause intellectual disability, delayed speech, and delayed motor development, for example learning to walk at eighteen months instead of twelve.
Many children with Fragile X also develop autism, ADHD, and seizure disorders. Individuals with Fragile X syndrome can have develop classic physical features as well - like a long and narrow face, a prominent jaw and forehead, and large ears that stick out.
These facial features might not be seen in an infant, but become obvious as the child becomes older. Males can also have larger than normal testes after puberty.
Fragile X is typically milder in females than males, and 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 which the process in development where each cell picks one X-chromosome to rely on – can make a female more or less likely to show symptoms.
Interestingly, FMR1 expansions are almost always inherited from the mother. Premutation carriers have too few repeats to get Fragile X, but they can have other symptoms, for example Fragile X-associated tremor ataxia syndrome, or FXTAS.
FXTAS is an adult-onset, progressive neurological disease that includes: intention tremor, which shaking when movement is initiated; ataxia, which can make walking difficult; memory and cognitive problems, and white matter changes detected by brain MRI.
Female premutation carriers can also get FMR1-related primary ovarian insufficiency, where the ovaries shut down early and menopause starts before age 40.
Fragile X, FXTAS, and FMR1-related primary ovarian insufficiency are diagnosed by a DNA test that counts the number of CGG repeats.
It’s important to make the diagnosis in order to counsel the individual about the risk of these diseases in current and future family members.
FMR1 testing is often done for individuals with intellectual disability, developmental delay, or autism, and carrier testing can be done for pregnant women.
Treatment of Fragile X is directed at individual symptoms, for example special education for intellectual disability, stimulants for ADHD, and evaluation by a reproductive endocrinologist for premature ovarian insufficiency.
Alright, as a quick recap, Fragile X syndrome is a genetic disorder caused by expansion of over 200 CGG triplet repeat in the FMR1 gene on the X chromosome.
It’s more likely to cause symptoms in males than females, and these symptoms include intellectual disability and autism, a long, narrow face, a prominent jaw and forehead, large ears, and large testes in adolescent males.
Premutation carriers, who have an intermediate number of repeats, can have Fragile X tremor ataxia syndrome and premature ovarian failure.