“On February 9th, 2015, Zeina was taken from my family and I. Zeina was 18 months when she was diagnosed with a severe postnatal neurological disorder known as Rett Syndrome that only affects girls. Rett syndrome varies in degrees and has very unique and distinct qualities. Due to her diagnosis, Zeina has regressed over the years. Year by year, I had to watch her lose her ability to walk, grasp objects with her hands, eat on her own, and stand-up straight. As she was losing her physical abilities, she did not gain any mental abilities such as the ability to make sense of the world through thinking, logic, and reasoning. She did not develop language or ways to communicate. Zeina needed round-the-clock care and my 2 sisters, mother, and I provided her with that. Our father left us which made it harder, but we would do anything for Zeina. Due to her syndrome, she also developed scoliosis, which was severely impacting her health. Her hips, spine, and neck were constantly in excruciating pain. They became shifted and unaligned with her body. Through it all though, she kept a smile on her face. 
We cannot bring Zeina back, but we can help other girls suffering with Rett Syndrome. This disorder has the potential to be reversed, but lacks the funding. I am not sure we will even make a hundred dollars from this, but every penny helps. If you cannot donate money, it is understandable, but spreading the message is just as valuable. Together, we can help cure Rett.”
One of my best friends lost the most important person in the world to her a few days ago. Instead of wallowing in her grief like I probably would have done had I been in her situation, she wants to help others who may suffer from Rett Syndrome. If you can donate, please do so. If you cannot donate, please reblog this and spread the word. Thank you. x

I knew how to read long before I could speak. There were no responses I made that would have given anyone any indications that I was reading. I even tore the pages and ate them because I wanted to keep the words. There was no way that anyone could tell that I was reading or not. I did not react or respond appropriately because I could not.

Why is there a definitive response needed from students that cannot give a definitive response? Once you’ve already done ‘cat’ and 'dog’ move on to something else. The response you are waiting for may not come. Taking in is something we can do. It takes time to sort out and even longer to express. What I want to understand is why a response is needed. Just provide the same education as you would everyone else without depending on response or indication of knowing what may or may not be known. Is it at all possible to merely provide an education?

Once I suffered Guillain Barre syndrome after an allergic reaction to a flu shot, and was paralyzed for a time. I couldn’t bat a fly on my face. My mom insisted on a homebound teacher, although I couldn’t even breath on my own and was unresponsive. The teacher came by and gave me an education that would have been the same as any other student my age. I could not respond. Did not respond. He could have been instructing the wall paper for all the indicative responses I gave. I was given tests even. He read them out and read out the multiple choice answers as well, going on to the next question without ever receiving any sort of reply.

Eventually he was gone. Never knowing he ever made a difference, perhaps wondering if it was just two hours a day of talking to himself. Actually he did some of this. Talking absently as if to no one was listening. Going through history and science and literature. But my mind drew pictures taking me to places he described. Discovering sciences. Such subjects that were never before wasted on me.

It was the best education I received. Without the teacher ever knowing that it meant anything at all. Like giving an education to someone in a coma never knowing if the other person is receiving the intended message. He just provided an education he would have given to regular students. except he had no way of knowing if I was learning anything. He just came in every day and followed through to the next lesson, continuing where he left off the day before. With no indication that the lifeless vegetable in front of him was taking in anything or not.

It was years later when I could express the remembered lessons. By then he was dead. Some sort of cancer or something and I could never tell him the impact he made. He provided an education without needing any proof or definitive responses that I was receiving The gift he was providing! He gave me lessons no one else ever gave me because I couldn’t indicate where I was at any given moment.

That’s what I wish teachers would do, just provide the education everyone should have access to no matter what. Teach what you would everyone else. Why do you need an definitive response from someone who may not be able to? Since there is no way of knowing what they may or may not know and neither be able to determine what they understand or not understand, how about this not being the priority but just dish out the education. Don’t wait for the proof that may not come.

My teacher died due to illness never knowing if I received anything. He could have been just wallpaper talking for all he knew, even mentioned that at one point, but he always went on to the next lesson, the next story, as scheduled, regardless. So what if it took ten years before I could express the lessons learned. And so what that he was long dead before any definitive responses to anything he ever presented to me would show. He was the best teacher I ever had and died never knowing it.

Proof was something he did not need to educate. He just did it. You may be stuck on the 'cat’ and 'dog’ bit, waiting for a definitive response. Do as he did and move on already. Go to the next lesson plan. You might be surprised how interesting Shakespeare can be. Hey

I couldn’t tie my shoelaces but still loved history, even as I was spinning 'supposedly’ unaware.

Sometimes too much time is spent on lessons when people need a definitive response to something they are trying to teach. Forget that….just teach. Give out the lessons. Just provide an education. Stop looking for proof that it’s being received. As Nike says. “just do it”.

October is Rett Syndrome Awareness month!
It’s also Awareness month for a lot of other great causes, but Rett Syndrome is something you most likely haven’t heard of. It’s a rare neurogical condition which effects almost exclusively girls. The girls typically develop normally until around 6-18 months when they begin to ‘regress’, losing any skills they have gained. It’s often described as 'the symptoms of autism, cerebral palsy, Parkinson’s, anxiety and epilepsy all in one little girl.’
Girls with the condition cannot talk, though research shows they are capable of understanding much more than they can express. Only around half can walk. Almost all have no functional hand use, often experiencing repeated uncontrollable hand movements. Other symptoms include seizures, breathing difficulties, scoliosis and digestive issues. Girls are often very sociable, but find it almost impossible to commmunicate.
Currently there are virtually no treatments. But, research has shown that Rett Syndrome can be reversed in mice, there is no brain damage! Right now, research is continuing with the hopes of developing treatments and even bringing this reversal to humans.
I’ve been looking into Rett as a project for school and as part of that I interviewed the mother of a local girl with the condition. It was really amazing to hear about everything her daughter had to deal with on a daily basis, and how they have all adapted and remain hopeful and patient. But what shocked me most was that the woman said there was very little professional, never mind public, awareness of the disorder! This delays diagnosis for many girls and without awareness, there is little funding for research. If the public aren’t interested, then money doesn’t get raised and grants rarely get given.
We could see this be the first curable neurological disorder, and give these girls their freedom.

