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Understanding the Pathophysiology of Rett Syndrome: Setting the Stage for Future Developments

  • Authors: Eric Marsh, MD, PhD; Jeffrey Neul, MD, PhD
  • CME / ABIM MOC Released: 12/23/2022
  • Valid for credit through: 12/23/2023, 11:59 PM EST
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Target Audience and Goal Statement

This activity is intended for neurologists, pediatricians, and primary care physicians.

The goal of this activity is for learners to better understand the pathophysiology of Rett syndrome.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Pathophysiology of Rett syndrome


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  • Jeffrey Neul, MD, PhD

    Professor of Pediatrics, Division of Neurology, Pharmacology, and Special Education
    Annette Schaffer Eskind Chair and Director
    Vanderbilt Kennedy Center
    Vanderbilt University Medical Center
    Nashville, Tennessee


    Jeffrey Neul, MD, PhD, has no relevant financial relationships.


  • Eric Marsh, MD, PhD

    Associate Professor of Neurology and Pediatrics 
    Clinical Director, Orphan Disease Center 
    Children’s Hospital of Philadelphia
    University of Pennsylvania Perelman School of Medicine
    Philadelphia, Pennsylvania


    Eric Marsh, MD, PhD, has the following relevant financial relationships: 
    Consultant or advisor for: Acadia Pharmaceuticals Inc.; Stoke Therapeutics (former)
    Research funding from: Curaleaf Inc
    Contracted researcher for: Acadia Pharmaceuticals Inc.; Epigenyx Pharmaceuticals; Marinus Pharmaceuticals, Inc.; Stoke Therapeutics; Takeda Pharmaceuticals; Zogenix Pharmaceuticals


  • Pakinam Aboulsaoud, PharmD

    Medical Education Director, Medscape, LLC


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  • Susan L. Smith, MN, PhD

    Associate Director, Accreditation and Compliance, Medscape, LLC


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Understanding the Pathophysiology of Rett Syndrome: Setting the Stage for Future Developments

Authors: Eric Marsh, MD, PhD; Jeffrey Neul, MD, PhDFaculty and Disclosures

CME / ABIM MOC Released: 12/23/2022

Valid for credit through: 12/23/2023, 11:59 PM EST




Dr Jeffrey Neul:

Hello, I'm Dr Jeffrey Neul, director of the Vanderbilt Kennedy Center and professor of pediatrics in pharmacology and special education at Vanderbilt University Medical Center in Nashville, Tennessee. Welcome to this podcast series titled, Bringing Focus to the Diagnosis and Management of Rett Syndrome. Today joining me is Dr Eric Marsh. Dr Marsh, if you could please introduce yourself.

Dr Eric Marsh:

Hi, Jeff. Thank you for inviting me here today. My name is Eric Marsh. I'm a pediatric neurologist at the Children's Hospital of Philadelphia and associate professor of neurology and pediatrics at Pearlman School of Medicine at the University of Pennsylvania and clinical director of the Penn Orphan Disease Center and an attending neurologist at the Children's Hospital of Philadelphia.

Dr Jeffrey Neul:

Excellent. Welcome, Eric, and thanks so much for joining me. Today's episode is titled Understanding the Pathophysiology of Rett Syndrome: Setting the Stage for Future Developments. So maybe we could start by having a brief discussion about the genetics of Rett Syndrome because I think obviously that provides some insight into the pathophysiology. So Eric, could you tell us a little bit about the genetics of Rett Syndrome?

Dr Eric Marsh:

Sure, Jeff. As you're well aware, Rett Syndrome was originally a clinical diagnosis, but the gene has been discovered about 25 years ago and it was found to be on the X chromosome and the gene is MECP2, or the Methyl-CPG2 Binding Protein, which is a protein that's important for chromosomal structure and transcriptional regulation. So it is important for allowing DNA to be opened or closed, to have other transcription factors or regulatory elements come in and transcribe the DNA to RNA so that proteins can be made.

Dr Jeffrey Neul:

Okay. With Rett Syndrome, it has a lot of neurological problems. What do we know about where this gene and [how] the protein acts in the body and what cells does it have an impact on?

