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Neurofibroma Educational Series: Neurofibromatosis type 2: an update
The Comprehensive NF Center @ NYU presents:
Neurofibroma Educational Series: Neurofibromatosis type 2: an update
Communication Access Realtime Translation (CART) was provided in order to facilitate communication accessibility and may not be a totally verbatim record of the proceedings.
Contents
- Meeting Discussion
- Citations / Papers Mentioned
- Questions / Comments Form: Share thoughts and questions with NYU for Future Events
Event Date: 1-31-12
Carole Mitchell:
Hello. And welcome to the NF Education Series lecture. I'm Carole Wind Mitchell and I'm the Nurse Coordinator of the NF Center at NYU. Along with Dr. Jeff Allen, Dr. J. Thomas Roland and Dr. John G. Golfinos, we are part of a multidisciplinary center located at NYU. I wanted to introduce Dr. Jeff Allen to say a few words. We appreciate your being here. We look forward to helping you learn more about genetics. And we wanted to thank Dr. John Pappas also for speaking with us tonight. First I'd like to introduce Dr. Jeff Allen, Director of our NF1 Center.
Dr. Jeff Allen:
We've had a number of presentations in this forum. Some have related to NF1, and some have related to NF2. Tonight is NF2. The center has been in existence for three years -- three-and-a-half years. Carole has been with us for one year. And she's our organizer and coordinator. A number of you know her. Some of you I recognize because you come here for your care. Others I don't. We're very excited to have Dr. Pappas tonight who is part of our program. He will see all of our new patients who need to have confirmation of the diagnosis of NF1 or NF2, and he helps us with the management and the planning. A lot of exciting things are happening in this field here at NYU and nationally. And perhaps we'll allude to some of that during Dr. Pappas's presentation. I don't want to take his valuable time.
A number of you I recognize as patients or family members of patients. And if you are, could you just raise your hand so we know a little bit about what you'd be interested in. And a number of you maybe have just generic interest in these conditions. Am I going too fast? Certainly you're going to learn a heck of a lot tonight. So welcome. Write your questions down. And a number of us will try to answer them. If not, we'll find answers for you.
Carole Mitchell:
To introduce Dr. Pappas. Dr. John Pappas is Board Certified in Pediatrics and Clinical Genetics. He's been practicing Clinical Genetics since 1993 and has been the Director of the NYU Clinical Genetic Services since 2001. While his main interests include accurately diagnosing genetic conditions in children and adults, since his training, Dr. Pappas's interest has been the unusual or partial presentations of genetic syndromes.
His research interests include the study of the differences in the presentation of a particular genetic syndrome among individuals. Common reasons for referral to his genetic services include tumor predisposition syndromes condition such as NF1, NF2, and Schwannomatosis. Without further ado, I present Dr. John Pappas.
Dr. Jeff Allen:
One further. Dr. Pappas as some of you may have read today was quoted in the 'Wall Street Journal'.
Carole Mitchell:
I didn't know that. What was the quote?
Dr. John Pappas:
It's there, but it doesn't matter.
Dr. Jeff Allen:
You can tell them about it.
Dr. John Pappas:
I can tell you the story later.
Thank you very much for coming here. And thank you very much to. Even though we've been with Dr. Jeff Allen from the beginning of the Neurofibromatosis Center, I'll speak about Neurofibromatosis Type 2, especially the genetics of the disease.
The term Neurofibromatosis is not correct when it comes to NF2, because it's not associated with Neurofibromas. It's associated primarily with Schwannomas occasionally you can see Neurofibromas.
It's a condition that you can see at birth incidence in one out of 30,000 approximately. To put this in perspective with other tumor predisposition genetic syndromes; Neurofibromatosis Type 1 is about one in 2,700. Familial Adenomatous Polyposis which is a tumor condition of the gut, it's about one in 9,000 or so. NF2 is one of the less common conditions. We see NF2 with all ethnicities and races.