Please spread the word. To find out more, visit the websites of Reverse Rett or RSRT. There’s also a wonderful video here describing 'A Father’s Words’ on Rett. 

Mouse Version of an Autism Spectrum Disorder Improves When Diet Includes a Synthetic Oil

When young mice with the rodent equivalent of a rare autism spectrum disorder (ASD), called Rett syndrome, were fed a diet supplemented with the synthetic oil triheptanoin, they lived longer than mice on regular diets. Importantly, their physical and behavioral symptoms were also less severe after being on the diet, according to results of new research from The Johns Hopkins University.

(Image caption: Mitochondria (arrows) in muscle cells from mice with Rett syndrome improved in appearance after the mice were given triheptanoin oil. Top: Muscle from mice given regular food. Bottom: Muscle from mice given food supplemented with triheptanoin. Left: Healthy mice. Right: Mice with a genetic mutation that mimics Rett syndrome.)

Researchers involved in the study think that triheptanoin improved the functioning of mitochondria, energy factories common to all cells. Since mitochondrial defects are seen in other ASDs, the researchers say, the experimental results offer hope that the oil could help not just people with Rett syndrome, but also patients with other, more common ASDs.

A description of the research was published on Oct. 9 in the journal PLOS ONE.

ASDs affect an estimated one in 68 children under 8 years of age in the United States. Rett syndrome is a rare ASD caused by mutations in the MECP2 gene, which codes for methyl-CpG-binding-protein 2 (MeCP2). Rett syndrome includes autismlike signs, such as difficulty communicating, socializing and relating to others. Other hallmarks are seizures, decreased muscle tone, repetitive involuntary movements, and gastrointestinal and breathing problems. These other signs are also seen in some patients with other ASDs, suggesting underlying similarities in their causes. While the causes of most ASDs are unknown and thought to be complex, Rett syndrome is unique — and could be a source of insight for the others — because it is caused by an error in a single gene.

The research team used mice lacking the MeCP2 protein, which left them with severe Rett syndrome. In examining those mice, what stood out, according to Gabriele Ronnett, M.D., Ph.D., who led the research project at the Johns Hopkins University School of Medicine, was that they weighed the same as healthy mice but had large fat deposits accompanied by lower amounts of nonfat tissue, such as muscle. This suggested that calories were not being used to support normal tissue function but instead were being stored as fat.

This possibility led Ronnett and her research team to consider the role of mitochondria, which transform the building blocks of nutrients into a high-energy molecule, ATP. This molecule drives processes such as the building of muscle and the growth of nerve cells. Mitochondria use a series of biochemical reactions, collectively called the TCA cycle, to make this transformation possible. According to Susan Aja, Ph.D., a research associate and lead member of the research team, “If the components of the TCA cycle are low, nutrient building blocks are not processed well to create ATP. They are instead stored as fat.”

Ronnett suspected, she says, that some of Rett syndrome’s neurological symptoms could stem from metabolic deficiencies caused by faulty mitochondria and reduced energy for brain cells. “Rett syndrome becomes apparent in humans 6 to 18 months old, when the energy needs of the brain are particularly high, because a lot of new neural connections are being made,” says Ronnett. “If the mitochondria are already defective, stressed or damaged, the increased demand would be too much for them.”

Previous small clinical trials in people with a different metabolic disorder suggested that dietary intervention with triheptanoin could help. Triheptanoin is odorless, tasteless and a little thinner than olive oil. It is easily processed to produce one of the components of the TCA cycle.

When Rett syndrome mice were weaned at 4 weeks of age, they were fed a diet in which 30 percent of their calories came from triheptanoin, mixed in with their normal pelleted food. Though far from a cure, the results of the triheptanoin treatment were impressive, the researchers say. Treated mice had healthier mitochondria, improved motor function, increased social interest in other mice and lived four weeks — or 30 percent — longer than mice who did not receive the oil. The team also found that the diet normalized their body fat, glucose and fat metabolism.

“You can think of the mitochondria of the Rett syndrome model mice as damaged buckets with holes in them that allow TCA cycle components to leak out,” says Aja. “We haven’t figured out how to plug the holes, but we can keep the buckets full by providing triheptanoin to replenish the TCA cycle.”

“It is still too early to assume that this oil will work in humans with ASDs, but these results give us hope,” says Ronnett. “It’s exciting to think that we might be able to improve many ASDs without having to identify each and every contributing gene.”

According to Aja, additional mouse studies are needed to learn if female mice respond to the treatment, to perform a wider range of physiology and behavior tests, and, importantly, to assess the effects of triheptanoin treatment on the brain, which is considered the main driver of many Rett symptoms. The team would also like to provide triheptanoin at earlier ages, perhaps via the mothers’ milk, to mimic developmental ages at which most children are diagnosed with Rett syndrome.

Triheptanoin is currently made for research purposes only and is not available as a medicine or dietary supplement for humans.

UC San Diego Research Funded By CIRM to Identify Potential Autism Drug Targets

A researcher at the University of California, San Diego School of Medicine is among principal investigators at 10 California institutions receiving Early Translational IV Research grants, totaling $40 million, approved today by the governing board of the California Institute for Regenerative Medicine (CIRM) at its meeting in San Diego.

