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L'X fragile sera vaincu | Fragile X will be conquered

Archive for XF veille web / FX web watch

AUTISME et X FRAGILE: Même mécanisme génétique, même espoir de traitement?

Neuron et Science Transational Medicine |

(…) Leurs travaux indiquent donc une convergence possible des mécanismes causant l’autisme et l’X fragile: L’association présentée dans l’étude n’est pas avec le gène FMR1 lui-même, mais avec les gènes qui sont «en aval» de celui-ci. Ce sont les gènes qui produisent des régulateurs du gène FMR1 et, en gros l’empêchent de produire correctement la protéine FMRP. « Nous avons aujourd’hui une forte preuve statistique sur le lien entre l’autisme et le syndrome de l’X fragile », explique le Dr Wigler. «Notre découverte a des implications importantes pour la thérapie des TSA et montre que l’autisme est en grande partie un désordre moléculaire de la neuroplasticité, le mécanisme par lesquel notre système nerveux s’adapte aux changements.”


Studies highlight promise of fragile X treatment

Jessica Wright, 30 April 2012 |

A promising approach to treating fragile X syndrome could benefit people even after the critical window of early brain development, and alleviate core symptoms of autism, according to two studies published this month.

Fragile X syndrome is caused by the loss of a single protein, FMRP, and is characterized by intellectual disability, unusual physical features and hyperactivity. As many as 30 percent of individuals with the syndrome also have autism; however, the underlying biology of fragile X syndrome may be distinct from that of autism.

The first study, published 12 April in Neuron, provides the first published evidence that many symptoms of fragile X syndrome may be reversible after they have developed1.

Although the results were shown only in mice, they suggest that a similar effect might be seen in people with the disorder, researchers say.

“Parents of adult patients have always thought that these kinds of new treatments might be too late for them, but this gives them a lot of hope,” saysRandi Hagerman, medical director of the MIND Institute at the University of California, Davis. Hagerman was not involved in the new study, but is conducting clinical trials for fragile X therapeutics.


L’X fragile, un retard mental réparable ?

Le MONDE. fr |

Jusqu’ici, les retards mentaux étaient considérés comme irréversibles. Peut-être plus pour longtemps. En traitant par une petite molécule des souris adultes atteintes du syndrome de l’X fragile – la cause de déficience intellectuelle héritée la plus fréquente chez l’homme -, des chercheurs suisses et américains ont corrigé des signes cardinaux associés à ce trouble du développement cérébral : hyperactivité, déficit d’apprentissage et de mémorisation, sensibilité aux convulsions. Des altérations morphologiques cérébrales, tel un excès d’épines dendritiques, ont aussi régressé.


FRAXA Research Outlook 2012 – Treatment Trials and the Next Wave of New Drugs

Fragile X research continues to progress at a break-neck pace and 2012 promises to be a watershed year: the landscape may be very different by this time next year!


ATTENTION : Fragile X research symposium, Sherbrooke, Québec, Canada

We will hold our first Fragile X research symposium (English & French) in Sherbrooke, Québec, Canada. Dr. Paribello from the FX Canadian Research Foundation will attend, amongst others, 29th of October 2011. / For more info please contact, Dr. François Corbin : Francois.Corbin@USherbrooke.ca

ATTENTION : Symposium sur le syndrome du X fragile, Québec

ATTENTION ! : un 1er symposium sur le syndrome du X fragile se tiendra à Sherbrooke, Qc, le 29 octobre 2011. Au programme : Dr. Carlo Paribello, Président de la Fondation canadienne de recherche sur l’X fragile, Dr. Vincent des Portes du CHU de Lyon (France) et Dr. Khandjian (Québec). L’événement aura lieu dans l’amphithéâtre du CHUS/Université de Sherbrooke. Pour plus d’info veuillez contacter Dr. François Corbin Francois.Corbin@USherbrooke.ca

Workings of brain protein suggest therapies for inherited intellectual disability, autism

Cell Press via Eureka Alert |

Researchers now have a much clearer understanding of how mutations in a single gene can produce the complex cognitive deficits characteristic of Fragile X Syndrome, the most common inherited form of intellectual disability. As the majority of patients with Fragile X Syndrome also display autism-like symptoms, the findings offer hope for treating both conditions.

A report in the July 22nd issue of the journal Cell, published by Cell Press, defines a set of messenger RNA (mRNA) molecules that the Fragile-X mental retardation protein (FMRP) binds in the brains of mice. Many of these mRNAs encode proteins that function at neurons’ connection points. When properly bound, FMRP prevents the translation of these mRNAs into proteins until the time is right.

“By understanding for the first time the direct targets of FMRP and its actions, we open up a whole world of potential avenues for therapies designed to make kids with Fragile X or autism better,” said Robert Darnell, a Howard Hughes Medical Institute investigator at The Rockefeller University.

“The power comes from taking two diseases with similar symptoms and looking at what is in common,” added Jennifer Darnell, also at The Rockefeller University. Of the almost 850 identified targets of FMRP, she explained, it is likely only a much smaller subset has a real impact on health or disease.

The Darnell team’s breakthrough uses a technique they developed a few years ago based on a “biochemical trick”. They use ultraviolet light to solidify the bonds between a protein, in this case FMRP, and the mRNAs it binds. Those protein-mRNA complexes could then be isolated and sequenced to reveal a “beautiful map” of the mRNA transcripts and precisely where they are bound to FMRP.

The experiments reveal that FMRP specifically binds to the protein-coding portions of those brain mRNAs. Jennifer Darnell said that distribution is unlike what they’ve seen before and looked much like the distribution of ribosomes, the cellular components that assemble proteins.

Further experiments suggest that FMRP acts as a “brake,” reversibly stalling ribosomes after they bind mRNA. Robert Darnell likened FMRP to the nozzle at the end of a hose. It allows the mRNA transcripts to be loaded with ribosomes in the locations where they will be needed, and when the time is right, bursts of translation (protein synthesis) can occur. That sort of tight control is likely to be critical for the formation and plasticity of neural connections, the cellular foundation for learning and memory.

Their basic scientific discoveries suggest two different overall strategies for treating Fragile X Syndrome: by lowering the activity of particular proteins normally kept under wraps by FMRP or by replacing FMRP’s ability to stall ribosomes. Notably, the Darnells say the latter is exactly what antibiotics do to slow the growth of bacteria.

“We may be able to take the edge off of the extra protein synthesis,” Jennifer Darnell said.

Ultimately, there will be more to the story, Robert Darnell added. “FMRP is one of many regulatory proteins in the neuron. It doesn’t work all by itself.”


Mouse study raises questions about fragile X treatment

Deborah Rudacille, Sfari.org |

Blocking a chemical messenger — a much-touted approach to treating fragile X syndrome — is unlikely to completely reverse symptoms of the disorder, according to a provocative new study1.

Multiple drug candidates in clinical trials to treat fragile X syndrome are based on blocking group 1 metabotropic glutamate receptors (mGluR), a set of chemical messenger receptors involved in cell signaling. Animal studies, including an influential 2007 report2, have shown that reining in the runaway signaling by these receptors decreases seizures and other manifestations of over-excitation of the brain.

In the new study, published online in May in Behavioural Brain Research, researchers cut expression of mGluR1 and mGluR5 by half using a genetic approach rather than chemical inhibitors. The 2007 study used the same approach, but this time, the researchers saw an increase in seizures and only modest behavioral improvements.


UIC to Study Medication for Autism Spectrum Disorders

An experimental drug to treat social withdrawal in children and young adults with autism is being studied in a clinical trial at the University of Illinois at Chicago’s Institute for Juvenile Research.

Children with autism — or autism spectrum disorders — often have difficulty communicating and interacting with others. Although behavioral and psychological interventions are often beneficial, currently there is no medication to address social communication difficulties, a core symptom of ASD.

A drug treatment is needed that would address symptoms that are “often disabling for patients and families,” says Dr. Edwin Cook, professor of psychiatry and director of autism and genetics at UIC.

UIC is the only study site in Illinois and one of 25 sites nationwide. The study is sponsored by Seaside Therapeutics, Inc.

The clinical trial will enroll approximately 150 patients diagnosed with autism spectrum disordersbetween ages 5 and 21 to evaluate the efficacy, safety, and tolerability of STX209 (arbaclofen).

Participants in the 22-week study will be randomized to receive either the study drug, STX209, or a placebo. The clinical trial will include screening, treatment, withdrawal of medication, and a follow-up period. Subjects who complete the study may be eligible to enroll in a subsequent open-label study in which all subjects are treated with STX209.


Fragile X Culprit Fails to Keep Protein Production Under Control

New laboratory studies indicate that the neurological problems caused by Fragile X syndrome, the most common form of inherited intellectual disability, may be due to excess synthesis of certain neuronal proteins that must be present at exactly the right time and place for an individual to learn.

In patients with Fragile X syndrome, which affects approximately one in 5,000 males and half that number of females worldwide, mutations in the gene encoding the Fragile X mental retardation protein (FMRP) can cause cognitive dysfunction and facial abnormalities, among other symptoms. The majority of children with Fragile X syndrome also exhibit behaviors typically associated with autism.

“This work closes a loop between molecular biology and human cognition.”

Robert B. Darnell


Clinical trial for fragile X syndrome treatment

health.universityofcalifornia.edu |

UC Davis will participate in a nationwide trial targeting adolescents and young adults with fragile X syndrome.

The UC Davis MIND Institute is participating in a nationwide, multicenter clinical trial of an investigational medication that has shown clinically meaningful improvements in social functioning in adolescents and young adults with fragile X syndrome.

“This investigational drug has the potential to play a much-needed role in improving the core symptoms of fragile X syndrome and helping patients and families achieve an improved quality of life,” said Randi Hagerman, medical director of the UC Davis MIND Institute and the clinical trial lead investigator.

The medication is known as STX209, or Arbaclofen. It is an oral selective gamma-amino butyric acid type B (GABA-B) receptor agonist being developed by Seaside Therapeutics Inc. of Cambridge, Mass., which is sponsoring the trial.

The study will measure the efficacy, safety and tolerability of Arbaclofen for patients between 12 and 25 years of age with fragile X syndrome, who will receive the medication or a placebo followed by a withdrawal period. The UC Davis MIND Institute will enroll 12 participants.

Fragile X syndrome is the leading genetic cause of intellectual disability and the leading single-gene cause of autism. It is the result of the mutation of a single gene, the fragile X mental retardation 1 (FMR1) gene on the X chromosome.

The FMR1 gene produces a protein needed for normal brain development. Individuals with fragile X syndrome lack this protein and, as a result, the majority of affected individuals have significant intellectual disabilities and require lifetime care.

There currently are no Food and Drug Administration (FDA)-approved treatments for patients with fragile X syndrome.

For further information concerning the clinical trial, please contact Lindsey Partington at (916) 703-0471 or lindsey.partington@ucdmc.ucdavis.edu.

