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RETT SYNDROME RESEARCH TRUST WEBSITE
GERMAN TRANSLATION
[SPANISH] Escoliosis en Síndrome de Rett

This blog post will deviate from our typical scientific pieces to focus on a clinical aspect of Rett: scoliosis. As a mother, I can testify that the mere thought of scoliosis surgery makes my knees weak and my stomach queasy. I’ve spoken to enough parents during the past decade to know I’m not alone in these emotions. My hope is to engage families and their network of doctors, therapists and educators in a dialogue about the potential treatment and – even better – the prevention of scoliosis in Rett Syndrome.

My daughter with Rett is 13 years old, and she is on the severe end of the spectrum. One area in which we’ve had some success is orthopedics. We’ve managed to improve her scoliosis through an intense program of physical therapy (PT), massage, chiropractic and cranio-sacral work.

Below are excerpts from a conversation with Dr. Vishal Sarwahi, the Director of the Spine Deformity Service and a team member of the Rett Syndrome Center at Children’s Hospital at Montefiore, in the Bronx, NY, run by Dr. Sasha Djukic.

MC: I think of Rett as exerting its power over our children 24 hours a day.  One way to fight back the physical challenges Rett imposes is through therapies. One hour a day of impactful physical therapy brings the score, so to speak, to Rett 23, Child 1.  Each time my daughter visits her therapist she goes in with a slight curve and comes out straight.  It’s a constant battle. Rett pulls her one way, we pull her the other.  The key is to fight that battle each day or you lose ground.

So one thing I would like to share with parents and get them thinking about is an intensity level that may be crucial.  Without evidence-based research, which is currently lacking, proving that intensity is important is very difficult.  Families are left to negotiate with their schools and their insurance companies.

VS: You are right. There is no clear scientific evidence that physical therapy can alter the natural history of scoliosis.  If parents ask me if physical therapy helps – the answer is a resounding YES.  But is there any scientific evidence that it will change the natural history of scoliosis? The answer is NO – because, to date, there are no published studies.  Personally I am confident that PT, if done properly by a good therapist, and as you say, for an appropriate amount of time, is very helpful.  But it’s difficult to put a number to the required hours.  I would say perhaps an hour per day to work on various forms of activities to condition the back and keep it strong, and not just the back but the abdominal muscles as well.

Your own daughter, who does not walk independently, is a great example because scoliosis tends to happen more commonly in kids who do not ambulate.  And the fact that she has been through growth spurts without having major changes in her back is key.  The problem is scientifically proving that it’s the PT that is responsible.  How do we know whether she is in the small percentage of cases that have very minor scoliosis?

MC: Actually, her scoliosis has gotten better.   How many kids with Rett have curves that get better?

VS: Very few

PANCREATITIS

MC: Can you talk a little bit about pancreatitis and the increased risk after surgery that parents should be aware of?  This is one of several concerns about which parents can take a proactive stance, if they are well-informed.

VS: Yes, individuals who undergo scoliosis surgery have a higher risk of pancreatitis.  There are some studies which show that the risk is even higher in kids with neuromuscular disorders. It’s very difficult to understand why they get pancreatitis – there are multiple theories.  One theory is that maybe the morphine they get for pain shuts down the sphincter and there’s some regurgitation of juices back into the pancreas, causing a chemical pancreatitis.  It usually presents in the first week after surgery and can affect between 15 – 30% of patients.  In our center we don’t see it as frequently, our percentages range from 10-15% perhaps because we follow a much stricter protocol than most, including routinely checking pancreatic enzyme levels.  In nonverbal children we palpate the belly and if the heart rate goes up that suggests the child is in discomfort or pain.  If the enzymes are on the higher side we can do an ultrasound to rule it out.  The treatment is no food by mouth until the enzymes resolve. Bottom line, pancreatitis in the nonverbal patients is something we have to look for.  If the parents are aware, if the physicians are aware, if the surgical team is aware then it’s more likely that it can be diagnosed sooner.  Not sure we can say that it can be avoided,  but it can be diagnosed sooner and at least be taken care of, because the complications sometimes are severe.

MC: Pain medications are another issue that I find very concerning.  There are publications that say that children with Rett Syndrome have great tolerance for pain.  I’m not always sure that their pain is properly cared for after surgery.  My personal hypothesis is that they feel pain just like the rest of us but they don’t express it the way we would expect them to react to pain.  And so I sometimes think the interpretation is that they don’t feel pain or they have a high pain threshold.  And I’m not sure that’s it at all.

VS: So this is a topic very close to my heart, actually.  It’s very difficult for us to gauge pain.  First, I always trust the parent.  One thing I teach my residents is that the mother knows best.  If the mother says the child is in pain then the child is in pain.  But even a mother sometimes has difficulty gauging pain levels.  So we look at the blood pressure and heart rate.  Shallow breathing can often mean pain.  And at the Rett center we also take into consideration that children with Rett can have a very irregular breathing pattern.

MC: What about seizures?  I mean how often would you expect to see a child having seizures after surgery as this can be very jarring to the body.

VS: Of course, the neurologist has to be on board and part of the team. And much depends on the fixation that has been used. For our children, seizures—or even if a child were to take a tumble—should not cause damage per se. I don’t brace any of my children after surgery, or use casts.