What do we mean by a genetic condition? Almost all disorders, have a genetic disposition. But especially with NF2 there is a gene that has to be changed in order to have the condition. So as you see up there in blue, I have two lines. They represent the two genes, one from the father, and one from the mother, that we have for NF2. These two genes make a protein. And this protein is important. The name of this protein is Merlin. As you see, we have two copies of these genes in every cell. And in order for a tumor to form, both of the copies have to have a change, or mutation as we call it. Some individuals do not have a mutation in every cell even though they have NF2. They have only mutations in a few cells. And in one copy of the two genes. This is called Mosaicism. To remind you from high school, the inheritance of autosomal dominant conditions like Neurofibromatosis Type 2, one of the parents have a mutation, a little change in one of the two genes. It passes this gene down to the child, the child will have NF2. If passes the other gene to the child without the mutation, the child will not have NF2. For every parent that has NF2, the risk of having a child with NF2 is 50 percent. Once you know the genetic change (mutation), you can test it in pregnancy or before actually conceiving with pre-implantation diagnosis. Many times in this talk, I'm not going to go into detail but please write down your questions and we'll discuss them afterwords.
What happens in the cell in order to go for a cell that has a mutation to become a tumor? It's actually the happening of another mutation, of an additional mutation. So a cell that has a mutation in one copy of these two genes, let's say the one that was inherited by the father here, has to get a mutation in the copy that is inherited from the mother in order for the cell to become a tumor. This second mutation is not inherited. It happens in the cell, in that particular cell that initiates the tumor. There is a lot of research that is going on to find out why the second mutation happens.
These are pictures that I like, but I don't like to confuse you. But I'll tell you a few simple things that I think are important. This is a picture of chromosomes. Right here. It's a picture of chromosomes. We have 46 of those. Every chromosome has thousands of genes inside. All together 23,000 different genes that are squeezed into these 46 chromosomes that are the packages of the genes.
As you see, we have two copies of chromosomes, two copies of chromosome one, two copies of chromosome two. One comes from the mother, the other from the father. Here in chromosome 22 is the gene for NF2. We also have two copies of chromosome 22, one from the father, the other from the mother.
So here is a detailed representation of chromosome 22. This is a picture from a public database containing information of all the research and all the bits and pieces that were found on chromosome 22, all the little DNA pieces. If you follow this line, all these little pieces we know are associated with NF2.
If we go a little further up, another gene called SMARCB 1 is associated with Schwannomatosis which is a condition that for long was thought to be part of NF2. I'm telling you this because there is a lot of research nowadays that has to do with the location of these genes. And how we'll be able to distinguish the conditions and create different indications for testing and treatment.
Every gene is made out of small bits of information that are called Exons. If you've seen a genetic report, maybe your genetic report, they mention Exons, they mention also the boundaries between the Exons and other parts of DNA that are not so important that are called the Introns. All these bits of information are important in order to make the protein.
And the protein that's called Merlin is important to regulate functions in the cell. This is a representation of the cell. Actually if you see here Merlin is stained yellow - orange, it's near the nucleus of the cell. You can also see the Neuron Axons here and the cytoplasm that's stained green in this picture.
This slide demonstrates the existence of Merlin in the Neurons. It interconnects with many other proteins, and it's important for cell division, for cell growth, and for the regulation of the survival of the cell. Actually if Merlin is not working, the cell can become immortal and you realize that that can lead to a tumor.
All this work that is done in flies and in mice is almost ready to be translated to medications for humans. And we'll speak about that.
Coming back to the clinic. This table shows the most common presenting symptom in individuals with NF2. This refers to ringing in the ears, Tinnitus.
I'll go through some examples of patients that came for genetic testing. Of course, I have changed their stories so they're not recognizable. This is from long ago from a medical student who came from Europe to rotate with me. What we observed is that she was actually using the telephone only in one ear. She discussed with us that she was losing hearing from one ear. After audiology evaluation, and an MRI, she was found to have right Vestibular Schwannoma, or Acoustic Neuroma. We were able to do a genetic test, and we found no mutations in her blood. She went back to Europe where she had excision of her tumor, and genetic testing in the tumor found two mutations. If you remember, we need actually two mutations in order for a tumor to form. One mutation was a stop codon; it means mutation that stops the translation of the gene so the protein is not totally made. The other was a deletion means that a big chunk of the gene is missing.
After we knew the mutations, she actually had testing in her blood again, and knowing what to look for, they were able to ascertain one of the mutations in some of her cells in the blood. Why is this important? First of all, we know how this mutation relates with her outcome. And we'll speak about that. But for her, it was important for reproductive reasons. If the mutation is in the blood, it also be in the ovaries. This means that she has a chance to have a child with a mutation.
This is another case. It's a 48-year old man as you see with bilateral hearing loss. He presented with bilateral Vestibular Schwannomas. We tested his blood, and in the blood actually we found a deletion mutation, a mutation that actually changes the gene by taking out the big part of the gene. He was very interested about testing his kids at the time of the diagnosis. He had two boys, 8 and 10. And the question is do we test the boys? The answer is yes, because the recommended surveillance actually starts between age 10 and 12 with MRI, and audiograms.
