What does the future hold for Hunter Syndrome patients?

We've covered the treatments for Hunter Syndrome currently available today, but what does the future have in store?

Today, I'd like to highlight two promising methods to treat Hunter Syndrome.

Hematopoietic Stem Cell Transplantation

Hematopoietic Stem Cell Transplant (HSCT) therapy is the transplantation of healthy stem cells, which contain a working copy of the IDS gene, which is responsible for Iduronate-2-Sulfatase production, into the body of a patient with Hunter Syndrome. 

These transplanted stem cells would then take root in the patient's body in a process called engraftment and then develop into other healthy blood cells which produce the enzyme I2S.

HSCT therapy is nothing new though, bone marrow transplants (A rich source of hematopoietic stem cells) have been a mainstay treatment for certain cancers such as leukemia for many years now.

Due to advances in surgical and treatment procedures, what was once considered a high risk operation is now gaining ground as a potential frontline response to genetic diseases like Hunter Syndrome

A bone marrow transplant, one of the most common forms of HSCT therapy

The advantages of HSCT therapy include

• Only one treatment is needed if engraftment is successful the first time
• Donated stem cells will differentiate into cells which continuously produce the enzyme I2S, which better mimics normal secretion by a healthy person
• These cells are not limited to areas with good blood circulation, therefore the enzyme will be able to access hard to reach places such as the brain or the joints

In addition, a study comparing the effectiveness of HSCT therapy and enzyme replacement therapy found that both were equally effective in restoring growth rates in young patients, meaning that HSCT therapy could potentially serve as an alternative form of treatment to enzyme replacement therapy at a fraction of the cost.

However, one of the major downsides to HSCT therapy is transplant associated mortality due to the immunosuppression of the patient during the course of the treatment as well as the associated risk of rejection of the transplant.
As of 2002, approximately 6% of patients who went through HSCT therapy did not survive the operation, making this a relatively high risk procedure reserved for treatment of diseases which have even higher rates of mortality.

In the future, advances in medical technology and healthcare will likely further reduce the mortality rate associated with HSCT therapy, and thus see an increase in widespread usage of HSCT therapy to treat genetic diseases such as Hunter Syndrome.

Gene Therapy

In gene therapy, a working copy of the IDS gene must be administered to the patient, get to the cells that need repair, enter the cell and integrate the working copy of said gene into the X chromosome, which then is able to produce the enzyme normally. 

This is normally done by engineering a virus or other carrier molecules called vectors to carry a functioning copy of the IDS gene. 

The vector is then administered to the patient, where it then enters the cells carrying the defective IDS gene and replaces it with a working copy.

This would mean that a successful integration of a working copy of the IDS gene into the X chromosome of the patients cells would allow them to produce the enzyme I2S like a healthy person would.

The advantages of gene therapy are the same as those of HSCT therapy, since both restore the body's ability to produce the enzyme I2S naturally.

Gene therapy does have an edge over HSCT therapy as there is no need for immunosuppression throughout the procedure, meaning the patient is at less risk of being caught with his pants down by an opportunistic infection.

In addition, there is no risk of Graft versus Host Rejection, an extremely painful condition that is a potential side effect of any transplantation.

A basic diagram of gene therapy

The tricky part is getting the gene to integrate with the chromosome in the first place, as it's possible for the inserted gene to not enter the chromosome but still produce the enzyme anyway.

This lack of integration is called transient expression, and as it suggests, only results in temporary improvements as the working gene is not passed down to the next generation of cells.

In addition, getting the gene into the right place in the chromosome is a problem in itself, as inserting the gene into the middle of another gene sequence will cause a whole host of other problems, such as the disabling of other genes or deactivating some cancer suppression genes, just to name a few.

Another potential problem is the cost associated with such therapies.

As gene therapy is still a fairly new field, more research is needed to develop new technologies and biopharmaceutical processes that will hopefully reduce the hefty price tag associated with such treatments.

To date, there is only one clinically approved gene therapy treatment (Glybera, used to treat lipoprotein lipase deficiency) and it comes with a whopping cost of US $1.6 million PER treatment, making it one of the most expensive therapies available today.

With the growth of the biomedical sector worldwide, I expect that the field of gene therapy will continue to grow as well, perhaps one day leading to a revolutionary discovery that would allow gene therapy to be widely available to people from all walks of life.

Thanks for sticking with me for this long, I hope I've been able to teach you at least a little about Hunter Syndrome!