Alysson R. Muotri, PhD, assistant professor of pediatrics and cellular and molecular medicine, will receive approximately $1.85 million for his research using induced pluripotent stem (iPS) cells, with the aim of identifying novel small molecule drugs with the potential to treat autism spectrum disorder.

“This project is based on the hypothesis that astrocytes, one of the main support cells in the central nervous system, play an important role in the formation and function of neural connections,” said Muotri.

Astrocytes will be obtained by in-vitro differentiation of iPS cells derived from patients with autism spectrum disorder. Muotri and colleagues did something similar in 2010 when they used iPSCs from patients with Rett syndrome to create the first functional human cellular model for studying the development of autism spectrum disorders.

“This work is important because it puts us in a translational mode,” Muotri said. “It helps expand and deepen our understanding of autism, from a behavioral disorder to a developmental brain disorder. We can now look for and test drugs and therapies and see what happens at a cellular and molecular level.”

More here

An X-linked Autism Spectrum Disorder

Rett syndrome is a postnatal neurodevelopmental disorder defined as an X-linked autism spectrum disorder. Put simply, it affects the development of the nervous system after birth. The underlying genetic defects have been associated with the X-chromosome, and it is a disorder which comes under the Autism Spectrum of disorders.

Rett syndrome principally affects women. Approximately 1 in 10,000 women are affected by this disorder. Despite being a genetic, developmental disorder, the symptoms for Rett Syndrome do not usually present until about 6 months following birth. What seems to be occurring is that impairment in the development of the nervous system is having a deleterious effect on learning. The symptoms are characterised by:

  • Normal development during gestation and for the first few months following birth, followed by a phase of developmental regression
  • Deceleration of head growth
  • Breathing disturbances during (but not limited to) waking
  • Loss of acquired skills in manual dexterity and hand movements resulting in repeated hand movements such as clapping, hand squeezing, wringing, and rubbing
  • Evidence of social withdrawal
  • Loss of learned vocabulary

Classical Rett syndrome exhibits most of the aforementioned symptoms and is usually the severe form. Variant Rett syndrome exhibits fewer of the described symptoms, so may appear to be more ‘mild’. In Variant Rett syndrome, there is improvement in the social withdrawal and communication symptoms into the mid to late teens. Disturbances in movement persist, however. There is also the risk of Rett syndrome patients undergoing scoliosis. Scoliosis is extreme curvature and twisting in the structure of the spine, showing some impairment in skeletal development also.

X-ray of scoliosis in a teenager, picture from The Lancet p.1533 vol.317 (2008)

Rett syndrome has been linked to a mutation in the X chromosome. In particular, this mutation occurs within the MECP2 gene. This gene codes for a protein involved in regulating the activity of some other genes by switching off their function. The mutations responsible for Rett Syndrome appear to inactivate the MECP2 gene, thus impairing gene silencing. Ordinarily, different genes are expressed during different stages of development. In Rett syndrome, genes from an earlier developmental stage which should be turned off to allow for a shift in genetic profile, remain switched on thus confusing the developmental progress. This disrupts the pattern of genetic expression, and has knock on effects on later development.

Rett Syndrome is part of the Autism spectrum disorders due to the social withdrawal which makes up part of the syndrome. Social skills rely on aspects of learning, and learning appears to be affected in Rett syndrome, as is evident from the loss of learned (acquired) skills. Learning is a process which involves modifications of the existing wiring of the brain, as well as forming new connections between neurons. This can be seen as a developmental process as neurons must produce new proteins and modify their structure and function. The impairments to cognitive and social function which occurs due to Rett Syndrome may be attributed to the effects of the mutations on learning and general development.

In studies comparing the size and weight of brains from average girls with those of Rett Syndrome sufferers, scientists found a reduction in weight of the brain of between 14-34% demonstrating a deficit in brain development. Regions which were affected the greatest were the cerebral cortex, midbrain and basal ganglia. Consistent with the symptoms, the cerebral cortex is principally associated with higher cognitive function and learning. The midbrain is part of the brain stem, and is involved in regulating basic processes such as respiratory rhythm and heart rate. The basal ganglia have some involvement in learning, as well as being the coordinators of limb movement.

A simple diagram of brain anatomy. I put this here because it shows the locations of the brainstem, cortex and the basal ganglia. The basal ganglia are a set of structures which include the structure highlighted in the diagram (which is the thalamus) are actually difficult to show a diagram of the brain such as this, as they’re actually buried within each hemisphere, and this picture only shows a section down the centre of the brain ( a sagittal section).

There are neuronal circuits in the brain stem which regulate breathing, outside of conscious influence. Impairment in the development of these circuits disrupts the function they’re supposed to carry out and this can have a knock on effect on how the brain coordinates breathing. The breathing difficulties appear to be most pronounced during waking hours, but do occur at night - albeit to a lesser extent. This has been attributed to the different neurochemical states the brain occupies during sleeping and waking. What this means is that some populations of neurons which use different neurotransmitters as their means of communication with each other, are implemented during sleep.  Activating a different system of neurons which is less affected by the underlying pathology of Rett syndrome may produce less negative effects on breathing. There may be impairment in the connections from arousal centres which feed into the breathing circuits to match their function with the organisms current state of arousal (sleep/wakefulness).

Rett syndrome is still a poorly understood disorder, and the science behind how it affects breathing still has some way to go. So far, our understanding tells us this much, but this complex disorder demonstrates the complex array of functions genes carry out, and how a large part of our seemingly fluid mind is at the mercy of basic genetics.

Another FC story: a truly blind facilitator

This one from a mother and daughter I know. They both have Rett syndrome, the mother mild and the daughter severe. The mother was just diagnosed as having autism and a severe intellectual disability growing up, until she learned to write, and later speak. Her daughter will probably never speak but does type using FC.

