15 mai 2007

Identification d'un gène associé à l'autisme

Institut Pasteur

Une équipe de l'Institut Pasteur vient d'identifier un nouveau gène associé à l'autisme. Le rôle clé de ce gène dans la synthèse de la mélatonine apporte de nouvelles informations sur ce trouble du développement, atteignant les jeunes enfants, et dont l'origine demeure encore très mystérieuse. Ces travaux sont publiés en avant-première sur le site de la revue Molecular Psychiatry.

L'autisme est un syndrome complexe, classé parmi les troubles envahissants du développement, qui apparaît avant l'âge de 3 ans. Il est caractérisé par des déficits dans les interactions sociales et la communication, associés à un répertoire de comportements restreints, répétitifs et stéréotypés. Aujourd'hui, un enfant sur 200 serait atteint d'autisme, avec une fréquence quatre fois plus élevée chez les garçons.

Depuis plusieurs années, de nombreuses recherches ont été menées pour identifier les gènes associés à l'autisme. En 2003, puis en 2006, deux études menées par le groupe Génétique humaine et fonctions cognitives dirigé par Thomas Bourgeron à l'Institut Pasteur (1) avaient permis d'identifier, chez certaines personnes atteintes d'autisme ou du syndrome d'Asperger (forme moins sévère de l'autisme), des mutations altérant des gènes (NLGN3, NLGN4 et SHANK3) impliqués dans la formation des synapses, zones de communication entre les neurones.

Cette équipe de l'Institut Pasteur s'est depuis intéressée à une région particulière des chromosomes X et Y, appelée région pseudo-autosomique 1 (PAR1). Des altérations de cette région avaient été observées chez des personnes avec autisme, mais le ou les gènes en cause n'avaient pas été identifiés.

Le groupe de l'Institut Pasteur, en collaboration avec l'Inserm, des services de psychiatrie parisiens (CHU de Créteil et hôpital Robert Debré de l'AP-HP) et du département de psychiatrie de l'université de Göteborg (Suède), a étudié dans cette région PAR1 un gène, appelé ASMT. Ce gène code une protéine de la voie de synthèse de la mélatonine. La mélatonine est produite principalement la nuit par la glande pinéale et joue un rôle important dans la régulation des rythmes biologiques circadiens (nuit/jour), comme les rythmes veille-sommeil.

Un taux bas de mélatonine chez les personnes avec autisme avait déjà été rapporté par trois équipes indépendantes, mais la cause du déficit n'était pas connue. Dans ce nouveau travail, les chercheurs ont observé que plus de la moitié des enfants atteints d'autisme avaient des taux bas de mélatonine (moins de la moitié du taux témoin) et que cette faible concentration était corrélée à un déficit de l'enzyme ASMT. De plus, des mutations du gène ASMT qui altèrent l'expression ou la séquence de la protéine ont été identifiées chez certains sujets, démontrant ainsi l'origine génétique du déficit enzymatique chez quelques familles.

Les auteurs de ce travail insistent sur le fait que la présence d'un taux bas de mélatonine chez une personne n'est pas obligatoirement associé à l'autisme. "En effet, explique Thomas Bourgeron, plusieurs parents d'enfants atteints d'autisme ont des taux bas de mélatonine sans avoir de troubles autistiques. Ainsi, les conséquences directes de ce déficit en mélatonine restent [à] préciser.

Notre hypothèse est que la baisse en mélatonine pourrait avoir un rôle direct sur les réseaux neuronaux et ainsi amplifier l'effet d'autres atteintes génétiques chez l'enfant ou indirectement affecter les rythmes veille-sommeil rendant les enfants atteints plus vulnérables à d'autres facteurs de sensibilité".

Les troubles du sommeil sont très fréquents chez les personnes avec autisme et deux études récentes montrent que l'utilisation de la mélatonine semble améliorer le sommeil des enfants. Ces études, qui ont testé l'efficacité de la mélatonine dans l'autisme, ne concernent malheureusement qu'un nombre restreint d'enfants et nécessitent d'être approfondies afin de mieux évaluer l'efficacité de la mélatonine sur l'amélioration du sommeil et des autres troubles présents chez les personnes atteintes comme les troubles du langage et de la communication sociale.

