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Number of rare diseases in Kuwait high

COMMON bone conditions such as osteoporosis are well identified and treated, though rare bone diseases still continue to remain rare. There has been a sudden increase in rare diseases in the Middle East as well. In this interview, Philip Beales, Professor of Medical Genetics, explains the genetic causes of rare diseases and how the UCL Institute of Child Health (ICH) has shed light on a key enzyme involved in the development and maintenance of bone which could help find future therapies to treat rare and common diseases.  LMS (Lenz-Majewski Syndrome) which has been identified by the international study as the mutated gene in people is a skeletal disorder which causes bone malformations and also affects the brain. So far, only ten cases of this syndrome have been identified.

Question: What is a rare bone disease?
Answer: It’s literally numbers in the sense that the condition is present in the population in less than one or fewer than one in 2000 persons. In such cases, it is considered rare. Of course, it is not a very helpful term but it is helpful when you consider that there are around 6000 described rare entities or rare diseases in their own right. So you will find that some of these are clearly incredibly rare, one in a million. So bringing them all together, actually it is a convenient way of addressing what is becoming an unmet need in a large population. The fact that having this disease isn’t very common, most health services aren’t geared up to dealing with people who have this unusual condition, they are more geared up to dealing with blood pressure, diabetes and obesity. One of the problems you will always hear from patients is this diagnostic odyssey is that patients go many years without a diagnosis and that has been the case for a long time. But the changes in the genetic technology has now enabled us to rapidly get to a diagnosis that previously had been left and the care for patients with rare diseases is usually suboptimal for the same reasons that the health services are not geared up to looking after them. But to take care of these patients is a multi team approach.

Q: What are the genetic causes of rare bone disease?
A: As I said, on the web and various databases there are now about six to seven thousand listed rare genetic disorders described in detail. Only 2,300 of those actually have a gene associated with them and the underlying fault in the particular gene. There’s still at least two- thirds of these to be sorted out, but there are a number of international and national programs that are going on where the majority of these conditions will be solved. I think in about 4 to 5 years time from now, we will be able to solve about up to a 5000 out of the 6000. But the benefit of finding the genetic cause of a particular condition, particularly a rare one or even common one is that it’s multi-folded because the first thing is you instantly have a diagnostic test, so not only does it confirm the disease in that patient it also enables a carrier test to be developed for other members of the family who might be at risk, brothers or sisters. And then the final component obviously of understanding the genetic cause of any condition is that it can tell you how that disease arises and what are the developmental processes that cause the disease, which is a prerequisite for thinking about therapies and so now we are getting nearer to many of these conditions and we are able to think about instant therapies or develop therapies like gene therapy.

Q: Is the number of rare disease in Kuwait very high?
A: Yes, it is very high because of the simple fact that the cultural norm is to marry within the family and so it’s not a character problem in any way, it’s simply that you are increasing the statistical probability that you are going to keep, if its what’s called a recessive disease. The number is also high in Bangladesh, Pakistan and India.

Q: How do rare diseases develop? Does it start very early in children or does it come with age-related changes?
A: Depends on the disease; you can have a disease that’s affecting just one part of the body, like the eye in the form of blindness. Some of the conditions I work on have blindness but affects virtually every part of the body, so they would have obesity, diabetes that’s actually one of the most common conditions in the rare disease. A condition called Bardet-Biedl syndrome has been documented on being more common rare disease in this country, and the most common rare disease in Europe is Cystic fibrosis but for the Bardet – Biedl syndrome may be 1 in 50 people or more in this country are carrying it so it’s one of the most common one in Kuwait and so that affects every part of the body. The problems could be obesity, diabetes, blindness, kidney failure, some kids are born with extra fingers and toes. About 5 to 10 percent of the children affected by this disease will not make it to their 5th birthdays.

