Prader-willi syndrome – causes, symptoms, diagnosis, treatment, pathology

Prader-Willi syndrome is a genetic disorder
that, in infancy, causes poor feeding and low muscle tone, and then in childhood, and
then overeating, intellectual disability, and low sex hormones starting in childhood. It happens when a handful of genes on chromosome
15 aren’t transcribed into messenger RNA and therefore aren’t expressed. Among these are SNRPN which stands for Small
Nuclear Ribonucleoprotein Polypeptide N and a cluster of snoRNAs, which stands for small
nucleolar RNAs; these genes all have protein products that modify other RNAs. Now – normally, the copies of the genes contributed
by the mother, or maternally derived genes, to this region, are silenced, or turned off,
and only the genes from dad, or paternally-derived genes, get expressed. This special genetic process is called imprinting,
where only one copy of the gene gets expressed, not both. This differs from most genes in the genome,
where both the maternal and paternal copies are expressed. The maternal copies in this region are imprinted
and therefore silenced. And this silencing of the maternal copies
is an epigenetic process. In the word “epigenetic”, “epi” means
outside of, and “genetic” refers to the DNA sequence of A’s, C’s, G’s, and T’s. So epigenetic silencing of a gene means turning
vit off while keeping the DNA sequence itself the same. The Prader-Willi genes get turned off when
methyl groups get attached to the DNA, a process that happens way back when the mother was
making an egg. Even after fertilization of the egg and all
of the cell divisions it takes to make a person, that epigenetic mark remains – a reminder
to keep those maternally-derived copies of the genes turned off. Unfortunately, this means that if paternal
copies of the genes don’t get expressed, then there aren’t any backup copies being
expressed, and so no copies get expressed! And this is what happens in Prader-Willi syndrome! Now, there are a few ways these paternal genes
wouldn’t be expressed. The most common one is a deletion on the paternal
genes spanning Prader-Willi region. Many deletions also include a nearbyl gene
called OCA2, which codes for a pigment that gives color to eye, hair, and skin. So the Prader-Willi patients with deletions
that encompass OCA2 can have a light complexion. A second way is called maternal uniparental
disomy, which means two chromosomes from one parent—the mother. If both copies of chromosome 15 were derived
from the mother, that means all the prader willi genes are methylated and silenced, since
there’s no unsilenced paternal genes. This can happen when the primary oocyte in
the female, which eventually becomes an egg cell, undergoes nondisjunction during meiosis
I, resulting in an egg cell with two maternal chromosomes, and after combining with a sperm
cell, a zygote with three copies—called trisomy 15. Since trisomy 15 isn’t compatible with life,
the fetus only survives only if they lose one copy of the chromosome in the early embryo,
called trisomy rescue. If it’s the paternal chromosome 15 that’s
lost, the result is maternal UPD 15. A third way to get Prader-Willi syndrome,
is a mutation in the imprinting center, which is a sequence of DNA near the Prader-Willi
genes that directs imprinting via sex-specific methylation. If the paternal imprinting center is mutated,
the region gets methylated and those genes get turned off, meaning that both the maternal
and paternal genes are silenced. Sometimes that methylation occurs on the paternal
chromosome even when there’s no imprinting center defect, and that’s called an epimutation. Normally the paternal grandmother’s methylation,
after being passed to the father, would be erased when the father’s making sperm. But in epimutations it doesn’t get erased
and gets passed on. Finally, there might be a translocation, which
is when two chromosomes swap material. Translocations can disrupt SNRNP and move
the small nucleolar RNA genes away from their imprinting center, causing them to get methylated
and turned off. Usually, newborns with Prader-Willi syndrome
have low muscle tone making them extremely floppy. They have a poor sucking reflex, which makes
it hard for them to take milk, and can have failure to thrive which means that they have
poor weight gain. By late infancy, eating gets better, but then
turns into overeating because the child feels hungry even with a full stomach – a problem
caused by dysfunction of the hypothalamus. Without restricting access to food, a child
with Prader-Willi can becomes morbidly obese, which can lead to other conditions like type
II diabetes and obstructive sleep apnea. Children often have distinct physical features
like almond-shaped eyes, a narrow forehead, and a thin upper lip as well as small hands
and feet. They can also have developmental delay and
a low IQ. In Prader-Willi, the hypothalamus has issues
secreting gonadotropin releasing hormone and growth hormone releasing hormone as it should,
which can cause decreased sex hormone levels and short stature, respectively. Now, with Prader-Willi, there’s a mutation
in the Prader-Willi gene region on the paternal chromosome. But one thing to be aware of, is that a mutation
to the same region of genes on the maternal chromosome can affect a gene called UBE3A,
which is only expressed on the maternal chromosome and imprinted on the paternal. If this happens, it causes Angelman syndrome,
which results in severe intellectual diability, seizures, and ataxia. This region, therefore, is more accurately
called the Prader-Willi/Angelman region—paternal mutations leading to Prader-Willi syndrome,
and maternal mutations lieading to Angelman syndrome. Diagnosis of Prader-Willi is done by looking
for evidence of a genetic mutation linked to Prader-Willi. For treatment or management, it’s often
necessary to restrict the amount of food that a child with Prader-Willi eats, and this is
often done by locking the refrigerator and cupboards. In addition, giving growth hormone can help
improve overall height and lean body mass. Unfortunately, there is no medicine or surgery,
that has worked to control the overeating. Alright, as a quick recap, Prader-Willi syndrome
is an imprinting disorder, where mutations on only the paternal copy of a chromosome
causes the disease. In infancy it causes low muscle tone and poor
feeding, and then in childhood it causes overeating which can lead to obesity, as well as inadequate
genital development and low IQ. Thanks for watching, you can help support
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  1. Such a great video as always!! Random question, but will you be posting the downloadable script? I saw that some of your videos have them and they're so helpful I don't want to miss it! Thanks!