At the UC Davis MIND Institute, world-renowned scientists engage in research to find improved treatments as well as the causes and cures for autism, attention-deficit/hyperactivity disorder, fragile X syndrome, Tourette syndrome and other neurodevelopmental disorders. Advances in neuroscience, molecular biology, genetics, pharmacology and behavioral sciences are making inroads into a better understanding of brain function. The UC Davis MIND Institute draws from these and other disciplines to conduct collaborative, multidisciplinary research. For more information, visit mindinstitute.ucdavis.edu.


From kittens to Fragile X: Do all autisms share a common thread?

Researchers at Children’s Hospital Boston and the Massachusetts Institute of Technology collaborate to learn more about the neurological underpinnings of autism.

By Mustafa Sahin |

Mark Bear’s research interests have taken him from studying vision in kittens to learning and memory in mouse models, and more recently, to the study of Fragile X syndrome, one of the leading genetic causes of autism and intellectual disability in humans.

Along the way, he has made several ground-breaking contributions to neuroscience – one of which he described as one of MIT’s presenters at this week’s inaugural CHB-MIT Research Enterprise Symposium, which kicked off an exciting new scientific collaboration between MIT and Children’s.

I have followed Mark Bear’s work since I was an undergraduate at Brown University, where he used to teach the Introduction to Neuroscience course.

That’s where I first learned about the seminal experiments in kittens (see this PDF), showing that covering one eye at birth rewires their brains not to “see” out of that eye, work that Bear was continuing to refine. Our paths crossed again more recently due to our common interest in studying autism. While his lab was working on Fragile X syndrome, my lab has focused on understanding brain wiring abnormalities in another genetic cause of autism, Tuberous Sclerosis Complex.

Bear has discovered a particular way that the brain rewires and changes its configuration of synapses, or points of connection between neurons, in response to experience. Just like cars, synapses need both a gas pedal and a brake. The gas pedal is the strengthening (potentiation) of the synapse, while the brake is weakening (depression) of the synapse. If either the gas pedal or the brake is not working, the synapse doesn’t function properly. Together, these faulty synapses cause the larger neural circuit to function abnormally.


The next step toward treatment for the core symptoms of autism

Blog.autismspeaks.org, by Chief Science Officer of Autism Speaks, Geraldine Dawson, Ph.D.

I often get the question: How is the research we are funding on single gene disorders, such as Fragile X, relevant to the larger population of individuals with ASD? My answer is that, although autism has many different causes – including single gene mutations, multiple genetic factors, and even environmental factors – it is likely that these causes affect common underlying biological pathways. By studying the “simpler” single gene disorders, especially by studying animal models of these disorders, we can discover these pathways and develop medications that hopefully can help restore the functioning of these pathways.

As you will see in the press release, this strategy is being implemented by Seaside Therapeutics. With the help of funding from Autism Speaks and NIH, Mark Bear and other scientists developed an animal model for Fragile X and discovered that glutamate, an excitatory neurotransmitter, is affected by the Fragile X mutation. An overabundance of glutamate is interfering with the ability of neurons to communicate with each other (synaptic functioning). SeasideTherapeutics then tested a medicine, STX209 (arbaclofen), which helps to restore normal synaptic functioning, in a clinical trial with people with Fragile X. They found encouraging results! The next step, which was launched yesterday, is to test the efficacy of STX209 in individuals with ASD. The hope is that this medicine will improve social behavior and reduce irritability (e.g. aggression, tantrums) in people with ASD.

In the press release Randall L. Carpenter, M.D., President and Chief Executive Officer of Seaside Therapeutics says, “In our open-label Phase 2a study of STX209, we observed significant improvements in social impairment—a core symptom of autism spectrum disorders—including symptoms such as preference to be alone, being withdrawn or isolated, and lack of social reactivity. We are spearheading late-stage development of a drug candidate that has the potential to change the treatment paradigm for autism spectrum disorders—addressing core symptoms—and are truly excited about the prospect of helping patients and their families achieve an improved quality of life.”

Arbaclofen acts by stimulating the release of GABA in the brain. To make an simplified analogy, if we think of glutamate as the accelerator pedal in brain, then GABA is the brake pedal. By reducing glutamate through stimulating GABA receptors, the first clinical trial with people who have Fragile X syndrome demonstrated positive effects on behavior.

In Phase 2b of the trial, 25 sites will conduct a randomized, placebo-controlled trial of arbaclofen, enrolling 150 people with ASD for a total duration of treatment of 12 weeks. For more information about the clinical trial visit http://www.clinicaltrials.gov .

We will be sure to keep you informed as this study and other translational research progresses!


Drug trials for fragile X syndrome lead the way for autism therapies

Randi Hagerman, Sfari.org |

A number of targeted trials on drugs that have the potential to reverse many of the behavioral and cognitive features of fragile X syndrome, are under way. Human and animal studies have shown that these medications can reverse many of the neurobiological and phenotypic features of fragile X syndrome. Along with these new trials, we will need accurate endpoints that can reliably measure the drugs’ effectiveness.

Fragile X syndrome is the most common inherited cause of intellectual disability and single-gene cause of autism. The full mutation has more than 200 repeats of a DNA sequence — CGG — at the front end of the FMR1 gene. This repeat number leads to a shutdown of the gene and a lack of the protein that it normally produces, fragile X mental retardation protein, or FMRP. The lack of FMRP causes fragile X syndrome and intellectual disability, in addition to autism, in 30 percent of individuals and pervasive developmental disorder-not otherwise specified in another 30 percent.

Between 55 and 200 repeats in the FMR1 gene causes what is called a premutation. The premutation leads to autism at a much lower rate — approximately ten percent of boys and less than two percent of girls.

The fragile X mutations cause autism through different molecular pathways. The absence or deficiency of FMRP affects the levels of many genes important for synaptic plasticity — how neurons strengthen important connections — and the outgrowth of neurites, the formation of new connections between neurons.

The fragile X premutation leads to higher levels of the RNA message for the FMR1 gene, which can bind to important proteins and dysregulate neuronal functions, leading to early cell death.

Promising trials:

Novartis and Roche both have an inhibitor of mGluR5, which activates a pathway that is overactive in those with fragile X syndrome.


Top of the class

Virginia Hughes, Sfari.org |

‘Tis the season of graduations, even for autism drugs.

About a year ago, a small biotech company announced that one of its compounds improved social behaviors in a group of 15 children with fragile X syndrome. Last week, the drug matriculated to a phase-3 trial — the last and most difficult step on the long road to regulatory approval.

The drug, called arbaclofen or STX209, was developed by Seaside Therapeutics in Cambridge, Massachusetts. A decade ago, neuroscientist and Seaside founder Mark Bear had shown in mice that the cognitive problems of fragile X syndrome are caused by runaway glutamate, a common neurotransmitter.

STX209 acts on this pathway: it activates gamma-amino butyric acid type B (GABA-B) receptors, effectively putting the brakes on glutamate signaling.

In Seaside’s new trial, 120 individuals with fragile X will receive either STX209 or placebo for eight weeks. The company plans to enroll participants ranging in age from 12 to 25 years at 20 different clinics across the U.S.

Seaside is also investigating whether the drug can improve social problems of people who have autism but not fragile X syndrome. Many studies have implicated glutamate signaling and GABA-B glitches in people with autism.

Last fall, the company’s researchers reported that STX209 quells tantrums, irritability and social withdrawal in children with autism. That study was ‘open-label’: the participants’ doctors and parents knew they were taking the drug, making them susceptible to the placebo effect.

The company plans to launch a placebo-controlled trial of STX209 in autism this summer.


Fragile X protein acts as toggle switch in brain cells

Shared.web.emory.edu |

New research shows how the protein missing in fragile X syndrome – the most common inherited form of intellectual disability – acts as a molecular toggle switch in brain cells.

The fragile X protein, called FMRP, hooks up with a group of molecules called microRNAs to switch the production of other proteins on and off in response to chemical signals, scientists at Emory University School of Medicine have discovered.

The results appear in the June 10 issue of Molecular Cell.

“For learning and memory to take place, neurons need to be able to make new proteins on demand, at particular synapses in a localized way,” says senior author Gary Bassell PhD, professor of cell biology and neurology at Emory University School of Medicine. “It appears that FMRP has evolved to use microRNAs to control the synthesis of proteins at synapses.”

The research team included the first author, Ravi Muddashetty PhD, and contributing co-authors, Vijayalaxmi Nalavadi PhD, Christina Gross PhD, Xiaodi Yao, Oscar Laur PhD and Lei Xing PhD. This research was done in collaboration with Stephen Warren PhD, professor and chair of the Department of Human Genetics.

In fragile X syndrome, FMRP’s absence leads to overactive signaling and unregulated protein production at synapses, the junctions between brain cells where chemical communication occurs. This leads to structural changes at synapses and an impairment of cells’ ability to respond to chemical signals, which in turn interferes with learning and memory.

Muddashetty and Bassell focused on a particular protein called PSD-95, whose production they had previously discovered was regulated by FMRP – although they didn’t know how FMRP exerted its control. PSD-95 appears to have an important role in anchoring together signaling molecules at synapses, the parts of neurons directly involved in learning and memory. Mice lacking the gene for PSD-95 develop normally but have more difficulty learning the location of a hidden platform in a water maze, compared with normal mice.

“The changes at synapses seen in fragile X syndrome are probably not caused by the overproduction of a single protein,” Bassell says. “But we think that losing the ability to make PSD-95 on demand is an important component.”

In cultured neurons, Muddashetty studied part of the RNA molecule encoding PSD-95, which responds to excitement by the neurotransmitter glutamate. This way he could dissect which proteins and RNA molecules were needed. Interfering with a particular microRNA, called miR-125, could stop the PSD-95 RNA from responding to glutamate signaling and could even drive neurons to produce more protrusions at their synapses.

MicroRNAs are involved in a process called RNA interference, whose discovery earned the 2006 Nobel Prize in Medicine. RNA interference is a way that short RNA molecules (microRNAs) can silence a stretch of genetic code.

These tiny RNA molecules have become a widely used laboratory tool for shutting off a specific gene. When the RNA molecules are introduced into the cell, they are actually hijacking a machine inside the cell called RISC (RNA-induced silencing complex). MicroRNAs normally govern the activity of RISC, which can prevent a given gene from being translated from RNA into protein.

In a sense, FMRP is acting as a “RISC manager.” Together with microRNA, it clamps down on an RNA, preventing the synthesis of protein, until glutamate signals force them to loosen up. Thus, FMRP determines when the protein should be made at the synapses.

“Future work may uncover whether this is a general mechanism to guide specific miRNAs onto target mRNAs at synapses,” the authors write.

The finding illustrates how microRNAs are emerging as key players in neurological development and disease, Bassell says. Since a given microRNA can regulate hundreds of targets, one potential drug strategy for fragile X syndrome would be to aim at restoring microRNA function.

The research was supported by the National Institutes of Health, the Fraxa Research Foundation and National Fragile X Foundation.


