Les scientifiques décodent les détails moléculaires d'un défaut

En utilisant un modèle animal, les neuroscientifiques de Göttingen ont examiné les effets des mutations génétiques à l'origine de l'autisme chez l'homme. Ce sont des mutations sur des gènes qui portent les instructions de construction pour des protéines de la famille de neuroligines. L'étude éditée dans la revue scientifique Neuron (le 21 septembre 2006) prouve que les neuroligines assurent la transmission de signaux entre les cellules nerveuses. Dans le cerveau des souris génétiquement modifiées pour être sans neuroligines, les points de contact par lesquels les cellules nerveuses communiquent, les synapses, ne se développent pas. Les chercheurs supposent que des troubles similaires se retrouvent chez les patients autistes.

L'autisme est l'une des maladies psychiatriques les plus communes. Environ 0,5 % des enfants en bas âge présentent un syndrome apparenté du « spectre autistique ». Les principaux symptômes de ce trouble du développement sont le retard ou l'absence de langage, des troubles du comportement social et des stéréotypies. Chez de nombreux patients, il existe une déficience mentale. Les personnes avec autisme qui présentent un haut niveau de fonctionnement cognitif ou des compétences exceptionnelles dans un secteur particulier, appelés « autistes savants », comme le personnage principal du film « Rain man», sont rares.

Jusqu'au milieu du siècle dernier, le comportement particulièrement froid des mères était considéré comme la cause de l'autisme. Cependant, la théorie « des mères frigidaires » a été réfutée. La croyance très répandue dans les années 90 que le vaccin ROR (Rougeole, Oreillons, Rubéole) pourrait être la cause de l"autisme chez les enfants en bas âge ne repose sur aucune base scientifique. Aujourd'hui, il est clair que les facteurs génétiques sont la cause principale de l'autisme. Les études sur les jumeaux monozygotes sont particulièrement convaincantes sur ce point - la probabilité que le vrai jumeau d'une personne autiste soit également atteinte d'autisme varie entre 80 et 95 pour cent.

En 2003, le généticien français Thomas Bourgeron a montré dans une recherche sur les familles avec plusieurs enfants autistes que les mutations dans les deux gènes NLGN3 et NLGN4X ont entraîné un arrêt complet de la fonction des gènes et ont déclenché l'autisme chez les patients affectés. Le travail de Bourgeron a causé une onde de choc parmi les instituts neuroscientifiques du monde entier, ou les gènes NLGN n'étaient pas inconnus. Ils sont responsables de la création de deux protéines, neuroligine-3 et neuroligine-4, qui sont considérées comme jouant un rôle important dans la structure des contacts entre les cellules nerveuses.

Les cellules nerveuses communiquent entre elles en des points de contact spécialisés appelés synapses. Une fois stimulée, une cellule de transmission nerveuse émet des neurotransmetteurs. Ces signaux moléculaires atteignent la cellule réceptrice et modifient son niveau d'activité - pourvu que la cellule réceptrice dispose 'd'antennes' sur ses synapses - de sites de réception spécifiques à ces signaux chimiques. Les scientifiques pensent que ce processus pourrait être perturbé si les cellules nerveuses ne disposent pas de neuroligines.

Au moment de la découverte de Bourgeron, Nils Brose et Frederique Varoqueaux, neuroscientifiques à l'institut de Médecine Expérimentale Max Planck à Göttingen, en collaboration avec leurs collègues Weiqi Zhang et Thomas Südhof travaillaient déjà sur les neuroligines depuis dix ans - mais chez les souris et non chez l'homme. « Nous avions même déjà créé des souris mutantes qui, en termes fonctionnels, portaient les mêmes mutations que celles qui se produisent chez les patients autistes. Nos souris manquaient également soit de neuroligine-3 soit neuroligine-4, » indique Brose. Les chercheurs étaient en possession du premier modèle animal génétique de l'autisme.