ALLERGIC REACTIONS

MC: Another area of concern for Rett Syndrome patients, some of whom have mitochondrial and other issues, is the type of anesthesia. So what kind of background work is done to determine what kind of anesthesia is going to be used?

VS: Our approach to anesthesia is always multidisciplinary. We go over the precautions and contraindications.  At our center we actually have two anesthesiologists, and a pediatric anesthesiologist is always involved in the scoliosis surgeries.

MC: I understand at Montefiore you routinely test for metal allergies before surgeries. I can’t imagine anything more horrific than to put all of the hardware in and then have to take it all out due to an allergic reaction. I know from speaking with parents that most Rett patients are not tested for this prior to surgery.  My own daughter has never worn jewelry or belt buckles, so the possibility of allergies naturally coming to light may be slim.

VS: Typically an allergy to metal has a very slow onset. It’s not like anaphylaxis where you see it right away.  Nevertheless we have decided to routinely test although it’s expensive and time consuming.  Better to be safe.

MC: Congratulations to your center for taking a precautionary approach, and I hope this will become more widespread. At least our readers are now armed with the knowledge to ask for this testing if it is not offered as a matter of course.

LOOKING AHEAD

MC: Now for more of a research question… Where do you see the science moving? I mean do you think that eventually these types of scoliosis that are neuromuscular, neurogenic in nature, do you think they will be preventable at some point or treatable in such a way that surgery will no longer be necessary?

VS: Well, my hope is yes. As of now, a gene for idiopathic scoliosis, which is the most common scoliosis and not the neuromuscular type, has been identified. Whether that is the only gene, and how that gene expresses itself, is still unknown.  For neuromuscular scoliosis it’s unclear if there’s a specific scoliosis gene that is causing it.  And in Rett Syndrome, is it a gene directly associated with MECP2 or is the scoliosis secondary to a neuromuscular imbalance?  It may be the latter.  My fervent hope is once again that we figure out how to fix that.

MC: Do you think that there should be more exploration, beyond PT or bracing, to help correct this imbalance, along the lines perhaps of the use of Botox?

VS: Well I do find it difficult to accept the philosophy that scoliosis in Rett Syndrome is inevitable.  I find there’s this philosophy every child is doomed to have it and there’s very little to do.  If parents and doctors believe that you fall into a vicious cycle and there’s not enough focus on innovative strategies.

MC: I agree with you. In general, the literature about Rett talks about these four stages, and the motor degeneration at the fourth stage.  I can’t help but think that what may be contributing to this degeneration is that the children are growing bigger and heavier, they aren’t receiving the same level of services that were available when they were younger through the schools and other programs, and the parents are getting older and more tired, So there’s an overall reduction in resources and therapies, fewer therapists involved, and we have to wonder how much degeneration is due to the disease itself and the natural progression, and how much is due to external circumstances.

VS: There’s always the question of nature versus nurture in Rett, and it may be that with optimal and very individualized services for each child and adult, there is much more wiggle room, more variation and chance for solid improvement than the Rett community as a whole has had the opportunity to fully explore and document. But I think this type of discussion is interesting; it raises awareness and challenges us to do better.

MC: Thank you, Dr Sarwahi, for your time and the care with which you address these issues.  I hope we can continue to dialogue as we look toward new and innovative approaches.

 

RETT SYNDROME RESEARCH TRUST WEBSITE
[SPANISH] Redefiniendo la Función de la Proteína del Síndrome de Rett

[ITALIAN] Ridefinire le Funzioni della Proteina Chiave della Sindrome di Rett
[GERMAN SUMMARY] MeCP2 – Neudefinition der Funktion des Rett-Syndrom Proteins
[GERMAN TRANSLATION]

Just before the holidays I had an opportunity to discuss with Adrian Bird the new data reported in his latest paper, published today in Molecular Cell. Most readers of this blog will know that Prof. Bird discovered the MeCP2 protein in the early 1990s while working at the Research Institute for Molecular Pathology in Vienna. Almost a decade later, Huda Zoghbi’s finding that mutations in MeCP2 cause Rett Syndrome propelled Prof. Bird into the realm of neuroscience. He found himself working, for the first time, on scientific issues with great relevance to human disease. In 2007 he published the dramatic reversal experiments.

We’ve come to expect novel and significant insights from the Bird lab; this new paper redefines our concept of both the scope and function of MeCP2. In the words of co-author Peter Skene, it may be “the watchdog of the neuronal genome.”

READ FULL PRESS RELEASE

Dr. Adrian Bird

MeCP2 Goes Global

MC: I found the data in your latest paper regarding the high levels and broad distribution of MeCP2 to be quite striking.

AB: Yes, MeCP2 is exceptionally abundant. Most transcription factors, proteins that turn genes on or off, exist in 10,000 to at most 100,000 molecules per cell. We are seeing 100 to 1,000 times more than that of MeCP2.  In fact, there is almost as much MeCP2 in the nucleus as there are nucleosomes, which are the fundamental repeating structural units of chromatin. That means that there is enough MeCP2 to potentially cover nearly all of the genome.

MC: I was intrigued by the fact that MeCP2 binds to non-genes as well as genes.

AB: As far as MeCP2 is concerned it doesn’t seem to care whether it binds to genes or not. It simply binds everywhere there are methyl groups.

MC: So MeCP2 follows methylation across the genome.