Plus que jamais, la recherche des gènes associés à l'autisme nécessite la collaboration des familles pour mieux poursuivre ces nouvelles pistes d'étude et préciser les origines de ces troubles complexes.

© News Press 2007

14 mai 2007

Scientists link autism to DNA regions

ST. LOUIS, May 14 (UPI) -- U.S. scientists using a statistical approach have discovered regions of DNA that appear to be linked with autistic spectrum disorders.

The researchers at the Washington University School of Medicine in St. Louis and the University of California-Los Angeles identified two regions of DNA linked with autism. They found the suspicious DNA with a much smaller sample of people than has been used traditionally in searches for autism genes.

Co-principal investigator Dr. John Constantino of Washington University said past research has isolated a few regions of DNA linked to autism, but very few of those studies have been replicated, so no specific autism genes have yet been identified.

"Those older studies used what's called an 'affected sib pair' design that looks for genetic markers in siblings with autism," said Constantino. "That approach has worked well for single-gene disorders, but autism is a complex disease that may involve many genes that each make very small contributions. When that's the case, it's harder to find genetic markers."

Constantino and co-principal investigator Dr. Daniel Geschwind of UCLA detail their study in the April issue of the American Journal of Psychiatry.

Copyright 2007 by United Press International. All Rights Reserved.

09 mai 2007

Autisme et mercure : mythe et réalité

Présentée hier à Seattle à l’occasion de la sixième réunion internationale de la recherche sur l’autisme, une étude menée par des chercheurs canadiens réfute le mythe tenace plaçant le mercure comme étant à l’origine du développement de l’autisme et autres troubles envahissants du développement (TED).

C’est à l’Hôpital de Montréal pour enfants du Centre universitaire de santé McGil (CUSM) que les études ont été menées par des chercheurs canadiens : celles-ci ont révélé que le taux de mercure contenu dans des échantillons de cheveux et de sang provenant d’enfants autistes (71 au total) et de leurs mères ne sont pas statistiquement différents de ceux prélevés chez des enfants non autistes (76 enfants « contrôles »). Pas de lien, donc, entre mercure et autisme.

Parallèlement à cela, les variations du taux de mercure selon les enfants autistes ne peuvent être corrélés à la gravité de leurs symptômes.

Cette étude canadienne soulève tous les soupçons portés sur l’hypothétique corrélation entre l’exposition au mercure et l’autisme. Les doutes étaient portés sur les vaccins pédiatriques contenant du thimérosal, les amalgames dentaires et le méthylmercure contenu dans l’alimentation.

Le Dr Eric Fombonne, de l’Université McGill a précisé : "Nos conclusions n’appuient pas l’hypothèse selon laquelle l’autisme serait une forme d’intoxication au mercure. Les taux de mercure que nous avons détectés chez les enfants atteints d’autisme et leurs mères se situaient dans la fourchette normale de la population en général".

Ainsi, les résultats de cette étude confirment l’inutilité des thérapies de chélation, couramment pratiquées aux Etats-Unis et utilisées pour traiter l’autisme. Ces thérapies ont pour but d’extraire les métaux lourds de l’organisme via des éléments spécifiques et cela, non sans risque.

Ainsi, le mercure, discrédité par cette nouvelle étude canadienne, vient de prouver l’inefficacité de ce type de thérapies. Il en est ainsi de même pour le plomb et l’arsenic.

«Maintenant qu’on a la certitude que le mercure n’a absolument rien à voir avec l’autisme, il faut répéter que la chélation est non seulement inutile mais dangereuse.», ajoute le Dr Fombonne.

L’autisme, trouble du développement, touche aujourd’hui près de 10 personnes sur 10 000.