Une étude éditée par Brose, Varoqueaux et Zhang dans le journal spécialisé Neuron a prouvé que ce modèle met en évidence un défaut de fonctionnement dans la transmission des signaux entre les cellules nerveuses. Avec son collègue Varoqueaux, Brose a créé une lignée de souris qui non seulement ne dispose pas de neuroligine-1 ou de neuroligine-2, tous deux associées à l'autisme, mais qui manque des quatre variantes connues de la protéine simultanément. Les conséquences sont encore plus dramatiques qu'avec les patients autistes, chez lesquels la mutation porte seulement sur un gène de neuroligine. Sans aucune neuroligine, les fonctions du système nerveux se délitent complètement et les animaux génétiquement modifiés meurent juste après la naissance. Cependant, leurs cellules nerveuses peuvent être examinées en détail. Selon Brose, « elles fournissent des résultats importants non seulement pour la recherche de cerveau en général, mais également sur les causes possibles de l'autisme. Nos investigations prouvent que les neuroligines règlent la maturation des synapses. Elles s'assurent qu'il y a sufisamment de protéines réceptrices sur la membrane synaptique de la cellule de réception. »

Ce qui était à l'origine un pur projet de recherche fondamentale a acquis une pertinence médecale. « Ce que nous voyons chez nos animaux mutants en déficit de neuroligine est une forme plus intense du défaut de fonctionnement qui se produit dans le cerveau des personnes autistes, » dit Brose. « Je pense que l'autisme est une maladie des synapses, un synaptopathie. » Les chercheurs de l'Institut Max Planck de Göttingen veulent maintenant effectuer une analyse de la biologie comportementale des souris mutantes non plus privées de tous les neuroligines, mais seulement privées de neuroligine-3 ou de neuroligine-4, ainsi que le sont les patients avec autisme qui présentent des mutations de neuroligine. Les souris mutantes appropriées sont disponibles dans le laboratoire depuis longtemps, « mais nous avons commençé il y a seulement quelques mois à analyser leur comportement avec des spécialistes , » dit Brose. Les premiers résultats semblent plein de promesses - les souris mutantes en neuroligine-4 ont évidemment des comportements sociaux perturbés et des comportemements anxieux. « Si nous réussissons à observer des changements comportementaux très similaires à l'autisme chez notre souris mutante, alors le passage au diagnostic expérimental et à la thérapie sur le modèle animal deviendra possible. »

D'un point de vue génétique, les scientifiques de Göttingen disposent du meilleur modèle animal connu pour l'autisme dans le monde entier. Cependant, il y a une limite : très peu de cas d'autismes sont provoqués par des mutations de neuroligine et, à de rares exceptions, personne ne sait quels sont les défauts génétiques des nombreuses personnes atteintes d'autres formes d'autisme.

Vaccine avoidance caused measles outbreak

ATLANTA, Aug. 3 (UPI) -- The Atlanta-based Centers for Disease Control and Prevention said a measles outbreak in 2005 was caused by parents who chose not to immunize their children.

The CDC National Center for Immunization study, published in the New England Journal of Medicine, said the outbreak began when a 17-year-old girl attended church in Indiana after visiting an orphanage in Romania, where measles is common, The Wall Street Journal reported Thursday.

The study said all but one of the 34 people involved in the outbreak attended church with the girl; 82 percent were school aged, and 20 were home schooled.

The church's minister estimated that 10 percent of congregants at the church avoided vaccination after hearing that the treatments could cause autism. However, U.S. vaccinations do not include the mercury-based chemical thimerasol, which has been the root of the autism worries.

Kim Mulholland, a professor at the London School of Hygiene and Tropical Medicine, said in commentary accompanying the study that parents should not "respond to spurious claims about the risks of vaccine by refusing to vaccinate their infants."

Copyright 2006 by United Press International. All Rights Reserved.

Malheureusement, les nouvelles de l'innocuité du vaccin ROR et du thimerosal ne font pas la une des journaux, contrairement aux prétentions des spécialistes de l'épouvante et de la pseudoscience.

Study clears MMR vaccine of autism link

Pervasive developmental disorders (PDD) like autism and Asperger Syndrome have been on the rise for years. Measles Mumps Rubella (MMR) vaccines and thimerosal–containing vaccines (which are approximately 50 percent ethylmercury) have been suggested as possible causes. A new MUHC study published in the scientific journal Pediatrics tomorrow, assesses the link between childhood immunizations and PDD in 28,000 Quebec children and finally clears MMR vaccines and thimerosal–containing immunizations as risk factors.

"There is no relationship between the level of exposure to MMR vaccines and thimerosal–containing vaccines and rates of autism," says Dr. Eric Fombonne, Director of Pediatric Psychiatry at The Montreal Children's Hospital of the MUHC and lead investigator of the new study. Thimerosal was used to prevent bacterial and fungal contamination in the manufacture of various vaccines until its elimination from vaccine formulas in 1996 in Quebec. "According to our data, the incidence of autism was higher in children who were vaccinated after thimerosal was eliminated from vaccines," says Dr. Fombonne.