AB: Indeed, and this tracking of DNA methylation could explain the reversibility of severe Rett symptoms that we see in mice.  The important developmental step is to establish the correct pattern of methylation, and that appears to happen normally in Rett patients.  Once you have that pattern set down, and you put MeCP2 back in, as we did in our reversal experiment, the protein simply goes where it’s told by methylation and resumes its function.

The Genome – It’s Not All About Genes

MC: This is probably a good time to remind our readers that only 5% of the genome is made up of genes.  The rest comprises what is still sometimes referred to as “junk DNA” because scientists have not been able to ascribe any function to it. I’ve always found the term “junk DNA” a bit arrogant – I doubt that 95% of our genome is junk and in fact recent work has suggested that the junk might in fact have important regulatory functions.

AB: You are absolutely right; we shouldn’t dismiss any of the genome as junk.  Much of this so- called “junk DNA” has actually been conserved over many millions of years and that fact alone suggests that there is a good reason for that “junk” to be there.

MC: In recent years the idea that MeCP2 binds to methylated DNA has been questioned a bit. This paper reaffirms and expands on that. Where is this leading us?

AB: I think this confirmation, combined with an abundance of MeCP2 sufficient to cover all the methyl groups in the genome, is telling us something about the function of MeCP2.

MeCP2 Redefined

MC: So can we still say that Rett symptoms are caused by faulty repression of downstream genes by MeCP2?

AB: That remains a hypothesis that needs proving. We are still waiting for evidence that particular genes, when misexpressed due to mutated MeCP2, are causing Rett. We have a lot of work yet to do to figure out the connection between the absence of repression by MeCP2 and the symptoms of Rett.

MC: So what about the papers that claim particular genes are targets of MeCP2?

AB: Indeed, there have been quite a lot of papers – some written by our lab- which say that certain genes appear to be changed when MeCP2 is missing. The finding is followed up with biochemistry experiments which show that MeCP2 binds to these genes, so the data seems to make sense. However, once you find that MeCP2 binds absolutely everywhere, the concept of target genes becomes a bit less interesting and perhaps less relevant.

MC: If MeCP2 is not a transcription factor, as previously thought, what would you call it?

AB: I would call it an alternative linker histone 1.  Ages ago we showed that MeCP2 and the linker histone, HI, compete with each other to assemble chromatin on methylated DNA.  In this paper we show that when MeCP2 is absent, the amounts of HI, which are normally very low in the brain, go up dramatically.  In that sense MeCP2 clearly resembles a histone.

MC: Let’s give a bit of background for our readers. Histones are proteins which act as spools around which DNA is wound. This winding, or compaction, allows the 1.8 meters of DNA material to fit inside each of our cells. There are two classes of histones – core histones and linker histones.  Core histones form the spool around which DNA winds – resembling beads on a string. And linker histones are the DNA separating the beads. HI is one of two linker histones.  So, in effect, linker histone is the string between the beads of a necklace.

Might It Be Simpler?

MC: Yet another observation of your paper is that MeCP2 is likely performing the same function throughout the brain.  Please elaborate.

AB: Some think that MeCP2 does different things in different neurons.  Our data suggests that the pattern of MeCP2 binding is similar regardless of the brain region.  My emphasis has turned to the idea that, in the absence of MeCP2, there is a generic problem with neurons and that the regional effects have something to do with what those neurons do in the brain and not so much that MeCP2 does different things in different places.  In other words, MeCP2 does the same thing everywhere but its consequences are different.

Currently there is a lot of data from many labs pulling us in multiple directions. I would like to see if we can slice through all that complexity and say, in all these neurons this is what is wrong.  I’m excited about the possibility that perhaps it’s not that complicated after all.

MC: That would be an elegant and welcome scenario. Thank you, Prof. Bird, for discussing your latest paper.  I look forward to bringing our readers an update soon regarding your work.

RETT SYNDROME RESEARCH TRUST WEBSITE
SINDROME DE RETT Y EL DSM V – traducido

As many parents may already know, the Diagnostic and Statistical Manual of Mental Disorders, known as the DSM, is in the process of reevaluating criteria for the new edition to be published in 2013, the DSM V. There is discussion among members of the Rett community and the Asperger’s community about the decisions to drop both diagnoses from the manual. How this change might impact services, particularly intensive educational intervention for Rett children, is unknown and will probably vary from state to state. People who would like to express their opinions to the DSM committee may do so until April 20, 2010.

RSRT scientific advisory board member and Rett Syndrome researcher Huda Zoghbi , M.D. discusses the DSM reclassification with Monica Coenraads.

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Huda Zoghbi will be appearing on the Charlie Rose Show on Tuesday, February 23. The episode, entitled “The Developing Brain” is part of the “Charlie Rose Brain Series” hosted jointly with Nobel Laureate, Eric Kandel, Ph.D. of Columbia University.

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MC: What do you think was the impetus behind removing Rett Syndrome from the DSM?

HZ: My understanding is Rett was originally included in the DSM because it was a disorder with autistic features of an unknown cause. Now that the genetic cause has been identified, the rationale for removing Rett is that it is more its own distinct entity. Another reason pertains to the transient nature of autism features in Rett patients but this is not exactly the case. Rett patients do not have language skills and continue to manifest stereotyped behaviors for decades. Although some might acquire some social interaction skills through eye-pointing this is not true for all cases.