Source: 

http://www.researchgate.net/publication/264245057_Impact_of_Enzyme_Replacement_Therapy_and_Hematopoietic_Stem_Cell_Therapy_on_Growth_in_Patients_with_Hunter_Syndrome
http://www.citelighter.com/science/health/knowledgecards/bone-marrow-transplant
http://www.oncolink.org/treatment/article.cfm?c=15&id=323

http://www.haematologica.org/content/89/10/1238
http://www.bionews.org.uk/page_204696.asp

Treating Hunter Syndrome

Like most genetic disorders, Hunter Syndrome has no known cure at the present day. 

Instead, treatments for Hunter Syndrome are palliative in nature, that is, they focus on treating symptoms and making life generally more bearable for the patient.

These can include

• The use of mechanical respirators to aid breathing and to prevent sleep apnea
• Surgically removing enlarged tonsils to clear the airway and make breathing easier
• Physiotherapy to maintain joint flexibility even as Glycosaminoglycans accumulate in the joints
• Installing a shunt to drain fluid buildup in the brain, which may be applying pressure to certain parts of the brain
• Replacing heart valves that no longer function properly

These treatments generally occur throughout the patients life as they do not address the root of the disorder, which is the body's inability to produce the enzyme iduronate-2-sulfatase.

Fortunately, new forms of treatment have been developed to combat this disease.

Enzyme replacement therapy is exactly what it sounds like, introducing a purified form of the iduronate-2-sulfatase enzyme into the body of a patient to increase the concentration of the enzyme in the body.
First undergoing clinical trials in 2006, idursulfase (under the trade name Elaprase) is now the main method of managing Hunter Syndrome.

The purified I2S enzyme is injected into the patient to restore lost function

Enzyme replacement therapy is not without it's downsides though.
One of the main problems with enzyme replacement therapy is that it's a very expensive drug,
Patients have to be injected with idursulfase once a week for the rest of their lives, and each little vial of the drug is already costly in itself.
Treating a single patient for a year is estimated to cost a whopping US$375,000 per year!

Since the drug is delivered through the bloodstream, this also means that the enzyme is also unable to reach certain parts of the body that are not well connected to the circulatory system or consist mainly of hard connective tissue.
In particular, the drug is unable to penetrate the blood-brain barrier to relieve symptoms in the brain, which means that enzyme replacement therapy is only marginally effective at reliving neurological symptoms associated with Hunter Syndrome.

What about the other methods of treating Hunter Syndrome though?
We'll talk more about that in the next post!

Next up: The future of Hunter Syndrome treatment

Sources:
http://hunterpatients.com/managing-hunter-syndrome/managing-symptoms/
http://www.mayoclinic.org/diseases-conditions/hunter-syndrome/basics/treatment/con-20026538
http://www.forbes.com/2010/02/19/expensive-drugs-cost-business-healthcare-rare-diseases.html

Diagnosing Hunter Syndrome

With a greater understanding of just how serious Hunter Syndrome is, it's pretty obvious that the earlier this disease is diagnosed, the better it is for the patient right?
But have you ever wondered how this disease is diagnosed? Fret not, because that's what I'll be blogging about today!

First, a quick recap on the basics of Hunter Syndrome

• A genetic disease that causes a deficiency in the enzyme iduronate-2-sulfatase
• X-Linked recessive disease, guys are more likely to be affected by this disease
• Most commonly results in an affected individual when the defective X chromosome is inherited from a carrier mother.
• Rare, with approximately 1 in 150,000 males affected worldwide
• This enzyme deficiency has a wide range of effects on the body

Common inheritance patterns of Hunter Syndrome

There are two main types of diagnosis for this disease.

The first, Pre-natal diagnosis, is done before the child is born when prospective parents suspect that their child might have a defective gene, generally due to either side having a medical history of Hunter Syndrome in their families.

This is mainly done through amniocentesis, where the fluid surrounding the fetus is sampled to obtain the amniotic cells present inside. These cells contain the genes of the fetus, which can then be karyotyped to check if the fetus does have Hunter Syndrome.

However, sometimes some children develop Hunter Syndrome even though their parents have no history of the disease.

These children are usually diagnosed in the early stages of development (1-2 years) but some only develop symptoms in their early 20s

Some of the more common symptoms that serve as warning signs are

• Changes in facial features such as broadening of the nose bridge
• Enlarged spleen or liver
• Skeletal deformities

However, these symptoms alone do not mean that the child does have Hunter Syndrome.

To confirm the diagnosis, doctors prescribe several laboratory tests, the most common being 

• Blood tests for iduronate-2-sulfatase activity
• Urine tests to measure the amount of Glycosaminoglycans in the urine

In addition to these, genetic testing can also be done to check for the presence of  a defective I2S gene.