This next patient came to us with a lot of different symptoms as you see in the slide. His symptoms started early, in his childhood and his father also had a brain tumor and Neurofibromas. This case fulfilled the criteria for NF2. And testing in him and his father revelaed a mutation called spice site. Spice site is a mutation that changes the way the cell actually puts together these little information boxes, the Exons in order to make the protein.
He had two sisters that were younger. One of them was found to have the mutation. And she decided to actually use pre-implantation diagnosis as a means of reproduction. This means that she went through IVF, In Vitro Fertilization, and they tested the embryos before they implanted.
What's the clinical criteria for making the diagnosis for NF2? You see them there. I will not go one by one. I'll stop in a few important features of NF2.
One very important characteristic of NF2 is the Vestibular Schwannoma. Usually when it's associated with the condition, it starts early. Other tumors that are common include Meningiomas, peripheral nerve tumors or Schwannomas of the nerve. Schwannoma means tumor of the out layer, the insulation of the nerve.
Another characteristic that is slightly under estimated is an opacity in the back of the lens of the eye that's like a cataract. But rarely associated with severe vision loss like a cataract. There are also reports in childhood with tumors of one of the nerves other than Acoustic Neuromas.
Vestibular Schwannoma or Acoustic Neuroma is the characteristic tumor of NF2. It's associated with a ringing in the ears, hearing loss, and balance problems. The problem with the tumor is that tumor growth can cause compression in important parts of the brain. The brain stem has to do with vital functions, like breathing, regulation of the heart rate. Vestibular Schwannoma can happen without being associated with NF2. Actually the majority of individuals who have unilateral, on one side, Vestibular Schwannomas do not have NF2. As you see here,individuals that are older than age 30 and have a unilateral Vestibular Schwannoma are at very low risk of developing NF2. So it's a common tumor in the population. And only five percent of them are bilateral. And when they're bilateral, when they affect both ears, then we have to think about NF2.
So an individual who is older, who has a unilateral Vestibular Schwannoma we don't think about doing the genetic testing for NF2, and is not at risk of having a child with NF2.
A few things about Meningiomas. Meningiomas are common, as you see here. Approximately half of the individuals with NF2 will develop Meningiomas. And they can occur around the brain or the spine. That's why surveillance includes brain and spinal MRIs. Of course, Meningiomas can occur again in older individuals without NF2, without Neurofibromatosis Type 2. And in this case, again, we don't offer genetic testing. It's an isolated tumor.
We offer testing for NF2 in a young individual, especially younger than 25 that presents with meningioma.
About spinal tumors: Two thirds of individuals that are diagnosed with NF2 will have spinal tumors, and they're schwannomas. Other tumors, especially ependymomas are also common. There was a conference in 2011 of the Children's Tumor Foundation, they included Ependenomas as a criteria for diagnosing NF2.
To reiterate how we go about genetic testing for NF2. If we have a family history or a fulfillment of the criteria for NF2, then we draw blood. If it's only one individual in the family that has NF2, then we prefer to start by testing the tumor, if an operation is planned. And if the mutations are established there, then we test the blood. In the laboratory, there is a specific order of doing the test. First they look for big deletions of the gene, and then for smaller mutations. Large deletions of the gene are associated with a mild phenotype. Mild phenotype means mild presentation: the tumors are smaller, they don't grow fast. They're not multiple Meningiomas and not a lot of spinal tumors. When we have big deletions in our genome, usually we see intellectual disability, but not with NF2. So when they find a deletion, a big deletion in the genome associated with the NF2 gene, we don't expect any intellectual problems.
I will not go into detail about this. But this slide tells you that for every type of mutation that we find, we have an idea of how NF2 will progress in the individual. This correlation is nonexistent in many genetic disorders but we have the luxury of knowing this correlation in NF2.
Also, if the mutation happens in a few cells but not in every cell, Mosaicism, typically NF2 is milder.
Let's come to treatments. As you know, the treatment of the Vestibular Schwannoma, the tumor of the acoustic nerve, is surgical. And in individuals with NF2, we try to avoid radiation. Why? Because every cell has the mutation, and radiation is instigating a second mutation in the cell that can create another tumor.
