Some cases of autism may be traced to the immune system of mothers during pregnancy

UC-Davis discovery could lead to prenatal identification and prevention

(SACRAMENTO, Calif.) – New research from the UC Davis M.I.N.D. Institute and Center for Children’s Environmental Health has found that antibodies in the blood of mothers of children with autism bind to fetal brain cells, potentially interrupting healthy brain development. The study authors also found that the reaction was most common in mothers of children with the regressive form of autism, which occurs when a period of typical development is followed by loss of social and/or language skills. The findings, to be published in the March 2008 issue of Neurotoxicology, raise the possibility that the transfer of maternal antibodies during pregnancy is a risk factor for autism and, at some point, that a prenatal test and treatment could prevent the disorder for some children.

“While a growing body of research is dedicated to finding distinctions in the immune systems of children with autism, this is one of the first studies to identify immunological factors in mothers that could be linked to autism in the very earliest stages of life,” said Judy Van de Water, senior author of the study and professor of rheumatology, allergy and clinical immunology. “Our results should lead to more research on the prenatal environment and the onset of autism. We are also optimistic that in the future a prenatal test and therapeutic intervention preventing IgG exposure during pregnancy could protect some children from ever getting autism.”

Van de Water and her team began their research with blood samples from 123 mothers – 61 whose children have autism and 62 whose children are typically developing. They isolated IgG antibodies from the samples then exposed the antibody to fetal brain tissue by western blot analysis, which detects antibody reactivity to proteins. The outcome revealed a highly specific reactivity pattern to two fetal brain proteins in seven of the 61 samples from the autism group, six of which were from mothers of children who had regressive autism. None of the IgG samples from mothers in the control group produced this same result.

“We’re not entirely sure why the IgG response against fetal brain proteins was so specific for later onset autism,” said Van de Water. “It’s possible that early exposure to maternal antibodies sets in motion a biological path to autism with the behavioral outcomes not apparent until much later. It’s also possible that an environmental exposure sometime after birth could be required to set this process in motion. We are hopeful that this study will help build our understanding of the foundations of the regressive form of the disorder.”

Characteristic features of autism – social deficits, language impairments and limited, repetitive behaviors – are often clear early in an affected child’s life. Other children seem to progress normally until 12-to-24 months of age, when developmental milestones disappear. These distinct pathways have led clinicians to identify autism as one of two types – early onset or regressive – potentially with distinct causes and disease processes.

IgG antibodies are responsible for long-term immune system responses to infection, but they can also contribute to autoimmune diseases such as arthritis, multiple sclerosis and lupus. IgG also crosses the placenta in order to provide key immune system protectants to a growing fetus and newborn child, which is a key reason why Van de Water decided to investigate the role of IgG as a potential factor in autism.

Van de Water next wants to know if IgG in women during the time of their pregnancies produces the same response to fetal brain proteins. Women in the current study were two-to-five years beyond childbirth. She will now conduct the same study with women who are pregnant and already have a child with autism, because such women are much more likely to have another child with the disorder.

“If women in this next phase of the study give birth to a child eventually diagnosed with autism, blood analyses from all stages of her pregnancy will give us a clear picture of the immune system factors that were in play during gestation and could have altered her child’s neurodevelopment,” Van de Water said.

Other key next steps are to identify the specific proteins targeted by autism-specific maternal antibodies and their role in neurodevelopment and to determine whether or not exposure to maternal IgG during pregnancy leads to behavioral or social distinctions in offspring. Animal model studies are now under way to help answer these questions.

“Our outcome leads autism science in many new and exciting directions,” said Daniel Braunschweig, pre-doctoral fellow of immunology in the Van de Water lab, lead author of the current study and recent recipient of an Autism Speaks mentor fellowship to further pursue this research. “We now know we should be looking for the clues to the onset and pathology of autism much earlier than was initially assumed. Future studies should consider the immune system interactions between mother and child as a focal point in creating greater understanding of, and eventually finding effective preventions for, this complex neurodevelopmental disorder.”

“This finding is important because it provides important clues about the potential maternal contributions to autism risk in a subset of children who may develop autism,” said Isaac Pessah, director of the UC Davis Center for Children’s Environmental Health and professor of molecular biosciences. “We’re determined to find out what causes autism. Studies conducted in the Van de Water lab are giving us valuable insights as to when and where in the developmental process we should be looking for those causes.”

“We’re very interested in understanding the underlying causes of autism,” said Cindy Lawler, scientific program director at the National Institute of Environmental Health Sciences. “This finding, in combination with other new research findings coming from NIH-funded studies, demonstrates the complexity of this disorder and underscores the importance of understanding how the mother’s immune system can influence early brain development.”

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The study, “Maternally Derived Antibodies Specific for Fetal Brain Proteins,” was funded by the National Institutes of Environmental Health Sciences, the U.S. Environmental Protection Agency and the M.I.N.D. Institute. A copy can be requested from newsroom@elsevier.com or downloaded at www.sciencedirect.com.

The UC Davis M.I.N.D. (Medical Investigation of Neurodevelopmental Disorders) Institute is a unique collaborative center that brings together clinicians, scientists, parents and educators for research on causes, treatments, preventions and cures for autism, fragile X syndrome, Tourette’s syndrome, attention-deficit/hyperactivity disorder and other neurodevelopmental disorders. For more information, visit www.mindinstitute.org.

The UC Davis Center for Children’s Environmental Health and Disease Prevention is a multi-disciplinary research effort established to examine how toxic chemicals may influence the development of autism in children. Toward that goal, the center is conducting two large-scale research projects: the Childhood Autism Risks from Genetics and the Environment (CHARGE) study and Markers of Autism Risk in Babies—Learning Early Signs (MARBLES) study. For more information, visit www.vetmed.ucdavis.edu/cceh.

Editor’s note: B-roll of blood sample processing for immunological studies of autism in the Van de Water lab is available on request.

MMR links to autism dismissed by huge study

Sarah Boseley, The Guardian

There is no evidence to link the MMR vaccination to autism in children, according to a substantial new study published today.

In the biggest review conducted to date, scientists from Guy's Hospital in London, Manchester University and the Health Protection Agency, analysed the blood from 250 children and concluded that the vaccine could not be responsible.

The study, which was funded by the Department of Health and is published in the journal Archives of Disease in Childhood, was initiated five years ago and comes a decade after a scare about the vaccination - which protects against mumps, measles and rubella - led to a big drop in the number of children given the jab.

The theory put forward by Dr Andrew Wakefield and colleagues was that the measles virus in the MMR caused bowel disorder and subsequently autism.

However, the blood samples taken from all the children in today's study did not support that analysis. The research specifically looked for traces of measles virus in the blood of 250 children who had been given the MMR vaccination, 98 of whom had an autistic spectrum disorder.

The scientists found no difference in levels of measles virus or antibodies between those who had been diagnosed with autism and those who had not.

The tests also showed no signs of bowel disorders developing either.

The children, aged about 10 years old, had been given the first MMR jab but not all had the booster. The researchers found that those with autism or learning difficulties tended not to have had the second jab, which they say is of concern.

Professor David Salisbury, director of immunisation at the Department of Health, said: "It's natural for parents to worry about the health and wellbeing of their children and I hope this study will reassure them that there is no evidence linking the MMR vaccine to autism."

Public health experts will be hoping this study can lay to rest the controversy.

The Department of Health stressed the quality of the study and in a statement said it had "linked very careful assessment and diagnosis of a child's condition, with expert analysis of blood samples".

Dental Tooth Fillings Containing Mercury Don't Affect Children's Brain Development, Study Suggests

ScienceDaily (Jan. 27, 2008) — Dental amalgam tooth fillings do not adversely affect children's brain development and neurological status, researchers report in the February issue of The Journal of the American Dental Association.

The authors of the report—members of a joint team from the University of Lisbon, Portugal, and the University of Washington, Seattle—studied the possible neurological effects of dental amalgam tooth restorations. Dental amalgam contains elemental mercury combined with other metals such as silver, copper, tin and zinc to form a safe, stable alloy. Dental amalgam has been used for generations to fill decayed teeth that might otherwise have been lost.

Beginning in 1997 and continuing for seven years, the authors studied 507 Portuguese children aged 8 through 12 years who received either amalgam or resin-based composite fillings. They conducted routine clinical neurological examinations to assess two types of neurological signs: hard (indicating damage to specific neural structures) and soft (subtle signs of central nervous system dysfunction that likely point to immature sensory-motor skills rather than to any structural damage in the brain). The researchers also evaluated the children for presence of tremor.

