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

Archive for November, 2010

Antibiotic proves promising as fragile X treatment

Sfari.org |

Minocycline, an antibiotic approved to treat various infections including acne, can increase vocalizations and provide long-lasting improvements in anxiety in a fragile X mouse model, according to two posters presented at the Society for Neuroscience annual meeting in San Diego.

Minocycline is a new treatment for fragile X syndrome that showed promising results in a preliminary uncontrolled human study. It is undergoing more rigorous clinical testing at the University of California Davis MIND institute.

In one of the new studies, the researchers gave minocycline for four weeks after birth to mice lacking the fragile X mental retardation protein, or FMRP. The treatment eases symptoms of hyperactivity and anxiety in these mice, and the effect lasts for at least four weeks after stopping treatment.


Molecular mechanisms: Fragile X mutation worsens memory loss

Jessica Wright, Sfari.org |

Genes responsible for Alzheimer’s disease and fragile X syndrome — a form of mental retardation linked to autism — may operate through the same pathway, according to a study published in July in The Journal of Neuroscience.

Fruit flies with a mutation in presenilin, a gene linked to inherited Alzheimer’s disease, show long- and short-term memory loss at an earlier age than do controls, the study shows. This effect is even more dramatic — cutting the fly’s age from 30 to 5 days — when the mutation is combined with a second one in the fly fragile X gene, dFMR1.


Put to the Test

The American Prospect, Harold Pollack | October 20, 2010 |

Genetic screening is more accessible than ever, and health-care providers are scrambling to catch up.

(…) Promising treatments are now on the horizon for fragile-X syndrome. These are not cures, but they may modestly improve social functioning. As better treatments become available, they will strengthen the case for newborn screening, at least for the full mutation. The development of effective drugs to address the specific mechanisms behind fragile-X syndrome would create “a whole different game,” says University of Chicago pediatrician and ethicist Lainie Friedman Ross. “But, right now, first of all, we would tell you that if you had a [son with the full mutation], he needs occupational, physical therapy, speech therapy. What do you tell a mother who has a girl with fragile X? When one-third won’t need those services ever and another one-third may or may not and only one-third definitely need it?” (…)


How do the Behaviors Seen in Persons with Fragile X Relate to Those Seen in Autism?

The National Fragile X Foundation |

Many parents are confused about their child’s diagnosis. On the one hand, they’ve been told that their child has autism, “autistic spectrum disorder,” or some degree of autistic-like characteristics. In addition, they may have also been told that their child has fragile X syndrome or that he or she is going to be tested for fragile X.

The association between autism and fragile X was first reported by Brown et al. (1982) and was subsequently confirmed by many others leading to an extensive field of research. In discussing this association it is important to remember that autism is defined behaviorally using the criteria of the DSM IV manual which include lack of social reciprocity or responsiveness, abnormal use of language and communication, and a restricted repertoire of activities and interests. Autism is a heterogenous disorder which means that there are several known causes of autism including phenylketonuria (PKU), tuberous sclerosis and 15q duplications. However fragile X is the most common known cause of autism so far identified. Autism is strongly genetic and it is likely that the inheritance of multiple genes predisposing an individual to autism is necessary in many cases for the full behavioral syndrome to be manifested.

The typical features of fragile X syndrome (FXS) i.e. hand biting, hand flapping, poor eye contact, shyness, and social anxiety are probably related to the sensory hyperarousal that has been documented by many investigators including Belser and Sudhalter (1995), Miller et al. (1999), and Roberts et al.(2002). These features are often also referred to as autistic-like features because they can be seen in individuals who have autism without fragile X. Most children with fragile X, however, are interested in social interactions and do not meet the diagnostic criteria for autism.


Mouse model hints at Alzheimer’s therapies for fragile X

Sfari.org |

Lowering the levels of proteins associated with Alzheimer’s disease can improve symptoms of fragile X syndrome in mice, according to a poster presented Wednesday at the Society for Neuroscience annual meeting.

Fragile X syndrome is the most common inherited cause of cognitive disability, and the most common known cause of autism. It is caused by a mutation in the FMR1 gene, which encodes FMRP, a regulatory protein.