We also provide anticipatory guidance. For example, these tumors are associated with balance issues and under water disorientation that can create problems. A referral to an audiologist is paramount. Lipreading, sign language, and hearing aids or cochlear or brain stem implants when they're appropriate. Nowadays the treatment modalities extend into experimental medications. There are studies to establish quality of life measures in order to test the medications. From good studies of quality of life, it seems that most people summarize their disease with loss of hearing, loss of mobility and balance and facial disfigurement. Pain and social and emotional problems.
Surveillance with annual MRI, beginning at the age of 10 or 12 if we have a genetic confirmation of a condition in the child. Hearing evaluations with brain stem potentials. And the ophthalmology evaluations, eye exams for cataracts.
We try to avoid radiation. There are a lot of studies comparing radiation (gamma knife - fractionated stereotactic radio surgery) and surgery for Acoustic Neuromas. The procedures involving radiation are designed for unilateral Acoustic Neuromas not associated with NF2.
The genetic testing gives the ability to have a conclusive diagnosis, design the appropriate treatment and provides the ability to test relatives conclusively. In our genetic service, we provide a letter with a mutation in order to facilitate the testing of the relatives, and also facilitate discussion among relatives.
So because we know all this information about the protein, Merlin, that's associated with NF2, and we know that this is involved in the growth of the cell, and cell proliferation, some medications emerged. All these weird letters I have in the slide are growth factors that are up-regulated when the NF2 gene is not working which means the protein is no good. So there are medications that are specific inhibitors. Monoclonal antibodies of growth factors. These were tried in mice. They were tried in cell systems. And eventually in humans. Especially the trial with Avastin that was reported in the 'New England Journal of Medicine' by Dr. Scott R. Plotkin, showed that they were able actually with therapy to shrink some Vestibular Schwannomas and preserve some hearing.
Our doctors here, Dr. Jeff Allen, Dr. Matthias A. Karajannis were involved with a study with Lapatinib. Actually Dr. Matthias A. Karajannis contributed to a 2011 publication in the 'American Journal of Medical Genetics' about a consensus for treatment.
All of the doctors that care for patients with NF2 came to a consensus of how to treat patients and how to offer clinical trials. This is the algorithm of how to present the possibility of a clinical trial. If you are interested, at the end of the talk which is coming soon, I can go through that.
This is actually the last slide. You know Dr. Jeff Allen, Dr. J. Thomas Roland, Dr. John G. Golfinos, Dr. Matthias A. Karajannis here who are treating NF2 and are involved with the trials. You know Carole who coordinates everything. I'll introduce you also to the website, clinicaltrials.gov, which many trials are cataloged. It's a public website, you can search it. And I'm ready for questions.
FROM THE AUDIENCE:
You were talking about being able to test woman's eggs. Can you check men's sperm as well?
Dr. John Pappas:
Actually we're not able to test the eggs. In some cases we're able to test the sperm, but not the eggs. What is actually routinely done is to test embryos. By in vitro fertilization you create embryos. At the stage of 8 to 15 cells, you take one cell and test for the mutation. Couple who go through this procedure can decide to implant embryos without the mutation.
FROM THE AUDIENCE:
How do you find spinal tumors? How do they appear?
Dr. John Pappas:
They can be seen by surveillance spinal MRIs, or clinically presenting usually with pain. If you're not a known NF2 patient and you don't have surveillance, pain is usually the presenting symptom.
FROM THE AUDIENCE:
If you're getting brain MRI's every year, would they normally do spinal MRI's as a matter of course?
Dr. John Pappas:
Most of the time it includes brain and spinal.
FROM THE AUDIENCE:
Once they know it's NF2.
Dr. John Pappas:
But you have to have the diagnosis established. They're not going to do a spinal MRI if you have a unilateral Acoustic Neuroma.
FROM THE AUDIENCE:
You had a slide which had clinical trials of drugs. How far away are they from prescribing these to people and treating people?
Dr. John Pappas:
I don't know anything that's beyond Phase Two. Phase Two is efficacy studies with human subjects; Phase One is safety. Phase Zero is about establishing biological function of the medication. Phase Two is the New England article that I presented about Avastin. Before approval of the medication for NF2 we need Phase Three trials; I don't know how long it's going to take and how much money will invested by the pharmaceuticals. The thing is that because Merlin is so central in the cell, it attracted a lot of interest by pharmaceuticals. So it may be sooner than we think.
FROM THE AUDIENCE:
So at this time we're primarily doing development tumors and using that as the primary source of treatment for patients only with the bilateral NF2 diagnosis.