Q: How does it affect the brain development?
A: Again it depends on which condition it is because if the gene isn’t really active in the brain it won’t have any effect; but again this condition I am talking about Bardet-Biedl syndrome does affect the brain in many ways. First of all, the patients have learning difficulties, they can be mild or severe and the other aspect is that there can be parts of the brain that haven’t formed properly. So they can have balance problems like if it affects the back of the brain. The part called the cerebellum when affected can cause poor coordination. Moreover, by doing MRI scans on the brains of several patients suffering from Bardet – Biedl syndrome has revealed more things. There is a part of the brain called the hippocampus, which is called that because it resembles the seahorse and comes from a Greek word and it’s that part of the brain which is responsible for our memory and intellect.

We found that we can manipulate this part of the brain and correct certain defects, which will improve the condition of patients who will have less learning difficulties later in life so that they can look after themselves. Most of our patients need support later in life, so in other words they are going to be unemployed; they are not going to be able to live by themselves most of the time, but if we can intervene in children then more of them can get to adulthood and become active members of the society and work.

Q: How rare is the rare bone disease?
A: 1 in 17 people in Europe have this disease.

Q: What is LMS?
A: This is the condition called Lenz-Majweski Syndrome, where the patients have intellectual disabilities but they have a bunch of other problems that include an usual phase and major bone problems. Some of the problems are thickening of short and long bones and thickening of bones in the head. These patients are dwarfs and have short limbs, have all sorts of bone problems and very thick bones, but this is incredibly rare and there are only a handful of patients in the world. But by understanding what causes it which is the purpose of this particular study we have discovered for the first time a common component of cell membranes. It has an affect on the development of the brain’ but it also has an effect on the development of the cells that go to make up the skeleton and the important part is that this gives us potential insight into the understanding of causes or treatments perhaps of osteoporosis which is much more common. However, this is the opposite of osteoporosis in the sense that it’s Osteosclerosis. It means that this particular gene is a major player in the way bone is being formed.

Q: How does LMS cause bone malformations?
A: We don’t really know. There is this protein called phosphatidylserine synthase 1 which is an enzyme which is an important part of bone formation. So it’s part of the pathway that leads to bone formation. Not much is known about it so we still have to do a lot of research in this area. But it links for the first time this group of proteins to bones so there could be an opportunity to look at treatment.

Q: Osteoporosis is a more common condition, how has this new discovery at UCL helped with it?
A: It makes the link for the first time between this protein called phosphatidylserine which is a common part of our membrane of all of our cells and bone metabolism. So it is early days but it gives us a new insight into how bone is formed and eventually we expect that by teasing out the pathway in more detail. We will be able to find treatments for conditions such as osteoporosis or other bony conditions.

Q: Is Bardet-Biedl syndrome inherited from parents?
A: Yes it has to be inherited from parents. Parents are carriers so they are not affected in any way because they have one faulty copy of the gene and then the defected child has inherited two faulty copies of the gene but their brothers and sisters who may be unaffected probably are also likely to inherit one copy of the faulty gene.

Q: What were the various challenges you faced during the discovery at UCL?
A: The first challenge was actually finding the gene and that now is driven by our relatively new center that has been running for 3 years, called the Center of Translational Genomics and our job is to find undiscovered genes in problem patients and rare conditions. And the second challenge, once we found the gene was to work out what does the gene do so we are able to get an idea of the gene just by looking at online databases, but we knew what the name of the protein was and where it’s found. So it’s found in the membrane of the cell. The next job was to do some experiments and find the right team which is why I got in touch with the team from the University of Alberta in Canada and so we had to get their expertise to determine what happens if you knock down this particular protein in a cell, so we took patients cells and were able to show that this protein is not functioning properly in those cells and in my own lab we showed that this protein is actually working and for that we used zebra fish because they have the same gene. That helped us understand a bit more.

Q: Will this new enzyme target future therapies?
A: It is the first insight into bony development so this could lead to a whole new area of research around this one protein but we might be able to unearth new treatments to turn this gene on, or turn this gene off.