After seven years, the two groups of children did not differ in terms of the presence or absence of hard signs or tremor. They also didn't differ in terms of the presence or absence or severity of soft signs at any point. Also, as expected in healthy children, the severity of any neurological soft signs diminished as the children aged.

"Even at the levels of amalgam exposure in this study (a mean of 7.7-10.7 amalgam surfaces per subject across the seven years of follow-up)," the authors write, "[we] conclude that exposure to mercury from dental amalgam does not adversely affect neurological status.

"These data indicate the absence of a generalized negative effect on children's nervous system functions stemming from the presence of dental amalgam," they continue, "and while we cannot rule out potential adverse reactions in individual children, we found no indications of any."

JADA, a monthly journal, is the ADA's flagship publication and the most widely read scientific journal in dentistry.

Adapted from materials provided by American Dental Association.

Inherited Retardation And Autism Corrected In Mice

ScienceDaily — Researchers at MIT's Picower Institute for Learning and Memory have corrected key symptoms of mental retardation and autism in mice. They have significantly alleviated a wide range of abnormalities due to fragile X syndrome by altering only a single gene, countering the effects of the fragile X mutation.

The work also indicates that a certain class of drugs could have the same effect. These drugs are not yet approved by the FDA, but will soon be entering into human clinical trials. There is currently no treatment or therapy for fragile X syndrome, whose symptoms include mental retardation, epilepsy, and abnormal body growth.

Fragile X syndrome (FXS), affecting 100,000 Americans, is the most common inherited cause of mental retardation and autism. The MIT researchers corrected FXS in mice modeling the disease. "These findings have major therapeutic implications for fragile X syndrome and autism," said study lead author Mark F. Bear, director of the Picower Institute and Picower Professor of Neuroscience at MIT.

The findings support the theory that many of FXS's psychiatric and neurological symptoms-learning disabilities, autistic behavior, childhood epilepsy- stem from too much activation of one of the brain's chief network managers-the metabotropic glutamate receptor mGluR5.

"Fragile X is a disorder of excess-excess synaptic connectivity, protein synthesis, memory extinction, body growth, excitability-and remarkably, all these excesses can be reduced by reducing mGluR5," said Bear, a Howard Hughes Medical Institute investigator.

Individuals with FXS have mutations in the X chromosome's FMR1 gene, which encodes the fragile X mental retardation protein, FMRP. The MIT study found that FMRP and mGluR5 are at opposite ends of a kind of molecular seesaw. They keep each other in check, and without FMRP, mGluR5 signals run rampant.

Bear and colleagues study how genes and environment interact to refine connections in the brain. Synapses are the brain's connectors and their modifications are the basis for all learning and memory. There's a growing consensus among researchers that developmental brain disorders such as FXS, autism and schizophrenia should be considered "synapsopathies"- diseases of synaptic development and plasticity (the ability to change in response to experience).

Dendritic spines--little nubs on neurons' branchlike projections-receive many of the synaptic inputs from other neurons. Abnormal spines have long been associated with various forms of human mental retardation. In FXS, spines are more numerous, longer and more spindly than they should be. Thin spines tend to form weak connections.

The research team found that a 50 percent reduction in mGluR5 fixed multiple defects in the fragile X mice. In addition to correcting dendritic spines, reduced mGluR5 improved altered brain development and memory, restored normal body growth, and reduced seizures-many of the symptoms experienced by humans with FXS.

The researchers used genetic engineering to reduce mGluR5, but the same thing could be accomplished by a drug. Although not yet approved by the FDA, mGluR5 blockers are entering into human clinical trials. "Insights gained by this study suggest novel therapeutic approaches, not only for fragile X but also for autism and mental retardation of unknown origin," Bear said.

Earlier this year, MIT Picower Institute researcher Susumu Tonegawa and colleagues reported positive results using a different approach to reversing FXS symptoms. Tonegawa and colleagues identified a key enzyme called p21-activated kinase, or PAK, that affects the number, size and shape of connections between neurons.

This research is scheduled to be published in the Dec. 20 issue of Neuron. In addition to Bear, authors include Brown University graduate student Gul Dolen; Picower Institute postdoctoral fellow Emily Osterweil, B.S. Shankaranarayana Rao of the National Institute of Mental Health and Neuroscience in India; MIT graduate students Gordon B. Smith and Benjamin D. Auerbach; and Sumantra Chattarji of the National Center for Biological Sciences and Tata Institute of Fundamental Research in India.

This work is supported by the National Institute of Mental Health; the National Institute of Child Health and Human Development; the National Fragile X Foundation; FRAXA, a Fragile X research foundation; and the Simons Foundation.

Adapted from materials provided by Massachusetts Institute of Technology.

Missing Protein May Be Key To Autism

ScienceDaily — A missing brain protein may be one of the culprits behind autism and other brain disorders, researchers at MIT's Picower Institute for Learning and Memory report in the Dec. 6 issue of Neuron.

The protein helps synapses develop. Synapses--through which neurons communicate with one other-underlie our ability to learn and remember. Now Li-Huei Tsai, Picower Professor of Neuroscience at MIT, has uncovered an enzyme that is key to that protein's activity.

Synapses are complex structures consisting of ion channels, receptors and intricate protein complexes that all work together to send and receive signals. Improperly formed synapses could lead to mental retardation, and mutations in genes encoding certain synaptic proteins are associated with autism.

Tsai studies a kinase (kinases are enzymes that change proteins) called Cdk5. While Cdk5's best-known role is to help new neurons form and migrate to their correct positions during brain development, "emerging evidence supports an important role for Cdk5 at the synapse," she said.

To gain a better understanding of how Cdk5 promotes synapse formation, Tsai's lab looked into how Cdk5 interacts with synapse-inducing proteins-in particular, a protein called CASK. CASK--a key scaffolding protein-is one of the first proteins on the scene of a developing synapse.

Scaffolding proteins such as CASK are like site managers, supporting protein-to-protein interactions to ensure that the resulting architecture is sound. Mutations in the genes responsible for Cdk5 and CASK have been found in mental retardation patients.

"We found that Cdk5 is critical for recruiting CASK to do its job for developing synapses," Tsai said. "Without Cdk5, CASK was not in the right place at the right time, and failed to interact with essential presynaptic components. This, in turn, led to problems with calcium influx." The flow of calcium in and out of neurons affects processes central to nervous system development and plasticity--its ability to change in response to experience.

Gene mutations and/or deletions in synaptic cell surface proteins and molecules called neurexins and neuroligins have been associated with autism. The problem with CASK recruitment investigated by the Tsai laboratory creates the same result as these genetic changes.

The Picower study also provides the first molecular explanation of how Cdk5, which also may go awry in neurodegenerative diseases such as Alzheimer's, promotes synapse development.

"There are still a lot of unknowns," said Tsai, who is also a Howard Hughes Medical Institute investigator. "Causes for psychiatric disorders are still very unclear, but accumulating evidence strongly suggests that alterations in the synaptogenesis program can lead to these serious diseases."

In addition to Tsai and Picower researcher Benjamin A. Samuels, co-authors are associated with Harvard Medical School; Johns Hopkins University School of Medicine; McLean Hospital in Belmont, Mass.; and Academia Sinica in Taiwan.

This work is supported by the National Institute of Neurological Disorders and Stroke (NINDS).

Adapted from materials provided by Massachusetts Institute of Technology.

Autistic Children May Have Abnormal Functioning Of Mirror Neuron System

ScienceDaily (Nov. 29, 2007) — Using a novel imaging technique to study autistic children, researchers have found increased gray matter in the brain areas that govern social processing and learning by observation.

"Our findings suggest that the inability of autistic children to relate to people and life situations in an ordinary way may be the result of an abnormally functioning mirror neuron system," said lead author Manzar Ashtari, Ph.D., from the Children's Hospital of Philadelphia in Pennsylvania.

Mirror neurons are brain cells that are active both when an individual is performing an action and experiencing an emotion or sensation, and when that individual witnesses the same actions, emotions and sensations in others. First observed in the macaque monkey, researchers have found evidence of a similar system in humans that facilitates such functions as learning by seeing as well as doing, along with empathizing and understanding the intentions of others. Dr. Ashtari's study found the autistic children had increased gray matter in brain regions of the parietal lobes implicated in the mirror neuron system.