R.S. Muddashetty, V.C. Nalavadi, C. Gross, Xiaodi Yao, L. Xing, O. Laur, S.T. Warren; and G. Bassell. Reversible inhibition of PSD-95 mRNA translation by miR-125a, FMRP phosphorylation and mGluR signaling. Mol. Cell (2011).

Writer: Quinn Eastman


New research aims to shed light on abnormal brain development

Via Eurekalert |

Vancouver, BC – Local researchers are finally on the road to developing targeted treatments for serious, life-long disabilities such as autism and schizophrenia, thanks to new genomics research focusing on abnormal brain development.

With funding from Genome British Columbia, Dr. Daniel Goldowitz of the UBC Department of Medical Genetics and the Centre of Molecular Medicine and Therapeutics, is opening the mysterious world of the developing brain by mapping the genes in the cerebellum and studying which genes influence abnormal development.

The $330,000 (CDN) project, Functional Characterization of the Transcriptional Network Driving Mammalian Brain Development, will determine which genes are activated and essential during brain development so researchers can better understand development-related diseases such as autism spectrum disorder, schizophrenia and fragile X mental retardation. One key to understanding these disorders lies in the study of a region of the brain that has been difficult to map, the cerebellum.

If the researchers can identify key genes involved in the early development of the cerebellum and that influence the rest of brain development, they may be able to encourage or restart plasticity, the brain’s ability to heal and change. These discoveries are anticipated to lead to new drugs and cognitive treatment for people with abnormal brain development.

“All of our incoming sensory information is received by the cerebellum where it can be compared and contrasted,” says Goldowitz. “So you can imagine if there is a mismatch between information coming in and going out – that there would be a serious problem. You might create another world to try and help you cope like with schizophrenia, or within autism you might shut down incoming information to cope.”

“Our long term goal would be to develop tools for early diagnosis of, and possible therapies for brain disorders such as autism,” says Goldowitz. Increased knowledge and understanding of the genetic wiring of the cerebellum will also open the door to new therapeutics for deadly childhood brain cancers.

Working in close collaboration with Dr. Harukazu Suzuki and colleagues at the world-renowned RIKEN Institute in Japan, the researchers will use cutting-edge genomic technology to identify gene regulatory networks, which control how the cerebellum develops.

The partnership with the RIKEN Institute will allow the researchers to capitalize on world-leading genomic technologies to study the gene expressions and interactions of the cerebellum at a level of resolution never before attained.

“Up until now, we couldn’t manage the data sets because they were just too large,” says Goldowitz. “Through with this international partnership, we should be able to see which genes are turning on other genes so that we can build networks that show the architecture of the developing cerebellum.”

“Genome BC is pleased to support this innovative and exciting research in brain development,” says Dr. Alan Winter, President and CEO of Genome BC. “This is exciting on many levels. It offers promising new therapies for developmental and neurological disorders and makes practical use of the latest genomic technologies. In addition, it extends BC scientific excellence into new international collaborations with esteemed researchers at the RIKEN Institute in Japan.”

Genome BC has funded this project as part of its Strategic Opportunities Fund, which funds projects with direct impact on industry and other end-users.


Seaside Therapeutics Advances Fragile X Drug

By Lisa Jarvis, cenblog.org |

Some great news out today for parents of kids with Fragile X, a neurological disorder that is also the most common genetic cause of autism: Seaside Therapeutics has begun a Phase III trial of STX209, which could potentially be the first drug available to treat the underlying symptoms of the disorder.

Fragile X, a disorder that, like autism, impacts the way brain cells communicate, is caused by a mutation to the FMR1 gene. People with Fragile X suffer from over-stimulated synapses, creating a kind of signaling noise that prevents them from easily learning through experience.

STX209 is a single-isomer version of the already-approved muscle-relaxant baclofen, a GABA-B receptor agonist. It was identified as a potential treatment for Fragile X after doctors noticed a child who was given the drug to treat a gastrointestinal problem also showed improvements in cognitive function and behavior. Seaside separated out the two isomers and found the efficacy in one isomer and the majority of the negative side effects in the other.

Those following drug development in Fragile X know that both Novartis and Roche have seen promising results in small Phase II trials of compounds that act like a brake on mGluR5, a neurotransmitter receptor that MIT neurologist Mark Bear found to be overstimulated in people with Fragile X. STX209 works by dampening the activity of mGlur5, although the Seaside has another compound in development that works directly on the protein.

Seaside expects to sign up 120 people, ages 12 to 25, with Fragile X, in its Phase III trial, and start a second study for kids ages 5 to 11 in early summer. The trial ages are notable because the Novartis and Roche trials were both conducted on adults ages 18 and up; because the side effect profile of baclofen is well understood, FDA has been willing to allow STX209 to be tested in children.

The continued success of the drug could have implications for the broader autism community. Seaside has already begun testing STX209 in autism with the idea that some of the neurological breakdown could happen along that mGluR5 signalling pathway. And although the trial was small—and was open label, meaning doctor’s knew the kids were getting the drug—the biotech firm was encouraged to see signs of similar improvements in social behavior and cognition as in the Phase II study in Fragile X.

Ultimately, Seaside hopes to develop drugs for other single-gene mutations with links to autism, with the hopes of helping both those patients as well as the broader autism population. The story is still evolving, but it’s encouraging nonetheless to see some good news in a area that is seriously in need of new treatments.


Seaside Therapeutics commences STX209 Phase 3 study in fragile X syndrome

Via news-medical.net /Published on June 2, 2011 at 8:19 AM |

Seaside Therapeutics, Inc. announced today the initiation of a randomized, double-blind, placebo-controlled Phase 3 study to evaluate the effects of STX209 (arbaclofen) on social impairment in adolescents and adults (ages 12 to 25) with fragile X syndrome. A second study in children (ages 5 to 11) is expected to begin in early summer. STX209 is an oral selective gamma-amino butyric acid type B (GABA-B) receptor agonist.

“STX209 may be able to play a much needed role in improving the core symptoms of fragile X syndrome and in helping patients and their families achieve an improved quality of life,” said Randall L. Carpenter, M.D., President and Chief Executive Officer of Seaside Therapeutics. “In our Phase 2 study, we were very excited to observe clinically meaningful improvements in social impairment in patients receiving STX209—marking the first time a drug candidate has positively impacted a core symptom of fragile X syndrome. The Phase 3 study is the most comprehensive study ever undertaken in patients with fragile X syndrome and represents the first time that a drug candidate will be evaluated for a core symptom of fragile X syndrome as the primary endpoint.”

Source: Seaside Therapeutics

Autistic children use iPad at Toronto school to reach out and communicate

By Pat Hewitt, The Canadian Press

TORONTO — Four-year-old Satu Kuisma smiles as she finds a picture of herself and touches it on the screen.

When teacher Sabrina Morey asks the kindergartner to tell her what she did in class that day, Satu taps away on the iPad, selecting pictures for eating, drawing and playing on swings.

Communication can be a struggle for Satu, who has a rare chromosome disorder. Born at just 2 1/2 pounds, she has had developmental delays, one of the most prominent being her speech. But she’s among dozens of non-verbal children at a Toronto school who are learning to communicate through touch technology.

Satu and the other students at the Beverley School are involved in a research project with University of Toronto professor Rhonda McEwen aimed at determining if devices like iPads make it easier for developmentally challenged children to communicate and interact with others.

So far, McEwen says, the answer is yes.


Seaside Therapeutics Publishes Review of Advances in the Treatment of Fragile X Syndrome in American Chemical Society Chemical Neuroscience

— Research Highlights Paradigm Shift in Drug Development for Neurodevelopmental Disorders Facilitated by New Understanding of Fragile X Syndrome Pathophysiology —

CAMBRIDGE, Mass.–(BUSINESS WIRE)–May 18, 2011 – Seaside Therapeutics today announced the publication of a review paper detailing the evolving scientific and drug development landscape for fragile X syndrome, the most common inherited form of intellectual disability and the most common known cause of autism. The cognitive impairment associated with fragile X syndrome and other intellectual disabilities has long been considered permanent and untreatable, and drug development efforts have largely focused on relieving the symptoms of these disorders rather than correcting the underlying cause(s). This review article draws upon more than 100 studies to propose a paradigm shift in the approach to drug development for intellectual disabilities based on a new-found understanding of the core pathophysiology of fragile X syndrome. This paper highlights a number of recent scientific advances in understanding the genetic and biologic causes of fragile X syndrome, which are informing the development of novel therapeutic candidates to address the root cognitive deficits of fragile X. This work may have application to the treatment of other neurodevelopmental disorders.

The paper, “Fragile X Syndrome (FXS) – an update on developing treatment modalities,” was published online in the journal ACS Chemical Neuroscience and includes a discussion of the mGluR theory of fragile X syndrome. This theory is based on research suggesting that inhibition of group I mGluR signaling reduces protein synthesis and, in turn, may correct the cognitive and behavioral phenotypes associated with fragile X syndrome. Multiple genetic and pharmacologic studies support mGluR5 inhibition as a promising therapeutic opportunity, providing compelling evidence that altering mGluR5-dependent protein synthesis may directly affect the synaptic alterations underlying the fragile X phenotypes. Additionally, the importance of gamma-aminobutyric acid (GABA), the main inhibitory transmitter in the central nervous system, has recently emerged and been show to oppose the action of mGluR5, providing a novel mechanism for therapeutic inhibition. Studies examining induced seizure activity in mice suggest that the opposing actions of mGluRs and GABA-B receptors provide a therapeutic path for fragile X syndrome. This novel insight reinforces the potential for GABA-B agonists like Seaside Therapeutics’ drug candidate STX209 to counter the effects of mGluR5 in fragile X syndrome and possibly correct specific deficiencies in GABA neurotransmission. This finding could have broad applications in research to treat intellectual disability.

Dr. Aileen Healy, Vice President of Research at Seaside commented, “We are now beginning to believe that intellectual disability is not, as previously understood, an immutable condition. Translating our understanding of the biological effects of key genetic mutations has revealed a variety of promising mechanistic approaches to treat fragile X syndrome, which I believe represent an exciting opportunity to realize the mission of developing effective therapeutics for patients in need.”

About STX209:

STX209 is a selective gamma-amino butyric acid type B (GABA-B) receptor agonist. Pathologies observed in certain neurodevelopmental disorders, including fragile X syndrome (FXS) and autism spectrum disorders (ASD), are believed to be caused by excessive activation of glutamate receptors and abnormally high ratios of excitatory to inhibitory neurotransmission in the brain. GABA-B receptors play an important role in modulating the release of glutamate and maintaining the optimal excitatory-inhibitory balance. STX209 has demonstrated efficacy in preclinical models, suggesting that the functional deficits of individuals with FXS and ASD may be ameliorated by modulating glutamate release and optimizing the ratio of excitatory to inhibitory neurotransmission.

STX209 has successfully completed the largest ever randomized, blinded, placebo-controlled trial (Phase 2) in patients with fragile X syndrome and an open-label Phase 2 exploratory trial in patients with autism spectrum disorders. Later stage trials in both indications are expected to begin by summer 2011.

