In this video we'll get a quick overview of fragile X syndrome. So this is a genetic disorder that causes intellectual disability, behavioral and learning related challenges. so when the X chromosome of these fragile X syndrome patients are seen under the microscope one can see a fragile end and that is basically the X in the fragile X syndrome and we'll try to understand why this occurs and what's the molecular basis of this so the occurrence of fragile X syndrome is one in 4,000 males and one in 7,000 in females so it's more common in males in a moment it would be clear But let me tell you that this is the most common inherited cause of intellectual impairment just after the Down syndrome. So basically, Fragile X syndrome is occurring due to a mutation in the gene that lead to the production of fmr1 protein and this is located in the x chromosome so normally the fragile x mental retardation protein is produced from this gene and in this particular scenario due to a mutation there is an abrogation in this protein production and also since this protein is not important for the brain activity in the normal scenario the normal activity of the brain is altered which leads to mental retardation and social problems So, Fragile X syndrome is X-linked genetic disorder. This is important to understand. And that is why males are more susceptible to develop this disease compared to the female because they have only one X chromosome. Okay, let's talk about the distinct physical characteristics of Fragile X syndrome. So, there are several behavioral issues, but also the physical characteristics are distinct. Generally, these patients have long face, abnormally large ears. prominent jaw and forehead. So the intellectual disability, learning disabilities, attention disorder, these are common in this particular disease. It's very common intellectual disability disorder just after the Down syndrome. So, these individuals show hyperactivity, social anxiety, repetitive behavior like playing with a toy all the time or doing some sort of hand gesture or some kind of like a gesture very repetitively and there are social withdrawal that these babies doesn't like to play or interact with the other child of the same age group. Also, these individuals have delayed speech and language developmental problem. So now let's try to understand the molecular basis in a bit more details. So in the X chromosome, there is FMR1 gene. And in the 5'UTR of the FMR gene, that means the untranslated region of the FMR gene, there are multiple CGG repeats. Now, normally, there are like 5 to 44 CGG repeats. That's okay. And this is important for the function of the gene. And this is how normally this gene is regulated. But sometimes this repeats. CGGs occur more in number and this is due to a problem during the process of replication. Anyway, there are intermediate, pre-mutation and full mutation kind of changes. So, in case of full mutation, these CGG repeats are more than 200 in number and that lead to pathogenic situation where the protein is non-functional. So, when there are so many CGG repeats, what happens is there is basically methylation of these CGG residues and these methyl group often lead to heterochromatinization. That's why some part of the chromosome where the FMR1 gene is becomes extremely heterochromatinized and condensed. And that makes it appear like a brick in the tail of the X chromosome. and thereby the fragile X name was given anyway let's talk about the normal function of the fragile X mental retardation protein because once we understand how this protein is important in context of brain development we can understand the disease pathology better So, first of all, Fragile X mental retardation protein is important for mRNA translation at the synapses. So, it binds to specific mRNAs, particularly those mRNAs which are involved in synaptic plasticity which modulates specific synaptic activity and synaptic strengthening. Also, it regulates dendritic mRNA transport and localized translation at the dendrites. So, FMRP binds to mRNAs and facilitates their transport in the dendritic spines which are site for synapse formation. And point number three is synaptic structure and the overall dendritic arborization is regulated by fragile X mental retardation protein because once this protein is non-functional or mutated in this case it has been seen the dendrites are abrogated. Lastly, it regulates synaptic plasticity. Generally, FMRP is reported to regulate long-term potentiation, also long-term depression. So, all these categories of function somehow lead to the synaptic plasticity, synaptic architecture and neuronal connectivity. That kind of explains why there are mental problems in these patients. okay delving deeper into the neuronal insight this is how a normal neuron look like if you zoom into the dendrites there are multiple dendritic spines and if you notice these mushroom like protrusions are known as mushroom spines exactly due to their morphology but these are mature synapses they would be able to form mature synapses and functional synapses but in fmr1 knockout neurons in mouse model has shown that often you these synapses are immature and dysmorphic in shape and that has a lot to do with how the synapses are formed and how the synaptic plasticity