The study included 13 male patients diagnosed with high-functioning autism or Asperger syndrome and an IQ greater than 70 and 12 healthy control adolescents. Average age of the participants was about 11 years. Each of the patients underwent diffusion tensor imaging (DTI), a technique that tracks the movement of water molecules in the brain.

DTI is traditionally used to study the brain's white matter, as well as the brain fibers. However, Dr. Ashtari's team applied it to the assessment of gray matter by employing apparent diffusion coefficient based morphometry (ABM), a new method that highlights brain regions with potential gray matter volume changes. By adding ABM to DTI, the researchers can detect subtle regional or localized changes in the gray matter.

In addition to the gray matter abnormalities linked to the mirror neuron system, the results of this study revealed that the amount of gray matter in the left parietal area correlated with higher IQs in the control group, but not in the autistic children.

"In the normal brain, larger amounts of gray matter are associated with higher IQs," Dr. Ashtari said. "But in the autistic brain, increased gray matter does not correspond to IQ, because this gray matter is not functioning properly."

The autistic children also evidenced a significant decrease of gray matter in the right amygdala region that correlated with severity of social impairment. Children with lower gray matter volumes in this area of the brain had lower scores on reciprocity and social interaction measures.

"Impairments in these areas are the hallmark of autism spectrum disorders, and this finding may lead to greater understanding of the neurobiological underpinnings of the core features of autism," said study co-author Joel Bregman, M.D., medical director of the Fay J. Lindner Center for Autism.

Autism is the fastest growing developmental disability in the United States and typically appears during the first three years of life. Children with autism are hindered in the areas of social interaction and communication skills. According to the Centers for Disease Control and Prevention, as many as 1.5 million Americans have autism.

Results of the study conducted at the Fay J. Lindner Center for Autism, North Shore-Long Island Jewish Health System in Bethpage, N.Y., were presented November 28 at the annual meeting of the Radiological Society of North America.

Co-authors are S. Nichols, Ph.D., C. McIlree, M.S., L. Spritzer, B.S., A. Adesman, M.D., and B. Ardekani, Ph.D.

This study was supported by The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System and the National Center for Research Resources/National Institutes of Health.

Adapted from materials provided by Radiological Society of North America.

The MMR story that wasn't

Whatever you think about Andrew Wakefield, the real villains of the MMR scandal are the media.

Ben Goldacre
Wednesday July 18, 2007
The Guardian

Whatever you think about Andrew Wakefield, the real villains of the MMR scandal are the media. Just one week before his GMC hearing, yet another factless "MMR causes autism" news story appeared: and even though it ran on the front page of our very own Observer, I am dismantling it on this page. We're all grown-ups around here.

The story made three key points: that new research has found an increase in the prevalence of autism to one in 58; that the lead academic on this study was so concerned he suggested raising the finding with public heath officials; and that two "leading researchers" on the team believe that the rise was due to MMR. Within a week the story had been recycled in several national newspapers, and the news pages of at least one academic journal.

But where did the facts come from? I contacted the Autism Research Centre in Cambridge: the study the Observer reported is not finished, and not published. The data has been collected, but it has not been analysed. Unpublished data is the antithesis of what science is about: transparency, where anyone can appraise the methods, and the results, and draw their own conclusions.

This study is the perfect example of why this is important: it was specifically designed to look at how different methods of assessing prevalence affected the final figure. So it is no surprise that one of the results from an early analysis is high, "one in 58", using techniques which deliberately cast the widest net. But even other figures in the initial analysis were less dramatic, and similar to current estimates, and the Observer admits it was aware of them. It seems it simply cherry picked the single most extreme number and made it a front page splash story.

The Observer is unrepentant: it says it has the "final report", from 2005. I can't get it to show it to me but the Cambridge team suspect the paper has seen the last of the quarterly progress reports to the funders. So how did the Observer manage to crowbar MMR into this story?

First, it claimed that the lead researcher, Professor Simon Baron Cohen, "was so concerned by the one in 58 figure that last year he proposed informing public health officials in the county." Prof Cohen is clear: this is inaccurate and scaremongering.

And the meat? The Observer claims that "two of the academics, leaders in their field, privately believe that the surprisingly high figure [one in 58] may be linked to the use of the controversial MMR vaccine." This point is repeatedly reiterated, with a couple of other scientists disagreeing to create that familiar, illusory equipoise of scientific opinion which has fuelled the MMR scare in the media for almost a decade now.

But in fact, the two "leading experts" who were concerned about MMR, the "experts", the "leaders in their field", were not professors, or fellows, or lecturers: they were research associates. I rang both, and both were very clear that they wouldn't describe themselves as "leading experts". One is Fiona Scott, a psychologist and very competent researcher at Cambridge. She said to me: "I absolutely do not think that the rise in autism is related to MMR." And: "My own daughter is getting vaccinated with the MMR jab on July 17."

She also said, astonishingly, that the Observer never even spoke to her. And in the Observer's "readers' editor" column one whole week later, where the Observer half heartedly addressed some of the criticisms of its piece, the Observer persisted in claiming she believes MMR causes autism: it believes it knows the opinions of this woman better than she knows her own mind. Despite her public protestations. The only voice that Dr Scott could find - bizarrely - was in the online comments underneath the readers' editor piece, where the Observer continued to call her an MMR "dissenter", and where she posted an impassioned and slightly desperate message, protesting her support of MMR, and threatening legal action.

That's one of the leading experts. The other is Carol Stott. She does believe that MMR causes autism (at last). However, she is no longer even a "research associate" at the Autism Research Centre.

Carol Stott works in Dr Andrew Wakefield's private autism clinic in America, which the Observer failed to mention, and she was also an adviser to the legal team which failed in seeking compensation for parents who believed that MMR caused their child's autism, which the Observer failed to mention. She was paid £100,000 of public money for her services. She says her objectivity was not affected by the sum, but even so this seems an astonishing pair of facts for the Observer to leave out.

And were Stott's views private, or secret, or new? Hardly. Stott is so committed to the cause against MMR that when the investigative journalist Brian Deer exposed the legal payouts in 2004, although she had no prior contact with him, she spontaneously fired off a long series of sweary emails titled "game on": "Try me, shit head ... Believe me, you will lose ... so go fuck yourself. Got it yet shit head. Try me ... Twathead ... waiting ... oh yes ... Stick that where it feels good. Shit head ... well, ur a bit slow on the uptake ... Give it time I s'pose. Twat." And so on.

On the phone I genuinely warmed to her, and she regrets that many people have fallen into entrenched positions on MMR on both sides. But she's not a leading expert (as she herself agrees); she's not a sombre Cambridge academic suddenly expressing a fresh concern (her views are very public); and in any case, even she is very clear that this new research reported in the Observer would tell us nothing whatsoever about MMR causing autism.

Nothing has changed, and this scare will never be allowed to die. If we had the right regulatory structures, almost every section of the media would be in the dock, alongside Wakefield.

Researchers Reverse Symptoms In Mice Of Leading Inherited Cause Of Mental Retardation

Science Daily — Researchers at the Picower Institute for Learning and Memory at MIT have, for the first time, reversed symptoms of mental retardation and autism in mice.

In Fragile X, there is a mutation in a gene called FMR1 on the X chromosome. (Credit: Image courtesy of NIH/National Human Genome Research Institute)

The work will be reported in the online early edition of the Proceedings of the National Academy of Sciences the week of June 25-29.

The mice were genetically manipulated to model Fragile X Syndrome (FXS), the leading inherited cause of mental retardation and the most common genetic cause of autism. The condition, tied to a mutated X chromosome gene called fragile X mental retardation 1 (FMR1) gene, causes mild learning disabilities to severe autism.

According to the Centers for Disease Control, FXS affects one in 4,000 males and one in 6,000 females of all races and ethnic groups. The prevalence of autism ranges from one in 500 to one in 166 children. There is no effective treatment for FXS and other types of autism.

"Our study suggests that inhibiting a certain enzyme in the brain could be an effective therapy for countering the debilitating symptoms of FXS in children, and possibly in autistic kids as well," said co-author Mansuo L. Hayashi, a former Picower Institute postdoctoral fellow currently at Merck Research Laboratories in Boston.

The study identifies a key enzyme-a chemical reaction-inducing protein-as a possible target for an FXS drug. The enzyme, called p21-activated kinase, or PAK, affects the number, size and shape of connections between neurons in the brain.