"In the past, concern about a potential link between MMR vaccinations and autism led some parents to take the drastic step of refusing to inoculate their children against dangerous childhood diseases like measles," says Dr. Fombonne. "This action resulted in resurgence of the measles, which caused the deaths of several young children in Europe." Dr. Fombonne's study indicates that autism rates continued to increase even with reductions in the use of MMR vaccinations. "We hopes this study will finally put to rest the pervasive belief linking vaccines with developmental diseases like autism," says Dr. Fombonne.

Autism is a neuropsychiatry disorder that impairs a child's ability to communicate and interact with others. The prevalence is about 65 cases per 10,000 people (about 1 child in 155) making autism one of the most common childhood disorders. The Psychiatry Department at The Montreal Children's Hospital sees about 350 new cases of autism each year. However, Dr. Fombonne stresses that there is no demonstrated autism epidemic. He attributes the rise in autism rates to a broader definition of autism and greater awareness of the disorder.

From McGill University

Draw line under MMR scare, plead top doctors

· 'More children will die' unless jabs get all-clear
· Warning as England faces big measles epidemic

Ian Sample,
science correspondent
Tuesday June 27, 2006
The Guardian

A group of Britain's leading paediatricians and childhood vaccination experts has warned that more children will die unless a line is drawn under the autism and MMR (measles, mumps and rubella) vaccine controversy.

In an open letter, 30 scientists, including some of the country's most eminent child health experts, say that an overwhelming body of evidence shows the vaccine is safe. They add that urgent immunisations are necessary to prevent potentially devastating outbreaks among schoolchildren.

The warning comes as England faces its biggest measles outbreak in 20 years, fuelled by the refusal of some parents to have their children immunised because of now discredited claims linking the MMR jab and autism.

The letter, whose signatories include Patricia Hamilton, president of the Royal College of Paediatrics and Child Health, and Professor Sir David Hall, a paediatrician at Sheffield University, says: "The time has come to draw a line under the question of any association between the MMR vaccine and autism. The UK's children are in danger of serious illness or death if they are left unimmunised."

This month, the Health Protection Agency reported 449 cases of measles so far this year - more in just six months than the 438 reported cases in 2003. In 2005, there were only 77 reported cases.

Confidence in the MMR vaccine slumped in 1998 when a team led by Andrew Wakefield at the Royal Free hospital, north London, published research in the Lancet on bowel disease and autism. Dr Wakefield later suggested that there might be a link between autism and the MMR jab. He now faces professional misconduct charges brought by the General Medical Council.

In the letter, the scientists raise concerns that many children born during the height of the MMR scare are now set to enter schooling without the immunisation. "We are now faced with a potentially serious situation. Years of low uptake mean large numbers of unprotected children are now entering school. Unless this is rectified urgently, and children are immunised, there will be further outbreaks and more unnecessary deaths," it says.

Although immunisation rates are rising, they are still below the 95% level the World Health Organisation says is needed for "herd immunity". A year ago MMR uptake stood at 70.8% in London and 83% for the whole of the UK. The letter adds: "It is not too late to avert this predictable tragedy. It is time that due weight is given to the overwhelming body of scientific evidence in favour of the vaccine. Misguided concepts of "balance" have confused and dangerously misled patients. We all, media, politicians and health professionals, have a responsibility to protect the health of our children."

David Elliman, a consultant in community child health at Great Ormond Street Hospital, and a signatory of the letter, said that a vast body of research now vindicated the MMR vaccine, but he added that some media reports remained "partisan" in their coverage of research into the vaccine.

"Parents should be wary of simplistic headlines and information they read on the internet," he added.

Publish or be damned

Ben Goldacre

The Guardian

MMR is back. "US scientists back autism link to MMR," squealed the Telegraph. "Scientists fear MMR link to autism," roared the Mail. "US study supports claims of MMR link to autism," croaked the Times, a day later.

Strap me to the rocket and print my home address in the paper, I'm going after them again. So what was this frightening new data? Well it's hard to tell, since it hasn't been properly published anywhere yet. This is now standard operating procedure for all scare stories, because journalists have learnt that informed and informative public debate on unpublished research is basically impossible. So it turns out that these three stories were all about a poster presentation at a conference that had yet to occur on research not yet completed by a man with a track record of announcing research that then does not appear in academic journals.