About Fragile X Syndrome:

Fragile X syndrome is a neurodevelopmental disorder characterized by impaired social function, cognition and speech, as well as attention deficits and low functional independence. It is the most common inherited form of intellectual disability and affects roughly 100,000 individuals in the U.S. It is also the largest known cause of autism. Fragile X syndrome is caused by a mutation of a single gene, the Fragile X mental retardation 1 (FMR1) gene, on the X chromosome. The FMR1 gene produces a protein needed for normal brain development. Individuals with fragile X syndrome lack this protein and, as a result, the majority of affected individuals will have significant intellectual disabilities, requiring life-time care. To date, there are no approved treatments for this disorder. The FDA has designated fragile X syndrome as an orphan disease.

About Seaside Therapeutics:

Seaside Therapeutics, Inc. is creating novel drug treatments to correct or improve the course of fragile X syndrome, autism and other neurodevelopmental disorders. The Company is dedicated to translating breakthrough discoveries in neurobiology into therapeutics that improve the lives of patients and their families. For more information please visit www.seasidetherapeutics.com.

Mark Bear: Charting New Waters

Entrevue avec Mark Bear, auteur de la théorie des mGluR, théorie en amont des études cliniques en cours dans le syndrome du X fragile (avec les antagonistes mGluR5 et l’arbaclofen), théorie annonciatrice, aussi – espérons-le – d’un changement de paradigme dans le traitement de la déficience intellectuelle d’origine génétique.


By Madeline Drexler, hhmi.org |


Mark Bear—a champion helmsman and neuroscientist at the Massachusetts Institute of Technology—says he applies the same principles to racing and research.

“You begin with probabilities. You don’t know a priori whether heading off to the left side of the racecourse or the right is the way to go. So you collect information, make observations, test hypotheses. You do a few pilot experiments, sailing upwind a little in either direction, to see what looks promising. You make a plan, and take measurements of whether or not the plan is working. If you made a wrong guess, you make on-course corrections.

“But what really separates great sailors from less great sailors,” adds the HHMI investigator, “is that they see things that other people don’t.”


Fragile X and Rett Syndrome – Opposite Ends of the Bell Curve?

Rettsyndrome.wordpress.com |

Mark Bear, Ph.D. of MIT is the most recent addition to RSRT’s portfolio of funded scientists. Prof. Bear studies “synapses” the gaps between nerve cells where chemical or electrical signals are exchanged. The strengthening and weakening of synapses contributes to learning and memory but when impaired can lead to neurological disorders.

Much of the excitement in the Fragile X community comes courtesy of the Bear lab. His discoveries have spawned a series of clinical trials.
New York Times

Monica Coenraads, Executive Director of RSRT, recently caught up with Prof. Bear to discuss his Fragile X research and how it might extend to Rett Syndrome.

MC: Prof. Bear, thank you for taking time to discuss your research with us. Many of our readers will have heard of the ongoing Fragile X clinical trials and are eager to understand how your research might also impact Rett Syndrome. Please explain the so called “mGluR Theory of Fragile X” which was discovered in your lab.

MB: Sure. Synaptic function requires the synthesis of proteins in the synapses, so that supply can keep up with demand.  Demand is registered, in part, by activating metabotropic glutamate receptors (mGluR).  So the more active the synapses are, the more glutamate is released and the more protein is made. Like in many systems there are checks and balances, and one of those is the negative regulation of protein synthesis by FMRP, the protein made by the Fragile X gene, FMR1.  Normal synaptic function requires a sense of balance between driving protein synthesis through mGluRs, and inhibiting protein synthesis through FMRP. In Fragile X the FMRP protein is missing so it’s like driving a car with no brakes – your foot is on the gas but there is no way to stop. So there’s excessive protein synthesis which leads to a myriad of deleterious consequences. The approach that holds a lot of promise is to inhibit mGluR which in essence takes your foot off the gas.

Now that theory has been pretty widely validated and at least in the animal models of Fragile X  many features of the disorder can be corrected by inhibiting mGluR.

MC:  You theorize that Rett Syndrome is at the other end of the spectrum, instead of too much protein synthesis, there’s too little protein synthesis. What’s behind this hypothesis for you?


Hope builds for treating intellectual disabilities

By Melissa Healy, Los Angeles Times |

Slouched sideways at his desk in the front row of class, a sneakered foot jittering distractedly, Chase Brown could be any 14-year-old in academic captivity.

As the discussion turns to the American history of slavery, the teacher draws Chase back from his apparent reverie. A classmate has said that Abraham Lincoln freed the slaves. Does Chase agree or disagree?

Chase locks eyes with his teacher. “I agree,” he says emphatically.

It is a moment of triumph for Chase, one of an estimated 90,000 in the U.S. who live with an inherited form of intellectual disability known as fragile X syndrome. Only a year ago, he would have fled the classroom, thrown something at the teacher or stayed mute. Last year, he tested below first-grade level in all academic domains.

Impulsive, distracted and quick to boil over, he seemed incapable of learning. This year, he can sit in a classroom for half an hour before needing a “sensory break”: a walk around the parking lot to clear his overstimulated brain. He is reading at a fourth-grade level, following class discussions, looking teachers squarely in the eyes and answering questions. On a surprising drug — a workhorse antibiotic used since the 1960s to treat acne, skin infections, strep throat and chlamydia — Chase is learning.


Researchers Link Fragile X Syndrome, Epilepsy

By Mallika Manyapu, Emorywheel.com |

Emory researchers have discovered a connection between fragile X syndrome — the most common form of mental impairment — and epilepsy, according to an April 12 University press release.

Fragile X syndrome is characterized by a lack of the protein Fragile X Mental Retardation Protein (FMRP), which regulates neural firing, leaving neurons hyperexcitable and overactive in its absence, said Gary Bassell, a principal investigator and professor in the School of Medicine. These excessive neural impulses lead to repeated seizures or epilepsy, according to Bassell.

The researchers found that FMRP is responsible for the production of another vital protein, Kv4.2, which regulates electrical signals in the brain. However, a lack of FMRP will cause brain cells to produce less Kv4.2, which causes many proteins and neural processes to be continuously active and can lead to impaired learning, seizures and epilepsy.

“Everything is heightened and exaggerated for a person with fragile X,” Bassell said.

Researchers conducted the study using genetically engineered mice to serve as animal models for fragile X syndrome. The researchers also worked with 3-((2-Methyl-4-thiazolyl)ethynyl)pyridine (MTEP), a drug that inhibits particular neural processes such as glutamate signaling.

Because glutamate signaling removes Kv4.2 from certain pathways, drugs such as MTEP that inhibit this process keep higher levels of Kv4.2 in the appropriate channels to control neural impulses, Bassell said.

MTEP provides particular therapeutic effects in the genetically-engineered mice, showing restored levels of the Kv4.2 protein in mice missing the fragile X protein FMRP. This means that drugs such as MTEP could potentially reduce the severe epileptic effects of fragile X, he said.

According to Bassell, this study is particularly important to future clinical trials and treatments of fragile X syndrome because at least 20 percent of people with diseases like fragile X have epilepsy or epileptic symptoms.

“We were interested in the molecular basis for why patients with fragile X and other autistic diseases had epilepsy,” Bassell said. “Drugs like MTEP may be used in clinical trials to treat fragile X, but we may want to design direct drugs that specifically target the essential molecule.”

Their conclusions were published on April 13 in The Journal of Neuroscience. The research was funded by the National Institutes of Health and the National Fragile X Foundation.

The primary authors were Christina Gross, a postdoctoral fellow in Bassell’s lab in the of Department of Cell Biology and Neurology, Xiaodi Yao, a Ph.D. candidate, and Dan Pong (’09C).


Les Journées internationales Jérôme Lejeune, un congrès unique

Newspress.fr | Communiqué – Fondation Jérôme Lejeune – 13/04/2011 10:32:26

« Les Journées internationales Jérôme Lejeune, un congrès unique dans le domaine de la recherche thérapeutique pour les déficiences intellectuelles d’origine génétique »

Pr William Mobley,

Université de Californie, Président du département des Neurosciences

Entrée dans l’ère des essais cliniques, intérêt marqué de l’industrie pharmaceutique, participation nombreuse : à l’occasion de la mise en ligne des interventions des orateurs à ce congrès, achevé samedi 26 mars, la Fondation Jérôme Lejeune dresse un premier bilan très encourageant des avancées de la recherche de traitements pour les maladies génétiques de l’intelligence.

Plus de 200 experts internationaux ont présenté à l’Institut Pasteur des résultats prometteurs. De la génétique moderne (étude du rôle de l’ADN, exploration de l’ARN et des micro ARNs, rôle des protéines et de leurs interactions) à la création de nouvelles voies thérapeutiques ciblées, en passant par la mise au point de nouveaux modèles de souris, les échanges ont été utiles, dynamiques et fructueux.

La ténacité des chercheurs dans l’exploration de ces pistes a permis de mettre en lumière des mécanismes communs à différentes déficiences intellectuelles dont la trisomie 21, le syndrome de l’X fragile ou le syndrome de Rett.

Le point culminant de ce congrès a été de confirmer l’entrée de la recherche dans une nouvelle ère : celle des essais cliniques. On peut parler d’un tournant historique, celui de ne plus s’en tenir aux recherches expérimentales chez l’animal, mais de commencer à tester l’activité de produits sur l’expression des gènes et sur les anomalies des neurotransmetteurs directement chez l’homme.

Pour la trisomie 21 par exemple, le Pr Mara Dierssen du Centre de Génomique de Barcelone, qui avait lancé un essai clinique dans sa phase pilote en janvier 2010, a révélé les premiers résultats lors du congrès : après un mois de traitement seulement, des effets positifs sur la mémoire et la psychomotricité des patients ont pu être observés. Cet essai est financé par la Fondation Jérôme Lejeune. D’autres essais cliniques ont été annoncés pendant le congrès : l’un à Denver a été lancé par le Pr Alberto Costa sur un antagoniste des récepteurs NMDA (résultats attendus dans un an), l’autre à San Diego est en préparation par le Pr William Mobley pour tenter d’inhiber les neurotransmetteurs GABA-b avec de nouvelles molécules.

Par ailleurs, les 2ème Journées internationales Jérôme Lejeune ont permis de constater que tout traitement envisagé devra nécessairement s’accompagner de programmes éducatifs innovants pour améliorer les connections synaptiques et favoriser une meilleure action des médicaments.

Il a aussi été observé une nette amélioration de la proximité entre la recherche et la clinique ainsi qu’une nouveauté : l’intérêt marqué de l’industrie pharmaceutique pour le développement de médicaments dans ce domaine. En 2004, lors des 1ère Journées, cela n’était pas encore le cas.

Enfin, la dernière session, ouverte au grand public a réuni près de 500 familles et accompagnants à qui ont été présentés les progrès réalisés dans la prise en charge médicale globale des personnes atteintes de déficiences intellectuelles d’origine génétique, en particulier pour l’amélioration des troubles du sommeil.