Halting PAK's enzymatic activity reversed the structural abnormality of neuronal connections found in the FXS mice, said co-author Susumu Tonegawa, 1987 Nobel laureate and Picower Professor of Biology and Neuroscience. "Strikingly, PAK inhibition also restored electrical communication between neurons in the brains of the FXS mice, correcting their behavioral abnormalities in the process," he said.

There are known chemical compounds that inhibit the enzymatic activity of PAK. These compounds or versions of them may be useful in the future development of drugs for treating FXS, he said.

"These are intriguing findings because the expression of the gene that inhibits PAK occurs in the third week after birth, which means that the neuronal abnormalities in the fragile X mouse are reversed after they appear," said Eric Klann, a professor at New York University's Center for Neural Science. "This is very exciting because it suggests that PAK inhibitors could be used for therapeutic purposes to reverse already established mental impairments in fragile X children."

Restoring neuronal connections

Tonegawa, Hayashi, MIT graduate student Bridget M. Dolan of the Department of Biology and colleagues study the molecules that govern the formation of neuronal connections in the brain. They explore how abnormalities in these molecules could interfere with an animal's behavior.

In the brain, small protrusions called dendritic spines on the branch-like dendrites of one neuron receive chemical signals from other neurons and communicate them to the main cell body. The numbers and shapes of dendritic spines are key to normal brain function.

FXS patients have higher numbers of dendritic spines in their brains, but each spine is longer and thinner, and transmits weaker electric signals, than those in non-affected individuals. When the enzymatic activity of PAK was inhibited in the FXS mice, abnormalities in their spine number and structure-as well as the weaker electrical communication between their neurons-were reversed.

Reversing behavioral symptoms

The FXS mice exhibited symptoms similar to those in FXS patients. These included hyperactivity; purposeless, repetitive movements reminiscent of autistic people; attention deficits and difficulty with learning and memory tasks.

"These behavioral abnormalities are ameliorated, partially or fully, by inhibiting the enzymatic activity of PAK," Tonegawa said. "Notably, due to an elegant genetic manipulation method employed by the Picower Institute researchers, PAK inhibition in the FXS mice did not take place until a few weeks after appearance of disease symptoms. This implies that future treatment may still be effective even after symptoms are already pronounced."

"While future studies will be necessary to further characterize the precise molecular nature of the interaction between PAK and FMR1, our findings clearly demonstrate that PAK inhibition can counteract several key cellular and behavioral symptoms of FXS," the authors noted.

In addition to Tonegawa, a Howard Hughes Medical Institute investigator, Hayashi and Dolan, authors include colleagues at the National Institute of Mental Health and Neurosciences; the Tata Institute of Fundamental Research in India; and Seoul National University in Korea.

This work was supported by the FRAXA Foundation, the Simons Foundation, the Wellcome Trust and the National Institutes of Health.

Note: This story has been adapted from a news release issued by Massachusetts Institute of Technology.

Protein mutations link to autism

Scientists have discovered how mutations in two key proteins may lead to autism.

They have shown one protein increases the excitability of nerve cells, while the other inhibits cell activity.

The University of Texas team found that in normal circumstances the proteins balance each other out.

But the study, published in Neuron, suggests that in people with autism the balance between the proteins is knocked out of kilter.

The findings back the theory that autism involves an imbalance between excitatory and inhibitory connections between nerve cells.

The proteins, which serve to physically link nerve cells together, were discovered by the team at the university's Southwestern Medical Center more than a decade ago.

However, until the latest study their exact function had been unclear.

Lead researcher Dr Ege Kavalali said: "Mutations in these proteins have recently been linked to certain varieties of autism.

"This work provides clear insight into how the proteins function. We can never design a therapeutic strategy without knowing what these mutations do."

Bridge between cells

The proteins - neuroligin-1 and neuroligin-2 - create a physical bridge at the junction - or synapse - of nerve cells, enabling them to make connections with others.

In studies on rats the researchers showed that raising levels of both proteins in nerve cells led to the creation of extra synapses.

Neuroligin-1 was associated with excitatory connections and neuroligin-2 with inhibitory connections.

When they introduced a mutant form of neuroligin-1 thought to be carried by some people with autism the number of synapses fell dramatically - and the cells became significantly less excitable.

Infants are born with far more synapses than survive to adulthood. Active synapses proliferate during development, but inactive synapses are culled.

The latest research suggests that carrying a mutant form of neuroligin-1 may depress the number of synapses that make it into adulthood.

This could hamper the ability of nerve cells to make the usual connections, and lead to the deficits seen in people with autism.

It affects the way a person communicates and interacts with other people.

Communication problems

People with autism cannot relate to others in a meaningful way. They also have trouble making sense of the world at large.

As a result, their ability to develop friendships is impaired. They also have a limited capacity to understand other people's feelings.

Autism is often also associated with learning disabilities.

Professor Simon Baron-Cohen, director of the Autism Research Centre at the University of Cambridge, said research into the role of neuroligins in autism was important.

He said: "We need to know more about both the genes that code for neuroligins, and the neuroligins themselves, to establish if they play a specific role in the cause of autism spectrum conditions and in which subgroup.

"Understanding how the autistic brain is different to the neurotypical brain will have significant implications for education and intervention."

Dan Olmsted, la propagation de rumeurs et la science

EDITORIAL

Dan Olmsted ferait mieux de s'occuper ne pas s'occuper de sujets qui le dépassent. Journaliste d'une série d'articles qui ne font que marteler les mêmes erreurs, dans l'espoir sans doute de les rendre plus crédibles, il finit surtout par lasser même les parents les plus crédules.

Dans le dernier opus, il nous parle des coïncidences et arrive à s'étonner lui-même. Ainsi, il affirme:

The autism rate rises in tandem with increasing numbers of vaccines that contain a known neurotoxin, ethyl mercury.

Public health authorities say that's coincidence.

Effectivement, les autorités médicales ont raison. Ce sont des coïncidences. Pour le prouver, il suffit d'en trouver d'autres. Le taux d'autisme augmente aussi avec l'utilisation des téléphones portables, des ordinateurs, de la crème solaire, des congés payés, de l'élargissement de la définition de l'autisme, etc. Bref, de tout ce qui augmente en fonction du temps. En statistiques, on appelle ça une corrélation temporelle. Dans le langage courant: une coïncidence.
Dan Olmsted oublie tout simplement de dire que la fameuse 'neurotoxine', le thimerosal, en fait un adjuvant permettant d'activer les défenses immunitaires et donc de limiter les doses et le nombre de piqures, a été retiré des vaccins infantiles depuis plus de dix ans et que le taux d'autisme n'a pas décru pour autant. Et ça, Mr Olmsted, ce n'est plus une coïncidence, c'est une démonstration de la fausseté flagrante de cette théorie.

Mr Olmsted continue dans son obsession:

Parents say their children became autistic after receiving mercury-containing vaccinations, sometimes several shots in one day.

Pediatricians call that coincidence, too.

Incroyable, l'autisme arrive dans une période de vaccin ! A-t-il eu des enfants ? Il suffit de calculer le nombres de vaccins que le nouveau-né reçoit dans les trois premières années de sa vie et de diviser par 36 pour savoir qu'il n'y a pas beaucoup de mois sans piqure. Quel est le risque qu'un autisme, qui se manifestera pendant ces trois premières années, soit remarqué à 15 jours maximum d'une piqure ? A peu près une chance sur une. Plus qu'il n'en faut pour que certains parents en quête de sens opèrent une corrélation douteuse.
Si l'autisme se déclenche aussi à chaque fois à moins de trois jours du dernier repas de votre bambin, faut-il aussi le priver de nourriture ? Ca aussi, c'est un événement qui a une chance sur un de se produire.
Rappelons encore que les vaccins, contrairement aux affirmations mensongères de Mr Olmsted ne comportent plus de thimerosal depuis plus de dix ans. Ou en est la fantastique décrue de l'autisme qu'on peut donc légitimement attendre depuis sept ans ?

Olmsted continue ses divagations:

Another remarkable fact that caught my attention: Autism was first identified in both the United States and Europe at almost exactly the same time. Child psychiatrist Leo Kanner published his landmark paper at Johns Hopkins University in Baltimore in 1943; pediatrician Hans Asperger published his -- about a slightly less severely affected group of children -- in Vienna in 1944. Cut off by a world war, neither knew of the other's work.