The story is that Arthur Krigsman may have found genetic material (RNA) from vaccine-strain measles virus in some gut samples from children with autism and bowel problems. Some believe that this could implicate the vaccine in causing health problems.

But let's not forget, the Mail was promoting Dr Krigsman's research back in 2002: at that time, he was putting endoscopes into the bowels of young children with autism, and said he had found evidence of inflammation. Four years later, looking on PubMed, the standard database for all medical papers, it seems this research still has not been published in a peer-reviewed academic journal. Forgive my bluntness, but it seems a shame to go poking around up there if you're not going to write up your findings properly.

Meanwhile the Telegraph says his latest unpublished claim replicates similar work from 1998 by Andrew Wakefield, and from 2002 by Professor John O'Leary. But there is no such work from 1998 by Dr Wakefield, at least not on PubMed. Meanwhile it is well documented that other labs have tried to reproduce the 2002 study and come back with different results, and that the protocol was likely to have problems with false positives because of the tests used: two perfect examples of the importance of research being fully written up and published, so it can be replicated and assessed.

I could go on, but instead, here is the news you didn't read: in the May issue of the Journal of Medical Virology there was a similar study, only this one has actually been published. It looked for measles RNA in children with regressive autism after MMR vaccination but found no evidence of the magic vaccine-strain measles RNA to implicate MMR, and perhaps because of that unfrightening result, the study was loudly ignored by the press. Like all science in the real world it has its flaws, but because it has been published in full, I can read it, and pick holes in it.

In the spirit of science, the least opponents of MMR could do is share their data, and most importantly publish their scientific work, in full, openly, before their peers, rather than the press.

Vulnerability To Measles Among Nursery School Children Risen Sharply

Science Daily — Vulnerability to measles infection has risen sharply among nursery school children in Scotland since 1998, despite recent increases in MMR uptake, reveals research published ahead of print in the Archives of Disease in Childhood.

There are now 25 postcode districts. where more than one in five nursery school children is potentially at risk of catching measles, compared with just three in 1998, when unfounded claims that the vaccine might be linked to autism provoked widespread alarm.

MMR was introduced across the UK in 1988. The recommended schedule is for the first dose to be given at the age of 13 months, with the second dose at between 3 years and 5 years of age.

The researchers looked at the vaccination records for Scotland for all children born between 1987 and 2004, accounting for over one million children.

The records show that the sharpest decline began for children born from 1999 onwards, rather than for those born in 1997 as might be expected. This suggests that the negative publicity had a gradual but cumulative effect, say the authors.

The most affluent sectors of the population tended to either have their children vaccinated early or not at all, the figures show. But parents in the most deprived areas of Scotland tended to delay vaccinating their children.

The increased risks of measles to nursery school children are concerning, particularly in the areas of greatest deprivation, where the risk of measles outbreaks would add to existing health inequalities, say the authors.

Although rates of MMR vaccine uptake have increased across Scotland, these have not yet reached the levels before 1998, and are not expected to reach the levels required for population protection among young schoolchildren, say the authors.

Note: This story has been adapted from a news release issued by BMJ Specialty Journals.

Experts Question Prevalent Stereotypes About Autism

Science Daily — As theories about autism spread like wildfire in the media and the general public, a panel of autism experts will reflect on the validity of four widely held - and potentially inaccurate - assumptions about the developmental disability.

Drawing on the latest in autism research, a psychologist, an epidemiologist, a psychiatrist and a physician will critically assess widespread stereotypes about autism during a symposium entitled "Science of Autism," at the 2006 Annual Meeting of the American Association for the Advancement of Science (AAAS).

"With the surge in both scientists and society turning their attention toward autism, there comes responsibility," says Morton Gernsbacher, a Vilas Research Professor of psychology at the University of Wisconsin-Madison and the symposium's chair and organizer.

"It behooves us as scientists to distinguish uninformed stereotypes from scientific reality and to move beyond myths and misconceptions."

During her talk, Gernsbacher will cast doubt on the prevalent notion among autism researchers that autistic individuals lack a "theory of mind." The belief that autistic children lack a sense of both their own minds and those of others emerged about 20 years ago, becoming a seemingly undisputed tenet in the literature since then, says Gernsbacher.