They have used a lot of ingenious ways of proving that her daughter is really the one doing the typing. But one of them involved having a blind facilitator. As in, the facilitator himself was literally blind and could not see the letter board. They set everything up like usual, to show to a skeptical teacher. Then without telling the facilitator, they flipped the letter board upside down.

The daughter of course continued to type perfectly accurate responses. The facilitator was very confused and somewhat agitated about the whole thing, and kept asking “are you sure you meant to hit that letter?” But she firmly continued to type on her upside down letter board, and the facilitator clearly had no idea she was typing anything other than gibberish. He was able to give her hand the support it needed to type without having to see the letters, because it was her hand he was focused on.

After that incident, the teacher no longer doubted that the daughter was doing her own work. I’ve never doubted it either. Her daughter is highly sensing and has an entire way of communicating that doesn’t involve speech or typing at all. The content of her typing matches the person she comes across as on a sensing level. Hard to explain.

I wish she and her mother would write a book together because they have both done so many interesting things. But too much of their time is taken up by survival. The daughter has severe health issues and many times has had a projected lifespan of months. So working on a book would not be her priority. But I wanted to add this to my #fc tag for those interested in stories about FC, both done right and done horribly wrong, and my thoughts on the matter. I can’t consolidate all those ideas into one post so I keep them all in one tag for those who have expressed an interest in my experiences and opinions.

Homing In on Rett Mutations

Rett syndrome is all about loss. Like autism, this disorder of neurological development steals abilities from children. It strikes around their first birthdays, just as they are learning to walk and talk.

Unlike autism, whose cause remains a mystery, Rett syndrome has been definitively traced to mutations in a single gene. An X chromosome-linked disorder, it affects girls almost exclusively, causing regression in language acquisition and motor control as well as seizures and respiratory problems.

Identifying the faulty gene is only the first step on the road toward a better understanding of what goes wrong to cause Rett syndrome and what might correct it. HMS researchers working closely with collaborators from Edinburgh and Oregon are gaining deeper understanding of the specific molecular pathways behind the cluster of genetic mutations—any one of which can derail normal development by varying degrees.

Led by Michael Greenberg, the Nathan Marsh Pusey Professor of Neurobiology and head of the HMS Department of Neurobiology, the scientists express cautious hope that their work might one day pave the way for therapies to help Rett patients regain what they have lost.

“By getting into the detailed mechanisms, one might eventually come up with ways to essentially reverse the defect,” said Greenberg, senior author of a paper appearing in Nature and co-author of another published at the same time in Nature Neuroscience. Both papers focus on MECP2, a gene whose mutated form is associated with Rett.

At a crucial point in brain development, when girls are 6 to 18 months old, MECP2  normally functions to modify synapses that young brains are creating in response to sensory experiences that send signals to make neural connections. When MECP2 is absent, so is the necessary balance between synapses that increase activity and those that dampen it, a problem some suspect may also play a role in psychiatric diseases.

“MECP2 is in the nucleus of the cells of our brains in our first year of life. It’s sitting there waiting for a signal,” Greenberg said. “If MECP2 is there and can function normally, a sensory signal comes to MECP2, changes the DNA, turns on genes and engages in this process of synaptic development and maturation. If MECP2 is mutated in such a way that the complex that’s going to receive the signal can’t get it, it’s almost as if the brain is frozen in time. It can’t process the signal.”

Mutations to the gene MECP2 do different things, depending on which amino acid change is at fault: Either the protein isn’t made at all or the mutation occurs in a critical domain of the protein that is essential for its proper function.

Daniel Ebert, a postdoctoral fellow in the Greenberg lab, focused on chemical modifications to MECP2 that affect the gene’s most basic functions. Through a technique called phosphotryptic mapping, he discovered three new sites on MECP2 where neuronal activity induces chemical changes.

One of the sites on MECP2 is where the amino acid threonine 308 (T308) sits. When T308 is mutated, the chemical change that sensory experiences are supposed to produce doesn’t happen. This loss also disrupts how MECP2 interacts with a crucial protein complex called nuclear receptor co-repressor (NCoR). Together, MECP2 and NCoR are believed to refine neurodevelopment by repressing genes and regulating the number of synapses being built.

Mice engineered to have a mutation in T308 show Rett syndrome characteristics, suggesting a crucial role for chemical modifications to MECP2 caused by sensory experiences.

Scientists Matthew Lyst and Adrian Bird at the University of Edinburgh studied the domain where MECP2 binds to NCoR, a region of MeCP2 that controls gene expression involved in synaptic function. They showed how MECP2 mutations disrupt these interactions.

“Together the two papers provide a new, basic understanding of the mechanisms of MECP2 action and what may go wrong in Rett syndrome,” Greenberg said. “Instead of having to look at the whole MECP2 molecule, we now have a particular domain to focus on. We have a new protein complex, NCoR, to study, and we now need to figure out how these proteins work together to control synapse function. These findings are exciting because they open up a lot of new research directions.”

Greenberg and Bird have been collaborating with Gail Mandel of the Oregon Health and Science University as members of the MECP2 Consortium, launched in 2011 by Monica Coenraads of the Rett Syndrome Research Trust. Mandel is pursuing potential gene therapies based on MECP2.

Bird discovered MECP2 in 1992 and 15 years later made a startling discovery in mice that raised hopes for reversing Rett’s defects. Mice whose MECP2 genes were silenced went on to develop Rett-like disease, but once those genes were turned back on, they recovered their abilities. Rather than losing function forever, the mice returned to normal.

“Understanding the different ways in which MECP2 is mutated and how the mutations affect function is really going to be important for developing therapeutics,” Greenberg said.