MC: Yet, if knowing the genetic cause of a disorder is the rationale for exclusion, in time, as more genetic underpinnings of disease are identified there will be fewer and fewer left for categorization by the DSM.

HZ: Correct. That is why I actually do not agree with this approach. I think the approach should be to see what clinically fulfills criteria for autism. I would be in favor of a more precise categorization and dividing DSM V into two types: DSM V A and B. One would be used for syndromic autism and one would be non-syndromic autism. There would be genetic etiologies for both syndromic and non-syndromic.  Currently most of the known genetic causes are for syndromic autism but in time, as we do more sophisticated sequencing and we study patients with simplex autism (one case in a family, with no features other than classic autism) we will find etiologies  for non-syndromic as well. In my view this would be a much more useful distinction. Bottom-line: having a known genetic cause should not eliminate a disorder from DSM V.

MC: The decision to remove disorders identified with a genetic cause seems very black and white to me. While knowing the root cause of a disorder is hugely important it often also brings many unanswered questions. Let’s look at Rett Syndrome itself – a certain percentage of girls/women with a clinical diagnosis of Rett do not have an identified mutation. And then we have individuals with MECP2 mutations who do not have Rett Syndrome symptoms. So, using Rett as an example of a genetic disorder, the situation is certainly not black and white.

HZ: Absolutely. In fact, the girls who have MECP2 mutations who fit the clinical criteria for autism and do not have Rett symptoms make a very compelling case against the current draft of DSM V. They represent a troubling scenario for an important patient population – what diagnosis do we give them?  Where do they belong?  So now with the proposed DSM criteria we have a category of patients that are left unattended to in this manual.

MC: It seems to me that the Rett clinical community, in general, was in favor of removing Rett.  Do you have any insight into their reasoning?

HZ: The medical community appropriately focuses on clinical management:  what treatments can be delivered to the patient, what code is used in the medical records for billing purposes, etc.  These issues have probably driven the support of the clinical community for removal. On the other hand, if you are about solving the puzzle of these brain disorders and understanding the pathogenesis of the autism phenotype in Rett and beyond, then removal doesn’t make much sense to me.  If you believe that the DSM manual is a tool to help us better understand brain diseases and to highlight the commonalities and differences between them, then I don’t feel taking out Rett serves the cause of disease-oriented research.

MC: Once DSM V is finalized will we be able to call Rett an autism spectrum disorder or will that be a misnomer?

HZ: I don’t think it will be a misnomer because clinically Rett is an autism spectrum disorder. Just because it’s taken out of a manual does not change the phenotype of the disorder.  Imagine, for a moment, a girl comes to see me in the clinic. She used to speak but has experienced a loss of language, she has no social interactions, she has stereotypic behaviors. We evaluate her using ADOS (The Autism Diagnostic Observation Schedule – a standardized protocol for assessing social and communicative behavior) and the ADIR (Autism Diagnostic Interview-Revised) and the child fulfills all the criteria for an autism diagnosis. Yet she has a MECP2 mutation. What do you put in her chart?  It can’t say MECP2 mutation because that is not a clinical diagnosis, it’s a genetic one.

MC: Of course we are already facing these complicated issues. And I think the proposed changes in the DSM may further complicate things. As you can imagine, I’ve received a plethora of emails and phone calls from parents who are wondering what this may mean for their child in terms of losing services.  I think worries about losing medical services are probably not warranted. Worries about educational services, however, I’m much more concerned about. For example, it may become more difficult to obtain intensive ABA (applied behavioral analysis) programs and other educational supports where autism has blazed a trail.

HZ: Yes, I would agree with that prediction. It is really important to remember that autism spectrum disorders do not only overlap clinically but that some of their features respond to similar therapies in spite of different molecular causes. Therefore keeping an eye on the clinical similarities in face of genetic heterogeneity is one path to gain insight about the mechanisms underlying their common features and to develop therapies that might benefit more than one disease. I do hope the committee will take these far-reaching ramifications into account as they contemplate disease classifications.

MC: Thank you so much for sharing these thoughts with our readers. Parents and other advocates for those with Rett Syndrome, such as therapists, teachers or personal physicians, are encouraged to weigh in on this matter. Remember, the cut-off date for submitting comments to the committee is April 20.

MC: What do you think was the impetus behind removing Rett Syndrome from the DSM?

HZ: My understanding is Rett was originally included in the DSM because it was a disorder with autistic features of an unknown cause. Now that the genetic cause has been identified, the rationale for removing Rett is that it is more its own distinct entity. Another reason pertains to the transient nature of autism features in Rett patients but this not exactly the case. Rett patients do not have language skills and continue to manifest stereotyped behaviors for decades. Although some might acquire some social interaction skills through eye-pointing this is not true for all patients.

MC: Yet, if knowing the genetic cause of a disorder is the rationale for exclusion, in time, as more genetic underpinnings of disease are identified there will be fewer and fewer left for categorization by the DSM.

HZ: Correct. That is why I actually do not agree with this approach. I think the approach should be to see what clinically fulfills criteria for autism. I would be in favor of a more precise categorization and dividing DSM V into two types: DSM V A and B. One would be used for syndromic autism and one would be non-syndromic autism. There would be genetic etiologies for both syndromic and non-syndromic.  Currently most of the known genetic causes are for syndromic autism but in time, as we do more sophisticated sequencing and we study patients with simplex autism (one case in a family, with no features other than classic autism) we will find etiologies  for non-syndromic as well. In my view this would be a much more useful distinction. Bottom-line: having a known genetic cause should not eliminate a disorder from DSM V.

