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

Archive for autism

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.

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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!

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

Neurology.org |

Abstract

 

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.

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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.

(…)

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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.

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Une molécule pour combattre à la racine une forme de retard mental et d’autisme

Nadine Richon/Unicom |
Une étude européenne menée par Sébastien Jacquemont, au Service de génétique médi-cale CHUV-UNIL, montre avec un essai réalisé dans le cadre d’un partenariat académi-que et industriel que des améliorations sont possibles pour des patients atteints de trou-bles intellectuels jugés irréversibles.

Forme la plus fréquente de retard mental hérité, le syndrome de l’X fragile intéresse les cher-cheurs depuis de nombreuses années comme modèle monogénique pour l’étude du retard mental et de l’autisme. Cette maladie sous-diagnostiquée (un enfant sur 4000) se manifeste par une anxiété, une hyperactivité et des traits autistiques, les patients souffrant d’une incapa-cité à traiter les informations sensorielles. La découverte sur le chromosome X du gène FMR1 dont la mutation est responsable de la maladie date de 1991, mais personne jusqu’ici n’avait réalisé d’essai thérapeutique ciblé non pas sur un symptôme, par exemple l’anxiété, mais sur les mécanismes mêmes de la pathologie.

En collaboration avec Novartis, Sébastien Jacquemont et ses collaborateurs suisses et euro-péens ont traité 30 patients avec la molécule AFQ056. Celle-ci freine spécifiquement l’activité des récepteurs MGluR5 (metabotropic glutamate receptor 5), essentiels au bon fonc-tionnement cérébral. En effet, absente chez ces patients, la protéine FMRP ne remplit plus sa fonction de régulation de ces récepteurs. Grâce à ce «frein médicamenteux», certains enfants ont interagi davantage avec leurs proches, qui ont pu constater ainsi des améliorations impor-tantes de leur comportement.

Il se trouve que les patients concernés par ces améliorations partagent une spécificité généti-que : chez eux, le gène FMR1 muté est totalement désactivé. Appelée methylation, cette mo-dification chimique de l’ADN conduisant à l’inactivation complète d’un gène pourrait donc servir de bio-marqueur pour déceler les patients capables de répondre à ce type de traitement.

Publiée dans la revue Science Translational Medicine, cette étude représente un premier pas significatif pour le diagnostic et le traitement ciblé de l’X fragile, voire d’autres retards men-taux. Parmi les étapes suivantes, les mêmes équipes évaluent les effets à plus long terme sur le comportement et la cognition avec des essais en cours cette année au CHUV. Dans un futur à moyen terme, il s’agit d’étudier les bénéfices de cette molécule pour des sous-groupes d’enfants autistes. En effet, il est probable que certaines formes d’autisme partagent avec le syndrome de l’X fragile des mécanismes physiopathologiques similaires. «On a trop long-temps considéré les retards mentaux comme des troubles du développement irréversibles. Il est temps d’envisager des prises en charge spécifiques s’attaquant à la cause et pas seulement aux symptômes de ces maladies», souligne le Dr Sébastien Jacquemont.

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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.

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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.

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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.

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