One of FMRP’s targets is amyloid precursor protein or APP. In turn, APP can be processed by the body to form beta-amyloid, the molecule that forms plaques in the brains of people with Alzheimer’s disease.

“Our previous work has shown that amyloid precursor protein and beta-amyloid are increased in FMR1 knockout mice,” says study leader Cara Westmark, associate scientist in pathology and laboratory medicine at the University of Wisconsin.


Inner receptors may be important for fragile X treatment

Jessica Wright, Sfari.org |

Hidden targets: Drugs being developed for fragile X syndrome may be neglecting a large group of receptors that function from inside the cell.

Contrary to popular belief, receptors both outside and inside a cell regulate a cellular pathway that is overactive in people with fragile X syndrome, researchers reported Tuesday at the Society for Neuroscience annual meeting in San Diego. The finding could have significant implications for drug treatments of fragile X syndrome.

Inactivation of the fragile X mental retardation protein, or FMRP, leads to fragile X syndrome. Loss of FMRP leads to over-activation of a pathway controlled by a type of protein receptor called mGluR5.

mGluR5 receptors sit across membranes. They relay information by binding to a signaling molecule on one side of the membrane, leading to changes on the other. About 60 to 70 percent of mGluR5 receptors are on membranes inside cells, such as the nuclear membrane, but it’s unclear whether these receptors also affect the same pathways as the cell-surface receptors do.


Lithium targets key enzyme to improve fragile X symptoms

Sfari.org |

Lithium ameliorates some of the cognitive and behavioral deficits associated with fragile X syndrome by blocking GSK-3, an enzyme that plays a key role in development, researchers said Wednesday at the Society for Neuroscience annual meeting in San Diego.

Lithium improves hyperactivity, irritability and aggression in children with fragile X syndrome, which is caused by a loss of function of the FMRI gene. Mouse models of fragile X syndrome treated with lithium have also shown improvements in memory and other learning deficits associated with the disorder.

But lithium has unpleasant side effects, including frequent urination. “The main bothersome side effect is it makes the kids bed-wet again after parents spend years training them,” says Richard Jope, professor of psychiatry and behavioral neurobiology at the University of Alabama at Birmingham.

Jope studied lithium as a treatment for bipolar disorder for years before receiving a grant from the FRAXA Research Foundation to investigate its use in treating fragile X syndrome.


Fragile X mice have shortage of synaptic proteins

Virginia Hughes, Sfari.org |

The brains of young mice with fragile X syndrome show a dearth of two proteins that are important at the synapse, the junction between neurons, researchers reported Tuesday at the Society for Neuroscience annual meeting in San Diego.

Fragile X syndrome is a single-gene disorder that causes mental retardation and, often, autism. Jason Dictenberg’s team at Hunter College in New York showed that after being stimulated, neurons in fragile X mutants do not make a protein called postsynaptic density-95 or PSD-95, which is important for organizing other proteins at the synapse. The animals also make low levels of neuroligin-1 (NLGN1), a protein that interacts with PSD-95 and helps form excitatory synapses.

PSD-95 and the neuroligin family of proteins have been linked to autism and related disorders, suggesting that synaptic abnormalities underlie the overlap of symptoms, the researchers say.

“In the broad spectrum of autism, in all of these disorders, you have trouble with the synapse,” says Valerie Drouet, a postdoctoral fellow in Dictenberg’s lab.


Mark Bear’s Fight To Decode Autism

Après avoir fait la Une du New York Times, le 30 avril 2010, l’X fragile et Mark Bear défraient la manchette du magazine Forbes.

After ‘front paging‘ the New York Times, Fragile X makes headlines again, this time on Forbes.

– – –

Robert Langreth, 11.18.10, 01:40 PM EST, Forbes Magazine dated December 06, 2010 |

MIT researcher Mark Bear thinks that some forms of autism and mental retardation may be treatable with drugs already on laboratory shelves.

Mark Bear, 53, has been fixated on understanding the brain since he was 6–when he saw news commentators speculating about John F. Kennedy’s brain functioning after the shooting. He later became a neuroscientist, now at the Massachusetts Institute of Technology, spending most of his career doing basic research on how the brain’s cells form connections during learning.