05 mai 2007

Why Autistic Children Do Not Imitate Or Empathize: It Could Be A Dysfunctional Mirror-neuron System

Science Daily — New imaging research at UCLA shows that impairments in autistic children's ability to imitate and empathize can be linked to dysfunction in the brain's mirror-neuron system. In research to be presented May 4 at the annual International Meeting for Autism Research in Seattle, UCLA scientists demonstrated a clear link between a child's inability to imitate expressions on the faces of other people and a lack of activity in the mirror-neuron system (MNS).

Mirror neurons fire when an individual performs an action with a goal in mind. They also fire when one watches another individual perform that same action. Neuroscientists believe this "mirroring" is the neural mechanism by which the actions, intentions and emotions of other people can be automatically understood.

Individuals with autism can't rely on this system to read the minds of other people. Symptoms of autism include varying levels of difficulty with social interaction, including verbal and nonverbal communication, imitation, and empathy. These findings bolster the growing body of evidence that points to a breakdown of the MNS as the mechanism behind these symptoms.

"These results support the notion that a dysfunctional mirror-neuron system may underlie the impairments in imitation and in empathizing with other people's emotions typically seen in autism," said Mirella Dapretto, associate professor of psychiatry and biobehavioral sciences at the Semel Institute for Neuroscience and Human Behavior at UCLA and the David Geffen School of Medicine at UCLA. Dapretto and Stephany Cox, a research assistant in Dapretto's lab, are the lead authors of the study. "Together with other recent data, our results provide further support for a mirror-neuron theory of autism."

To measure mirror-neuron activity, the research used functional magnetic resonance imaging (fMRI) in 12 high-functioning children with autism as they viewed and imitated faces depicting several emotional expressions, such as anger, fear, happiness or sadness. Prior to the fMRI experiment, the children's imitative behavior was measured using scores from the Autism Diagnostic Interview (ADI-Revised), an instrument widely used to assess symptoms of autism. Children's empathic behavior was assessed using a child-modified version of the Interpersonal Reactivity Index (IRI), a previously validated scale that assesses four distinct facets of empathy.

The researchers found that, as expected, the level of brain activity in "mirroring" areas was related to the children's tendency to spontaneously imitate others, as well as to empathize with them. Specifically, significant negative correlations were found between symptom severity on the imitation items of the ADI-R and activity in the mirror area located in the brain's right inferior frontal gyrus. Additionally, significant positive correlations were observed between children's total scores on the empathy scale and activity within this mirror area and two other key regions in the brain involved in emotional understanding and empathy, the insula and amygdala.

"Simply put," said Cox, "the more the children tended to spontaneously imitate social behaviors or to empathize with the plight of others, the more brain activity we saw in the frontal component of the mirror-neuron system in the right inferior frontal gyrus. Conversely, the greater their impairments in these domains, the less activity we saw in this mirroring brain region.

"Importantly, these results indicate that abnormalities in the mirror-neuron system may negatively affect imitative behavior," she said. "In turn, this may lead to a cascade of negative consequences for the development of key aspects of social cognition and behavior in children with autism."

The research was funded primarily by a grant from the National Institute of Child Health and Human Development. In addition to Dapretto and Cox, the UCLA research team included Ashley Scott, Susan Bookheimer and Marco Iacoboni.

Note: This story has been adapted from a news release issued by University of California - Los Angeles.

Sperm Mutation Linked To Autism

Science Daily — University of Iowa researchers have learned more about a genetic mutation that contributes to autism. The mutation occurred in sperm cells of a father, who does not have autism, but passed the condition on to two of his children.

The investigators now know more about how the mutation causes problems with a specific gene and are testing for additional mutations of the same gene in other people with autism. Thomas Wassink, M.D., associate professor of psychiatry in the UI Carver College of Medicine, presented the findings May 3 at the annual International Meeting for Autism Research in Seattle.