Dr Eric Marsh:

Yeah, so like many neurodevelopmental disorders, MECP2 is expressed widely throughout the body in many different cell types, but its dysfunction seems to be primarily felt within the brain and why that occurs, we don't really understand. But this is true for many different neurodevelopmental disorders, which genes are expressed widely throughout the body, but with primarily neurologic symptoms. This is an area that a lot of people are trying to understand: what about brain transcription, or brain function, is unique such that you have more neurologic symptoms than systemic symptoms in a gene that's expressed diffusely throughout the body.

Dr Jeffrey Neul:

Yeah, and I remember that the MECP2 gene and protein, while it's in every cell in the body, is at much higher levels in neurons, so that might provide some insight why there maybe has a larger effect on neurons in other cells. Before we get more into discussing what we know about the science and the biology of MECP2, there are a lot of different mutations that have been associated with Rett Syndrome. Do we have a sense about how these mutations might relate to the clinical features, or the spectrum of symptoms? Does it provide any insight into the functional aspects of the protein?

Dr Eric Marsh:

Yeah, Jeff, so there is a fair amount understood about the mutational spectrum in MECP2 as it relates to disease. Interestingly, there are a handful of mutations that make up about 50%, or probably a little less, of the mutations that are seen in patients. And within that group of mutations there are two groups, one in which on a population basis, the patients seem to be a little bit more severe. And the other group, where on a population basis, the patients seem to be a little bit milder.

Now I stress the “on a population basis” because on any individual patient, it's hard to predict their phenotype based upon their genotype because of other variables that come into play. And the main one we think is X-inactivation, or lyonization, where in girls you have one good copy and one bad copy, and in every cell it is randomly assigned to either be the good copy or the bad copy. So you can imagine that depending on which individual cells or the amount of good copy or bad copy you have, it can modify the genotype such that the phenotype doesn't map exactly to a clear genotype-phenotype correlation. In addition, there are probably background genetic effects that come into play to modulate the phenotype so that while in the mutations that are more common, there's a population level of genotype-phenotype correlation. On an individual basis, there's not.

Dr Jeffrey Neul:

Yeah, there are these eight common ones that account for nearly 65% of people with Rett. Interestingly, the mutations also split between ones that cause truncation, or premature termination codons, so they truncate the protein and those that are missense, so they make a full-length protein but alter one amino acid. But interestingly, some of the severe ones are the early truncating mutations, so they break more of the protein, but the later truncating mutations are less severe. And some of the missense mutations, the ones that really affect some of the binding pockets for the DNA binding, which is one of the critical functions, seem to be associated with more severe features.

So we get some insight, I think, into the biology by that relationship of the type of mutations. So we understand there are different domains and different parts of the protein that are important and that correlates with different types of severity. So in thinking about having the information about the genetic cause of most cases, have people looked at this in animal models, cell models, or human tissue? And has that provided any insight or directions for targeting new therapies?

Dr Eric Marsh:

Yeah, so people have done experiments where they've looked at transcriptional changes in models, particularly in the mouse and cell types, to see what the broad patterns of transcriptional changes are. And interestingly, loss of MECP2 function results in low level broad changes in genes, but with particular pathways coming up as being misregulated multiple times, and this includes pathways of growth factors, of channels and receptors and a variety of other pathways that are subtly, but consistently, dysregulated. And understanding which pathways are dysregulated amongst all the genes that are dysregulated will allow you to start to think about therapeutic opportunities, if you can alter that pathway back towards the way it's normally supposed to be expressed, or normally supposed to function within the brain.

Dr Jeffrey Neul:

You started mentioning things like growth factors. I think that there had been some clear evidence pretty early on of altered expression of a very important growth factor in the brain, the brain-derived neurotrophic factor, critical for neuronal development and maintenance and maturation. Have lines of research to try to develop therapies been built from that kind of information of growth factors?

