In this lecture, we're going to discuss the Fragile X Syndrome.
So Fragile X Syndrome is a trinucleotide repeat disorder.
Basically, it has a bunch of CGGs
all repeating in the promoter region of FMR1 gene.
So what this does is it causes abnormal methylation
and silences the FMR1 gene.
The loss of FMRP protein results
and that critical in brain and testicular development.
The more repeats that there are
and this happens in subsequent generations of the disease,
the worse the disease gets.
So this is the most common genetic cause
of intellectual disability that's inherited.
It features facial features that are long in face
and these patients often have a prominent chin and prominent ears.
Also, they may develop macroorchidism
and large testes and that presents typically at puberty.
Females with the disease are 1 in 4,000 to 6,000 live births.
They may have more than 200 repeats on one allele
and they are much less severely affected than males.
This is because they have another x chromosome.
Females may present with mild intellectual disability
and the female cells turn off one x chromosome by methylation.
So, the severity depends on how many of the fragile X side are off
or how many of the good x chromosomes are off.
So, in males, the rate of the disease is 1 in 3,600 to 1 in 4,000 live births
but they are much more severely affected than females
and thus, we often think of this as a male disease.
If we see a patient with Fragile X, how do we diagnose it?
Well, generally what we'll do is molecular testing,
specifically testing that will count the CGG repeats within the target gene.
We basically analyze FMR1 gene methylation as well.
We also get ultrasound in this patient
specifically an echo to rule out cardiac abnormalities
and there are many different cardiac abnormalities that can arise
but primarily we're talking about aortic root dilatation
or may be mitrovalve prolapse.
So there's a few things we need to remember about Fragile X Syndrome.
Remember primarily, big ears, big testes,
a common cause of inherited intellectual disability.
Next, it's a CGG repeat disorder in the promoter region of FMR1.
More than 200 repeats in one allele in a female makes the diagnosis.
This is the most common cause of inherited intellectual disability.
Keep in mind that subsequent generations get worse
because they have more and more trinucleotide repeats.
In the first or early on in the generations of disease,
there's a phenomenon known as dementia from Fragile X.
This can happen in that the patient will have a generally normal life
and develop early onset dementia.
So that's a rare cause of picked-up dementia in the elderly
and you'll diagnose it often by younger generations from that person
who have more severe disease.
It's less severe in females significantly due to X inactivation
and there is variable penetrance
because it depends which x is being inactivated the most.
Also, remember the findings that are key are the long face,
the large chin, the large ears and the large testes.
So that's a quick review of Fragile X Syndrome.