Dr. John Pappas:
Right. I didn't go into detail, but one very important part of research that came last year is about early surgery to preserve hearing. This means that being a little more proactive surgically with very tiny tumors, less than 1. 5 cm. Large unilateral tumors of course you have to operate; but unilateral medium size tumors you may not operate to preserve hearing as long as possible. You let the tumor show you how actually it behaves, if it grows fast or not. If it doesn't grow fast, you stay and wait, or you may choose a clinical trial.
FROM THE AUDIENCE:
You say grow fast. How fast? You mean certain millimeters per year, per so many years?
Dr. John Pappas:
That's a good point. You have to follow it by certain MRI's that you can measure small growth. So you may have to do MRI's a little more frequently. But what's important is the hearing. This is the functionality. The tumor may grow, but if the hearing is preserved; you have time to decide. You follow both tumor growth and the progression of hearing loss.
FROM THE AUDIENCE:
If there's no hearing loss, and no symptoms from the tumor do you still perform surgery or radial surgery?
Dr. John Pappas:
Depends. If the tumor is very small, you may be able to perform surgery and preserve the hearing. You may wait if the tumor is more than 1. 5 cm. If it causes no symptoms.
FROM THE AUDIENCE:
You mentioned BAER testing in one of the slides.
Dr. John Pappas:
It's a special audiology test.
FROM THE AUDIENCE:
Are there any blood tests like the tumor markers to help see how fast these types of tumors grow?
Dr. John Pappas:
I don't know of any tumor markers for NF2. If you know any, Dr. Jeff Allen?
Dr. Jeff Allen:
I guess the most recent help that we get now is to do what we call volumetric analysis on MRI. We usually measured a two dimensional size of the tumor, length and width. Now we have computer programs which will analyze the length and the width on every slice of the tumor on the MRI, add it up, and create a volume. And we find that that's a much more sensitive indication of the growth rate of the tumor than a radiologist putting up pictures and saying I don't see a change. That innovation is now being incorporated in our clinical trials. And we have a percentage change, usually 15 percent volumetric change which would indicate whether a drug is working or a drug, if the tumor progresses, is not working. And in our clinical trials, obviously we look at other functional parameters. If it's a Vestibular Schwannoma, we look at hearing. Wherever the tumor is occurring. Those are things that we're learning to incorporate. I'm going to say one thing, John. You're looking at lots of years of taking care of NF2 patients. Going to these meetings now, which are incorporating larger numbers of clinicians and scientists over the past two to three years, I've never seen a period of so much unrest and uncertainty prevail in how to manage NF2 patients. If you think about it, the standard of care has been, just like Dr. Pappas says, surgery, either early or surgery late. Radiation therapy we don't particularly care for. But as we're learning how to use medications, think about it, nobody wants to have major brain surgery. But if you knew that you had even bilateral, both sides, NF2 with mild hearing loss, if you could take a medication that had acceptable side effects for a long period of time, and not have an operation, you'd probably do that. And so as we identify those medications now, as Dr. Pappas was alluding to, what we call the standard of care is going to change. And we see that with a lot of diseases. I think that is the hope.
I wanted to ask Dr. Pappas a question. As a doctor, a physician, and maybe a scientist, we think a little differently than maybe a patient. But let's say a patient is born with an altered cell, an altered chromosome 22, and a normal chromosome. It seems to be in NF2 the only real organ that's important is the nervous system. Is it true that that second mutation is only occurring in the nervous system? Or does it occur in other organs but it doesn't do anything? And if so, does it mean that the nervous system cannot protect itself as well from what we call second hits?
Dr. John Pappas:
I'll answer that. What happens is that all of our 23,000 genes are working a lot when we're embryos because they're making things (organs and organ growth). But as all the organs are done and the nervous system is done and we have hands and feet, then some of the genes are silenced, are switched down. It seems that this particular gene, NF2 is still active in the nervous system but not active in other tissues. So if another mutation happens in other tissues it may not be important because it doesn't make the protein. But the nervous system it does make the protein. We know that.
On the other hand, I agree with you, there are a lot of physicians that would like to give medications. I'm not a researcher. I'm a clinician. I don't do research at all. I just see people to do the genetic testing and discuss the genetic testing and the implications. That's all. But I admire the researchers, and I think it's important to stay in clinical trials when you take trail medication because if you don't, all this information about you is not going to help anybody else.