When the psychologist began delving into the question, however, she found that scientists usually ascertain how well individuals perceive the mind with tasks that require a relatively sophisticated level of linguistic ability. Since a common diagnostic criteria for autism is the impairment of communication skills, Gernsbacher says it's not surprising that most autistic children don't fare well on such theory-of-mind tests.

"I think we as a society fall prey to a slippery slope when we begin talking about members of our society as not appreciating that they or others have a mind," says Gernsbacher. "An uncritical acceptance of the hypothesis that autistic individuals lack a theory of mind can seriously compromise how autistic individuals are treated in the workplace, the community and society in general."

The other panelists will similarly address other stereotypes about autism. Judith Grether, an environmental epidemiologist who works for the state of California, will contest the popular notion that North America is reeling from an autism epidemic. Grether will make the point that a higher number of reported autism cases - due to looser diagnostic criteria - doesn't necessarily translate into an actual rise in the overall number of cases.

Panelist Irving Gottesman, a psychiatrist at the University of Minnesota, will similarly dispute the idea circulating among some researchers that childhood vaccines potentially cause autism. Recent large-scale literature reviews, he says, fail to support that link.

Finally, Laurent Mottron, an autism researcher and physician at Montreal's Hopital Riviere des prairies, will discuss the common idea that most autistic people are cognitively impaired. Mottron will assert that the numbers of cognitively impaired autistic individuals have been over-estimated - a fact that has important implications for the kind of therapies that autistic individuals receive.

Ultimately, Gernsbacher hopes that events such as today's AAAS symposium will help to set the record straight. "I would like scientists to become more skeptical of the stereotypes that flourish about autism and members of society to become more skeptical of the myths that are circulated."

Note: This story has been adapted from a news release issued by University of Wisconsin-Madison.

La peur du vaccin: c'est la faute aux médias

(Agence Science-Presse) - Le public a été "trompé" par les médias: ceux-ci ont réussi à lui faire croire que le vaccin rubéole-rougeole-oreillons n'est pas sécuritaire.

C'est l'opinion indignée qui se dégage d'une analyse britannique de la couverture journalistique à laquelle a eu droit cette controverse en Grande-Bretagne. Selon cette analyse, dont le New Scientist a obtenu copie, au sommet de la controverse, en 2002, au moins la moitié du public britannique croyait que les médecins étaient divisés quant au caractère sécuritaire –ou non– du vaccin. Alors qu'en réalité, l'opinion des médecins n'a jamais varié d'un iota: la très grande majorité accorde sa confiance à ce vaccin qui, depuis des décennies, a fait ses preuves.

Les premiers soubresauts de la controverse remontent à 1998, lorsqu'un gastroentérologue de l'Hôpital Royal Free de Londres, Andrew Wakefield, publie un article dans la revue médicale The Lancet: il y émet l'hypothèse d'une association entre le vaccin ROR et l'autisme chez les enfants. Les données sur lesquelles il s'appuie ne concernaient que 12 enfants, et ne permettaient de conclure à aucun lien: ce n'était qu'une hypothèse. Mais le fait que les médias aient par la suite choisi d'accorder un temps égal aux "deux côtés de la médaille" a conduit le public à croire que les deux hypothèses –un lien vaccin-autisme et une absence de lien– étaient d'égale valeur. "Notre étude confirme que les médias d'information ont joué un rôle capital", assure au New Scientist Justin Lewis, de l'École de journalisme de l'Université Cardiff.

Une hypothèse comme celle soulevée par Wakefield est indubitablement d'intérêt public. Mais la question n'est pas là. Une recherche qui remet en question le caractère sécuritaire d'un vaccin universellement accepté devrait être approchée avec la plus grande prudence, autant par les scientifiques que par les journalistes. Ce qui n'a pas été le cas, lit-on dans l'étude: sur 561 reportages publiés entre janvier et septembre 2002 –et dont la moitié sont concentrés pendant la "frénésie médiatique" allant du 28 janvier au 28 février 2002– plus des deux tiers mentionnaient le lien vaccin-autisme.

Seulement la moitié des reportages télévisés et un tiers de ceux de la presse écrite s'appuyaient sur le quasi-consensus de la communauté scientifique quant au caractère sécuritaire du vaccin ROR afin de contrebalancer l'hypothèse Wakefield.