Hi guys. we meet again after a long break. I know you guys miss me right? Because i miss you guys too!!. 

Ok now lets move on to our next topic. Can you guess what it is about? Hurm?..

.......................................................................................................................

Yeah correct.!! It is about promising research on Huntington Disease.

Ohh before we start, I'm so sad to announce that this will be our last topic that we discuss 

on Huntington Disease for this blog😢😢😢. Hope you guys will not dissapoint me by 

skipping this contents..

Now lets start on our topic.

According to the research done by the researchers from the University of British Columbia (UBC) and their colleagues on June 13, 2019, they have demonstrated for the first time that the drug, IONIS-HTTRX now known as RG6042 hereafter referred to as HTTRx successfully lowered levels of the mutant  huntingtin (mHTT) protein. HTTRx is a chemically modified synthetic oligomer that is perfectly complementary to a 20-nucleotide stretch of HTT mRNA. HTTRx binds to HTT mRNA by means of Watson–Crick base pairing, with hybridization resulting in endogenous RNase H1-mediated degradation of the HTT mRNA, thus inhibiting translation of the huntingtin protein.

Wait !! But, what is mutant huntington (mHTT) protein?

Mutant  huntington (mHTT) protein is the toxic protein that causes Huntington's disease in the central nervous system of the patients.

During the research, the trial enrolled 46 patients with early HD at nine study centres in Canada, the United Kingdom, and Germany. Of the 46 patients, 34 were randomized to receive the drug and 12 were randomized to receive placebo. Each participant received  HTTRx or placebo as a bolus intrathecal administration every 4 weeks for four doses and all study participants completed the study and have continued to receive the active drug in an ongoing open-label study.

The drug was administered monthly to patients via an injection directly into the cerebrospinal fluid. A cerebrospinal fluid (CSF) sample was obtained before each administration of HTTRx or placebo and either 4 or 8 weeks after the last dose was administered. The researchers, led by Dr. Sarah Tabrizi, director of the Huntington Disease Centre at University College London and global chief investigator of the IONIS-HTTRX clinical trial, found that the drug produced significant decreases in the levels of mutant huntington protein in the patients’ cerebrospinal fluid. No study participants experienced serious adverse reactions, suggesting that the treatment is safe and well tolerated by patients. In conclusion, they found that the antisense oligonucleotide drug HTTRx reduced the concentration of mutant HTT in the CSF of persons with Huntington’s disease. More generally, they found antisense-mediated protein suppression in the central nervous system of patients with a neurodegenerative disease.

The drug is currently being evaluated in a large, phase-three multi-centre clinical trial being performed at the Centre for Huntington Disease at UBC and other HD centres around the world. This study is designed to determine whether the treatment slows or stop the progression of the disease symptoms.

Ok guys, thats all for this time. I hope you guys can understand my explanation. If you guys want to
know detail about this research, just click link below

References : https://www.nejm.org/doi/10.1056/NEJMoa1900907

Hi guys, welcome back to our blog.

Before we discuss deeper about this disease, beware of disclaimer below.👇👇

if you are feeling that you want to stop reading right now since im telling you its complicated.  

DONT STOP !

do you give up when everything starts to become complicated ? no right ?! 

believe that every single knowledge that you learn will eventually lead you to some path that you have never imagine before.  💢

ok enough with motivation so lets start 🙌

today, i will share about you guys something regarding technology used in Huntington disease diagnosis and and treatment.

First thing first is, Technology  used to detect Huntington Disease

The discovery of the HD gene led to a genetic test to make or confirm the diagnosis of Huntington's disease. 

One of technology used to diagnose HD is through genetic testing. In this method, blood sample is used to analyzes DNA for the HD mutation by counting the number of CAG repeats in the huntingtin gene. Individuals who do not have HD usually have 28 or fewer repeats. Individuals with HD usually have 40 or more repeats.

you also can refer table below to know the number of CAG related to huntington disease

Number of CAG repeats and HD outcomes that lead to HD development.

Number CAG repeats	Outcomes
≤28	Normal CAG number; individuals will not develop HD.
29-34	Risk for next generation, although individuals will not develop HD.
35-39	Risk for next generation. Some, but not all carriers will develop HD.
≥40	Individuals will develope HD.

Predictive and diagnostic testing of HD require accurate sizing of the CAG repeat. Thus, PCR-based assays is used for sizing the HTT CAG repeat. It typically involve amplification using primers flanking the CAG repeat region, followed by capillary electrophoresis.