First Pre-Clinical Gene Therapy Study to Reverse Rett Symptoms

The concept behind gene therapy is simple: deliver a healthy gene to compensate for one that is mutated. New research published today in the Journal of Neuroscience suggests this approach may eventually be a feasible option to treat Rett Syndrome, the most disabling of the autism spectrum disorders. Gail Mandel, Ph.D., a Howard Hughes Investigator at Oregon Health and Sciences University, led the study. The Rett Syndrome Research Trust, with generous support from the Rett Syndrome Research Trust UK and Rett Syndrome Research & Treatment Foundation, funded this work through the MECP2 Consortium.

In 2007, co-author Adrian Bird, Ph.D., at the University of Edinburgh astonished the scientific community with proof-of-concept that Rett is curable, by reversing symptoms in adult mice. His unexpected results catalyzed labs around the world to pursue a multitude of strategies to extend the pre-clinical findings to people.

Today’s study is the first to show reversal of symptoms in fully symptomatic mice using techniques of gene therapy that have potential for clinical application.

Rett Syndrome is an X-linked neurological disorder primarily affecting girls; in the US, about 1 in 10,000 children a year are born with Rett.  In most cases symptoms begin to manifest between 6 and 18 months of age, as developmental milestones are missed or lost. The regression that follows is characterized by loss of speech, mobility, and functional hand use, which is often replaced by Rett’s signature gesture: hand-wringing, sometimes so intense that it is a constant during every waking hour. Other symptoms include seizures, tremors, orthopedic and digestive problems, disordered breathing and other autonomic impairments, sensory issues and anxiety. Most children live into adulthood and require round-the-clock care.

The cause of Rett Syndrome’s terrible constellation of symptoms lies in mutations of an X-linked gene called MECP2 (methyl CpG-binding protein). MECP2 is a master gene that regulates the activity of many other genes, switching them on or off.

“Gene therapy is well suited for this disorder,” Dr. Mandel explains. “Because MECP2 binds to DNA throughout the genome, there is no single gene currently that we can point to and target with a drug. Therefore the best chance of having a major impact on the disorder is to correct the underlying defect in as many cells throughout the body as possible. Gene therapy allows us to do that.”

Healthy genes can be delivered into cells aboard a virus, which acts as a Trojan horse. Many different types of these Trojan horses exist. Dr. Mandel used adeno-associated virus serotype 9 (AAV9), which has the unusual and attractive ability to cross the blood-brain barrier. This allows the virus and its cargo to be administered intravenously, instead of employing more invasive direct brain delivery systems that require drilling burr holes into the skull.

Because the virus has limited cargo space, it cannot carry the entire MECP2 gene. Co-author Brian Kaspar of Nationwide Children’s Hospital collaborated with the Mandel lab to package only the gene’s most critical segments. After being injected into the Rett mice, the virus made its way to cells throughout the body and brain, distributing the modified gene, which then started to produce the MeCP2 protein.

As in human females with Rett Syndrome, only approximately 50% of the mouse cells have a healthy copy of MECP2. After the gene therapy treatment 65% of cells now had a functioning MECP2 gene.

The treated mice showed profound improvements in motor function, tremors, seizures and hind limb clasping. At the cellular level the smaller body size of neurons seen in mutant cells was restored to normal. Biochemical experiments proved that the gene had found its way into the nuclei of cells and was functioning as expected, binding to DNA.

One Rett symptom that was not ameliorated was abnormal respiration. Researchers hypothesize that correcting this may require targeting a greater number of cells than the 15% that had been achieved in the brainstem.

“We learned a critical and encouraging point with these experiments – that we don’t have to correct every cell in order to reverse symptoms. Going from 50% to 65% of the cells having a functioning gene resulted in significant improvements,” said co-author Saurabh Garg.

One of the potential challenges of gene therapy in Rett is the possibility of delivering multiple copies of the gene to a cell. We know from the MECP2 Duplication Syndrome that too much of this protein is detrimental. “Our results show that after gene therapy treatment the correct amount of MeCP2 protein was being expressed. At least in our hands, with these methods, overexpression of MeCP2 was not an issue,” said co-author Daniel Lioy.

Dr. Mandel cautioned that key steps remain before clinical trials can begin. “Our study is an important first step in highlighting the potential for AAV9 to treating the neurological symptoms in Rett. We are now working on improving the packaging of MeCP2 in the virus to see if we can target a larger percentage of cells and therefore improve symptoms even further,” said Mandel. Collaborators Hélène Cheval and Adrian Bird see this as a promising follow up to the 2007 work showing symptom reversal in Rett mice. “That study used genetic tricks that could not be directly applicable to humans, but the AAV9 vector used here could in principle deliver a gene therapeutically. This is an important step forward, but there is a way to go yet.”

“Gene therapy has had a tumultuous road in the past few decades but is undergoing a renaissance due to recent technological advances. Europe and Asia have gene therapy treatments already in the clinic and it’s likely that the US will follow suit. Our goal now is to prioritize the next key experiments and facilitate their execution as quickly as possible. Gene therapy, especially to the brain, is a tricky undertaking but I’m cautiously optimistic that with the right team we can lay out a plan for clinical development. I congratulate the Mandel and Bird labs on today’s publication, which is the third to be generated from the MECP2 Consortium in a short period of time,” said Monica Coenraads, Executive Director of the Rett Syndrome Research Trust and mother of a teenaged daughter with the disorder.

Experimental Drug Extends Lifespan and Could Reverse Rett Syndrome: Mouse Study

Researchers demonstrate that treatment with small-molecule drug candidates significantly extends lifespan in male mice that model Rett syndrome and ameliorates several behavioral symptoms of the disorder in model female mice.