Compte-tenu de ces perspectives prometteuses, la date des prochaines Journées internationales Jérôme Lejeune ne pourra pas attendre à nouveau 7 ans. Elle est donc fixée en 2014.


Marinus Pharmaceuticals Announces U.S. Department of Defense Grant to Study Ganaxolone in Fragile-X Syndrome

NEW HAVEN, Conn., April 13, 2011 /PRNewswire |

Marinus Pharmaceuticals, Inc., the leader in the development of neurosteroids for central nervous system disorders, today announced the award of a $3 million grant by the U.S. Department of Defense to study its lead candidate ganaxolone for the treatment of Fragile-X Syndrome (FXS). Ganaxolone modulates GABA-A ion channels by selective binding to the neurosteroid receptor. Early research suggests that normalizing neurosteroid levels with ganaxolone treatment may eliminate the behavioral symptoms associated with FXS.

The $3 million federal grant was awarded to three University of California, Davis (UCD) researchers: Randi Hagerman, M.D., an international authority on Fragile X-related disorders; Michael Rogawski, M.D., Ph.D., a world-renowned epilepsy researcher; and David Hessl, Ph.D., an expert in psychophysiology studies. The group will enroll 60 children between the ages of six and 17 years to study the safety and effectiveness of ganaxolone for treating behaviors and anxiety common with FXS.

“The fact that a study with ganaxolone was awarded this grant is a testament to the potential for neurosteroid augmentation as a new treatment for FXS patients,” stated Gail Farfel, Ph.D., Chief Clinicaland Regulatory Officer of Marinus. “The scientific data suggests that ganaxolone may be ideally suited to reverse FXS symptoms related to the down-regulation of the neurosteroid binding site on GABA-A ion channels.”

“Over the next few months, we will work with UCD to provide ganaxolone for the FXS study and work on obtaining regulatory approval from the Food and Drug Administration to allow the researchers to conduct this study under Marinus’ Investigational New Drug Application,” commented Kenneth Shaw, Ph.D., Senior Vice President, R&D at Marinus.

About Ganaxolone

Ganaxolone is a synthetic neurosteroid and a derivative of the naturally occurring neuromodulator, allopregnanolone. Ganaxolone has been administered to more than 950 healthy adult volunteers and patients in Phase 1 and Phase 2 studies. Completed Phase II epilepsy studies have generated data supportive of the efficacy and safety of ganaxolone in the treatment of both children and adults suffering from refractory epilepsy (patients who continue to have seizures despite taking multiple anticonvulsant drugs). Scientific research has suggested that ganaxolone therapy may be useful in the treatment of several other central nervous system disorders including posttraumatic stress disorder (PTSD) and Fragile-X Syndrome (FXS). Ganaxolone is being developed as a first in class treatment in epilepsy, PTSD and FXS.

Marinus has successfully developed several proprietary and novel patented formulations of ganaxolone.

About Fragile-X Syndrome

The result of a defect on the X chromosome, Fragile-X Syndrome (FXS) is the leading cause of inherited mental disability and the most common single-gene cause of autism. The condition is estimated to affect one in 3,600 males and one in 4,000 females. Approximately one-third of all children diagnosed with Fragile-X Syndrome also have some degree of autism. Fragile-X symptoms include learning and memory impairment, anxiety, hyperactivity and social avoidance. Up to 30% of people with Fragile-X also develop seizures.


New clue found for Fragile X syndrome-epilepsy link

Emory University via Eurekalert.org |

Individuals with fragile X syndrome, the most common inherited form of intellectual disability, often develop epilepsy, but so far the underlying causes are unknown. Researchers have now discovered a potential mechanism that may contribute to the link between epilepsy and fragile X syndrome.

The protein that is missing in fragile X syndrome, FMRP, controls the production of a protein that regulates electrical signals in brain cells, scientists at Emory University School of Medicine have found. The results were published April 13 in the Journal of Neuroscience.

Individuals with fragile X syndrome tend to have a hyperexcitable nervous system, which can be displayed in several ways: hyperactivity, anxiety, increased sensory sensitivity, and epileptic seizures in 20 percent of all cases. The Emory team’s findings suggest that a therapeutic strategy against fragile X syndrome now being tested in clinical trials could also address this aspect of the disease.

“The link between fragile X syndrome and epilepsy was not well understood,” says senior author Gary Bassell, PhD, professor of cell biology and neurology at Emory University School of Medicine. “This finding might provide a molecular explanation that could also give some clues on therapeutic strategies.”

The co-first authors of the paper are postdoctoral fellow Christina Gross and PhD candidate Xiaodi Yao. They and their colleagues found that in mice missing FMRP – a model for humans with fragile X syndrome – brain cells produce less of a protein called Kv4.2.

FMRP is known to regulate several genes, and it’s possible that changes in others besides Kv4.2 contribute to the development of epilepsy. For many of the genes that FMRP controls, it normally acts as a brake, by interfering with the step in which RNA is made into protein. In FMRP’s absence, this leads to runaway protein production at synapses the junctions between brain cells where chemical communication occurs. Kv4.2 appears to be an exception, because in FMRP’s absence, less Kv4.2 protein is produced.

The protein Kv4.2 is an ion channel, which allows electrical charge to flow out of neurons when they are stimulated. Kv4.2 is the major ion channel regulating the excitability of neurons in the hippocampus, a region of the brain important for learning and memory. A mutation of the gene encoding Kv4.2 leads to temporal lobe epilepsy in humans.

In laboratory tests, drugs that tamp down glutamate signaling could partially restore levels of the Kv4.2 protein in mice missing the fragile X protein. This suggests that drugs that act against glutamate signaling, which are now in clinical trials, could reduce hyperexcitability in humans with fragile X syndrome.

Another strategy could be to identify drugs that target the Kv4.2 protein’s function directly, Bassell says.

Not all individuals with fragile X syndrome develop epilepsy. The loss of FMRP doesn’t shut Kv4.2 production off completely, and other genetic variations and environmental factors probably contribute to the development of epilepsy in individuals with fragile X syndrome, Bassell says.


Cell’s own machinery can deliver therapies to the brain

Jessica Wright, Sfari.org |

Exosomes, the brain’s system for delivering and recycling molecules, can be manipulated to carry therapeutic fragments of RNA or DNA across the blood-brain barrier and into neurons. The ingenious new technique was published 20 March in Nature Biotechnology.

As studies uncover the genetic and molecular causes of autism, gene therapy — silencing the expression or boosting levels of a particular gene product — could emerge as a therapeutic option.

Targeting these genes to brain cells is complicated, however. Injecting constructs into the blood delivers them indiscriminately to all tissues, and the blood-brain barrier prevents most molecules from crossing into the brain at all.

In the new study, researchers solved both problems by coating mouse exosomes — bubbles of membrane that pinch off and merge their contents when they fuse with another membrane — with a brain-targeting protein.


ADHD, autism or something else entirely?

Theconversation.edu.au |

Most people are not aware of fragile X syndrome but they may well be affected by it or know someone who is. Commonly under-diagnosed or misdiagnosed the condition is often mistaken for Attention Deficit Hyperactive Disorder (ADHD) or autism.

Prevalence of 1 in 2500 worldwide makes the syndrome the world’s most common cause of hereditary developmental difficulties in children.

Its effect is gender-specific with girls usually showing milder levels of intellectual difficulty than boys.

Caused by an abnormal expansion of DNA just above the tip of the X chromosome’s long arm, fragile X occurs across every culture. And unlike similar disorders, it is not related to the age of the mother at the time of conception.

Genetic path of the syndrome

Fragile X can be inherited from either a mother or father carrying an abnormal copy of the gene on their X chromosome.

Since the gene is on the X chromosome, a father cannot pass it on to his sons (fathers only pass on a Y chromosome to male offspring).

When the fragile X gene is passed on from a mother to her children, the gene may become altered to the point where it is unable to work properly. When this happens the gene cannot produce enough or any of the protein coded for it.

Although the exact function of this protein is not yet full understood, it is known to be critical to early intellectual and cognitive development. So the most prominent feature of fragile X is developmental difficulties.

The autism-fragile X link

One of the reasons why a diagnosis of fragile X is often delayed is because it shares many characteristics with autism.

Current research estimates that 25% to 35% of children who have fragile X are misdiagnosed as having autism due to the disorders’ many overlapping features.

Features common to both include language delay, echolalia, and repetitive speech alongside poor eye contact, and stereotypic movements such as hand biting and hand flapping.

Many children also display unusual reactions to environmental stimuli such as sudden noises e.g. sirens or alarms, movements, or changes such as a transition from one classroom activity to another.

The anxiety this provokes can often lead to hyper-arousal potentially leading to outbursts of aggression.

Common behavioural challenges in people with fragile X

Alongside hyperarousal, hypersensitivity is another early prominent behavioral feature in boys and girls with fragile X syndrome.

Children may become overwhelmed by the demands created by social involvement, novel or unexpected situations and changes, even the common transitions of daily life.

Another distinct and pervasive behavioral feature of the syndrome are attention and hyperactivity problems.

In the classroom, these behaviours can manifest themselves as difficulty in staying focused on a task for more than a few moments, difficulty in following very simple instructions, easy distraction by sudden noises or movements (e.g. scraping of a chair) and extreme impulsiveness.

The severity and prominence of these behaviours often contribute to a clinical diagnosis of Attention Deficit Hyperactivity Disorder (ADHD).

Another symptom is extreme shyness, which is experienced by many people with fragile X, especially girls, and can often hinder the desire to initiate friendships in childhood and adolescence.

The importance of accurate diagnosis

Misdiagnosis of children with fragile X denies them access to syndrome-specific resources and support systems. These would be most beneficial in early school years when intervention is most effective.

The physical features, social, behavioural and academic impairments present in people with fragile X differ from those with autism and ADHD so early intervention is doubly important.

Recognizing these features is critical to help clinicians properly diagnose the syndrome as early as possible in development so effective educational and clinical interventions can be implemented from a young age.

It is also important that resources are available for teachers from as early as preschool so that at every stage of academic transition, teachers and parents alike know what to expect and how to intervene with fragile X-specific educational resources.

The proposed development of “Building Links Australia” a virtual web resource for families, educators and clinicians will help create partnerships in understanding, intervening and treating children and adolescents with fragile X and other developmental disabilities across the academic trajectory.


April 7, 2011: FRAXA Awards over $1 Million in New Research Grants

Fraxa.org |

Each year FRAXA holds a contest to find – and fund – the most promising new projects aimed at discovering targeted, effective treatments – and ultimately a cure – for Fragile X and related autism spectrum disorders. These projects will begin shortly, and within a few weeks each team will have their own page on this website with more details. FRAXA will fund additional projects in the coming months.

Our competitive grantmaking process ensures that the best and most innovative research gets supported, that new scientists join the Fragile X field, and most important – that we get closer to a cure. FRAXA aims to advance the kind of translational research that is most likely to lead to improved treatment.