Today researchers are buzzing about Bear and his radical new theory that offers a real glimmer of hope that some forms of autism may be treatable with drugs. The causes of autism have mystified scientists for decades. It has been blamed on everything from genes to environmental toxins to the discredited concept that childhood vaccines are the culprit.

Bear’s work suggests that a specific class of drug already sitting on drug company shelves may help patients with an inherited disease called fragile X syndrome, a common cause of autism. It hits one in 5,000 kids and causes mental retardation, anxiety and autism-like symptoms. While years of research remain, Bear theorizes those types of drugs might have application beyond fragile X and into autism in general.

In the wake of his results Roche ( RHHBY.PK – news – people ) and Novartis ( NVS – news – people ) have begun testing an old class of experimental anxiety drugs called mGluR5 inhibitors in fragile X patients. Seaside Therapeutics, which Bear cofounded, licensed a similar drug from Merck ( MRK – news – people ) that is set to enter tests in fragile X patients early next year. Another Seaside drug showed promising early results in a study of 28 autism patients. (Bear owns 5% of the company.)

“I have been in this field for 25 years, and these last two years have been the most exciting in my career,” says Randi Hagerman, a developmental pediatrician at the MIND Institute at UC, Davis who is testing several of the drugs.

Bear’s work in fragile X started with a chance encounter a decade ago with Emory University geneticist Stephen Warren, who discovered the gene for fragile X in 1991. Bear gave a speech about how protein production was needed for certain basic cellular processes involved in memory. That grabbed Warren’s attention. He knew that the same gene that caused fragile X also helped control protein production. “After his talk I leaned over and said, ‘I have a mouse you have to look at,'” Warren says.


Canadian clinical trial of minocycline in Fragile X shows promise for future treatment!


Results of the first clinical trial of minocycline in Fragile X patients were recently published in BMC Neurology, and they suggest that this medication can improve many of the challenging behaviours commonly seen in Fragile X syndrome.

The trial was entitled “Open-label add-on treatment trial of minocycline in fragile X syndrome” and was published in BMC Neurology 2010, 10:91. The study included twenty males and females with Fragile X, aged 13-32, and was conducted by Dr. Carlo Paribello at the Surrey Place Centre Fragile X clinic in Toronto. The trial was funded by the FRAXA Research Foundation and the FXRFC.  Patients received either 100 mg or 200 mg of minocycline daily, and their behaviours were evaluated prior to treatment and again 8 weeks after daily minocycline.

Behavioural scores showed striking improvement and the drug was generally well tolerated. The most significant side effect noted was, in blood tests, an asymptomatic conversion to a positive ANA (Antinuclear Antibody) in two people. This is a nonspecific marker of immunoinflammatory connective tissue diseases, so physicians who prescribe minocycline should be aware of its risk for inducing potentially serious autoimmune reactions.

Minocycline belongs to a group of antibiotics called synthetic tetracyclines, and it has been used in people for more than fifty years to treat Lyme disease, acne, and other skin infections. In 2008 Dr. Iryna Ethell of the University of California at Riverside showed that minocycline, which inhibits MMP-9 activity, reverses behavioural and neuronal abnormalities in mice bred to mimic Fragile X.

This study suggests that minocycline can provide significant benefits to Fragile X patients.These findings are also consistent with the Ethell team’s results in mice, suggesting that minocycline modifies underlying neural defects that characterize Fragile X.

Dr. Paribello is continuing his study at the Surrey Place Centre Fragile X Clinic, with an extended treatment phase to investigate whether there is developmental or cognitive improvement with long term minocycline treatment.

For more info on treatments updates please visit the Fragile X Research Foundation of Canada (FXRFC)

Pour plus d’info sur les études cliniques visitez le site de la Fondation canadienne de recherche sur le syndrome du X fragile

Parents pledge six-figure sum to autism research centre


A couple have pledged a six-figure sum to increase understanding of a little-known genetic condition that affects their son. Gus Alusi and Reem Waines, whose son Kenz has fragile X syndrome, the main cause of inherited autism, are backing a new Edinburgh-based initiative.

