Fragile X Syndrome – causes, symptoms, diagnosis, treatment, pathology

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.


  1. Thank you so much for all the effort you put into all of your videos. I love them so much because the presentation is to the point and is entertaining enough to keep me focused to the end. Thank you again for these videos and keep up this wonderful work!

  2. Wow thank you for making this video, I had requested it a few months ago, can't believe it's already here ! thanks for all the hard work !


  4. Dear Sir,
    Can u please make a video on the latest treatment for B-cell acute lymphoblastic Leucemia by novartis called #kymriah ?

  5. Why is it mentioned it lies in the untranslated region and then that it produces a fmrp protein? Need some help here

  6. I worked with a patient with fX. He was the most passionate man ever! No matter the emotion he had it in the extremes, and I enjoyed them all even if it was a negative behavior.

  7. This channel is so amazing
    It's like you come here and know more what you can like
    Don't come to search what you want !!!

  8. "This is like getting lost in a video and watching the same part over and over."

    Well played Osmosis, well played…

  9. Found the channel some hours ago and wow, good job! I've never was a patron before but it wasn't even a question now: I became one of your supporter.
    Learning on Youtube is cool!
    (Guys, check Osmosis' Patreon page… they have nice wallpapers. 😉 )

  10. When it comes to genetic diseases please mention whether it is Autosomal or X-linked dominant or recessive type . FYI this is an X-Linked Dominant type.

  11. wow very helpful video, I have fragile x but My found out back in the 90s and doctors didnt knwo too much about it. fragile x is the main cause for depression anxiety social anxiety and low iq as well as many other struggles. Most Females are not severly affected like boys but some females do have struggle like myself. Thanks for sharing!

  12. Most of your videos are related to my course which is medical technology. It helps me a lot. Hopefully your can make more. Thank you very much.

  13. Can someone explain to me why the DNA Polymerase copies at 2:00 GCCGCCGCC instead of CGGCGGCGG. should it symbolize that he is confused ?

  14. Very accurate! Maybe you should have added that men carrying the premutation will always pass the premutation on to all their daughters. Funnily it doesn‘t mutate any further when recieved from the fathers side.
    I‘m doing a lot of research myself since I‘m a premutation carrier and also found the following things, too:

    Female induviduals carrying the premutation are at highest risk for premature menopause when their repeats range from 80-100

    Only 20% of female premutation carriers will experience premature menopause

    Men are more likely affected by Fxtas due to the same reason as females being less affected by fragile x syndrom

    fragile x is so unpredictable and so few is known about it. I‘m excited for what science will find out about it in future!

  15. Tell us all again why this foul plague hasn't been culled from the face of the earth through eugenic euthanasia of the living vectors of cursed malformed seed.

  16. The repeats amplify only during Oogenesis, not Spermatogenesis. Hence, the disease is less severe in father to child transmission.

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