Coincidence, say the experts, who attribute the timing to improving diagnostic techniques in both countries.

Mr Olsmted devrait relire l'histoire des sciences. Il trouverait de nombreux exemples de ce genre de 'coïncidences'. Mais ce domaine n'est pas non plus son fort.

Et ici, il commence à affirmer sans la moindre preuve, sur la base de coïncidences avec des vaccins qui ne contiennent rien de ce qu'il prétend:

If it's not a coincidence that autism arose simultaneously on separate continents, that suggests something happened in two places at once to trigger the disorder.

Là, il affirme que l'autisme n'existait pas avant les vaccins et que ces troubles sont apparus juste à ce moment. Or l'autisme ne pouvait pas être diagnostiqué avant qu'on ait défini ce qu'on entend par là. Les cas d'autisme d'avant cette définition étaient classifiés parmi les "folies", "retard mentaux", etc. Normal qu'on ne trouve aucun cas d'autisme au moyen âge, le mot n'avait même pas été inventé. Ce qui ne veut pas dire que la chose que ce mot recouvre aujourd'hui n'existait pas. Mr Olmsted prétendrait certainement que l'ADN n'existait pas avant qu'on le découvre ! C'est la génération spontanée version XXIème siècle.

Et Mr Olmsted saute immédiatement sur une conclusion, assez bête puisque les cas génétiques ont été montrés par plusieurs études sérieuses (ce blog leur est dédié):

And that would suggest genes are not the fundamental factor, though they certainly could be implicated in making some children susceptible to whatever the new exposure was.

Récapitulons: le thimerosal aurait déclenché une épidémie d'autisme qui continuerait d'augmenter depuis dix ans malgré son retrait des vaccins. Les gènes ne seraient pas un facteur fondamental mais l'épidémie touche quatre fois plus de garçons que de filles, signe impliquant généralement une sensibilité génétique sur le chromosome X ou Y.

Et Olsmted rabâche le même mensonge ad libitum:

Remember, this type of mercury didn't exist in nature; it's man-made, and Kharasch is the man who made it marketable.

Il oublie une fois de plus que ce dont il parle n'existe plus. Il continue, de façon assez ridicule, en prévenant maintenant qu'il fait des hypothèses:

So what might have happened -- warning, hypothesis ahead -- is that some early exposures to ethyl mercury came from inhaling or otherwise coming into contact with it via that agricultural route. And some of the children exposed to this novel and neurotoxic form of mercury developed a novel neurological disorder called autism.

Là, Olmsted se rend compte qu'il fait des hypothèses ! Parce que jusqu'à présent, il croyait exposer des faits ! Et il dérape: maintenant il n'accuse plus les vaccins mais s'apprête à accuser les pesticides. Alors bien sûr, personne ne prétendrait qu'il est bon pour la santé de respirer des pesticides à hautes doses toute la journée. Il y a même des règlements de plus en plus sévères contre ça.
Olmsted change de produit, et passe du thimerosal aux pesticides. Quelle rigueur dans la pensée ! Donc les autismes se trouveraient principalement chez les agriculteurs, si nous comprenons bien le cheminement tortueux de cette personne. Très bien !

Olmsted continue ses imprécations:

Now check this out: Among the earliest cases seen in Europe were 10 identified by a Dutch researcher named D. Arn Van Krevelen. One of the 10 fathers was a horticulturalist; another was a florist's salesman.

Alors les agriculteurs qui vaporisent les pesticides à haute dose n'ont rien mais un pauvre fleuriste s'en prend plein la figure ! Là, Olmsted prend carrément les parents d'enfants autistes pour des imbéciles.

Je laisse la conclusion à Olmsted:

Maybe that's no coincidence.

En effet, il n'y en a pas: Olsmted est fait pour l'astrologie, les tarots et la lecture des lignes de la main. Vu son peu d'attachement aux faits réels, il devrait éviter la science et même le journalisme.

Les vaccins, le thimerosal, la science et les rumeurs

EDITORIAL

La sensibilité des parents d'enfants avec autisme aux rumeurs est compréhensible. Toute explication, même irrationnelle, est bonne pour ceux qui subissent un mal qui frappe apparemment à l'aveugle. C'est une tendance naturelle de l'homme à projeter du sens dans ce qui nous entoure. Le processus n'est donc pas nouveau: avant l'ère scientifique, on imaginait un panthéon de dieux, l'influence des astres, ou des causes physiques imaginaires comme les 'humeurs', les 'méridiens', le 'terrain', etc.

Aujourd'hui, le recul de la religion et des anciennes superstitions aidant, ce sont les rumeurs colportées par Internet qui fleurissent. La 'preuve', c'est la multiplication de celles-ci depuis qu'Internet se démocratise. Evidemment, il s'agit ici d'une corrélation. Mais tout le monde peut comprendre rationnellement la causalité entre la pénétration d'Internet et la facilité de diffusion de rumeurs infondées.

Des rumeurs persistantes font état d'une corrélation entre l'administration de vaccins et l'incidence de l'autisme. En fait il y a plusieurs rumeurs différentes et incompatibles entre elles. L'une accuse un composant des vaccins, le thimerosal en particulier (un adjuvant qui était rajouté aux vaccins pour en accroitre l'efficacité et dont le mercure est un composant). Une autre accuse spécifiquement le vaccin ROR (rougeole-oreillons-rubéole) et le virus de la rougeole en particulier. Une troisième accuse le vaccin contre la varicelle. Aucun rapport entre ces trois rumeurs, mais elles sont souvent amalgamées par les parents d'enfants avec autisme. Une dernière rumeur, plus récente, accuse les téléphones portables tout en balayant du revers de la main les autres rumeurs, par des arguments rationnels qui permettent de la balayer elle-même !

Qu'en est-il en réalité ? Toutes les études accusant les vaccins ont été discréditées depuis plusieurs années par des analyses a posteriori. Les accusations de Wakefield contre le vaccin ROR a été discréditées lorsque la presse scientifique a révélé le conflit d'intérêt qui le liait à un des parents d'enfants en procès contre les services médicaux, ainsi que l'origine curieuse du financement de son étude, par ailleurs largement biaisée du point de vue technique.

Les accusations contre le thimerosal sont tombées lorsque le Danemark, qui a abandonné le thimerosal dans les vaccins infantiles depuis 1992 n'a pas vu diminuer l'incidence de l'autisme, au contraire. La Suède a suivi le même chemin que le Danemark et réduit considérablement l'utilisation du thimerosal depuis les années 1980. Là non plus, aucune diminution de l'incidence de l'autisme. S'il y a un ou des facteurs environnementaux impliqués, une chose est maintenant sure: le thimerosal n'a pas grand chose à voir avec.
Certains parents insistent sur les similitudes entre un empoisonnement au mercure et les symptômes de l'autisme. Outre que cette similitude est une vue de l'esprit, il est curieux qu'un empoisonnement au mercure soit soudainement sensible au sexe de l'enfant, au point qu'il touche dix fois plus souvent les garçons que les filles. Si c'est un facteur environnemental qui favorise l'autisme, ce facteur environnemental se préoccupe beaucoup du sexe de l'enfant, ce qui signalerait une sensibilité génétique portant sur le chromosome X (les enfants de sexe masculin n'en possédant qu'un, ils sont plus sensibles aux défauts génétiques sur ce chromosome). Le facteur génétique est donc une piste beaucoup plus crédible, même si un facteur environnemental est probablement à l'oeuvre, favorisant ces défauts chromosomiques.

Passons au téléphone portable. La aussi, il s'agit d'une corrélation temporelle (c'est à dire une coïncidence) qui est avancée par les parents d'enfants avec autisme. C'est la même corrélation temporelle qui leur permettait d'incriminer le vaccin ROR, introduit environ au même moment que se développait le téléphone portable. Mais c'est également au même moment que l'ordinateur individuel et ses nombreux produits toxiques, comme les PCB, est arrivé. Tous ces outils utilisent les mêmes technologies et donc leur apparition a été simultanée.
Alors pourquoi les téléphones portables et pas les ordinateurs ? Peut-être parce que les adeptes d'une théorie contre les ordinateurs portables ne pourraient plus justifier de leur utilisation d'Internet pour répandre la rumeur ! Alors que les téléphones portables, eux, n'ont pas cet 'inconvénient', vu qu'ils ne permettent pas la communication de masse.
Reste à savoir combien de temps les bébés passent avec le téléphone portable collé à l'oreille pour expliquer l'augmentation des cas d'autisme. Sachant que l'effet des ondes émises par les portables diminue considérablement dès lors que le téléphone est situé à 15cm de la tête, on se demande comment les bébés pourraient en pâtir, à moins de supposer que les parents laissent leur téléphone branché dans le berceau ou le landau du petit, ou que la mère le porte sur son ventre pendant toute la grossesse au lieu de le mettre comme d'habitude dans son sac à main. Cette théorie fera aussi long feu que les autres, sans doute, mais aura l'avantage sur les autres de ne pas causer de mort par défaut de vaccination.