Earlier this year, UI researchers and collaborators were part of an international team that identified, among other findings, deletions in a gene called neurexin 1, which caused the two cases of autism in one family. The UI researchers and collaborators were Wassink; Val Sheffield, M.D., Ph.D., UI professor of pediatrics and a Howard Hughes Medical Investigator; Kacie Meyer, a graduate student in Wassink's laboratory; and former UI investigator Joseph Piven, M.D., now professor of psychiatry at the University of North Carolina (UNC) and director of the UNC Neurodevelopmental Disorders Research Center,

"Genes with the most compelling evidence of causing autism appear to be components of a specific kind of neuronal connection, or synapse, called the glutamate synapse. The gene neurexin 1 was the fourth of these genes to be identified, and it is a scientifically interesting mutation because it wasn't found in either of the parents, who do not have autism," Wassink said.

Instead, the mutation is a germline mosaic -- meaning the deletion occurred only in the father's sperm cells when he himself was in gestation. As result, the father did not have autism, but his two children, both daughters, inherited from him a chromosome that was missing a small piece of DNA that contained neurexin 1. The daughters now have autism.

Because of this missing DNA, certain proteins cannot form that normally contribute to glutamate synapses and, by extension, normal development.

"Now, using this information, we can look in a very detailed way at this gene in other families and begin to understand what happens when this protein that is normally active in the brain is missing," Wassink said.

Knowing more about how the deletions function could eventually lead to the development of diagnostic and therapeutic tools.

About Autism: Autism is a complex brain disorder that inhibits a person's ability to communicate and develop social relationships, and it is often accompanied by extreme behavioral challenges. Autism spectrum disorders are diagnosed in one in 166 children in the United States, affecting four times as many boys as girls.

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

Autistic behavior seen in infant siblings

SAN DIEGO, May 4 (UPI) -- U.S. researchers say infants who have older siblings with autism often fail to seek emotional cues from adults as other toddlers would.

Psychology professor Leslie Carver of the University of California, San Diego, says the study, presented at the 2007 International Meeting for Autism Research in Seattle, is the first to investigate "social referencing" behavior in children from families at high risk for autism.

"Our results," Carver said in a release, "support two important ideas about autism: That those behaviors that are diagnostic of the disorder fall on one end of a broad behavioral spectrum, and also that there is a strong genetic component to autism, evidenced by the behavioral resemblance in close family members."

Social referencing involves checking in with the emotional displays of others and regulating our own emotions and behavior in response. While most children begin social referencing at about age of 1, this behavior is impaired in individuals with autism.

Copyright 2007 by United Press International. All Rights Reserved.

04 mai 2007

Children with autism have difficulty recognizing ordinary words

New research indicates that young children with autism have a difficult time recognizing ordinary words and more of their brains are occupied with this kind of task compared to typically developing youngsters.

“Rather than becoming an expert in recognizing words, their brains slow down,” said Patricia Kuhl, co-director of the University of Washington’s Institute for Learning and Brain Sciences and an expert in how babies acquire language. “Because these children can’t distinguish what should be a familiar word their brains work too hard and they are unable to focus on new words. When they can’t understand a word, they miss everything else that follows in a sentence.”

The research is part of an effort to understand why language disorders are a characteristic of children with autism as scientists begin to peer inside the brains of some of these children to understand what’s behind their language deficits.

Kuhl will present findings that compare 19-to 30-month-old typically developing and autistic children during a keynote address Friday (May 4) at the Sixth International Meeting for Autism Research in Seattle.

She and her colleagues placed caps fitted with 20 sensors on the heads of the children and recorded brain waves that “leaked through their scalp” as the babies listened to familiar words (ball, dog, cat, book) and words that would be unfamiliar (verb, pint, bide, rate). The children also were exposed to common words that were recorded and played backwards. Backwards words produce sound patterns that are not characteristic of any language.

The brains of typically developing infants responded with a unique pattern of activation for each of these types of words. The responses for known and unknown words were markedly different. With the backward words, the children’s brains reacted as if they were hearing something totally different from the other types of words and gave a different signal, according to Kuhl, who is a professor of speech and hearing sciences. In addition, brain activity was focused in the temporal lobes of both hemispheres of the brain for each word type.