Program Grants :::


Wisdom teeth and stem cells

ATLANTA — “Families that have children with special needs are desperately seeking answers.” And one of the last places Gail Heyman ever thought to look was in her son’s mouth. But there in the back, in the aptly named wisdom teeth, answers for researchers at Emory.

“Scott was not diagnosed until he was 9 years old.”

Scott Heyman has Fragile X, a genetic disorder. Scott’s mother Gail says, “Fragile X is the leading cause of mental impairment that is inherited.”


Autism, Alzheimer disease, and fragile X APP, FMRP, and mGluR5 are molecular links

Neurology.org |



The present review highlights an association between autism, Alzheimer disease (AD), and fragile X syndrome (FXS). We propose a conceptual framework involving the amyloid-β peptide (Aβ), Aβ precursor protein (APP), and fragile X mental retardation protein (FMRP) based on experimental evidence. The anabolic (growth-promoting) effect of the secreted α form of the amyloid-β precursor protein (sAPPα) may contribute to the state of brain overgrowth implicated in autism and FXS. Our previous report demonstrated that higher plasma sAPPα levels associate with more severe symptoms of autism, including aggression. This molecular effect could contribute to intellectual disability due to repression of cell–cell adhesion, promotion of dense, long, thin dendritic spines, and the potential for disorganized brain structure as a result of disrupted neurogenesis and migration. At the molecular level, APP and FMRP are linked via the metabotropic glutamate receptor 5 (mGluR5). Specifically, mGluR5 activation releases FMRP repression of APP mRNA translation and stimulates sAPP secretion. The relatively lower sAPPα level in AD may contribute to AD symptoms that significantly contrast with those of FXS and autism. Low sAPPα and production of insoluble Aβ would favor a degenerative process, with the brain atrophy seen in AD. Treatment with mGluR antagonists may help repress APP mRNA translation and reduce secretion of sAPP in FXS and perhaps autism.


Clear Neuroanatomical Differences Between Autism, Fragile X – Similarities End With Behavior

Deborah Brauser, Medscape |

March 31, 2011 — Distinct neuroanatomical patterns exist between fragile X syndrome (FXS) and autism of unknown cause, even though both disorders appear to share overlapping behaviors, a new imaging study suggests.

In a comparison study of 165 male toddlers, investigators found that compared with healthy controls, those diagnosed as having FXS or idiopathic autism (iAUT) had significant differences in the frontal and temporal gray and white matter regions often associated with social cognition.

However, the iAUT group had greater volume levels in these regions than controls, and the FXS group had lower volume levels.

“To better treat children who have these autistic syndromes, it’s important to identify the neurodevelopmental pathways that go awry. It then gives us a template to understand not only how things have gone wrong, but it can potentially tell us how to make it right,” coinvestigator Allan L. Reiss, MD, director of the Center for Interdisciplinary Brain Sciences Research and professor of psychiatry at Stanford University School of Medicine, California, told Medscape Medical News.



Asuragen Launches CE Marked IVD AmplideX™ Fragile X Test in Europe

Genengnews.com |

Asuragen, Inc. announced that they have achieved CE-marking and commercial launch in Europe of the AmplideX™ FMR1 PCR Kit for the detection of CGG repeats in the fragile X mental retardation (FMR1) gene. The AmplideX FMR1 PCR Kit is widely available through Asuragen’s recently established network of distributors in Europe. The AmplideX™ FMR1 PCR Kit is used as an aid in the diagnosis of fragile X syndrome and associated disorders, such as fragile X-associated primary ovarian insufficiency (FXPOI) and fragile X-associated tremor/ataxia syndrome (FXTAS). The Kit provides a high throughput PCR and CE analysis workflow that can accurately resolve sample zygosity and reproducibly detect the full range of full mutation alleles in a single reaction. These assay capabilities reduce the need for Southern blot testing to 2% or less of all samples.

According to Dr. Sara Seneca from the University of Brussels, Belgium, “This new technology has distinct advantages over existing methodologies and was easy to adopt for routine use in our clinical lab.” Dr. David Barton from the National Centre for Medical Genetics in Dublin, Ireland, also commented that “We have gained substantial efficiencies since adopting the AmplideX Kit for our Fragile X testing.”


Fragile X Researcher Honored by March of Dimes

cnbc.com |

Stephen T. Warren Receives 2011 Lifetime Achievement Award in Genetics A world-renowned fragile X syndrome researcher, who was the first to identify the long-sought genetic abnormality responsible for this disorder, will be honored by the March of Dimes.

Stephen T. Warren, PhD, the William Patterson Timmie Professor of Human Genetics and Charles Howard Candler chair of the Department of Human Genetics, as well as professor of biochemistry and pediatrics at Emory University School of Medicine, will receive the March of Dimes/Colonel Harland Sanders Award for Lifetime Achievement in the field of genetic sciences. Dr. Michael Katz, senior vice president for Research and Global Programs of the March of Dimes, will present the award to Dr. Warren today during the annual Clinical Genetics Meeting of the American College of Medical Genetics at Vancouver Convention Centre.

Fragile X syndrome is an inherited genetic condition that involves changes in the X chromosome and specifically the FMR1 gene. It is the leading cause of inherited intellectual disability. Fragile X can be passed on in a family by individuals who have no signs of this genetic condition. In 1991, Dr. Warren — initially funded by a March of Dimes Basil O’Connor Starter Scholar Award — and colleagues published their work on the genetic abnormality responsible for fragile X syndrome, as well as the affected protein. Dr. Warren has successfully applied his research findings to clinical settings.

Dr. Warren received his doctorate in human genetics in 1981 from Michigan State University and in 1985 joined the faculty of Emory University School of Medicine. Dr. Warren was elected to the Board of Directors of the American Society of Human Genetics in 1997 and elected its president in 2006. He was also editor-in-chief of The American Journal of Human Genetics from 1999 until 2005.

Dr. Warren has received many honors for his fragile X syndrome research, including the Albert E. Levy Faculty Award from Emory University, a MERIT award from the National Institutes of Health, the William Allan Award from the American Society of Human Genetics, and was elected to the Institute of Medicine of the National Academy of Science. He was also awarded the inaugural William Rosen Research Award from the National Fragile X Foundation.


Fragile X Premutation Disorders – Expanding the Psychiatric Perspective

PubMed Central | ncbi.nlm.nih.gov |


Fragile X premutation conditions are associated with a significant degree of psychopathology and thus are of interest to the psychiatrist. Remarkable advances at the molecular level have enhanced our understanding of fragile X premutation disorders.


The authors review the genetic, molecular, neuroimaging, and clinical (systemic, neurologic, and psychiatric) manifestations of the premutation carrier state (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene.


Clinical manifestations of psychiatric illness in premutation carriers include cognitive, mood, anxiety, and other psychiatric disorders. Fragile X premutation-associated conditions are part of the clinical differential diagnosis of several psychiatric syndromes, particularly in pedigrees with known fragile X syndrome (FXS) cases.


Fragile X-associated psychiatric manifestations serve as a useful model for a molecular genesis of neuropsychiatric illness. Because of the multigenerational expression of fragile X-associated neuropsychiatric illness, there is a prominent role for genetic testing and genetic counseling of patients and their relatives. Genetic testing is confirmatory of the FMR1 premutation and is an essential component of the clinical evaluation. Psychopharmacological and psychotherapeutic treatment of fragile X-associated psychiatric illnesses may improve patient function and assist in adaptation to the burden of a genetic neuropsychiatric illness.


FMRP function throughout life leading to targeted treatments for FXS

PubMed Central / ncbi.nlm.nih.gov |


FMRP is an mRNA-binding protein that is important for mRNA transport, mRNA stabilization and translation of mRNA into protein at the synapse [129-131]. FMRP is also a factor in the regulation of adult neurogenesis, so in the absence of FMRP there is dysregulation of glycogen synthase kinase (GSK)3β, reduced β-catenin and defective Wnt signaling. These alterations lead to downregulation of neurogenin 1, which is an early initiator of neuronal differentiation and an inhibitor of astrocyte differentiation [132]. Therefore, FMRP is important throughout life and there is a high incidence of motor problems, including Parkinson disease (PD), with aging in those with FXS [133]. In addition, in neuropathologic studies, there is evidence of migration problems in the hippocampus and in the cerebellum in those with FXS (Greco et al,. unpublished data), which are similar to those reported in individuals with autism [134]. These problems may be related to dysregulation of Wnt signaling in both FXS and autism.

Perhaps the most important change in protein expression in the absence of FMRP is the excess basal translation of proteins involved in the metabotropic glutamate receptor (mGluR) 5 receptor pathway [135]. Bear and colleagues have proposed the mGluR theory of FX, suggesting that the deficits associated with FXS are related to upregulation of the downstream effectors of the mGluR5 pathway, leading to enhanced long-term depression (LTD), and that treatment with an mGluR5 antagonist could be a targeted treatment for FXS [135,136]. Both FMRP and mGluRs play important roles in synaptogenesis and synaptic plasticity, and in the absence of FMRP there are long, thin and immature dendritic spines in both human and animal models of FXS [137-142]. There are also enhanced, abnormal epileptiform discharges consistent with an enhanced rate of clinical seizures in FXS [143,144].

Support for the ‘mGluR theory’ has been shown by generating FMR1 mutant mice with a 50% reduction in mGluR5 expression [145]. The mGluR5 deficiency rescued most of the KO mouse abnormalities including altered ocular dominance plasticity, increased density of dendritic spines on cortical pyramidal neurons, increased basal protein synthesis in the hippocampus, exaggerated inhibitory avoidance extinction, audiogenic seizures and accelerated body growth. However, macroorchidism was not rescued. This work is supportive of the proposal by Bear et al. [146]that excessive mGluR5 signaling is responsible for the psychiatric and neurological symptoms of FXS, including cognitive deficits, seizures, anxiety, perseverative movements and social deficits.

Use of mGluR5 antagonists in animal models of FXS further supports the mGluR theory. MPEP (2-methyl-6-phenylethynyl pyridine hydrochloride) is a potent, highly selective antagonist of mGluR5 receptors [147]. In vitro, both MPEP and fenobam, another mGluR5 antagonist, were able to rescue hippocampal dendritic abnormalities in the KO mice [148,149]. MPEP has reversed audiogenic seizures, epileptiform discharges, open field hyperactivity and the defect in prepulse inhibition (PPI) of the startle response in KO mice [148-150]. When MPEP and lithium, a partial mGluR5 antagonist that also blocks GSK3β, were given to dfmr1 loss of function Drosophila mutants, the flies had restored normal courtship behavior, memory and brain structural abnormalities through the reduction of mGluR activity [151]. MPEP is toxic to humans, so other mGluR5 antagonists including fenobam have been studied in FXS [152,153]. Fenobam was found to be safe in a single dose trial in 12 adults with FXS. There were improvements in hyperactivity and anxiety, and 50% showed at least a 20% improvement in PPI [152]. Currently there are two additional mGluR5 antagonists undergoing trials in adults with FXS at multiple centers [153].