MC: The decision to remove disorders identified with a genetic cause seems very black and white to me. While knowing the root cause of a disorder is hugely important it often also brings many unanswered questions. Let’s look at Rett Syndrome itself – a certain percentage of girls/women with a clinical diagnosis of Rett do not have an identified mutation. And then we have individuals with MECP2 mutations who do not have Rett Syndrome symptoms. So, using Rett as an example of a genetic disorder, the situation is certainly not black and white.

HZ: Absolutely. In fact, the girls who have MECP2 mutations who fit the clinical criteria for autism and do not have Rett symptoms make a very compelling case against the current draft of DSM V. They represent a troubling scenario for an important patient population – what diagnosis do we give them?  Where do they belong?  So now with the proposed DSM criteria we have a category of patients that are left unattended to in this manual.

MC: It seems to me that the Rett clinical community, in general, was in favor of removing Rett.  Do you have any insight into their reasoning?

HZ: The medical community appropriately focuses on clinical management:  what treatments can be delivered to the patient, what code is used in the medical records for billing purposes, etc.  These have probably driven the support of the clinical community for removal. On the other hand, if you are about solving the puzzle of these brain disorders and understanding the pathogenesis of the autism phenotype in Rett and beyond, then removal doesn’t make much sense to me.  If you believe that the DSM manual is a tool to help us better understand brain diseases and to highlight the commonalities and differences between them, then I don’t feel taking out Rett serves the cause of disease-oriented research.

MC: Once DSM V is finalized will we be able to call Rett an autism spectrum disorder or will that be a misnomer?

HZ: I don’t think it will be a misnomer because clinically Rett is an autism spectrum disorder. Just because it’s taken out of a manual does not change the phenotype of the disorder.  Imagine, for a moment, a girl comes to see me in the clinic. She used to speak but has experienced a loss of language, she has no social interactions, she has stereotypic behaviors. We evaluate her using ADOS (The Autism Diagnostic Observation Schedule – a standardized protocol for assessing social and communicative behavior) and the ADIR (Autism Diagnostic Interview-Revised) and the child fulfills all the criteria for an autism diagnosis. Yet she has a MECP2 mutation. What do you put in her chart?  It can’t say MECP2 mutation because that is not a clinical diagnosis, it’s a genetic one.

MC: Of course we are already facing these complicated issues. And I think the proposed changes in the DSM may further complicate things. As you can imagine, I’ve received a plethora of emails and phone calls from parents who are wondering what this may mean for their child in terms of losing services.  I think worries about losing medical services are probably not warranted. Worries about educational services, however, I’m much more concerned about. For example, it may become more difficult to obtain intensive ABA (applied behavioral analysis) programs and other educational supports where autism has blazed a trail.

HZ: Yes, I would agree with that prediction. It is really important to remember that autism spectrum disorders do not only overlap clinically but that some of their features respond to similar therapies in spite of different molecular causes. Therefore keeping an eye on the clinical similarities in face of genetic heterogeneity is one path to gain insight about the mechanisms underlying their common features and to develop therapies that might benefit more than one disease. I do hope the committee will take these far-reaching ramifications into account as they contemplate disease classifications.

MC: Thank you so much for sharing these thoughts with our readers. Parents and other advocates for those with Rett Syndrome, such as therapists, teachers or personal physicians, are encouraged to weigh in on this matter. Remember, the cut-off date for submitting comments to the committee is April 20.

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RETT SYNDROME RESEARCH TRUST WEBSITE

John Crowley’s life was bright: a recent MBA from Harvard Business School, a young family, and a blossoming career…the world was his oyster. And then John and Aileen received the shocking news that their toddler and newborn were both afflicted with Pompe Disease, a fatal neuromuscular disease. John’s fearless actions as he fights to save his children’s lives are portrayed on the big screen  in the new film by Tom Vaughan, Extraordinary Measures starring Brendan Fraser, Harrison Ford and Keri Russell.

VOTING OPPORTUNITY TO HELP RETT SYNDROME RESEARCH

The Extraordinary Measures website is highlighting video stories of hope and inspiration. One video will win $10,000 from CBS Films. Please visit and vote daily for “Reverse Rett Syndrome – Give Our Girls a Voice.

Below is an excerpt from a recent conversation between RSRT Executive Director, Monica Coenraads and John Crowley, currently President and Chief Executive Officer of Amicus Therapeutics.

Visit the Crowley Family Website

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MC John, congratulations on the movie. As can be expected, news of the film and your story have already attracted attention in the special needs community.  Your spectacular success inspires all of us who are dealing with rare childhood disorders. For me personally, the key message of the film is that parents can be instrumental in helping to move the science forward.

Let’s go back to when you and your wife received the diagnosis. Megan was a toddler and Patrick just a newborn. Many of the readers of this blog know how it feels to be hit with a terrible diagnosis. Was your first step to approach existing Pompe organizations or medical centers? How did you go about gathering information and how were your questions received?

JC This was in March of 1998 and the internet was a pretty new phenomenon but that was the first place we went.  We learned of the small but dedicated group of researchers around the world as well as numerous Pompe families that shared a lot in common with Aileen and I.  We were surprised by the abundance of information that was out there. We quickly realized that it fell on our shoulders as parents, more than anyone, to collect and to synthesize the scientific data as well as the clinical information that was available.