That's all I have for you today,

Next up: Treating Hunter Syndrome

Sources:

http://ghr.nlm.nih.gov/handbook/illustrations/xlinkrecessivefather

http://ghr.nlm.nih.gov/handbook/illustrations/xlinkrecessivemother

http://rarediseases.about.com/cs/huntersyndrome/a/022204.htm

http://www.mayoclinic.org/diseases-conditions/hunter-syndrome/basics/tests-diagnosis/con-20026538

http://nursingcrib.com/wp-content/uploads/2014/06/amniocentesis.jpg

The Systemic Effects of Hunter Syndrome

Hunter Syndrome can have a wide range of effects on the body, and not many of them are good.
This might seem ironic since the cause of Hunter Syndrome is pretty much just a missing enzyme in a lysosome, but once you consider how this enzyme is used all over the body, the wide ranging effects of Hunter Syndrome start to make sense.

Some of the more prominent physical changes in a Hunter Syndrome patient

Hunter Syndrome will also result in several physical changes as a patient grows, which are easily identifiable and characteristic of the disease.

• A prominent forehead and nasal bridge
• Thickened tongue
• Shorter stature due to bone deformities
• Broad chest
• Abdominal hernias, where some organs protrude out of the body cavity

Hunter Syndrome is know to affect large swathes of the body, some of the most commonly affected systems are

• The Nervous System
• The Skeletal System
• The Respiratory System

Effects on the Nervous System

The accumulation of Glycosaminoglycan(GAG) molecules in the brain interferes with the complex, delicate biochemical pathways involved in brain development. As the early years of a child are one of the most important periods of brain development, this usually results in stunted mental development, profound mental retardation as well as loss of certain cognitive functions.

Accumulation of GAG molecules can lead to irreversible mental retardation if left untreated

In addition, there may be a buildup of excess fluids in the brain, pressure from these fluids are known to affect the eyes as well as certain sections of the brain. This can cause severe headaches, interfere with vision and lead to various behavioral changes

The membranes that surround the spinal cord may become thick and scarred due to an excessive buildup of GAG around it. This causes pressure and compression of the upper spinal cord leading to fatigue in the legs and gradual weakening.

Effects on the Skeletal system

By far the most commonly affected system, all Hunter Syndrome patients experience some degree of skeletal problems, with the most commonly affected being

• The major joints such as the shoulder, elbow, wrist, hips and knees
• The skeletal structure

Accumulation of GAG molecules on the joints reduces the range of motion that joint is capable of, causing stiffness, reduced flexibility and possibly compressing the nerves around that area

This can lead to other secondary symptoms such as carpal tunnel syndrome.

The bone structure may also be deformed by excessive accumulation of GAG molecules, which generally results in stunted growth, broadening of the ribcage and of the skull.

Effects on the Respiratory and Circulatory System

One reason Hunter Syndrome can be extremely debilitating is due to tissue swelling caused by accumulation of GAG molecules. This is especially serious where the respiratory and circulatory system are concerned, as these systems are responsible for the distribution of oxygen around the body.

Common symptoms of respiratory stress include an enlarged tongue and thickening of the nasal passages and windpipe, which all serve to make breathing difficult by obstructing the flow of air into the lungs.. Respiratory infections and pneumonia are common side effects of this as well. Sleep apnea, a condition in which breathing is intermittently interrupted during sleep, is also often a common occurrence due to airway constriction.

Another effect of tissue thickening associated with Hunter Syndrome is the gradual thickening of the blood vessels in the heart.

In particular, the aorta and other associated blood vessels progressively get narrower, which leads to serious side effects such as heightened blood pressure levels.

If the heart valves are affected by this thickening, they may no longer be able to function normally due to the now irregular shape preventing proper closure of these valves. As a result, the heart is unable to efficiently pump blood to other parts of the body. This condition will gradually worsen and eventually lead to heart failure.

Heart valves are particularly susceptible to GAG buildup,
this can interfere with how the heart pumps blood to the rest of the body

So as you can see, Hunter Syndrome is an extremely debilitating disease which causes a whole lot of problems if left unchecked. Fortunately, with early diagnosis, many of these symptoms can be relieved to some extent.

But how exactly do we diagnose this disease?