Other mechanisms to downregulate glutamate release and modulate mGluR overactivity have been investigated. γ Aminobutyric acid (GABA)B receptor agonists, such as baclofen, inhibit both presynaptic release of glutamate and postsynaptic transmission and/or intracellular signaling downstream from mGluR5 [154-156]. Baclofen has been shown to be efficacious in treating hyperactivity [157], marble burying (Seaside Therapeutics, unpublished data) and audiogenic seizure phenotypes in FX KO mice [158]. A double-blind, placebo-controlled, crossover trial of arbaclofen, the right sided isomer of baclofen that is significantly more potent than regular baclofen as a GABA agent, has just been completed at multiple centers,and involved over 60 individuals with FXS (aged 6 years and older). The preliminary safety and efficacy results are positive, with improvement in the Clinical Global Impression Improvement scale in those with the most severe baseline ratings [159]. There are also preliminary studies that are taking place involving individuals with autism without FXS, and these studies have also produced preliminary positive results. Therefore, further studies on both FXS and autism are set to take place.

The GABAergic system is also dysregulated in FXS, and GABA agents are important to consider for targeted treatment studies in FXS. GABA is a major inhibitory neurotransmitter receptor in the brain, which is important in anxiety, depression, epilepsy, insomnia, and learning and memory [160]. GABA-mediated inhibition is important for terminating ictal discharges and the spread of hyperexcitability, which can lead to seizures [161].

There are two main subtypes of GABA receptors: GABAA and GABAB. The main difference between them is that the first is a ligand gated Cl- channel that gives fast inhibition, whereas the latter is a G-protein coupled receptor which gives slower and more prolonged inhibitory signals [162,163]. The metabotropic GABAB receptor can either be presynaptic and inhibit the release of neurotransmitters through downregulation of high-voltage activated Ca2+-channels; or, when postsynaptic, decrease neuronal excitability through its influence on K+ channels. Thus, GABAB agonists such as arbaclofen mediate their downregulating effects on either side of the synapse. The ionotropic GABAA receptor is usually localized postsynaptically, and their activation leads to opening of Cl- channels and hyperpolarization of the membrane potential, thus making it difficult for excitatory neurotransmitters such as glutamate to generate an action potential. GABAA receptors are more abundant than GABAB receptors in mammalian brain, and disorders such as epilepsy, sleep disorders and anxiety are now being treated using drugs that act on the GABAA receptor[164].

Direct binding between FMRP and the mRNA of the delta subunit of the GABAA receptor has been shown [165]. Reduced expression and dysfunction of several subunits of the GABAA receptor (α1, α3, α4; β1, β2; γ1, γ2 and δ) have been shown in FX animal models [166-168]. FMR1 Drosophila mutants destined to die from glutamate toxicity were rescued after administering molecules involved in the GABAergic pathway [166]. In addition, abnormal male courtship behavior and mushroom body abnormalities were rescued by GABA agents [166].

There is a profound reorganization of neocortical inhibitory circuits of GABAergic intraneurons in the KO mouse [164,167-173]. Recent evidence indicates that deficits in GABA-mediated inhibition may underlie many of the key symptoms in FXS, including the seizures, anxiety and autistic-like behaviors [167,169,173]. The neocortex in KO mice exhibits a marked reduction in the density of GABAergic interneurons that stain with parvalbumin. Moreover, electrophysiological studies in brain slices from these animals exhibit impaired GABAA receptor-mediated inhibitory function [174]. In addition to a gross reduction in GABA-mediated inhibition caused by the maldevelopment of inhibitory circuits and the loss of GABAergic interneurons, there is also evidence of altered GABAA receptor subunit expression in the FX KO mouse [167]. In particular, there appears to be a selective reduction in the expression of δ subunits [167,168]. Global expression analysis by means of the differential display in the FX mouse model revealed consistent underexpression of only three genes, one of which was the GABAA receptor subunit δ. As GABAA receptors are the major inhibitory receptors in the brain, and are specifically involved in processes that are disturbed in FX, including neuronal excitability (leading to enhanced seizure susceptibility), anxiety, sleep and learning, enhancement of the function of GABAA receptors may have major therapeutic benefits for FXS. Kooy and colleagues [175] have demonstrated that use of the GABAA agonist ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one) improved seizures in the KO mouse model of FXS. Ganaxolone is a 3β-methylated synthetic analog of the progesterone metabolite allopregnanolone, which is itself a neuroactive steroid. Unlike progesterone, neither allopregnanolone nor ganaxolone have direct hormonal activity via progesterone receptor activation, and cannot cause hormonal side-effects. However, allopregnanolone and ganaxolone are powerful positive allosteric modulators of GABAA receptors [161]. Human trials indicate that ganaxolone is well tolerated and that it may be efficacious in the treatment of diverse forms of epilepsy in children and adults [176-180]. Plans for studies on ganaxolone are currently underway in children and adults with FXS.

Minocycline, a widely used antibiotic used to treat acne and skin infections, is another promising drug that may target core symptoms of FXS and autism. Minocycline inhibits matrix metalloproteinase (MMP)-9 and reduces inflammation in the central nervous system. MMPs are enzymes involved in synaptic plasticity, and are associated with immature dendritic spine morphology [140,181]; MMP-9 is elevated in FXS. When minocycline was administered to FMR1 KO mice, their hippocampal neurons exhibited mature dendritic spines, and behaviorally, they showed decreased anxiety and improved exploration skills [140]. Off-label use of minocycline to treat 50 individuals with FXS resulted in two-thirds of families noticing positive improvements in their child’s language, attention and/or behavioral improvements while on the medication [182]. An open-label trial is ongoing to investigate the effects of minocycline on children with regressive autism at the National Institute of Mental Health (NIMH). Paribello reported beneficial effects on the CGI and the Aberrant Behavior checklist in an open trial of minocycline involving patients with FXS who were aged 13 and older [183]. Currently, a double-blind, placebo-controlled clinical trial is in progress at the Medical Investigation of Neurodevelopmental Disorders (MIND) Institute for individuals with FXS who are aged 3.5 to 16 years

FXS has led the way for targeted treatments in neurodevelopmental disorders, and many of the treatments guided by molecular abnormalities in FXS may also be helpful for non-FX autism. The treatment trials will now combine targeted treatments, which strengthen synaptic connections, with enhanced educational and behavioral interventions to further develop appropriate synaptic connections in FXS. These targeted treatments combined with educational interventions look promising for reversing the intellectual and behavioral problems of FXS. Because of the shared neurobiological and molecular pathways, these interventions will hopefully also prove helpful in a subset of patients with idiopathic autism



FX syndrome and autism are intertwined, because FMRP regulates the translation of many messages that affect synaptic plasticity and connectivity in the central nervous system. The absence of FMRP also leads to upregulation of mGluR5 pathways and downregulation of GABAA pathways. Targeted treatments to reverse these problems are currently being studied in patients with FXS. Many of these targeted treatments may also be helpful for ASD without FXS.


Closing in on targeted treatments for fragile X

UC Davis Health System, march 16 |

Maude Brownlie, who lives in Melrose, Scotland, wasn’t aware of her head tremors until her young granddaughter pointed it out. Over the next few years, the tremors worsened and spread, causing balance problems that resulted in several falls and phantom pains. She also began losing her words. A dynamic woman who adored being a grandmother, she became irritated, fatigued and depressed by her physical and cognitive decline.

Disheartened by the lack of information from her own physicians, Brownlie sought answers. Her daughter, whose sons had been diagnosed with fragile X syndrome, suggested she meet with the team at the MIND Institute at UC Davis Health System.

Randi Hagerman, medical director of the MIND Institute, discovered that Brownlie was a carrier of the premutation of fragile X. She diagnosed Brownlie with fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative condition that was causing her symptoms.

“I was very much against going and felt that it would be a complete waste of their time and our money,” she says. “How wrong I was!”

Fragile X is a family of genetic conditions that includes FXTAS, which Hagerman and her fellow researcher and husband, Paul, a molecular biology physician-scientist and director of the Neuro- Therapeutics Research Institute, discovered in 2001. It also includes fragile X syndrome (FXS), the most common cause of inherited intellectual disability and the most common known single-gene cause of autism, and fragile X-associated primary ovarian insufficiency (FXPOI), a problem with ovarian function that can lead to infertility and early menopause.

Brownlie and her family had consulted with the right team. Researchers at the MIND Institute are at the epicenter of robust basic and translational science research into psychopharmacological treatments for FXS and FXTAS.

“This is a most exciting time for us,” says Randi Hagerman, also the co-founder of the world-renowned National Fragile X Foundation. “Our goal is to reverse the neurobiological, structural and hopefully cognitive and behavioral abnormalities of fragile X.”

One in 129 women is estimated to carry the fragile X premutation. Like Brownlie, women typically show no neurodevelopmental deficits in youth. One in 3,600 individuals has the full mutation, which results in fragile X syndrome. Approximately one-third of all children diagnosed with FXS have autism and another third have some features of autism spectrum disorder (ASD).

The treatments in trial for FXS are designed to address the core of the genetic problem: the absence or deficiency of a single protein, the fragile X mental retardation protein (FMRP).

FMRP is a “mother protein” that controls the translation of about 800 genetic messages, many of which are important for synaptic plasticity. With fragile X syndrome, this protein is eliminated or deficient, thus interfering with normal brain development and learning.

One affected system, for example, is the metabotropic glutamate receptor 5 system (mGluR5), an excitatory system that leads to the weakening of synaptic connections. In a regularly functioning system, FMRP works something like a gatekeeper to keep mGluR5 activity in check. In the absence of FMRP, the gate is left open, and enhanced activity leads to weak synaptic connections throughout the brain. This leads to anxiety, hyperactivity, impulsivity, a short attention span and social deficits that can include autism.

In a pilot study reported in the Journal of Medical Genetics, researchers at the MIND Institute and Rush University Medical Center, Chicago, found that an mGluR5 antagonist called fenobam helped to lower mGluR5 activity, which calmed behavior and reduced hyperactivity and anxiety in patients with FXS. The New York Times reported in April 2010 that another antagonist was successfully used in a European medical trial. The principal investigators of that study were trainees from the MIND Institute: Sebastien Jacquemont and Vincent Des Portes.

The remarkable promise of mGluR5 antagonists is spurring further research. The MIND Institute has three additional clinical trials scheduled throughout 2010 and 2011.

Two pharmaceutical treatments that show particular promise for younger patients are arbaclofen and minocycline. A controlled trial of arbaclofen in children and adults with FXS was completed in April 2010, and preliminary positive results were presented at the 2010 International Meeting for Autism Research. A six-month double-blind controlled trial of minocycline, funded by the National Fragile X Foundation, began in February 2010 and studies children ranging in age from 3.5 years to 16 years.

Also under way is a study of memantine, a medication used to treat moderate to severe Alzheimer’s disease. The study is funded by the National Institutes of Health for people with the fragile X premutation who have FXTAS – like Brownlie. FXTAS is of special interest because it reveals a generational gap that the Hagermans uncovered.