The children with autism, however, showed no difference in their responses between known and unknown words, meaning they couldn’t differentiate between them. However, their brains did react to the backwards words, and the pattern of activity was somewhat similar to that of the typically developing children. Overall brain activity in the children with autism was more diffuse and not focused in the temporal lobes, indicating more of their brains were tied up trying to understand the words.

Earlier work by Kuhl showed dramatic differences in how children 32 to 52 months of age responded to a computer-generated warbling sound and “motherese,” or baby talk, a speech form that is rich in phonemes. When given a choice by letting them turn their heads in one direction versus the other, normally developing children consistently preferred to listen to motherese, a near universal form of baby talk that is directed at infants and young children. Children with autism preferred the warble sound and chose it consistently.

Youngsters with the most serious symptoms of autism had a stronger preference for the warble than did higher functioning children with autism.

Kuhl believes there is some good news for parents from these studies because there are indications that some autistic children are achieving some learning.

“One of the puzzles of autism is the variability of children with it,” she said. “We believe the highest functioning autistic children have some recognition of phonemes (the basic sounds of a language). And this new study shows autistic toddlers can differentiate between backward words, which are not characteristic of a language, and real words. So some learning has gone on.” “To crack the speech code children must be able to distinguish phonemes, understand known words and be able to decode the word order of a sentence in English or their native language.”

Kuhl said researchers need better measures and tools such as magnetoencephalography, which is a non-invasive technology, to test and look inside the brains of children with autism.

“We’d like to know what kind of knowledge these children may have locked up in their brains. Children at the high-functioning end of the autism spectrum may have quite a bit. The first possible use of this research would be as a predictor of which children with autism might be responsive to treatment. With these tools we may be able to identify a part of the brain that is not responding, and that may suggest treatments by developing more targeted interventions.”

###

The National Institute of Mental Health, the National Institute on Child Health and Human Development and the Cure Autism Now Foundation supported the research.

For more information, contact Kuhl at pkkuhl@u.washington.edu or (206) 685-1921.

Pas de lien entre autisme et mercure

Des chercheurs canadiens ont apporté de nouveaux éléments de preuves confirmant qu'il n'existe pas de lien entre l'autisme et le mercure.

Des équipes de l'Hôpital de Montréal pour enfants du Centre universitaire de santé McGill ont testé les taux de mercure dans des échantillons de cheveux et de sang provenant d'enfants autistes et de leurs mères et affirment que les taux observés ne sont pas statistiquement différents de ceux d'échantillons prélevés sur les autres enfants.

De plus, les chercheurs ont établi l'absence de lien entre le taux de mercure et la gravité des symptômes ainsi que le niveau de fonctionnement des enfants autistes.

Des hypothèses sur la relation possible entre l'exposition au mercure et l'autisme circulent depuis des années.

Les soupçons portaient particulièrement sur les vaccins pédiatriques contenant du thimérosal, les amalgames dentaires et le méthylmercure présent dans l'alimentation. "Nos conclusions n'appuient pas l'hypothèse selon laquelle l'autisme serait une forme d'intoxication au mercure. Les taux de mercure que nous avons détectés chez les enfants atteints d'autisme et leurs mères se situaient dans la fourchette normale de la population en général", a affirmé le Dr Eric Fombonne, de l'Université McGill, cité par la presse canadienne.

Les chercheurs affirment donc que l'une des retombées pratiques de leur étude est le constat de l'inutilité des thérapies de chélation pour traiter l'autisme.

Ces traitements visent à extraire les métaux lourds de l'organisme à l'aide de composés spécifiques. L'autisme est un trouble envahissant du développement. Il touche près de 10 personnes sur 10.000, sans considération sociale, ethnique ou raciale.

Cependant, on observe qu'il affecte majoritairement les garçons (quatre pour une fille), et que ses manifestations varient d'un enfant à l'autre, selon la Fédération québécoise de l'autisme et des autres troubles envahissants du développement.