The research is in Journal of Clinical Investigation. (full open access)

Research: “PTP1B inhibition suggests a therapeutic strategy for Rett syndrome” by Navasona Krishnan, Keerthi Krishnan, Christopher R. Connors, Meng S. Choy, Rebecca Page, Wolfgang Peti, Linda Van Aelst, Stephen D. Shea, and Nicholas K. Tonks in Journal of Clinical Investigation doi:10.1172/JCI80323

Image: X-ray crystallography shows at the atomic level how Tonks’ experimental drug for Rett syndrome, called CPT157633, binds to its target, the enzyme PTP1B, which helps regulate a key metabolic signaling cascade. Image credit: Tonks Lab, CSHL.
Eleanor Moore is fundraising for RETT UK

Okay y'all know Tyler is doing his fundraiser for the Trevor project Right now and it inspired my older sister to do something that means alot to us . We have a sister with a rare condition called rett Syndrome and her goal is £400. So far she’s raised £120 . At the end of the campaign in 4 week her and her boyfriend will be running a half marathon together and it would mean the world to me if you donated . Even a pound makes a difference

I’m gonna be honest people, communicating with a person who’s only “voice” is an eyebrow raise meaning “yes,” is incredibly frustrating

it can also bring some of the most fun, hilarious, exhilarating conversations you will ever have

because when you finally arrive at that thought they wanted to share, that hidden “yes” that holds so much relief for the nonverbal person, it may as well be “YES, THANK GOD, FINALLY,” you realize that while most conversations are free, some are hard-won, which, no matter what the topic, makes them unbelievably precious

Decoding Rett syndrome: New pieces to the puzzle

Rett Syndrome is a neurological disorder that affects about 1 in 10,000 girls. Back in 1992, University of Edinburgh researcher Adrian Bird discovered that the protein, MeCP2, plays a major role in the disease. The story of MeCP2 is in many ways a microcosm of human genetics. It has become the showcase gene for many complex epi-genetic phenomena including X-linked inactivation, DNA methylation, and genomic imprinting. These gender-specific bargaining chips provide compatibility in an evolutionary system where sex-chromosome provisioning is inherently assymetric. In two new papers, one in Nature and the the other in Nature Neuroscience, Bird and collaborator Michael Greenberg, show how mutations found in Rett Syndrome affect the interaction of MeCP2 with a key regulatory protein known as NCoR.

Nearly all cases of Rett Syndrome are caused by mutations at various postions in the MeCP2 gene. Bird and Greenberg analyzed the locations of these mutations using the RettBase MeCp2 database, and found they cluster to two primary locations—the well-known methyl-CpG binding domain, and a new hotspot within a transcriptional repressor domain (TRD). When they compared these locations with mutations found in the general population by using the Exome Variant Server, they found no overlap. This suggests the that the MeCP2 and TRD regions are the primary regions involved in Rett’s.

The researchers hypothesized that the newly found TRD region must act through a unknown regulator of MeCP2 function. Using mass spectrometry, they were able to identify several factors which they had purified from Mecp2-EGFP “knock-in” mice. Most of these factors turned out to be subunits of the co-repressor, NCoR, which was previously known to interact with MeCP2. This is the first identified example of a protein-protein interaction known to be disrupted in Rett’s.

In the Nature paper, the researchers further report that activity-dependent phosphorylation of MeCP2 mediates its interaction with NCoR. They used a technique known as phosphotryptic mapping to identify three sites that are directly phosphorylated in MeCP2 as a result of elevation in cAMP or BDNF. More generally, they showed that membrane depolarization, and therefore activity, results in the phosporylation.

One confounding factor in trying to pinpoint the mechanisms underlying Rett Syndrome is that both loss of MeCP2, and overexpression of MeCP2, can lead to the disease. In mouse models of the disease, this could be accounted for by the observation that both loss of NCoR binding, and constitutive binding of NCoR can lead to disease symptoms. While not a complete explanation of the role of MeCP2 in the disease, it provides some clues to help dissect the involvement of the many different kinds of mutations involved.

Despite the rarity of Rett’s syndrome, its impact on our understanding of human genetics and neural development should not be underestimated. As one of the autistic spectrum disorders, research on Rett’s helps connect molecular mechanics to behavior. For example, when MeCP2 is bound to DNA it can cause condensation of the chromatin structure, and also form complexes with histone deacetylaces. In demostrating that neural activity, and subsequent signal tranduction pathways, lead to modifications of MeCP2, the researchers have revealed a path from the environment directly to the genes.

The X-linked inactivation of one copy of the MeCP2 gene in females adds another layer of complexity to the disease. The celluar mosiac formed by the pattern of inactivation, particularly in the brain, needs more study to be undersatood. The fact that Rett’s symptoms can be “rescued” in mice by the expression of MeCP2 in postmitotic neurons is encouraging. In humans, Rett’s is frequently not observed untill the first or second year of life. As MeCP2 activation correlates with this period of rapid neural maturation, Rett’s is generally considered to be neurodevelopmental disease, as opposed to a neurodegenerative disease.

Rett’s is hardly ever observed in males for the simple reason that they fail to thrive long before birth. In those rare cases that a presumably XXY male child is rescued by the additional X chromsome, as in Klinefelder’s disease, rare opportunity to study the disease etiology is afforded. The efforts of these researchers, and the larger Rett’s community, together with the insights afforded by massive data collation have turned a rare disease into a primary source of knowledge about how evolution proceeds through the interplay of the sexes at the genetic and epigenetic levels.

Bone-marrow transplant reverses Rett syndrome in mice

Rare autism spectrum disorder is partially caused by faulty immune cells in the brain.

Bone-marrow transplant reverses Rett syndrome in mice

Rare autism spectrum disorder is partially caused by faulty immune cells in the brain.

18 March 2012

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Rett syndrome, an autism spectrum disorder, causes problems with communication, coordination and movement.