MC Your accomplishments bring to mind some parallels with another non-scientist father who advanced research— Augusto Odone, the father portrayed in Lorenzo’s Oil. In my conversations with  Mr. Odone a decade ago we shared our common experiences in being repeatedly told that parents cannot drive the science. What kinds of difficulties did you encounter as you decided to move forward on your own?

JC At times we were viewed as interfering with the established plans that some people had. We didn’t pay much attention to that. We felt that we could only add and not detract from the debate as we pushed for treatments for Pompe.  I was surprised by the competitive nature of academic research and the lack of communication and coordination between the different efforts. I don’t think that is something you can fix but you can incrementally improve the situation.

MC Academic research is indeed competitive; on the other hand, it’s the very nature of that competition that often yields progress and results. Do you think that as an advocate with a personal mission, your background in business and law has been a greater asset, actually, than if your degrees had been in science?

JC I think so. You don’t have to be a scientist to run a biotech. In fact most CEOs of biotech firms are not scientists, but business people and they bring a different skill set.  But you must possess the ability to understand and articulate your science, and your technology and your disease area as well as a Ph.D. or you will not have credibility. That was a steep learning curve for me.

MC How do you think the urgency that only a parent of afflicted children can bring to bear has impacted drug discovery efforts for Pompe Disease?

JC I think the science would have gotten there eventually but I believe that Aileen and I accelerated the timetable quite a bit by bringing focus to the existing resources as well as bringing additional resources to the table.

MC How important a role does public awareness or lack of awareness of a certain disease play in drug discovery?

JC We got approval for a treatment for Pompe without many people in the US knowing what the disease is. What I do think is hugely important however, is increased awareness about rare diseases in general. There are 7000 rare diseases that collectively affect over 30 million people. That is more than everyone who suffers from all cancers and AIDS combined. So taken together these diseases are not rare at all – in fact they are remarkably prevalent.  While the symptoms and severity of these rare diseases may vary, there are commonalities with regards to a framework of development for novel therapies that can and should be applied to all these disorders.

MC That’s an excellent point. Single gene disorders like Pompe Disease and Rett Syndrome give scientists the ability to work out the biology of a disease, which can sometimes be applied to more common disorders where the underlying cause is unknown.

JC I agree. I believe that rare diseases will unlock cures for a whole host of more prevalent diseases.

MC What role do you think research foundations run by people with a personal stake in the disease play in drug development?

JC They play a very critical role.  Research foundations absolutely accelerate the timeline to drug development.

MC I think one reason their role is so critical is that they often fund a different caliber of research. They are often less risk adverse and therefore willing to support projects that more conservative funding agencies, like the NIH, won’t touch.

JC I completely agree. The Cystic Fibrosis Foundation, as the prime example, puts hundreds of millions of dollars into cutting-edge research. The result is thirty drugs in the pipeline.

MC Let’s talk about the science, and your perspective on future developments for Pompe.

JC We have small molecule chaperone technologies in the pipeline at Amicus Therapeutics, the biotech firm where I am CEO. We are looking at monotherapy as well as combined approaches with these chaperone drugs in conjunction with the existing enzyme treatment. Furthermore, there are several next-generation enzyme replacement therapies at various companies. There are also gene therapy studies that we hope to get underway this year.

MC What are some things you know now about drug discovery that you wished you knew 10 years ago?

JC The list is too long. I’m glad that 10 years ago I didn’t know what I know now because I probably wouldn’t have taken the risks that I did!

MC Your kids must be very proud of you. Have they seen the film? How are they doing?

JC We saw the film together a few weeks ago. They are very excited. Megan and Patrick still have remarkable special needs but they also have remarkably special gifts. Megan just turned 13; Patrick will be 12 in March. Megan was able to blow out her birthday candles. The fact she could do that while on a ventilator is a gift, let alone the milestone of reaching her 13th birthday. The enzyme replacement medicine that we helped to discover, and which they have been taking for almost 7 years, stopped and reversed the life threatening enlargement of their hearts. They are still ventilator-dependent and in wheelchairs but the quantity of years and quality of life that the medicine bought us is extremely valuable.

MC Megan and Patrick are very lucky to have you as their father and their advocate.

You are played by Brendan Fraser in the movie. I actually knew Brendan when we were kids, because I was good friends with his older brother Kevin. The Fraser family lived in Holland as I did at the time and we attended the American School of The Hague. I lost touch with Kevin when I moved to the States, but perhaps you’ll intercede with Brendan and help me get to get back in touch with Kevin.

JC I’d love to.

MC John, thank you so much for taking the time for this conversation. We wish you continued success and look forward to updates as the work progresses. I can safely speak for the entire Rett family community when I say that your story inspires and lifts us.

JC Thank you, Monica. I hope that the film helps to raise the collective awareness of rare diseases and the struggles of families around the world.

RETT SYNDROME RESEARCH TRUST WEBSITE

by Monica Coenraads

Recently, RSRT Professional Advisory Council member Jonathan Epstein and I participated in the Partnering for Cures meeting in New York City organized by FasterCures, a think-tank of the Milken Institute. In attendance were over 600 people, including heads of medical research organizations, executives from pharmaceutical companies and biotechs, policymakers, philanthropists and representatives from NIH. The goal of the meeting was to identify the challenges involved with delivering treatments and cures and to brainstorm about possible solutions.