The centre is to be the first of its kind in the UK and will bring together scientists and specialist doctors. Between 12,000 and 15,000 people in the UK are affected by the syndrome. The condition is caused by a genetic mutation and can result in severe learning disabilities and language impairment, sensory hypersensitivity and anxiety and hyperactivity. The London-based family’s gift will help researchers focus on understanding the brain processes that underlie the conditions with the hope of developing more effective treatment for patients.


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SFN: Mark Bear on fulfilling the promise of molecular medicine in autism

Mark Bear à propos de sa théorie des mGluR5 lors de son passage à San Diego dans le cadre de la Society for Neuroscience 2010 et des avancées cliniques encourageantes dans le domaine du X fragile. |

On Saturday, I attended Public Symposium 2 on Autism, Progress & Prospects to hear what Mark Bear had to say about “fullfilling the promise of molecular medicine in Autism” Bear outlined two principle problems with the quest for molecular medicines – the brain is a complicated place, and most neurological disorders are as yet poorly defined (ie. symptomatically rather than biologically). Much of autism is of unknown genetic etiology, but the field has had more success studying syndromic forms of ASDs such as Rett Syndrome and Fragile X Syndrome, the latter of which is studied by the Bear lab.

Bear showed how the successes in fragile X research fit into a general model of the strategy for solving neurological disorders. The syndrome was characterized in 1943, but not identified as a silencing of the gene FMR1 by a CGG repeat until 1991, and a knockout mouse was made in 1994. A hypothesis of the involvement of excess mGluR5 was developed in 2002, and the phenotype of the Fmr1-KO was rescued by reduction in mGluR5 in a 2007 study. Currently mGluR5 NAM inhibitors are in phase 2 clinical trials.

Bear reminded us of the role of precise synaptic connections in sensory processing, and that the basis for this specificity is not genetics alone, but that experience modifies this connectivity during postnatal development, as Hubel and Wiesel showed in their studies of monocular deprivation. Bear has long been interested in the role of Group 1 mGluRs in the weakening of deprived eye synapses. In Huber et al, 2000, LTD was induced by administration of DHPG, an agonist of Group 1 mGluRs. This effect requires synthesis of protein at the synapse, leading to the hypothesis that mGluR5 signaling directly leads to removal of AMPA-Rs from the membrane, but additional protein synthesis is required to stabilize this cache and prevent them from returning back into the membrane. One of these proteins is FMRP.

Bear paused to discuss Fragile X, which is reported to be the most common inherited form of mental retardation, and is a “syndromic” disorder, meaning that there are many phenotypic components, ranging from physical abnormalities to cognitive/behavioral deficits.


X fragile : du nouveau à propos des tests cliniques à venir au Canada (AFQ056) | Treatment update Novartis plans New Phase 2 Fragile X Clinical Trial in Canada

Fondation canadienne de recherche sur l’X fragile / Fragile X researche foundation of Canada |

November 2010

In April of this year, the Swiss pharmaceutical company Novartis announced that their experimental drug known as AFQ056 had succeeded in a small European clinical trial in showing improvements in several behavioural symptoms that are troublesome for people with fragile X syndrome and for their families.  These exciting comments were disclosed in an interview with Novartis, and appeared in the April 29, 2010 issue of the New York Times Newspaper in the U.S.

While these are early results and further testing will be required to clearly demonstrate the safety and efficacy of the drug, the Fragile X Research Foundation of Canada is very excited to announce that Novartis will test their lead mGluR5 blocking drug, (known as AFQ056) to treat Fragile X in adult patients at several North American centres, including the Surrey Place Centre Fragile X Clinic in Toronto. The clinic is run by Dr. Carlo Paribello, President and Medical Director of the Fragile X Research Foundation of Canada.  Recruitment of participants for this trial is expected to start in January 2011 and more details regarding this study will become available in the near future in our newsletters and on the clinicaltrials.gov website.

Longtime FXRFC supporters will recall that the Foundation has been talking about the potential of mGluR5 drugs to treat Fragile X for several years now. Ever since the original finding in Mark Bear’s lab at Brown University in 2000, researchers have been working continuously to conduct the pivotal preclinical research which has validated these drugs as possible treatments for Fragile X.