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A bone-marrow transplant can treat a mouse version of Rett syndrome, a severe autism spectrum disorder that affects roughly 1 in 10,000–20,000 girls born worldwide (boys with the disease typically die within a few weeks of birth).

The findings, published today in Nature1, suggest that brain-dwelling immune cells called microglia are defective in Rett syndrome. The authors say their findings also raise the possibility that bone-marrow transplants or other means of boosting the brain’s immune cells could help to treat the disease.

“If we show the immune system is playing a very important role in Rett patients and we could replace it in a safe way, we may develop some feasible therapies in the future,” says Jonathan Kipnis, a neuroscientist at the University of Virginia School of Medicine in Charlottesville, who led the study.

Mutations in a single gene on the X chromosome, MECP2, cause the disease. Because they have only one X chromosome, boys born with the mutation die within weeks of birth. Girls with one faulty copy develop Rett syndrome.

Symptoms of Rett syndrome typically set in between 6 and 18 months of age. Girls with the disease have trouble putting on weight and often do not learn to speak. They repeat behaviours such as hand-washing and tend to have trouble walking. Many develop breathing problems and apnoea. Rett syndrome is classified as an autism spectrum disorder, and treatments focus on symptoms such as nutritional and gastrointestinal problems.

The MECP2 protein orchestrates the activity of many other genes, but how its alteration causes Rett syndrome is a mystery. “I wish I knew,” says Kipnis.

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Neurons express more MECP2 than any other cell in the brain, and restoring the gene’s function in mouse neurons reverses some disease symptoms2. Recently, however, scientists have begun to suspect that other brain cells are also involved. Re-activating MECP2 in brain-support cells called astrocytes treats gait problems and anxiety in mice3.

Kipnis and his team focused on another class of brain cell — microglia. They are the brain’s macrophages, a type of immune cell that sops up the detritus created by other cells. Studies have linked various immune cells to brain function, including repetitive and compulsive behaviour4, which led Kipnis to test whether replacing an immune system in mice lacking Mecp2 with cells containing the gene could improve symptoms.

To replace the mice’s immune systems, the team first exposed four-week-old mice to radiation to kill off their existing immune cells — including microglia — and then injected them with bone-marrow cells with a working copy of Mecp2. Stem cells in bone marrow form the immune system, including microglia cells.

Male Rett mice, with no working copy of Mecp2, typically die within two months, but the ones that received bone marrow from healthy mice lived up to a year, Kipnis says. The treated mice breathed easier, walked better and gained more weight compared with untreated mice. Female mice with just one working copy ofMecp2 develop Rett symptoms later than male mice, but a bone-marrow transplant improved gait, breathing and weight gain for them, too.

To determine whether microglia in the brain and not immune cells elsewhere in the body explain the effects, Kipnis’s team gave bone-marrow transplants to Rett mice that did not get a dose of radiation to their brains, sparing the existing microglia. The transplant did nothing for these mice.

Kipnis speculates that microglia from Rett mice have trouble clearing cellular rubbish in the brain, making it more difficult for their neurons to work properly. If this can be established with additional research, clinical trials of bone-marrow transplants may be worth trying, Kipnis says. With the Rett Syndrome Research Trust, based in Trumbull, Connecticut, he has begun approaching bone-marrow transplant centres with this possibility. "This is very, very preliminary,“ he cautions. "It works fantastically in mice, but we can cure almost anything in mice.”

Less drastically, Kipnis thinks that the disease could also be treated with drugs that improve microglia function. Girls with Rett syndrome have one working copy of MECP2, so half of their microglia may work.

Frauke Zipp, a neuro-immunologist at the Johannes Gutenberg University Mainz in Germany, agrees that a clinical trial of cell transplantation to treat Rett syndrome is far afield, but not inconceivable if additional research pins down their role in disease.

“These findings contribute to the idea that Rett syndrome is a very complicated disorder involving multiple cell types and systems,” adds Gail Mandel, a neuroscientist at Oregon Health Sciences University near Portland. Some form of gene therapy may be a way of fixing all these different problems, she says.




Statins Suppress Rett Syndrome Symptoms in Mice

Statins, a class of cholesterol-lowering drugs found in millions of medicine cabinets, may help treat Rett Syndrome, according to a study published today in Nature Genetics. The Rett Syndrome Research Trust (RSRT) funded this work with generous support from the Rett Syndrome Research Trust UK and Rett Syndrome Research & Treatment Foundation.

Rett Syndrome is a neurological disorder that affects girls. A seemingly typical toddler begins to miss developmental milestones. A regression follows as young girls lose speech, mobility, and hand use. Many girls have seizures, orthopedic and severe digestive problems, as well as breathing and other autonomic impairments. Most live into adulthood and require total, round-the-clock care. Rett Syndrome affects about 1 in 10,000 girls born in the U.S. each year.

The new study screened for randomly induced mutations in genes that modify the effect of the Rett gene, MECP2 (methyl-CpG-binding protein 2), in a mouse model. MECP2 turns other genes on or off by disrupting chromatin, the DNA-protein mix that makes up chromosomes.

The challenge of treating Rett Syndrome is what drove senior author Monica Justice, Ph.D., Professor in the Departments of Molecular and Human Genetics and Molecular Physiology and Biophysics at the Baylor College of Medicine, to look beyond MECP2, hoping to find new drug targets that might improve symptoms or even reverse the course of the disease. In 2007, Adrian Bird, Ph.D., Buchanan Professor of Genetics at the Wellcome Trust Centre for Cell Biology at the University of Edinburgh, showed that symptoms in mice are reversible regardless of the age of the animal.