is altered now let us delve into the molecular details so generally there are specific receptors known as bmp receptors shown here in red in the dendritic postsynaptic membrane there are lim1 kinase which inhibits the cofilin activity and ultimately it lead to the polymerization of actin. So a balanced inhibition of lim-1 kinase on cofilin is important for a proper polymerization of the actin and dendritic formation. So what happens in FMR1 knockout or when there are when mental retardation when FMR protein is non-functional is basically lim-1 kinase pose a strong inhibition on cofilin. That means the actin the the Actin cannot be severed. That means there are more and more actin polymerization which lead to an altered dendritic formation. So this is still a speculation that altered actin polymerization is associated with altered dendritic spine formation. So I have linked an article which describes all these detailed things in the description. Definitely check it out. So when it comes to the overall architecture of the brain, these mental, these basically fragile eggs babies shows a bigger size, slightly bigger brain size and dilated ventricle. So, enlarged head and dilated ventricle is pretty common in these babies. But this is not a differential feature because these kind of changes are often seen in patients with autism. So, autistic child has oversized brains and dilated ventricles, that's pretty common. Now, one of the structure that is getting affected in this particular case is the basal ganglia. And in the basal ganglia specifically, the caudate nucleus, which is the part of the basal ganglia, gets bigger in size. And these are the MRI findings that was found from the Fragile X syndrome babies. Now let's talk about the circuit activity. Now neurological alterations that is common in these patients are disrupted excitatory inhibitory balance. Now this has been figured out from the fmr1 knockout mouse models. Generally, in any neuronal circuit, there are excitatory and inhibitory drive. So, these blue ones are the excitatory neurons, these red ones are the inhibitory neuron. A proper balance and interaction between them is important. But what happens is in... In case of FMR1 and FMR1 knockout or the fragile X syndrome or many other autism related disorder, this circuit activity is disrupted. Too low activity or too high activity in the neuronal circuit is not good. A balanced level of activity is required. Disruption of these excitatory and inhibitory balance lead to alteration in the processivity of these synapses or these circuits. Often it increases susceptibility towards seizure. So uncontrolled activity in these patients often results in seizures. Now, one of the reason why there is an uncontrolled activity can be understood if we look at the synapse in bit more details. So the GABAergic synapses, that means the inhibitory synapses are bit non-functional because in the post synapse of the inhibitory synapses, there are GABA-A receptors which has several subunits and many of these subunits are bound to FMR1 protein in the normal scenario. So one can imagine when there is a mutation in these fmr1 gene which lead to faulty protein production would reduce these mrna expressions right or reduce the localization of these mrna into the synapses that leads to an alteration of gabardic inputs or gabardic functionality in a function in a neuronal circuitry you that means when the inhibitory drive is low automatically the excitatory drive would be high and all these information are obtained from the specific knockout mouse models when it comes to the inheritance pattern of fragile x syndrome this is x linked inheritance we already talked about it so males are more susceptible to develop this disease compared to the female female often becomes the carrier you Diagnosis can be done with looking at the distinctive facial features that we have mentioned earlier like longish face and then the big ears, prominent jaw ridge and the forehead expansion. Examination of the family history is important because it's a genetic disorder but ultimately genetic testing is the most important and confirmatory test for this. Looking at the number of CGG repeats is the key or the It's basically the basis of the deterministic diagnosis for Fragile X syndrome. There is no treatment available for Fragile X so far, but since the GABAergic signaling is altered, people are trying to impose more and more GABA agonist on. There are many clinical trials which try to improvise the GABAergic input and tamp down the excitatory overdrive in the circuits. But still, those are in clinical trial. So, what is the overall management? So, since this child doesn't talk that much, there could be important speech therapy, language therapy, there could be genetic counseling and supportive medications like SSRIs, dopamine agonist, all these kind of things can improvise the scenario a little bit. But these are all ways of managing the symptom, not curing the symptoms. So, I hope this video was useful and informative. If you like this video, give it a quick thumbs up. Don't forget to like, share and subscribe. We also post many notes and flashcards in our Facebook and Instagram page. Do check them out. And please share these videos with your friends. See you in next video.