  2. Mystery Diagnosis did an episode about a boy with Prader-Willi syndrome called "The boy who couldn't stop eating." You can find it on YouTube.

  3. PWS – is a mutation in chr 15 which leads to over production of ghrelin, is a polypeptide produced by GI cell which act on hypothalamus and stimulate appetite therefore PWS leads to morbid obesity ! This is my simple understanding about PWS

  4. thanks
    you are my hero …………..
    we took this lecture today , no one could understand anything from our professor .
    then I suggested to my classmates to try to find video about this syndrome in your channel .
    everyone one in my class thankful for you and your great explanation .

  5. Thank you, very informative. My daughter has isodicentric chromosome 15. I'd love to learn more about it from you guys 😉

  6. THANK YOU SO MUCH Osmosis you are really awesome ! this video really really helped me , i've been trying to understand genetics since months thank you and keep it up ! i am watching a lot of your videos ❤

  7. I think its wrong to call it an imprinting disorder, since imprinting of the maternal chr. 15 is a NORMAL thing. PWS occurs most commonly due to a DELETION on the paternal Chr.15 so its actually due to a deletion, well at least most commonly due to a deletion.

  8. When the allel inherited from mother is silenced/inactivated , it is known as maternal genomic imprinting.
    So in Prader Willi disease the basic underlying pathology lies in MATERNAL genomic imprinting, not PETERNAL.
    Am I right?

  9. Great video!!
    On a side note though, non-disjunction in meiosis II can also lead to two copies of maternal ch#15 in the mother's egg.

  10. Guys can u help me
    If paternal imprinting occurs it causes prader willi syndrome?
    If maternal imprinting occurs does it cause angelmann syndrome?

  11. excellent video.!!! Was looking for imprinting and found this. Didnt need to look for other videos for further explanation.

  12. Sorry for my ignorance, I’m just finding out about this and I’m interested since I’ve seen these behaviors many times before. If there is no medicine or surgery, are there at least therapies to control the urges to eat at all times?

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