Toutes ces rumeurs n'ont aucun fondement mais perdurent uniquement, à l'instar de toutes les légendes urbaines, colportées par des personnes qui n'ont généralement aucune formation scientifique ou médicale et sont prêtes à écarter tout argument rationnel qui irait à l'encontre de leurs convictions toutes faites. Elles sont très généreusement reprises par les médias en quête de scoop, quitte à faire du réchauffé.

L'effet global est que les scientifiques passent plus de temps à discréditer ces théories pseudo-scientifiques et moins de temps à rechercher les véritables causes. Sans oublier qu'elles ont diminué la couverture vaccinale nécessaire pour empêcher une épidémie de se produire. La conséquence est claire: de nouvelles épidémies de rougeole et de varicelle se produisent, là où elles avaient disparu depuis longtemps. L'Angleterre a été ainsi réexpédiée en quelques années dans le tiers-monde de la vaccination. Un enfant en est déjà mort. Est-ce que les convictions de quelques irresponsables valait ce prix ? Ceux qui le croient devraient pouvoir supporter de le dire en face aux parents de la victime.

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

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.

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.

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.

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.

Un espoir de traitement contre le syndrome de Rett

Par Destination Santé

A partir d'un modèle animal du syndrome de Rett, une équipe de l'INSERM est parvenue à réduire le nombre de décès par arrêt respiratoire grâce à l'administration quotidienne d'un antidépresseur, la desipramine.

Un médicament retiré du marché en 2003. « Il s'agit d'une vieille molécule et beaucoup de nouveaux inhibiteurs de la recapture de la sérotonine sont disponibles sur le marché. La décision de retrait du marché n'est pas liée à des problèmes de toxicité ni d'effets indésirables » de ce produit, souligne Laurent Villard, de l'unité INSERM 491 à Marseille.

Avec son équipe, il a montré que cette molécule « augmentait le taux de noradrénaline dans l'organisme (permettant ainsi) d'activer le système nerveux et de provoquer une stabilisation du rythme respiratoire ». Ces travaux sont aujourd'hui à la base d'un essai clinique de phase II en cours de réalisation. Dans quelques mois, 36 patients souffrant du syndrome de Rett seront ainsi traités pendant 8 mois. La suite dépendra des résultats de cet essai.

Source : INSERM, 11 avril 2007

La formation des souvenirs sociaux

Existe-t-il une mémoire spécifique pour les événements impliquant les humains? Des chercheurs français, du laboratoire Vulnérabilité, adaptation et psychopathologie (CNRS/université Paris VI) et canadiens, de l'Hôpital Douglas à l'Université McGill (Montréal), ont identifié la partie interne du cortex préfrontal comme structure clé pour la mise en mémoire des informations sociales.

Les événements sociaux tels qu'une fête entre amis, une réunion de travail ou une dispute avec son conjoint font partie intégrante de la vie quotidienne. Notre capacité à se souvenir de ces événements, et plus précisément à se souvenir des personnes et des relations que nous avons avec elles, est absolument nécessaire pour bien nous adapter à notre vie sociale. Au niveau cérébral, diverses régions du cerveau, en particulier l'hippocampe, sont directement impliquées dans l'apprentissage et la mémoire. Certaines de ces régions sont spécialisées dans l'apprentissage de certains types d'information, comme par exemple l'amygdale dans la mémoire des émotions.

Les équipes française de Philippe Fossati et canadiennes viennent d'identifier une région précise du cortex frontal, qui serait spécialisée dans l'enregistrement et l'apprentissage des informations sociales. En utilisant la technique d'imagerie par résonance magnétique fonctionnelle, ces chercheurs ont mesuré l'activité cérébrale de 17 volontaires lors de la réalisation d'une tâche de mémoire comprenant des images avec des scènes sociales (personnes en interactions) et non sociales (paysages sans personnage humain). Ils ont ainsi identifié la partie interne du cortex préfrontal, nommée cortex médial préfrontal, comme étant la structure-clé pour la mise en mémoire des informations sociales d'une image.

Des études précédentes réalisées par les mêmes chercheurs avaient auparavant associé cette région préfrontale à des processus de réflexion sur soi-même et sur autrui. Le travail des chercheurs suggère qu'au-delà des émotions, l'analyse des informations spécifiquement humaines pourrait faciliter l'apprentissage et la mémorisation, en mettant en jeu des structures cérébrales spécialisées dans l'analyse des états mentaux et l'empathie. Ce travail ouvre des perspectives importantes pour la compréhension des mécanismes des témoignages humains et des désordres mentaux (troubles schizophréniques, autisme), qui affectent les compétences sociales et relationnelles.

Source: CNRS

Des mutations génétiques accroîtraient les risques d'autisme

Agence France-Presse
Washington

De très petites mutations génétiques spontanées accroîtraient les risques d'autisme beaucoup plus que ne le pensait jusqu'alors la médecine, selon une recherche dont les résultats sont publiés jeudi aux États-Unis.

Ces mutations génétiques bien que rares sont 10 fois plus fréquentes chez des personnes souffrant de troubles autistiques que chez des sujets sains, indique cette étude qui paraît dans la revue Science du 16 mars.

Cette recherche a également montré que ces mutations étaient seulement deux fois plus fréquentes chez des personnes dont au moins deux membres de la famille étaient autistes, souligne le Dr Jonathan Sebat du Cold Spring Harbor Laboratory (CSHL) dans l'État de New York, un des coauteurs de ces travaux.

«Notre étude montre clairement que ces petits défauts génétiques sont fréquents dans l'autisme et apparaissent dans au moins 10 % des cas, plus particulièrement dans la forme sporadique de la maladie qui compte pour 90 % des cas», ajoute-t-il.

«La compréhension de l'autisme sporadique nécessitera différentes approches génétiques et d'élargir les études sur un grand nombre de familles dans lesquelles seul un des membres souffre de la maladie», poursuit le médecin.

Cette étude, financée en partie par l'Institut national américain de la santé (NIH), a porté sur des échantillons génétiques provenant de 264 familles.

Autisme: de nouveaux marqueurs génétiques identifiés lors d'une vaste étude

Par Louise DALY

CHICAGO (AFP) - Une équipe internationale de chercheurs a identifié de nouveaux marqueurs ADN pour l'autisme dans le cadre d'une des plus ambitieuses études portant sur les origines génétiques de ce trouble envahissant du développement de l'enfant.
Ces nouvelles données apportent une preuve supplémentaire du rôle, dans l'autisme, de gènes liés au système de neurotransmission via un messager chimique, le glutamate, dans le cerveau.

L'étude, que vient de publier en ligne la revue scientifique Nature Genetics, suggère aussi qu'une région du chromosome 11, jusqu'alors non répertoriée comme telle, pourrait renfermer certains des gènes impliqués dans ce trouble mal compris.

"Ces résultats sont l'une des pièces du puzzle. En identifiant ces gènes, nous pourrons détecter l'autisme chez des enfants dès le plus jeune âge et commencer plus tôt à les prendre en charge", explique une des chercheuses, Geraldine Dawson (Université de Washington), soulignant l'impact que cela pourrait avoir sur leur développement.

Les résultats s'appuient sur l'analyse de l'ADN de 1.200 familles ayant au moins deux enfants autistes, ce qui en fait la plus vaste étude génétique sur l'autisme jamais entreprise, selon les chercheurs.

Ils ont utilisé des puces à ADN pour détecter des similitudes génétiques parmi les familles de malades. Ils ont aussi recherché au sein de l'ADN des anomalies submicroscopiques.

L'étude montre en particulier le rôle des gènes codant pour des neurexines, des protéines intervenant dans la mise en place des synapses, les connexions permettant aux cellules du cerveau de communiquer entre elles.

Le glutamate accroît l'activité des neurones et joue un rôle important dans le cablage du cerveau au tout début du développement.