Whenever only a single peak is detected, additional tests such as PCR amplification of the adjacent CCG region and Southern blot are usually performed to exclude PCR amplification failure of large expanded alleles. The negative correlation between repeat length and amplification efficiency represents a significant deficiency of repeat-flanking PCR. Flanking sequence polymorphisms may also cause allele-specific PCR failure and lead to misdiagnosis

In marked contrast, triplet primed PCR (TP-PCR), a strategy that pairs a flanking primer with one that anneals randomly within the repeat to generate different-sized amplicons, produces good amplification and reliable detection of all expanded alleles regardless of size.

This is because TP-PCR products of expanded alleles generate a characteristic CE pattern that can be easily distinguished from the pattern from non-expanded alleles, which eliminates the need to perform labour-intensive Southern blot.

The TP-PCR strategy has been used to successfully detect an expanded allele of >200 CAG repeats, and to detect and size an expanded allele of ~180 CAG repeats.The American College of Medical Genetics and Genomics committee has also indicated that TP-PCR is the preferred method for genetic testing of HD

Seems kinda confusing right?!

if you are feeling rather bewildered right now, you can read further regarding this on this article. 

the link is as below 👇

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0180984

Not only that, other technology which is brain-imaging and function tests also used in HD diagnosis.This brain imaging test allow the doctors to asses the structure or function of the brain in order to diagnose for this disease.

The imaging technologies may includes:

Magnetic resonance imaging (MRI) 

 Computerised Tomography (CT)

               

These images may reveal any structural changes at particular sites in the brain affected by Huntington's disease, although these changes may not be apparent early in the course of the disease. These tests can also be used to rule out other conditions that may be causing symptoms.

THE CHROMOSOMES/GENES INVOLVED

Hi guys, do you still remember me? We talked about the Huntington's disease right previously?

Don't you ever forget that because we might not know that some of you are actually inherited this disease in your body. The previous post might help you to identify if you are having this inherited disease or not. 

So, we already know what it is actually about, it's prevalence and characteristics, symptoms, their unique features as well as how this disease inherited and developed.

Can you all guess what i'm going to share this time?

Noooo, it's still not finish yet. There's few things that we haven't talked about yet😄

Ahaaaaaaaaa!!! Correct!

I'm going to tell you what is the genes or chromosomes involved in this Huntington's disease.

Have you guys  ever wonder what happens to the genes in our body that lead to this disease? What did our genes do wrong in the body which affected our entire life? 😱

Hmm before I start, do you guys know what is the genes? And what is the difference between genes and chromosomes?

Okay, enough with all the questions, I know I ask too many questions right hahaha😂 So now, let me clarify all these things to you.

A gene is a piece of biological information you inherit from your parents. It is present in every cell of the body and tells cells what to do. Genes control cells by producing proteins, each gene is really a kind of recipe for making a certain protein. Genes are usually attached to a chromosome. Chromosome is a strand of DNA containing many different genes. Each human cell contains around 25,000 genes and most have 23 pairs of chromosomes. 

The Huntington's gene, the gene that determines whether you will develop Huntington's disease is attached to chromosome pair number 4. 

Previously, I had mention that this disease developed due to the mutation, isn't it?

Yes, it is due to a mutation in the HTT gene which cause the Huntington's disease. The HTT gene provides instructions for making a protein called huntingtin. Although the function of this protein is unknown, it appears to play an important role in nerve cells which is neurons in our brain. 

The HTT mutation that causes the Huntington's disease involves a DNA segment know as CAG trinucleotide repeat. This segment is made up of a series of three DNA building blocks which is cytosine, guanine and adenine that appears multiple times in a row. Normally, the CAG segments is repeated 10 to 35 times within the genes. In people with Huntington's disease, the CAG segment is repeated 36 to more than 1200 times. People with 36 to 39 times CAG repeats may or may not develop the signs and symptoms of Huntington's disease whereas people with 40 or more repeats almost always develop this disorder. 

Scary right?

But, what makes more scarier is when there is an increase in the size of the CAG segment. This will leads to the production of an abnormally long version of the huntingtin protein. The elongated protein is cut into smaller, toxic fragments that bind together and accumulate in neurons, disrupting the normal function of these cells. The dysfunction and eventually death of neurons in certain areas of the brain underlie the signs and symptoms of Huntington's disease. 

I know you kinda feel anxious and frightened now, but just bear with me a little bit. I want to add some more. 