Q: Why is this rare disease so undiagnosed and misdiagnosed?
A: One because it is incredibly rare, this is the problem with rare diseases there are no experts so a lot of patients keep going from one center to another till they find someone who is interested in their condition and knows something about the condition. So that’s the problem and until then there has been no test, now there is a test.

Q: Do you think that rare diseases are under-researched?
A: Absolutely, yes they haven’t been funded for many years because billions of dollars went into understanding the genetics of common diseases so the rare diseases were completely ignored but now the tables have changed. Now spending millions of dollars on common diseases has not really got so far and now everyone is turning towards rare diseases.

Q: What are the signs and symptoms of LMS?
A: The key manifestations are dental problems and one patient has had to get their tongues removed, because their tongues are very large. They have very prominent foreheads, widely spaced eyes and very thick skulls and very thick jaws as well they have other bony problems, short fingers and stubby toes, abnormal chest, spinal problems. One patient had very loose skin as well. These are the main things and learning difficulties and intellectual disabilities are associated with that as well.

Q: Is it true that too much tea can cause rare diseases?
A: There must be some study that must be saying that drinking some certain type of tea can pull calcium out of the bones, but regular tea can not cause any problems.

Q: Can you shed some light on the discovery and its benefits?
A: Well as I have said earlier on, it has made the first link between this particular enzyme in the cell membrane and bone formation. But that still needs to be worked upon much further but then the expectation that this might be to new therapies for bone disorders such as osteoporosis and bone density disorders.

Q: What message would you like to give the readers regarding bone diseases?
A: Well as its known, the most common one is the thinning of the bones and although there are some treatment around at the moment there is room for better treatment or better ways to avoid osteoporosis so these types of studies, maybe 10 years from now, might tell us that when you are in your 40s or maybe even earlier in your 30s you should start modifying your life in a particular way to avoid bone disease later on but what is known is that maintaining exercise, health and dairy products will help with maintaining healthy bones and teeth and Vitamin D as well. In the northern hemisphere, in the colder climates diseases like Rickets are fairly common until they fortified milk with Vitamin D but also the other thing is that Vitamin D which obviously maintains healthy bones is good to certain level as it can also cause cancer.
We found the genes using our Center of Transnational Genomics. We have transplanted that work here and all of the systems and the pipeline and the analysis software tools are being used here. Now we have discovered five new genes recently in the last few months using that same pipeline at Dasman Diabetes Institute and linking up with Kuwait.


Philip Beales is Professor of Medical and Medical Genetics at UCL and a Wellcome Trust Senior Research Fellow in Clinical Science. He is currently head of Genetics and Genomic Medicine at the UCL Institute of Child Health, Director of the Centre for Translational Genomics (GOSGENE) and head of the Cilia Disorders Laboratory at the UCL. Beales is best known for his clinical and genetic research (17 years) into rare diseases especially, the ciliopathies, leading research culminating in novel gene discoveries for Bardet-Biedl syndrome, Jeune Asphyxiating Thoracic Dystrophy, Cranioectodermal dysplasia, Acrocallosal Syndrome and several other disorders. He was the first to attribute the Bardet- Biedl syndrome phenotype to dysfunctional primary cilia. Beales continues to pursue his interests in early onset obesity, retinal and renal disease and more recently in translational science and therapeutics for ciliopathies.

He is a consultant in clinical genetics at both Great Ormond Street Hospital for Children and Guys Hospital, London and national lead for the NHS England specialist commissioned Bardet-Biedl syndrome clinical and diagnostic service. He is currently a member of the Wellcome Trust Rare Disease Strategy Group and sits on numerous advisory boards including the Mouse and Zebrafish SAB to the Sanger Institute and iRDiRC. Beales is chairman of the UCL Rare Diseases Steering Committee. He is also founding Co-editor in Chief of BMC CILIA and sits on several journal editorial boards. He was elected fellow of the Academy of Medical Sciences in 2011.

By Priyanka K. Oberoi
Arab Times Staff

By: Prof Philip Beales

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