Dr Eric Marsh:

Yeah. Yes, absolutely. So there has been over the years a number of studies, first in mice and then in people in a variety of different ways, to try to restore BDNF function since BDNF, as you said, is one of those growth factors that is dysregulated in MECP2 models, but also in individuals with Rett Syndrome. So people have thought about providing the growth factor, or upstream factors, that can then regulate BDNF function. And particularly, people have thought about using insulin-like growth factor one, or IGF-1, or derivatives of insulin-like growth factor one, particularly a molecule called trofinetide, to adjust BDNF levels in the brain.

Dr Jeffrey Neul:

Brain-derived neurotrophic factor seems promising, but it's very big and you can't get across the blood-brain barrier. But other ways, such as the IGF-1 or derivatives can cross. So I know that there's been animal work and human work using both IGF-1 and trofinetide, which now the IGF-1 had promising results in a phase one trial but did not find the same thing in a phase two. But with trofinetide that's carried into phase two and phase three trials, so you can see how that understanding of the pathophysiology has potential to unlock avenues of clinical therapy development that may be promising.

Dr Eric Marsh:

And one of the interesting things, particularly about Rett Syndrome, or MECP2 dysregulation is that there are potentially a number of different pathways that can be modulated in order to try to restore function back towards a typically developing brain.

Dr Jeffrey Neul:

And what about, given that it's a genetic disorder and you said that it's loss of functional of MECP2, what about trying to give that MECP2 back or something or replace it?

Dr Eric Marsh:

Yeah, so as you're well aware, there's a lot of work on many, many different genetic disorders for using gene therapy, or gene replacement therapy, to cure or improve the lives of individuals with genetic diseases. And there's been some successes already using a AAV, or adeno-associated virus delivery of different genes such as in spinal muscular atrophy. And people are moving forward with this in Rett Syndrome too, where people have shown in animal models that AAV delivery of MECP2 can restore the mouse to its more typical functioning and so that a gene replacement approach using AAV methodology is a potentially viable clinical approach. And indeed, a number of companies are moving forward towards humans to try this in people.

Dr Jeffrey Neul:

Yeah and I think that in something like spinal muscular atrophy where early on you have problems and what you have is a death of the primary motor neurons and then when you have the gene, now they stay alive. I think, in general, there'd always been a question if something like a neurodevelopmental disorder, such as Rett Syndrome, where there's not degeneration and it's something that comes on later and progresses, if there'd be potential to actually intervene later, or if the damage had already been done. But you know that critical mouse experiments, even before the AAV just turning the gene back on through genetic engineering, even after animals were sick, seeing the animals get better really provided a different concept of what might be possible in neurodevelopmental disorders.

Dr Eric Marsh:

It is actually that kind of groundbreaking experiment by Dr Berg Lab in England, which did show that you can, even late into the course of the disease in the mouse, the expression of the gene and restoring the protein can reverse the disorder. And it is the work in Rett Syndrome that has led many other different neurodevelopmental disorders to think that this is possible more broadly and that as when I started training, where we thought that it was too late for neurodevelopmental disorders, indeed that may not be the case and that a lot of these conditions could be reversible, or partially reversible, later on in life than we originally thought.

Dr Jeffrey Neul:

Yeah, yeah. And as you mentioned, a couple different companies have announced that they are starting gene therapy trials in Rett Syndrome. And I know that there's active pursuit of things, as you mentioned, the X chromosome inactivation, which can contribute to the variation in the clinical phenotype, but also provides an opportunity if you could reactivate the inactive chromosome that has the normal copy of MECP2, you might see the ability to restore function. So I think that this has been great. Obviously, it seems that the understanding of this genetic basis of most cases, the Rett Syndrome, being able to develop animal and cellular models and understand the pathophysiology really has provided a route to develop new therapy. So I think it's an exciting time and I think we'll see exciting things over the next couple years in Rett Syndrome. Eric, do you think that there's any other key takeaways or important points you'd like to mention?

Dr Eric Marsh:

Yeah, I think as you nicely just summarized, Rett is a prototypical example of how understanding the clinical condition, then learning about the genetics and the molecular and cellular biology that occurs with that can lead to different avenues of therapeutic approaches, and that our learnings from Rett really are going to be potentially applicable to many different neurodevelopment disorders in years to come.

Dr Jeffrey Neul:

Absolutely. Well Eric, thank you so much for this great discussion, and thank you all for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation.


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