Information was shared with participants via plenary sessions as well as panel discussions on focused topics. Forty-two research organizations, including RSRT, were selected to present their innovative strategies. I was delighted and honored to brief this elite group on Rett Syndrome and RSRT’s efforts.

The meeting also provided opportunities to schedule one-on-one “partnering” meetings. I took full advantage and met with a variety of representatives from biotech and pharma. It was also an opportunity to reconnect with people who have been mentors and advisors to me during the past decade. People like Richard Insel, EVP of Research for JDRF, and Katie Hood, CEO of the Michael J. Fox Foundation. In some cases I finally met, face to face, people with whom I’ve been speaking on the phone for years.

A common theme throughout the meeting was the fact that the most innovative and ambitious science is not being done at pharmaceutical companies or biotech, nor is it being funded by NIH. Rather, it’s being driven by disease-specific research organizations like ours.  Why is this?

  • First, because we have a single, urgent agenda – to make the patient better.  We are not encumbered by concerns over who gets the credit or the profit as long as our constituency is healed.
  • Second, we often have the most comprehensive and accurate information on the state of research for our particular disease. From that elevated knowledge base we are often in the best position to make well-informed decisions.
  • Third, we are prepared to fund risky and ambitious projects – the kind the NIH and many other funding agencies shy away from.

RSRT is proud to be part of this game-changing scientific movement.

At the crossroads of epigenetics and neurobiology, the Trust and our research projects are gaining traction. We look forward with hope and determination to the research developments of 2010. On behalf of our trustees, scientific advisors and professional advisory council we wish you and yours a wonderful holiday season.

RETT SYNDROME RESEARCH TRUST WEBSITE

podcast

Monica Coenraads, Executive Director of RSRT, was interviewed on October 1st by John Fossella, PhD, MBA, a neuroscientist at Mount Sinai in New York City.

Click here to visit his blog and access the podcast (15 min)

RETT SYNDROME RESEARCH TRUST WEBSITE
GERMAN TRANSLATION

by Monica Coenraads

Last week I attended a scientific meeting held in Stresa, Italy and organized by a parent group, Pro Rett Ricerca. One of the most well received talks of the speaking program was presented by Monica Justice, PhD of Baylor College of Medicine, who discussed data collected from her RSRT-funded project. What follows is an excerpt from a recent conversation between the two Monicas following the Italian meeting.

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MC: Dr. Justice, it was great to see you in Italy. I thought it might be helpful to give our readers some insight into your project. But first I’d like to start with you, the soul behind this impressive undertaking. How did you end up in science?

MJ: My grandfather was a vet and I had an uncle who was a physician. I have always had a deep love for animals so as a child and young adult I wanted to be a vet.  My father thought that was not an appropriate career for a woman and he and my uncle encouraged me towards the medical field. Early on, however, I realized that my true passion was in basic research.  I went to graduate school thinking I would focus on immunology and microbiology but my very first class would change my career path forever. My professor was switching into the mouse genetics field and invited me to join his lab.  I loved mouse genetics from the very start and knew immediately this was exactly where I wanted to be.

MC: Most lay readers of this blog will not have realized that mouse genetics as a field exists.  Can you elaborate on this specialty?

MJ: When I entered the field most mouse genetics was being carried out in a few labs, The Jackson Laboratories being the primary one in the US, and research centered around a few mouse mutations that primarily altered mouse coat color.  I think the perception from the science community at large was that we weren’t doing particularly important work. That perception changed with the introduction of very powerful research tools.   One such tool was the ability to alter genes in mouse embryonic stem cells to engineer DNA mutations at will. The second was the ability to use a strong mutagen, called N-ethyl-N-nitrosurea or ENU, to do forward genetics – more on that later. This was also the time when molecular biology was exploding.  Rather quickly the mouse became THE model organism of choice. I’ve ridden that wave since my graduate student days. Today nearly every institution that is doing cutting edge research has a mouse genetics core.  I suspect there are now about 2000 true mouse geneticists worldwide.  Nearly every person who works on human disease now works with mouse models.

MC: Please tell our readers the basics behind your Rett project.

MJ: Our Rett project is based on two discoveries:  1) that you could make the symptoms of Mecp2 mutant mice better if you  introduced brain derived neurotrophic factor (BDNF) and 2) Adrian Bird’s  finding that you could actually reverse very severe symptoms in the mice by reintroducing the gene. Because of those two findings I believe that Rett symptoms can be altered by other genetic mutations. I felt strongly that the genetic approach that I was familiar with would be an ideal strategy to try and identify suppressors of the symptoms of Mecp2 knockout (ko) mice.

So let me tell you a bit about the screen. I use a powerful mutagen, ENU, that induces mutations in mouse sperm at a very high rate. We give the mutagen to wildtype (normal) male mice and then mate them to female Mecp2 knockout mice. A certain percentage of their offspring will have no Mecp2 and a sporadic mutation somewhere in their genome.  We then analyze the mice very closely and look for any that appear healthier than your typical Mecp2 ko mouse.  For example, a Mecp2 male ko mouse is dead by 6-14 weeks. If a mouse in our screen lives much longer than that, we hypothesize that there is a mutation in another gene that suppresses the ill effects of having no Mecp2. We currently have mice that are over a year old and still do not show signs of Rett.