Si le programme génétique pour le système de neurotransmission au glutamate s'avère défectueux, cela pourrait expliquer les erreurs de cablage qui, selon certains chercheurs, seraient à l'origine de ce trouble du développement.

Ces travaux s'appuient sur des recherches antérieures qui avaient permis de trouver que plusieurs gènes-clés associés au système glutamatergique se trouvent des régions chromosomiques associées à l'autisme.

Décidés à approfondir ces résultats, les chercheurs prévoient aussi, dans une seconde phase de l'étude, d'isoler les gènes de la région du chromosome 11 qui pourraient jouer un rôle dans le développement du syndrome autistique.

"Nous trouverons dans les quatre ou cinq ans une poignée de gènes prédisposant à ce trouble", prédit un des chercheurs, le psychiatre Joachim Hallmayer (Stanford University).

Etant donné la complexité de ce trouble et la probabilité qu'il existe sous une grande diversité de formes chez les enfants atteints, il faudra probablement, met-il en garde, attendre "des années et des années" avant d'aboutir à une percée thérapeutique.

L'autisme, qui apparaît avant l'âge de quatre ans, plus souvent chez des garçons, n'est pas un trouble unique, mais recouvre un éventail de troubles envahissants du développement. Il est caractérisé par des déficits de communication et des relations sociales, associés à des comportements répétitifs. Certains enfants autistes n'apprennent jamais à parler.

Les causes restent inconnues, cependant il y a un consensus scientifique impliquant une origine partiellement génétique. Des dizaines de gènes pourraient être impliqués.

L'étude, à laquelle ont participé 120 scientifiques de 19 pays, a été effectuée dans le cadre du consortium Autism Genome Project, associant 50 centres de recherches publics et privés décidés à joindre leurs efforts pour accélérer l'identification de gènes de susceptibilité à l'autisme.

Largest-ever search for autism genes reveals new clues

The largest search for autism genes to date, funded in part by the National Institutes of Health (NIH), has implicated components of the brain's glutamate chemical messenger system and a previously overlooked site on chromosome 11. Based on 1,168 families with at least two affected members, the genome scan adds to evidence that tiny, rare variations in genes may heighten risk for autism spectrum disorders (ASD)*.

The study is the first to emerge from the Autism Genome Project (AGP) Consortium, a public-private collaboration involving more than 120 scientists and 50 institutions in l9 countries. Their report is published online in the February 18, 2007 issue of Nature Genetics.

With NIH support, the AGP is pursuing studies to identify specific genes and gene variants that contribute to vulnerability to autism. These include explorations of interactions of genes with other genes and with environmental factors, and laboratory research aimed at understanding how candidate susceptibility genes might work in the brain to produce the disorders.

"This is the most ambitious effort yet to find the locations of genes that may confer vulnerability to autism," said NIH Director Elias A. Zerhouni, M.D. "The AGP is revealing clues that will likely influence the direction of autism research for years to come."

"Although we know autism is highly heritable, complex gene interactions and submicroscopic anomalies create a din of statistical noise that drowns out detection of signals from linked sites in the genome," explained Dr. Bernie Devlin, University of Pittsburgh, who served as a corresponding author on the project along with the University of Toronto's Dr. Stephen Scherer. "To amplify these signals, we brought to bear gene chip technology with a huge sample, and also screened for these fine-level anomalies, factoring them into the analysis."

Clues emerged adding to evidence that implicates components of the brain's glutamate neurotransmitter system in autism. Glutamate increases neuronal activity and plays an important role in wiring up the brain during early development. Since autism likely stems from faulty wiring, a genetic blueprint gone awry in this pivotal neurotransmitter system is a prime suspect. Some key genes associated with the glutamate system are located in chromosome regions previously associated with autism, note the researchers.

Previous studies have also linked abnormal glutamate functioning to disorders such as Fragile X syndrome and tuberous sclerosis, which share some symptoms with autism. It's not unusual for individuals with either syndrome to be diagnosed with autism.

Among the new clues is stronger evidence for an association between autism and sites of genes for neurexins, molecules that build glutamate synapses – the connection machinery by which brain cells communicate.

A site on chromosome 11 most strongly linked to autism in this study harbors genes for proteins that shuttle glutamate across the synapse. Although detected previously, the linkage signal at this site was regarded as less important until now.

Submicroscopic anomalies – tiny deletions, or the doubling, tripling or even multiplying of stretches of genetic material – are relatively common in the human genome and aren't necessarily harmful. However, recent evidence suggests that these anomalies may contribute to risk for – or rarely even cause – autism if they affect certain sites associated with the disorder. The AGP researchers found a number of these variations in such suspect chromosomal locations in affected individuals, including deletion of a neurexin gene.

These anomalies can also make it more difficult to detect the genes that more commonly account for autism risk, say the researchers. Since each major autism candidate gene likely contributes to risk for a relatively small percentage of families, its linkage signal can easily be lost in the statistical noise generated by those of the anomalies – just as a high level of static can drown out a weak radio signal.

To amplify the power of possible linkages detected, the researchers analyzed many subsets of data, variously excluding from the sample factors like the submicroscopic anomalies, female sex, and ethnicity. These analyses unmasked several suggestive linkages that would otherwise have eluded detection.

Researchers last Fall reported (http://www.nimh.nih.gov/press/autismmetgene.cfm ) discovery of a gene version linked to autism and how it likely works at the molecular level to increase risk. The AGP researchers propose that multiple such gene variants, perhaps interacting with each other and with the tiny anomalies, contribute to risk. As more such genes are identified, studies of how they work in the brain – in mice and other model systems – will help to sort out the genetic and proposed environmental influences on autism spectrum disorders, say researchers.

A second phase of AGP studies will follow up on leads suggested in this first phase.

From U.S. NIH

Réversibilité des symptômes d’un désordre du spectre autistique

Le syndrome de Rett a été inversé dans son modèle génétique chez la souris.

Traduit de l'anglais par Danièle Langloys

La Fondation pour la recherche sur le Syndrome de Rett (RSRF) annonce les résultats d’une recherche-clé qui a permis d’inverser les symptômes du Syndrome de Rett sur son modèle génétique chez la souris. Ces découvertes, faites par Adrian Bird, Professeur de l’Université d’Edimbourg et président du conseil scientifique de la RSRF, ont paru en ligne dans Science Express le 8 février 2007. Le syndrome de Rett est une maladie neurologique de l’enfance qui est la plus invalidante physiquement parmi les troubles du spectre autistique. Les expériences ont été financées par la RSRF, l’association Wellcome, et la Fondation britannique pour le Syndrome de Rett, des Jeans pour des Gènes.

Causé par des mutations sur le gène MECP2, le syndrome de Rett affecte essentiellement les filles ; il frappe au hasard dans la petite enfance et affecte le langage, la mobilité et l’usage fonctionnel de la main. Beaucoup d’enfants se retrouvent en fauteuil roulant ; ceux qui marchent manifestent une démarche anormale, avec une raideur des jambes. Des problèmes respiratoires et des tremblements de type parkinsonien sont courants.

La restauration de l’entière fonctionnalité du gène MEPC2 pendant 4 semaines a fait disparaître les tremblements et normalisé la respiration, la mobilité et la démarche chez des souris qui avaient auparavant tous les symptômes et dans certains cas étaient à quelques jours seulement de la mort.

« Comme beaucoup d’autres, nous pensions que donner le MEPC2 à des souris qui étaient déjà malades ne marcherait pas », a dit Bird. « L’idée qu’on puisse remettre un composant essentiel après la survenue des dommages cérébraux et récupérer une souris apparemment normale semblait tirée par les cheveux, car les cellules du cerveau qui s’étaient développées en l’absence d’un composant-clé étaient censées avoir été endommagées de manière irréversible. Les résultats sont agréablement nets, cependant, et doivent donner de l’espoir à ceux qui sont affectés par ce trouble douloureux. »

Bird est professeur de génétique à l’Université d’Edimbourg et directeur du Centre Wellcome de Biologie Cellulaire. Le MEPC2, identifié pour la première fois en 1990 par Bird, est considéré comme une protéine qui régule l’expression d’autres gènes en les arrêtant au bon moment.

En 1999, Huda Zoghbi, Professeur et Docteur en Médecine au Départements de Génétique Moléculaire et Humaine, Pédiatrie, Neurologie et Neuroscience du Collège de Médecine Baylor, a découvert que le syndrome de Rett était causé par des mutations sur le gène MEPC2. Des mutations sur le gène MEPC2 sont maintenant observées dans quelques cas de schizophrénie, d’autisme classique et de handicaps d’apprentissage.