For you guys information, as the altered HTT gene is passed from one generation to the next, the size of the CAG trinucleotide repeat often increases in size. A larger number of repeats is usually associated with an earlier onset of signs and symptoms. This phenomenon is called anticipation. People with the adult-onset form of Huntington's disease typically have 40 to 50 CAG repeats in the HTT gene, while people with the juvenile form of the disorder tend to have more than 60 CAG repeats. 

Oh wait, what is the juvenile Huntington's?

Juvenile Huntington's is when the genes produces an even larger number of CAG repeats that with adult Huntington's, with the result that symptoms start to appear earlier which is before age of 21. Juvenile Huntington's is quite rare actually, less than 10% of people with the disease will have Juvenile-onset. People with Juvenile Huntington's often experience some symptoms that are quite different from adult Huntington's. If you have it, you are less likely to have the involuntary movements known as chorea. But, you are more likely to experience muscle contractions and stiffness, making the movements more slower and difficult. You may also develop epilepsy or seizures. 

Individuals who have 27 to 35 repeats in the HTT gene do not develop Huntington's disease, but they are at risk of having children who will develop this disorder. As the gene is passed from parent to child, the size of CAG trinucleotide repeat may lengthen into the range associated with Huntington's disease which is 36 repeats or more.  

You can refer to this graph below to help you gain more understanding on how the CAG repeats affect the generation. 

Hold on, we are almost close to the end!

Before I close this chapter for today since I'm already sleepy😴, I leave you with an image. I want you to digest this image clearly until you dream about it okay😉

The image below gives you an idea on how the genes altered which lead to Huntington's disease.

Finally, I'm done! Thank you for bear with me and you can always ask me if you have any curiosity regarding this topic. So,we talk again next time, okay? Have a nice day! 

Bye and assalamualaikum😊

INHERITANCE PATTERN OF DISEASE

Hi everyoneee!!! Welcome back to my blog ☺️

How're you guys doing? I know you must be very happy to be surrounded with your beloved family right.. hmmm I wish I was with them too :( But I cant,, because there is so many things need to be done. When I get up from sleep I immediately do my works for the entire day until they stuck in my mind and interrupt my sweet dreams. Ahh I need to get it done before going back to my hometown next week no matter what. I cannot let them lingering in my mind and keep following me everywhere, it is just so suffocating. 

Anyways,
Have you read my previous post? What do you think of it? 
It is good to know it right??  Because sometimes we just know the name of the disease but we never know what it's like. And sometimes, we see the abnormal signs which indicates the person is having a disease, but we don't know what it is.

Imam Syafi'e has once said, "the more knowledge that I gain, the more I know my ignorance"

So now, I want you guys to concentrate more this time, as I am going to tell you about this topic much deeper. 

Tonight, I want to share to you about how the disease develop, or how it is inherited.

Before we go into detail, let's read basic info about genes and chromosomes:

In all of the cells of our body, our genes are found on chromosomes (long strings of genes). We have many thousands of genes that provide information for our body to grow, develop and remain healthy. The gene sends messages to the cell to make important chemical products such as proteins. There are usually 46 chromosomes in each cell that are arranged into 23 pairs. One of each pair is passed on to us from our mother and the other from our father. 22 of these chromosome pairs are numbered. These numbered pairs are known as the autosomal chromosomes. 

The 23rd pair is made up of the sex chromosomes called X and Y. Since the chromosomes come in pairs, there are also two copies of each of the genes. The exception to this rule applies to the genes carried on the sex chromosomes called X and Y. A variation in a gene that creates a fault is called a pathogenic variant or mutation. Genes are sections of DNA that code for the proteins our body needs to function. A mutation in a gene will affect the body differently depending on how much it changes the resulting protein, how critical that protein is to the body and how much of that protein is needed in the body. 

Ok now, move on to the disease. 

Huntington's disease is an autosomal dominant disorder, whereby one mutated copy of the gene in each cell is sufficient for a person to be affected. This means that a person needs only one copy of the defective gene to develop the disorder. This defective gene is inherited from an affected parent either the mother or the father. In rare occasions, the condition may also result from a new (de novo) mutation in the gene and occur in people with no history of the disorder in their family. With the exception of genes on the sex chromosomes, a person inherits two copies of every gene (one copy from each parent). A parent with a defective gene could pass along the defective copy of the gene or the healthy copy. Therefore, each child in the family has a 50 percent chance of inheriting the gene that causes the genetic disorder. This disease usually begins between ages 30-45. It can also develop in childhood or adolescence, which is the juvenile form of Huntington's disease.