MC: How many mice has your project generated?

MJ: We have used about 10,000 mice at this point and envision needing 5,000 more to find and understand the current genes of interest. To reach saturation for our screen, meaning that we are confident that the mutagen has generated mutations in every gene that could potentially be a suppressor, we would need to screen through five times the number of males that we have done thus far. Statistically, I estimate that there are 25-50 suppressor genes that we would expect to find were we to hit saturation.

MC: What kind of precedents are there for success using ENU modifier screens?

MJ: The first successful modifier screens were done in bacteria and yeast. The technique gained momentum in the late 1980’s early 1990’s when Gerry Rubin carried out a modifier screen in the fruit fly for genes that would interfere with a particular pathway. Dr. Rubin is a famous scientist who now is the Director of the Howard Hughes Medical Institute Janelia Farm Research Campus.   Historically, people thought that fruit flies were the only organism that you could do this with. It’s clear now that the mouse is an equally powerful organism.  My graduate mentor, Vernon Bode, did a screen in mice for PKU modifiers, which was finished by Bill Dove at the University of Wisconsin Madison.  And an Australian group that works on diseases of the blood did an ENU mouse screen looking for genes that influence platelet counts.   Each of these screens was very successful.

MC: Is there data to show that modifier genes are the rule or the exception in disease?

MJ: That’s a very interesting question. I work in the Department of Human and Molecular Genetics at Baylor. What I see from many of my colleagues’ work is that genetic modification of disease is the rule and not the exception.

MC: Can you envision a situation where you find modifiers in the Mecp2 ko mice but those genes are not implicated in the human disorder?

MJ: I do not think that we will find modifiers that are mouse specific only. I believe that because the mouse model for Rett Syndrome is amazingly similar to the human disease.  Also, DNA methylation (which is critical to MECP2) and some of the possible functions of the MECP2 gene are highly conserved between species. So it’s very likely that the MECP2 gene in people and in mice is doing the same thing.

Justice2

MC: What do you foresee as the best possible outcome?

MJ: I foresee finding a molecule that would help forge neuronal connections, and help these connections be maintained and molded.
Furthermore, whatever molecules we find that suppress Rett symptoms may also give us important biochemical information on other genes that may interact with Mecp2.

MC: Did being at Baylor, a Rett hotspot, impact your decision of taking on this Rett project?

MJ: I have been very much aware of Rett since I moved to Baylor in 1998, a year before Huda Zoghbi identified the gene. I have been on the student committee of some of Dr. Zoghbi’s students, which kept me up- to- date on the ongoing work. MECP2 is a transcription factor and I’ve always been interested in transcriptional regulation. What really brought me into the project was when you called me up with a proposition.

MC: When I was the Director of Research at the Rett Syndrome Research Foundation (several years before the merger with IRSA to form IRSF) I piggybacked an early morning think tank during the RSRF Rett Syndrome Symposium in Chicago. About two dozen creative thinkers were kind enough to drag themselves out of bed and brainstorm with me about potential key experiments that could significantly move the field forward.  At the top of that list was an ENU mouse modifier screen. The group also gave me a list of potential people who could undertake such a laborious and intense project…it was a small list and your name was on it.  As you well know, RSRF then organized a workshop at the Mouse Genetics meeting, which took place in Charleston, SC in 2006. Those discussions led to the funding of your project.

MJ: I was so thrilled when you called. There was a time when I would have turned down this project.  But the timing of your call was perfect. The project appealed to me very strongly as a geneticist but also as a compassionate person who wants to make a difference in the life of others.

Your readers should also know that this is a project that the NIH would never have funded.  It was too risky and too “out there”.  I knew this was a viable technique and I was confident with the expertise of my lab with regards to mouse breeding, husbandry and handling that would move this project along quickly so I am very grateful to have had the funding to pursue this.   People should be aware of how much private foundations such as RSRT move the field forward by funding high risk, but high impact projects.

MC: Speaking of compassionate person, at the end of your talk in Italy you got a little emotional.  I was quite touched by that. Can you tell our readers what was going through your mind?

MJ: Yes, I got a little “verklempt” and I got teased quite a bit at dinner for that. I take this project very seriously because I feel that what we are doing could have an impact on people’s lives – an impact that perhaps wouldn’t happen without the screen – I guess as I was up there in front of scientists and the organizers of this meeting who have children suffering from Rett – the importance of our efforts hit me hard.

MC: Are you able to give our readers a hint at the data that your project has thus far yielded?

MJ: The project is at an exciting point.  We are close to identifying our first suppressor gene and we have a few more potential genes that we are pursuing as well.  Once they are identified we will begin experiments to confirm that they are indeed interacting with Mecp2m, first in the mice and then in people.  I also think the modifiers we have so far are just the tip of the iceberg.  So we have a lot more screening ahead of us.

I love this project, it’s fun, it’s exciting, and each new piece of data that we identify brings us closer to our goal.

MC: On behalf of families everywhere who love a child with Rett Syndrome we wish you Godspeed. We look forward to hearing about future progress.  Thank you also to Pro Rett Ricerca and especially Rita Negri and Laura Rassetti for their tireless work to organize this meeting.

MJ: It was my pleasure and honor to attend the meeting in this most beautiful area of Italy, near where you were born.