« Ces découvertes sont extraordinaires et sont pertinentes non seulement pour le syndrome de Rett mais aussi pour une classe plus large de troubles, dont l’autisme et la schizophrénie. La restauration réussie du fonctionnement normal démontrée sur l’exemple des souris suggère que si nous pouvons développer des thérapies pour pallier la perte du MEPC2, nous serons peut-être capables de rendre réversibles les dommages neurologiques chez les enfants et adultes atteints du syndrome de Rett, d’autisme et de troubles neuropsychiatriques apparentés », a ajouté Zoghbi.

Les expériences de réversibilité ont été effectuées dans le laboratoire de Bird par son adjoint de recherche, Jacky Guy. Employant une technologie connue sous le nom de recombinaison Cre-lox ¹, elle a créé des souris expérimentales dans lesquelles le MEPC2 a été inactivé par l’insertion d’une cassette stop ² dans le gène, ce qui provoque les déficiences neurologiques observées dans le Syndrome de Rett. L’inactivation pouvait être rendue réversible à volonté en enlevant la cassette stop, ce qui alors réactivait le gène MEPC2. Ceci a été réalisé en administrant aux souris un médicament qui faisait entrer l’enzyme Cre dans le noyau de la cellule où il pouvait alors déloger la cassette.

En plus de perdre leurs déficiences comportementales manifestes, les souris recouvraient aussi une fonction électrophysiologique-clé. On l’a déterminé en mesurant la LTP ³ (potentialisation à long terme), qui fournit une mesure quantifiable de la capacité des neurones à répondre à une stimulation. On pense depuis longtemps que la LTP reflète la base cellulaire de l’apprentissage et de la mémoire. Bien que la LTP chez les souris de l’expérience fût déficitaire, elle fut restaurée dans ses fonctions normales par les expériences de réversibilité.

« La réversibilité des déficiences neurologiques, rapportée dans le remarquable article de Guy et autres, est surprenante, parce que la cause des symptômes est apparue tôt dans le développement et on s’attendait à ce qu’elle soit permanente. On remarque tout particulièrement la restauration de la LTP, qui est le meilleur équivalent physiologique actuel de l’apprentissage et de la mémoire. Ces découvertes sont très encourageantes pour ceux qui cherchent des traitements parce qu’elles donnent l’espoir que les symptômes pourraient non seulement être stoppés dans leur progression, mais que le cours de la maladie elle-même pourrait être inversé », a affirmé Fred Gage, Docteur en médecine à l’Institut Salk d’Etudes Biologiques.

« Les résultats étonnants du Docteur Bird font entrer le Syndrome de Rett et les autres troubles du spectre autistique dans une nouvelle ère. Les expériences de réversibilité justifient une exploration conquérante de nouvelles étapes sur tous les fronts, de la découverte de médicaments à la thérapie génique. La RSRF concentre ses efforts pour identifier et accélérer les traitements pour les enfants et adultes qui en ont terriblement besoin », a ajouté Monica Coenraads, co-fondatrice et Directrice de recherche à la RSRF, et mère d’une jeune fille atteinte du syndrome.

¹-NdT : pour en savoir plus sur la Cre-Lox :
http://www.ipbs.fr/formation/biotech/knockout.pdf
²-NdT : on dit aussi en biologie "cassette de résistance".
³-NdT : en neurologie la LTP est une augmentation de la force chimique d’une synapse qui dure de quelques minutes à plusieurs jours.

Reversal of symptoms in an autism spectrum disorder

Rett Syndrome is reversed in genetic mouse model

The Rett Syndrome Research Foundation (RSRF) announces results of a landmark study reversing the symptoms of Rett Syndrome (RTT) in a genetic mouse model. The findings, by Adrian Bird, Ph.D., of the University of Edinburgh and Chairman of the RSRF Scientific Advisory Board, appear online in Science Express on February 8, 2007. Rett Syndrome is a severe childhood neurological disease that is the most physically disabling of the autism spectrum disorders. The experiments were funded by the Rett Syndrome Research Foundation (RSRF), the Wellcome Trust and the Rett Syndrome U.K./Jeans for Genes.

Caused by mutations in the gene MECP2, RTT affects primarily girls, striking at random in early childhood and destroying speech, normal movement and functional hand use. Many children become wheelchair bound; those who walk display an abnormal, stiff-legged gait. Disordered breathing patterns and Parkinson-like tremors are common.

Restoration of fully functional MECP2 over a four week period eradicated tremors and normalized breathing, mobility and gait in mice that had previously been fully symptomatic and, in some cases, only days away from death.

"Like many other people, we expected that giving MeCP2 to mice that were already sick would not work," said Bird. "The idea that you could put back an essential component after the damage to the brain is done and recover an apparently normal mouse seemed farfetched, as nerve cells that developed in the absence of a key component were assumed to be irrevocably damaged. The results are gratifyingly clear, though, and must give hope to those who are affected by this distressing disorder."

Bird is Buchanan Professor of Genetics at University of Edinburgh and Director of the Wellcome Trust Centre for Cell Biology. MeCP2, first identified by Bird in 1990, is considered to be a protein that regulates the expression of other genes by turning them off at the appropriate time.

In 1999 Huda Zoghbi, M.D., Professor, Departments of Molecular and Human Genetics, Pediatrics, Neurology, and Neuroscience at Baylor College of Medicine discovered that RTT is caused by mutations in the MECP2 gene. Mutations in MECP2 are now being seen in some cases of childhood schizophrenia, classic autism and learning disabilities.

"The findings are extraordinary, and are of relevance not only to Rett Syndrome but to a much broader class of disorders, including autism and schizophrenia. The successful restoration of normal function demonstrated in the mouse models suggests that if we can develop therapies to address the loss of MECP2 we may be able to reverse neurological damage in children and adults with Rett, autism and related neuropsychiatric disorders," commented Zoghbi.

The reversal experiments were carried out in the Bird lab by research assistant Jacky Guy. Employing technology known as Cre-lox recombination, she created mouse models in which MECP2 was silenced by insertion of a Stop cassette into the gene, resulting in the neurological deficits seen in RTT. Silencing could be reversed at will by removing the Stop cassette, thereby reactivating the MECP2 gene. This was achieved by treating the mice with a drug that caused the enzyme Cre to enter the cell nucleus where it could splice out the cassette.

As well as losing overt behavioral defects, the mice also recovered a key electrophysiological function of the brain. This was determined by measuring LTP (long-term potentiation) which provides a quantifiable measurement of the ability of neurons to respond to stimulation. LTP has long been thought to reflect the cellular basis of learning and memory. Though LTP in RTT mice models was defective, it was restored to normal function by the reversal experiments.

"The reversal of neurological defects, reported in the remarkable article by Guy et al, is surprising because the cause of the symptoms occurred early in development and was expected to be permanent. Of particular note is the recovery of LTP, which is the best current physiological correlate of learning and memory. These findings are very encouraging for those searching for a treatment because they give hope that the symptoms could not only be halted from progressing, but the course of the disease itself may be able to be reversed," stated Fred Gage, Ph.D. of the Salk Institute of Biological Studies.

"Dr. Bird's astonishing results usher in a new era for Rett Syndrome and other autism spectrum disorders. The reversal experiments provide justification for aggressive exploration of next steps on all fronts, from drug discovery to gene correction. The Rett Syndrome Research Foundation will be focused on a comprehensive effort to identify and speed treatments to the children and adults in dire need of them," commented Monica Coenraads, co-founder and Director of Research for RSRF and mother of a young daughter with the disorder.

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The reversal experiments were funded by the Wellcome Trust, the Rett Syndrome Research Foundation (RSRF) and the Rett Syndrome U.K./Jeans for Genes.

About the Rett Syndrome Research Foundation

The Rett Syndrome Research Foundation (www.rsrf.org) was created in late 1999 and is the largest private source of funds for biomedical research on Rett Syndrome.

About the Wellcome Trust

The Wellcome Trust is the largest charity in the UK and the second largest medical research charity in the world. It funds innovative biomedical research, in the UK and internationally, spending around £500 million each year to support the brightest scientists with the best ideas. The Wellcome Trust supports public debate about biomedical research and its impact on health and wellbeing. http://www.wellcome.ac.uk