Let us look at the definition of autosomal dominant disorder one by one:-

Autosomal: a gene located on a numbered chromosome and usually affects males and females in the same way. 
(Dominant gene mutation is located on an autosome, one of the chromosomes numbered 1-22).

Dominant: having power and influence over others. 
(Individuals who have a dominant mutation on one gene, and a working copy of that gene on the other partner chromosome, will be affected by that condition despite the working copy. Therefore although one of the gene copies is correctly sending the instructions to make the gene product, the other copy with the dominant mutation is not sending the correct message and overrides the action of the working gene).

Disorder: disease or illness

So, autosomal dominant disorder means, a disease where it develops when a person is having one copy of affected gene on numbered chromosomes. Dominant is different with recessive because, autosomal recessive need both copies of affected gene to develop the disease.

If a person has an autosomal dominant gene mutation, they do not have the ability to make enough of the correct gene product and will have symptoms of the genetic condition from birth or be predisposed to developing the condition later in life. In this case, person with Huntington's disease has mutated HTTgene.

It is hard to just imagine right. Therefore, here I provide you some illustration that can help you understand :). In this illustration, D represents mutated HTT gene while d represents normal copy of HTT gene. 

Dd		Affected by or predisposed to Huntington's disease. This person has the gene pair Dd. This means that one copy of the HTT gene is working and producing the correct gene product however the other copy (D) is not working. They develop symptoms of Huntington's disease. We need both copies of these gene to be working to not have the disorder. When this person has a child, there is a 50% chance they will pass on a working d gene to each of their children and a 50% chance they will pass on the mutated HTT gene which is not working (D)
dd		Unaffected person.          This person has the gene pair dd. This means that both copies of HTT gene are working and they are able to produce the gene product. They will not develop symptoms of Huntington's disease.          When this person has a child, they will only pass on the working gene copy (d)
DD		Affected by or predisposed to Huntington's disease.          This person has the gene pair DD. This means that both copies of HTT gene are not working and none of the correct gene product is being made.          This person has a double copy of a dominant mutation (DD) and is often more severely affected by the condition than someone with just one dominant mutation (Dd)

Where an autosomal dominant gene mutation is represented by ‘D’ and the working gene copy by ‘d’, There are three possible combinations a person could have. This is regardless of whether the person is a male or female.

Autosomal dominant inheritance when one parent carries
the autosomal dominant faulty gene copy (mutated HTT gene)

If both parents carry one copy of mutant gene, each of their children has 25% chance to be unaffected, 50% affected or 25% severely affected

Autosomal dominant inheritance when both parents carry
the autosomal dominant faulty gene copy (mutated HTT gene)

The child who inherits both copies of mutated HTT gene from his/her parents may be more severely affected than their parents, or may not even survive, and/ or have a younger age of onset for conditions that develop later in life, depending on the condition. 

That's all from me! I hope you guys have a better picture of how Huntington's disease inherited from one generation to another. Goodnight and have a sweet dream all!!

REFERENCE : https://www.genetics.edu.au/publications-and-resources/facts-sheets/fact-sheet-8-autosomal-dominant-inheritance

Unusual or unique features of Huntington Disease

Hello everyone!
We meet again this time.😆
I know that today is public holiday.
I am sure that all of you are having a good time be it with friends, family or just with your own-self or we called it me-time, right?🙈
Whatever it is, just be happy and don't forget your duty, okay?
Not to forget, happy deepavali for those who celebrate it!

By the way, do you still remember what we had wrote and post in this blog before?
If not, feel free to click on my last week post and READ IT. 👀

So, now, I want to share with you guys about the unusual and unique features of Huntington Disease.
First and foremost...

1) chorea.
What is that? hurmm..
Surely it is not the name of that well-known country that have a lot of beautiful and handsome artists. 💁

Chorea is jerky involuntary movements.



so, what's next?

2) dystonia
Dystonia is a movement disorder in which a person's muscles contract uncontrollably.



That is for unique motor features. Now, we move to cognitive features.

3) Difficulty in multitasking. It is difficult to organize, prioritize or focus on task. 



4) short-term memory loss



Last but not least, lets see what is the unique behavioural feature. This is more severe.

5) Anxiety



6) Depression.

Depression appears to occur because of injury to brain and subsequent changes in brain function.



Okay, that's all from us.
We hope you get the new knowledge regarding Huntington disease.
See you next time for more interesting info! Bye! ✋😎