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.
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