Researchers in university labs around the world have worked to confirm Mark Bear’s mGluR Theory of Fragile X since 2001 so that they could demonstrate to pharmaceutical companies that mGluR5 antagonists have specific therapeutic effects for Fragile X. This strategy has exceeded expectations, as three pharmaceutical companies are now in active clinical trials using mGluR5 antagonists for Fragile X. The FXRFC believes that it is essential to facilitate multiple research programs in order to bring new Fragile X treatments to patients, because any one drug faces many hurdles in the process of approval by Health Canada. The fact that many companies are also developing drugs in this class for other indications (like Parkinson’s disease) makes it even more likely that at least one mGluR5 antagonist will be available in the near future.


Research hub to tackle rare genetic illness

14 November 2010, By Lyndsay Moss, Health Correspondent |
A research centre aimed at finding new treatments for a distressing genetic mutation with strong links to autism is to open in Scotland this week following a determined fund-raising campaign.

The centre – the first of its kind in the UK – will focus on fragile X syndrome (FXS), which can cause severe learning difficulties, language impairment and behavioural problems such as anxiety and hyperactivity.


The Glutamate System: A Breakdown of the Neurobiology, and Current Therapeutic Research

Psychiatry Weekly, Gerard Sanacora, MD, PhD – Professor of Psychiatry and Director of the Yale Depression Research Program School of Medicine, Yale University

This interview was conducted on June 24, 2010 by Norman Sussman, MD


Glutamate is the primary neurotransmitter in the human brain. It was, however, one of the later neurotransmitters discovered, because it is literally one step off the Krebs cycle, and a critical component of general energy metabolism.

“Put glutamate in perspective this way:” says Dr. Gerard Sanacora. “If you add the number of neurons that are using serotonin, norepinephrine, dopamine, and some acetylcholine, they usually account for ~5% of the neurons in the brain, whereas glutamate and GABA make up ~50% and ~45%, respectively.”

The Mechanics of the Glutaminergic Spectrum

“There are two major classes of glutamate receptors: ionotropic and metabotropic.” says Dr. Sanacora. “The ionotropic receptors are very rapidly acting ion channels that allow either calcium or sodium to pass when glutamate binds. The metabotropic receptors act through G protein mediated systems, so they are thought to be slower acting and to modulate the effects of glutamate. Then within the ionotropics there are two major types of receptors: the NMDA receptor and the AMPA receptor.”

The NMDA receptor antagonist, ketamine, is an anesthetic agent that has recently become known for its antidepressive effects. Ketamine blocks the NMDA receptor, which limits the flow of calcium into the cell. It is unclear what mechanism might account for ketamine’s antidepressant effects, because, as Dr. Sanacora explains, ketamine paradoxically causes a release of glutamate.

“Blocking the NMDA receptor postsynaptically apparently causes a bolus release of glutamate from the presynaptic cell,” he says. “That leads to increased activation of some other glutamate receptors, including the AMPA receptor. The antidepressant effects of ketamine were blocked in two independent animal studies by giving an AMPA blocker. This suggests that the blockade of NMDA may be of secondary importance to the release of glutamate and stimulation of the AMPA receptor. Alternatively, it could be the ratio of NMDA to AMPA activation that is critical in producing the response.”

Therapeutic Potentials

Agents that block glutamate are well known to have an anesthetic effect. Increasing glutamate excitability, on the other hand, usually causes either excitotoxicity or seizure. Greater efforts have been underway in recent years to modulate this system in such a way to prevent the onset of seizure and excitotoxicity.

Several agents acting primarily on the glutamate system already hold a well-established benefit for psychiatric disorders. The efficacy of lamotrigine (a drug that modulates glutamate release) for bipolar disorder is the best documented. Memantine, an NMDA antagonist similar in some ways to ketamine, is indicated for treatment of Alzheimer’s disease.

Open-label studies of riluzole, which appears to modulate glutamate release and facilitate glutamate clearance, and is indicated for the treatment of Lou Gehrig’s disease, have reported favorable effects in patients with treatment-resistant bipolar depression, generalized anxiety disorder, and treatment-resistant unipolar depression.