Next up: Diagnosing Hunter Syndrome

Sources:
http://www.sleepapnoea.respironics.eu/media/what_is_osa.gif
http://images.medicinenet.com/images/ccf/42350_heartvalves.jpg

http://www.mayoclinic.org/diseases-conditions/hunter-syndrome/basics/complications/con-20026538

http://rarediseases.about.com/cs/huntersyndrome/a/022204.htm

The Biochemistry behind Hunter Syndrome

Welcome back everyone, today we'll be going over the molecular details of Hunter Syndrome and the effects it has on the body.

Connective tissue, the stuff that holds our organs and other fleshy bits together in our body, is composed of a vast network of scaffolds called the extracellular matrix. 

As with all living things, this meshwork needs to be constantly broken down and replaced to allow for continued growth. 

This is achieved by replacing molecules called proteoglycans, which function as building blocks of this framework.

Proteoglycans are broken down by enzymes in the lysosome into complex molecules called GlycosAminoGlycans, or GAGs, which are then processed further into simpler molecules.

However, in patients suffering from Hunter Syndrome, the enzyme iduronate-2-sulfatase (I2S) is either completely inactive or partially working and as a result, the body cannot properly break down two GAGs, Heparan Sulfate and Dermatan Sulfate.

Heparin Sulfate, one of the GlycosAminoGlycans involved in this nasty syndrome

Because of this, these two types of GAGs begin to accumulate in cells and interfere with other biochemical processes and bodily functions.

How does this interference affect the body though? And how serious is this disease really?

Find out in my next post.

Next up: The System-wide effects of Hunter Syndrome

-Abraham

Sources: http://www.sigmaaldrich.com/content/dam/sigma-aldrich/life-science/biochemicals/migrationbiochemicals1/heparinase_heparin.gif
http://hunterpatients.com/hunter-syndrome-basics/biochemistry/

The genetics of Hunter Syndrome

Welcome back everyone, today we'll be talking about the genetics of Hunter Syndrome and how it is passed down from one generation to another.

Hunter Syndrome is a genetic disorder, that is, it can only be 'caught' through your parents. But what are the chances of you getting this disease?

To understand this, we have to first understand the genetics of this disease.

Hunter Syndrome is an X-linked recessive disorder that is caused by a defective gene (IDS) on the X chromosome that codes for an enzyme called iduronate-2-sulfatase (Remember this name, we'll talk more about this enzyme later).

The 46 chromosomes in a normal human, now in a nice picture.
The affected X chromosome is highlighted in red

Since this disease is X linked, guys(XY) are more likely to be affected by this disease as girls(XX) have a backup gene on their other X chromosome even if they inherit a defective copy of the IDS gene.

However, since one of their X chromosomes has the defective gene, these girls are said to be carriers.

Guys don't have this backup plan though, since they only have one copy of the X chromosome so if they do inherit a defective copy...

Tough luck eh?

Since this disease is X-linked, inheritance patterns will depend on how affected the parents are.

Obviously, if both parents are affected, all their children will also be affected, but what about carrier mothers?

  

Are there any other possible inheritance patterns? Let me know what you think in the comments section!

Next up: The Biochemistry of Hunter Syndrome

Source:

http://ghr.nlm.nih.gov/handbook/illustrations/xlinkrecessivefather

http://ghr.nlm.nih.gov/handbook/illustrations/xlinkrecessivemother

https://www.mun.ca/biology/scarr/Human_Karyotype.html
http://www.eurogentest.org/index.php?id=623
http://ghr.nlm.nih.gov/handbook/inheritance/inheritancepatterns

What is Hunter Syndrome?

Hunter Syndrome, or Mucopolysaccharidosis, is an X-linked recessive genetic disorder that affects the body's ability to digest and break down certain types of sugars.

This disease occurs when a crucial part of a cell's machinery, called the lysosome, is unable to properly digest some molecules we need to function, leading to the accumulation of toxic substances inside the cell. Over time, these toxic substances poison the body and lead to serious complications such as mental retardation, skeletal changes and progressive deafness.

Little lysosome can't eat certain things though. And that's terrible :(

Hunter syndrome is a relatively rare disease, with approximately 1 in 150,000 males being affected, however, there are very few options available to treat this disease other than through symptomatic and palliative care.

Advances in medical technology and stem cell research have made stem cell transplants a potential avenue of treatment, while improvements in biological manufacturing have made enzyme replacement therapy a possible treatment option as well.

Now that you have a basic understanding of Hunter Syndrome, let's go into greater detail!

Next up: The Genetics of Hunter Syndrome

-Abraham

Sources:
http://fc06.deviantart.net/fs51/f/2009/289/c/1/Lysosome_Love_by_JynxMerlin.jpg
http://rarediseases.about.com/cs/huntersyndrome/a/022204.htm