Dr. Jeff Allen:
So is there -- for example, if you study blood and the DNA of blood of an NF2 patient.
Dr. John Pappas:
Merlin is not there as far as I know is not expressed in blood. Genes are always there but they're silenced in some tissues.
Dr. Jeff Allen:
Is the mutation rate similar in a blood cell as it is in a nervous system cell?
Dr. John Pappas:
The mutation especially in the blood cannot be seen because these particular blood cells that get a second hit in NF2 may be not viable; so you cannot actually study in lymphocytes. But you may be able to study the mutation in skin. So we start a different discussion here.
FROM THE AUDIENCE:
Are you aware of any I guess environmental factors which can help promote NF2 in people that might be Mosaic for NF2?
Dr. John Pappas:
We know by the famous researcher James Neel that the exposure to Atomic Radiation, like the Atomic Bomb, it's associated with new mutations. Other than that, no.
FROM THE AUDIENCE:
This is a follow-up. I'd like to tell you that I have NF2. My first tumor appeared at age 30 which at the time was about the age at which NF2 years ago was supposed to appear in people. I managed it in a way -- I have an Acoustic Neuroma which was radiated when it was discovered at about five millimeters. Radiated --
Dr. John Pappas:
Five millimeters?
FROM THE AUDIENCE:
Five millimeters. And at the time when they discovered in 1999, about 12, 13 years ago. When I discovered that I had this Acoustic Neuroma, I thought about what possible environmental factors, what could I possibly be doing that might have caused that. By that time I'd had several schwannomas, some with very elegant surgeries and to this day I have some hearing loss. My tumors have stopped growing for all intents and purposes.
Dr. John Pappas:
But you do have the mutation for the NF2 gene? Do you have a mutation or no?
FROM THE AUDIENCE:
I have NF2 -- I have unilateral Acoustic Neuroma, and I have many peripheral schwannomas, in the spine as well as in the hand, the Axila, in a variety of places I've had surgeries. By definition -- maybe someone could say I have Schwannomatosis. But I have unilateral Acoustic Neuroma and multiple Schwannomas and I have a first degree relative. I believe I was Mosaic for this condition. But the point I'm raising here, and I brought this to the attention of Dr. Korf, and other people at the CTF organization who seem to have ignored it, but I believe that in 1999 when I said to myself what was it in my environmental exposure or what have you, what was I doing that possibly could have helped promulgate this condition?
The only thing I could possibly come up with was that I was drinking a whole lot of diet sodas which we now know have Aspartame, and Aspartame is linked to tumor causing conditions and a variety of other conditions. It's so ubiquitous, in a society with 6 or 7,000 foods that it's in. For all intents and purposes since 1999 I've abstained from foods that have Aspartame in them. I'm now 25 years into having Schwannomas and they've stopped growing. My tumor in the brain has not grown from the time it was radiated. I've retained my hearing. So I submit to you that this is certainly anecdotal because it's only me that's experienced this, but it doesn't take a giant leap for me to figure that someone ought to look at Aspartame which we know has neurotoxic effects, breaks down formaldehyde.
Dr. Jeff Allen:
Your question.
FROM THE AUDIENCE:
I think someone ought to look into Aspartame as it relates to NF2.
Dr. John Pappas:
You may be right with this association. Sometimes there can be associations in front of our eyes and we cannot see them. I don't doubt that. The first step to look into this, if you would like, is to look if you are Mosaic or not for a mutation, or if you don't have a mutation or if you have mutations in other genes that are predisposing to your condition, and how this particular gene relates with toxicity of Aspartame or other toxins in the environment. There are ways actually to explore that.
FROM THE AUDIENCE:
I have a complicated question. I have a daughter who has NF2, was diagnosed at a young age. I was not diagnosed through the center. I went through the family tree and found my daughter was the only one with NF2. I've never had -- I did have a glitch. They did start a blood work and they stopped the funding for it so we never got the results of permutation was, and I'm a little confused with the Mosaic. Let me finish the question. Are there NF2s, why are some so much more severe than others for -- my daughter had three bilateral acoustic surgeries, has bilateral acoustics again, has been on clinical trials. And it's just like so complicated. People need to know that there are so many different variations.
Dr. John Pappas:
You raise a lot of nice questions. The first question is about how to practically do the genetic testing which is the bane of my existence.
FROM THE AUDIENCE:
Is it too late to find out what her?