Exploring cholesterol metabolism in neurological diseases is an emerging area, with statin drugs being tested in fragile X syndrome, neurofibromatosis, amyotrophic lateral sclerosis, and other conditions. But it hadn’t been on the radar for Rett Syndrome. “Our screen was to see if we could suppress the symptoms to reveal alternative pathways to treatment. The cholesterol hit was a big one,” Dr. Justice said. The screen was unbiased – the researchers were looking for any gene that would interact with MECP2 in a useful way, rather than employing a candidate gene approach based on hypotheses.

Dr. Justice and her team injected healthy male mice with a chemical called ENU (a form of nitrosourea) that mutates sperm stem cells randomly, then mated the males to Rett females. The researchers then looked for offspring that should have developed the syndrome (according to their genes), but didn’t (according to their good health).

Key to the investigation was being able to tell sick mice from healthy ones. Fortunately this turned out to be easy. The rescued mice didn’t develop the characteristic tremor, trouble breathing, poor limb-clasping, and general scruffiness of their affected cage-mates. They moved around more, performed better on mobility tests and lived longer.

Once the rescued mice had been identified the random gene mutations from the 24,000 genes that make up the mouse genome had to be pinpointed. “With next generation DNA sequencing, we are finding mutations so easily and quickly. It’s amazing,” said Dr. Justice, compared to the old days of setting up many more generations of crosses to narrow down a part of the genome harboring a gene of interest.

“We are only15% of the way through the screen, and so far we have identified 5 modifiers. The most drug-targetable is a gene called squalene epoxidase (Sqle), which encodes a rate-limiting enzyme in the cholesterol biosynthetic pathway. Frankly, this discovery was a surprise,” Dr. Justice said.  It’s important to note that this enzyme is different from the rate-limiting enzyme (HMG CoA reductase) influenced by statin drugs.

Cholesterol is of course best known for its negative effects on the cardiovascular system, but the lipid has multiple roles in the brain: it helps to form the myelin insulation on neurons and takes part in membrane trafficking, dendrite remodeling, synapse formation, signal transduction, and neuropeptide synthesis.

The next step was to test several statins (fluvastatin and lovastatin) on Rett mice. Like the Sqle mutation, the drugs improved symptoms. Treated mice performed well on mobility and gross motor tests, had better overall health scores and lived longer. The drugs didn’t, however, improve breathing.

“When we saw the mutation in a cholesterol pathway enzyme, we immediately thought of statin drugs. Now that our eyes have opened to what is going on, we have a multitude of drugs that modulate lipid metabolism that we can try in addition to statins,” said first author Christie Buchovecky, graduate student in the Justice lab.

With additional RSRT funding, pediatric neurologist and Director of the Tri-State Rett Syndrome Center in the Bronx Dr. Sasha Djukic undertook a detailed review of lipid data in girls with Rett Syndrome. She found that a subset have elevated cholesterol levels which normalize as they age. These data are not included in the Nature Genetics publication but will be part of a subsequent paper. Dr. Djukic is now planning a clinical trial.

Drs. Justice and Djukic caution that carefully designed and rigorously executed clinical trials are essential to test whether what works in mice will also work in girls with Rett Syndrome. Clinical trials should also determine the most effective timeframe for treatment, ways to identify which girls are most likely to respond, (for example, will statins help girls with Rett who do not have elevated cholesterol?), which drugs to trial and what dosages are effective but not toxic.

“Although statins are blockbuster drugs taken by a large percentage of the population they are not without risks and side-effects, and data on statins in the general pediatric population are quite limited. One of the key objectives of the clinical trial will be to determine correct dosages for Rett symptoms. It’s important to note that the mice in Dr. Justice’s study received very low doses of statins. I urge parents to resist any temptation to medicate their children with off-label statins,” cautions Dr Djukic. “The only way to know if this class of drugs will be efficacious in Rett is through controlled trials. Working with Dr. Justice and RSRT we will be bringing families additional information as soon as possible.”

“The biggest finding is the discovery that this pathway is so important to the pathology of the disorder; it suggests new directions for trying to learn more about Rett Syndrome,” Dr. Justice explains. “Emerging evidence from both mice and humans suggest that Rett Syndrome may have a component of disease that is metabolic. Certainly, this study will further clarify our data, and may suggest avenues for treatment that were previously unexplored.”
Fundraising update and IT band-aid


We exceeded my initial goal by raising $635! A reminder that there’s just over a month left for me to raise money for the International Rett Syndrome Foundation in honor of my second-cousin and goddaughter, Melaina. Let’s see if we can double that and then some by October 2nd to raise $1500!  Groundbreaking research has already found that some of the symptoms can be reversed in mice (woohoo, science!), so the funds are critical to keep the research going. Funds also go directly to the care of the people affected by Rett, so every penny goes towards a good cause :)

p.s. I had to set up a new donation page b/c the first one expired it’s accepting of donations. 



This past week, I ran a lot more than I have been in the previous weeks…which was basically following the training plan (I survived a 16-mile long run! My longest to date!) But since I haven’t been consistent that means I overdid it. Apparently, my tried and true method of procrastination, followed by intense, binge-like activity does not translate well to running. Doh! 

I noticed on my last two runs this week that I was feeling stiffness and pain in the IT band area.

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The good ol’ Internet pointed me towards many resources on Iltiotibial (IT) Band Syndrome. This website from a podiatrist that writes for Runner’s World magazine was comprehensive and easy to understand. It seems that one of the major contributors to this problem are weak hip abductor muscles (aka gluteus medius).

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When weak, the IT band basically overcompensates to provide hip stability. The two times I’ve tried physical therapy, I’ve been told that I had weak hips. So, I guess I really do have to do those exercises, huh? Here’s a link to the Livestrong website with instructions for some easy exercises like the clamshell, which is my personal favorite because while I’m doing it, I like to imagine that I’m Olivia Newton-John in the Physical music video. (Warning: this video isn’t exactly NSFW, but it’ll probably be really awkward if someone catches you watching it).