“Research by Mark Bear and others suggests that metabotropic glutamate 5 receptor (mGluR 5) has a big determinant over local protein synthesis at the synapse,” says Dr. Sanacora. “Stimulation of the mGluR 5 tends to rev up local protein synthesis, opposing the effects of the fragile X protein, the role of which seems to be to decrease local protein synthesis. Fragile X protein knockout mice exhibit many of the features of fragile X. But if you give an mGluR 5 antagonist, you can reverse all of those things, except for the macroorchidism. This was described as a balancing act between maintaining local protein synthesis and spine density. Fragile X is associated with long, flimsy dendritic spines. Blocking mGluR 5 in the Fragile X protein knockout mice normalizes spine shape and density. So the spines look more normal, and the behaviors look more normal. This is quite exciting from a neuroscience perspective. This mGluR 5 antagonist may, hopefully, be translated not only to fragile X but maybe to autism, as well, since there is some evidence that autism might be involved in the same spine-density abnormalities.”


Autism Consortium 2010 Symposium: New therapeutics focus, family resource guide announced

Autism Consortium 2010 Symposium: New therapeutics focus, family resource guide announced

Researchers, clinicians and parents gather to discuss latest autism research

Boston – November 1, 2010 – The Autism Consortium, an innovative Boston area collaboration of researchers, clinicians, funders and families dedicated to catalyzing research and enhancing clinical care for autism spectrum disorders (ASDs), announced that it will begin a new initiative on Translational Medicine and Autism Therapeutics. The new focus was introduced at the Consortium’s fifth annual symposium held October 26th, 2010, at Harvard Medical School in Boston.

“As scientists are starting to connect genetics to brain function and behavior, we believe it is time to capitalize on these findings and focus our efforts on helping to fulfill the promise of translational medicine for people with autism and their families,” said Peter Barrett, partner in the Life Sciences group at Atlas Venture and chair of the Autism Consortium’s board of directors, who spoke at the Symposium. The annual meeting gave scientists, clinicians, parents and service providers an opportunity to gather to hear about the latest information on causes of autism, research into new methods for diagnosis, and advances in therapeutics for people with autism spectrum disorders.

As part of the new therapeutics initiative, the first session of the afternoon brought together speakers representing clinical trials for therapeutics in three autism-related disorders: Rett Syndrome, Tuberous Sclerosis and Fragile X. Capitalizing on this opportunity, Robert Ring, PhD, the Senior Director and Head of the newly established Autism Research Unit within Pfizer Global Research and Development spoke about how academia and the pharmaceutical industry can leverage collaboration in the pursuit of autism therapeutics.

“The future of therapeutic discovery and development for patients living with autism cannot be built without a strong foundation of collaborative partnership between industry and academia,” said Dr. Ring. “Non-profit organizations like the Autism Consortium will be critical partners in bringing these collaborative partnerships together.”

In addition to Pfizer, attendees included representatives from a number of pharmaceutical companies including: Biogen Idec, Bristol Myers Squibb, Hoffman-LaRoche, Merck, Novartis, Sanofi-Aventis, Seaside Therapeutics, and Shire.


Next Decade Of Brain Research Promises New Answers

In the decade since the first draft sequence of the human genome was released, a new field – neurogenetics – has taken wing, said leaders in the field from Baylor College of Medicine and Emory University School of Medicine in Atlanta in an overview published in the journal Neuron.

It was already building toward such success. In the 1990s, using the tools available at the time, scientists had already found critical genes such as that for Duchenne muscular dystrophy, Charcot-Marie Tooth and fragile X, said Dr. Huda Y. Zoghbi, professor of molecular and human genetics, pediatrics, neuroscience and neurology at BCM, and Dr. Stephen T. Warren, professor of human genetics, pediatrics and biochemistry at Emory. Zoghbi is also director of the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital and a Howard Hughes Medical Institute investigator.
Mapping and sequencing

Zoghbi and her colleagues at BCM cloned the gene for Rett syndrome in 1999, a success made possible by the intense mapping and sequencing efforts of the X chromosome that preceded it. In their essay, Zoghbi and Warren note that national investment in such research has already paid off, not only in diagnosis and understanding of such diseases but also in the outlook for families afflicted by the disorders.