Dr. John Pappas:
It's never too late to do this testing. How do we do the testing? By convincing insurance to pay. So we write letters and make sure that they pay, and we don't do it as research. We do it as a clinical test so they can provide a written report to whoever requests the test. You can have it and see the mutation and we can discuss it. NF2 has high panetrance which means that once you have the mutation, you have the condition, but to what degree you're going to show the condition is variable even in the same family. People who have the exact same mutation in the same family may present differently. The third thing is that your daughter may have a mutation in NF2 and nobody else has the mutation because it can happen also as a new mutation. It happens frequently in the sperm. Every ejaculate has 25 to 50 million sperm inside and a lot of them are mutated for different conditions.
The father is more likely to have a mutation in the sperm versus the mother in her eggs . That's all we know.
Dr. Jeff Allen:
Answer her question, should every prospective NF2 patient have genetic testing?
Dr. John Pappas:
Sure. That's my job. This is what I say. Come to us for genetic testing .
Dr. Jeff Allen:
The answer is yes.
Dr. John Pappas:
The answer is yes. I try to make it light but the answer is yes.
FROM THE AUDIENCE:
We came for treatment and the individual patient as to how severe their mutation is or whatever the Merlin that makes everything grow. It's a little confusing.
Dr. John Pappas:
It is confusing. It may change because as we learn more we may actually tailor some of the treatments to the mutations. Not right now, but we're still actually learning. All this confusion is not bad. It's good. It means a lot of people are working and a lot of people have opinions. Every opinion is good and should be respected. The more we learn the better it is. I think the more we learn about ourselves the better it is.
FROM THE AUDIENCE:
Meningioma, if it's surgically removed, what dangers of the surgery or should you wait and see if you're not having any symptoms from it?
Dr. John Pappas:
Most surgeons actually are not eager to take out Meningiomas unless they're very symptomatic. Correct me if I'm wrong.
FROM THE AUDIENCE:
25 millimeter is large enough?
Dr. Jeff Allen:
I'm going to make a suggestion. For individual cases like that, why don't you come up after. But let's focus on NF2-related generic questions. Okay?
FROM THE AUDIENCE:
Two questions. One, if I understood what you just said, are you saying that most sporadic NF2 starts with the male, the father?
Dr. John Pappas:
No. Don't blame the father for everything. You can do it --
FROM THE AUDIENCE:
I plan to.
Dr. John Pappas:
The thing is it most frequently happens in the individual sperm actually that fertilize the egg for the individual. But it can happen in the egg also.
FROM THE AUDIENCE:
Also if you could just tell us the status of PTC299?
Dr. John Pappas:
I can read it. These are reported and are public. Actually if you look at the report from the latest CTF reportsI can give you that. I have it here.
Dr. Jeff Allen:
Barbara is asking the question related to your question. There is a drug that was under clinical trial by a company called PTC, it was 229, which had the capability of allowing a cell to basically read beyond what they call a stop codon. All of a sudden the RNA is reading the DNA and they read the stop codon and you get a small protein which doesn't work. This drug allowed it to jump over that message and read a larger protein. So this sounded brilliant, and this drug was experimented in Cystic Fibrosis, Duchenne Muscular Dystrophy, genetic disorders.
Dr. John Pappas:
And Becker Muscular Dystrophy.
Dr. Jeff Allen:
And also Dr. Plotkin conducted a brief trial in NF2. He hasn't published that. But for the other --
Dr. John Pappas:
For PTC299, there is a publication.
Dr. Jeff Allen:
What about for other diseases? Does that concept work?
Dr. John Pappas:
Yeah, it works in principle. But there are many, many cells that use the same mechanism as a normal mechanism, that this medicine overrides and the side effects actually start accumulating over a few years. It's not a good medication.
Dr. Jeff Allen:
It's exciting. That's why if you had a drug that had a very specific function, and you knew which patients had the mutation, then you could recall those patients and conduct a very specific trial to address that mutation. That's just why I think that Dr. Pappas should do genetic testing on everybody who has a potential genetic disorder. Sooner or later we're going to have a very specific treatment.
FROM THE AUDIENCE:
Dr. Pappas, I'm interested in knowing what is the likelihood of an individual below the age of 30 with no symptoms with a unilateral Vestibular Schwannoma to actually have or develop NF2?
Dr. John Pappas:
Below the age of 30, actually it is relatively high. These are the patients that I see because in order to know for sure, you have to see if the mutation is there. So if you find the mutation, then you know for sure you have NF2. If you don't find it then it's much less likely.
