080210xf's Blog

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

Archive for April, 2011

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.

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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).

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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.

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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.

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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.

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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.

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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.

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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 :::

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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.”

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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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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.

(…)

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