“Current research on FXS and autism has led to dramatic advances in understanding aging and even dementia,” Randi Hagerman explains. “We now know the premutation can cause problems in adult life, including depression, anxiety, mood instability, early cognitive decline, difficulties with ovarian failure and FXTAS. It’s all related.” Brownlie found relief with a treatment regimen of memantine and an antidepressant. When she returned to the MIND Institute for an annual evaluation, her tremors had been greatly reduced and her depression was gone.

“She was a completely changed woman,” Hagerman says.

“My experience with the MIND Institute and UC Davis has had a hugely beneficial outcome,” Brownlie says. “I am really enjoying … my ‘new self.’ My energy levels, self-esteem and confidence are back to what they were five years ago. My aim now is to persuade the other FX carriers in my family to be assessed by the team at the MIND Institute. Or, just maybe, some interested professionals in the U.K. will come on board and extend the research so that treatment is available here.”

“Our team is on the cusp of finding effective drugs to mitigate fragile X syndrome’s devastating impact,” Hagerman says, “and we are leading the way to restoring quality of life for all generations of families affected by fragile X.”


Neuroscience drug discovery center opens at Vanderbilt

by Bill Snyder | Posted on Friday, Mar. 11, 2011 — 2:55 PM

(…) With Seaside Therapeutics in Cambridge, Mass., the team is trying to “tune down” excessive signaling through two different pathways. The goal is to relieve – for the first time with a drug – learning, memory, social and behavioral problems associated with Fragile X syndrome, the most common inherited form of mental retardation and the most common genetic cause of autism. (…)

‘Mice that model fragile X syndrome have trouble changing their minds…’

Jessica Wright, Sfari.org |

Mice that model fragile X syndrome have trouble changing their minds, according to a study published in the Proceedings of the National Academy of Sciences in February. This behavior is accompanied by fewer connections between neurons in the prefrontal cortex — a brain region involved in higher-level cognition, such as decision-making.

Fragile X syndrome is a disorder that has some overlap with autism and includes defects in mental flexibility, such as the inability to respond to changing conditions or to shift attention. The prefrontal cortex regulates these processes and is likely to play an important role in the disorder.

Mice lacking the fragile X mental retardation gene FMR1 show deficits in behaviors controlled by the prefrontal cortex, according to the study. These mice learn easily that poking their noses into any of five holes leads to a food reward, but they take much longer than control mice do to adjust when only the hole accompanied by a blinking light gives out a reward.

Fragile X mice also appear to have a favorite hole: they show a strong preference for a certain hole even once it stops giving out food.

The same mice also have lower levels in the prefrontal cortex of several proteins that help transmit neuronal signals — including those encoded by the autism-associated gene NR2A, also known as GRIN2A, and the Williams syndrome gene PSD-95.

Levels of NR2A are lower in the prefrontal cortex of mice that take longer to adjust in the hole test, suggesting a direct correlation between this protein and the behavioral deficits.


mGluR5 inhibition and Fragile X syndrome, pain, anxiety, depression and gastroesophageal reflux disease (GERD)

Addexpharma.com |

Dipraglurant (ADX48621) is a negative allosteric modulator (NAM) of metabotropic glutamate receptor 5 (mGluR5). This mechanism has been clinically validated and has blockbuster potential in several indications, including: anxiety; gastroesophageal reflux disease (GERD); acute treatment of migraine; Fragile X syndrome; Parkinson’s disease levodopa-induced dyskinesia (PD-LID); and nonparkinsonian dystonias, like idiopathic torsion dystonia (ITD, also early-onset generalized dystonia) and cervical dystonia (spasmodic torticollis).

PD-LID and dystonia have been chosen as the lead indications because preclinical data indicate that dipraglurant may be particularly well suited for these indications. Specifically, dipraglurant is the first drugcandidate in preclinical testing reported to reduce both of the major PD-LID symptoms, chorea (rapid uncontrolled movements) and dystonia (writhing and cramping movements). While dystonia is a significant problem for PD patients, dytonias also occur as a variety of separate conditions of either primary (e.g. hereditary) or secondary (drug-induced or otherwise acquired) origin. There are currently no products specifically licensed for treatment of dystonias and there is a large unmet medical need with substantial commercial potential for an effective product in this indication. This differentiation may ultimately mean that dipraglurant could become the best-in-class product for PD-LID and one of the first meaningful treatments for dystonia.

Because of its unique properties (and their long standing interest in the mGluR5 NAM mechanism) The Michael J. Fox Foundation for Parkinson’s Research awarded a USD900,000 grant to Addex to support the Phase IIa PD-LID trial of dipraglurant in September 2010. The foundation, which involves some of the world’s leading Parkinson’s researchers via its scientific advisory board, is known for actively supporting cutting edge research and products.

An immediate release formulation of dipraglurant, dipraglurant-IR, will enter Phase IIa clinical testing in patients with PD-LID in the first half of 2011.

Development of an extended-release formulation of dipraglurant was performed in 2010 and Phase I testing of dipraglurant-ER will commence mid-2011. Dipraglurant-ER has been developed for clinical testing for treatment of non- Parkinsonian dystonia and potentially by a licensee for other indications, including Fragile X syndrome, pain, anxiety, depression and gastroesophageal reflux disease (GERD), all of which have validation. A Phase IIa study of dipraglurant- ER for the treatment of non-Parkinsonian dystonias, is scheduled to start in 2012.


Maladies rares : les médecins très mal (in)formés

Doctissimo.fr |

Les patients atteints de maladies rares sont souvent confrontés à une errance diagnostique, en partie liée à un manque d’informations des professionnels de santé. Pour réduire les inégalités de soins qui en découlent, un effort à destination des médecins apparaît primordial.

(…) Cette méconnaissance des maladies rares est à l’origine même de l’errance diagnostique dont sont victimes la plupart des patients, errance qui est de 8 ans en moyenne pour le syndrome de l’X fragile


L’X fragile sur M6 | Santé : Vincent, 16 ans, “X fragile”

Santé : Vincent, 16 ans, “X fragile”…
On compte jusqu’à 8.000 maladies rares. Des maladies dont les noms sont parfois très énigmatiques tel que le syndrome de l’X fragile, qui touche en majorité des garçons. Parmi eux : Vincent, 16 ans, qui, malgré le handicap, s’accroche à son rêve…
Vidéo ici

Left behind

Deborah Rudacille, Sfari.org |


Meanwhile, a survey exploring the lives of 328 men and women with fragile X syndrome found that those who have both fragile X and autism have less independence than those with fragile X alone. The most common leisure activities among both men and women with fragile X syndrome are watching television, playing video games and listening to music — all solitary in nature, the researchers note.



Genetic background alters behavior of fragile X mice

Deborah Rudacille, Sfari.org |

Six strains of mice lacking a gene associated with fragile X syndrome show radically different behaviors though they share the same mutation, researchers reported in January in Autism Research1.


Fragile X syndrome is caused by the complete or partial loss of FMR protein, which results from a full or partial mutation of theFMR1 gene. People with the syndrome combine varying degrees of intellectual disability with seizures, irritability, hyperactivity, anxiety or self-injurious behavior. Up to one-half of people with fragile X syndrome also meet diagnostic criteria for autism.

Researchers suspect that the wide range of fragile X symptoms is the result of differences in genetic, environmental and perhaps epigenetic factors — which affect gene expression without altering DNA2.



February 14, 2011


WASHINGTON, DC – U.S. Representatives Gregg Harper (R–Miss) and Eliot Engel (D–NY) today announced the reinstatement of the Congressional Fragile X Caucus in the U.S. House of Representatives. The gentlemen will serve as the panel’s top Republican and Democratic members, respectively.

The bipartisan caucus is committed to increasing awareness of Fragile X-associated Disorders and improving the health of children and adults across the country living with this intellectual disability. Fragile X-associated Disorders are genetic – resulting in behavioral, developmental and language disabilities throughout a person’s lifespan.

“As the parent of a 21-year-old son with Fragile X Syndrome, I understand fully the daily challenges faced by families with special needs children,” said Harper. “For our family, Fragile X has become a lifelong labor of love and daily blessings.”

“Fragile X syndrome is perhaps the most common cause of inherited mental impairment,” added Engel. “I am eager to serve as co-chair of this Congressional Caucus, with my friend and colleague Rep. Harper, to bring this issue before the public and strive to enhance public and private abilities to advance our knowledge of this syndrome. The striking rise of autism is reason enough for this Caucus to exist but there are other conditions caused by this genetic disorder and we must do what we can to help the people with Fragile X syndrome and their families.”

For Fiscal Year 2011, the caucus – in close cooperation with the National Fragile X Foundation (NFXF) – reached many of its targeted objectives. The group worked with Members of Congress to push the National Institutes of Health (NIH) Research Plan on Fragile X Syndrome and Associated Disorders and urged Congress to continue providing resources for translational research that shows significant promise of a safe and effective treatment for this disability.

The panel also requested that the Department of Defense (DOD) expand the Peer Reviewed Medical Research Program to include Fragile X-associated Disorders in the eligible research topics for Fiscal Year 2011. Additionally, the Caucus advocated for sustained support to grow the National Fragile X Public Health Initiative and the Fragile X Clinical & Research Consortium in order to expand to geographically underserved regions.

“These accomplishments have had a significant impact on the Fragile X community, but this is only the beginning of Fragile X advocates’ promising journey,” added the chairmen. “We will maintain our efforts to ensure that every youth with a significant disability has the opportunity, encouragement and support to become gainfully employed in an integrated setting, pursue a post-secondary education, and contribute to and meaningfully engage in typical community settings upon leaving high school.”

Fragile X-associated Disorders are linked to a mutation on the X chromosome, and are the most commonly inherited form of intellectual disabilities. Fragile X is also connected to reproductive problems in women – including early menopause and a Parkinson’s-like condition in older male carriers.

Today, over 100,000 Americans live with Fragile X Syndrome and over one-million Americans carry a Fragile X mutation and either have, or are at risk for developing a Fragile X-associated Disorder. As many as one in 130 women are estimated to be carriers of the Fragile X mutation according to current studies.


Syndrome du X fragile : entrevue avec Pr. Vincent Desportes

Fondation Jérôme Lejeune |


Quels sont les effets du médicament constatés lors de cet essai ?

Son effet sur l’ensemble des troubles comportementaux est apparu très clairement : l’irritabilité et les comportements répétitifs sont diminués, les patients sont apaisés, plus attentifs, plus réceptifs. En revanche, il faudra un essai sur une plus longue durée et davantage de patients pour savoir s’il a un effet direct sur la déficience intellectuelle ou si celle-ci est réduite simplement du fait de la réduction des troubles comportementaux. De manière inattendue, nous avons observé que les patients les plus améliorés étaient ceux chez qui le gène en cause (FMR1) était totalement inactivé ! C’est un argument fort pour espérer que ce médicament cible un mécanisme essentiel et constitutif du syndrome de l’X fragile.