FROM THE AUDIENCE:
So you basically don't develop NF2. You're born with it.
Dr. John Pappas:
You're born with it.
Dr. Jeff Allen:
One or two -- two more questions. One?
FROM THE AUDIENCE:
Do you find that patients with NF2 are still being treated on a presumption of the symptoms as they present rather than on the diagnostic and genetic testing? Are we still at that phase where if it looks like a duck, it's a duck, rather than doing all the genetic testing?
Dr. John Pappas:
It depends. In our Neurofibromatosis Center, with individuals that are involved in these type of trials and knowledgeable of the criteria like with Dr. Matthias A. Karajannis, we try to do the treatment rationally. Sometimes you cannot because if you have a patient that insurance does not approve the MRI, does not approve the testing, you have to go with clinical findings. You have to do whatever you can do.
FROM THE AUDIENCE:
How expensive is this testing?
Dr. John Pappas:
About $1,800, if I remember.
FROM THE AUDIENCE:
It's not recognized by insurance companies?
Dr. John Pappas:
If you speak to the first coordinator of insurance, they're not going to know it, they're not going to approve it. But usually we write an initial letter, we get a response. If they approve it, fine. If not, then we appeal it. At some point I'm speaking to the Medical Director, the Medical Director usually gives the approval.
FROM THE AUDIENCE:
And it's a blood test on the patient?
Dr. John Pappas:
It's a blood test or a test of the tumor. Either.
Dr. Jeff Allen:
One last question, and before you go if you've enjoyed this, you have other areas of interest, I would advise you either to write them down and leave it with us, if you have Carole or my or Dr. Pappas' E-mail, send us a note and we'll try to put another talk together for you. And if you have any specific personal questions, come up and speak to one of us and we'll try to answer them. Our last question.
FROM THE AUDIENCE:
What's the overall prognostic picture of patients with NF2?
Dr. John Pappas:
It's quite variable. There are people who have NF2 that live independent lives and work with no problems. But there are people who very quickly develop a lot of tumors. It's a spectrum.
Dr. Jeff Allen:
It's a hard question. You know and I know there are NF2 patients out there who don't know they have the disease. Doctors tend to see patients who have the more severe forms of the disease. The answer to your question is if there were a country that did MRI scans on every patient or genetic testing, you would clearly be able to answer that. But as physicians we're only here to help those who come to us, which are usually patients with symptoms. I think that's the bias. But Dr. Pappas will tell you that in families where we're able to track patients, then you see very different kinds of clinical outcomes. That's where you get the feeling for the variability.
I think for those patients who suffer from this, it's a burden. It's a real burden. And the families as well. And we are here to help in all the diverse ways, not just the diagnosis, but in the management of symptoms, and all the other problems that people with the illness suffer from. Physical therapy is necessary, hearing restoration, the activities of daily living, et cetera. So it's a real commitment on the part of a program.
FROM THE AUDIENCE:
I would just want to add because you're being very modest that my son comes to NYU and there is no doubt research has clearly shown that people that come to centers of excellence have better outcomes. And the fact that there are so many knowledgeable people here that can give you the newest information is critical versus the doctor who sees maybe none and takes a guess and treats it like a traditional brain tumor or hearing loss, and bad things happen to patients who go to those kind of centers. Jeff is one of the best, and has been really among the longest. So he's got a great history with how this disease tracks in different age groups.
Dr. Jeff Allen:
It's a team approach, Barbara. You know that. The world is interconnected. John has alluded to that. We are so well informed because we have access to the Internet and the national meetings, and the Foundations, don't forget, the Children's Tumor Foundation which really supports a lot of these conferences. And we need to raise money, as you all know, for the scientists. It's a very complicated task. I want to thank Dr. Pappas again. Carole, wherever you are, for organizing, thank you. Give us your questions or what you'd like to learn more about.
Communication Access Realtime Translation (CART) is provided in order to facilitate communication accessibility and may not be a totally verbatim record of the proceedings.
Citations / Papers Mentioned
- Dr. John Pappas 'Wall Street Journal': Santorum Returns to Campaigning after Daughter's Health Improves
- Dr. Scott R. Plotkin 'New England Journal of Medicine': Hearing Improvement after Bevacizumab in Patients with Neurofibromatosis Type 2
- Dr. Matthias A. Karajannis 'American Journal of Medical Genetics': Consensus recommendations for current treatments and accelerating clinical trials for patients with neurofibromatosis type 2
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