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Autism breakthrough: gene defect link
The Australian
Mark Henderson | July 11, 2008
MANY cases of autism are caused by genetic defects that disrupt the brain's ability to learn, according to groundbreaking research that promises to lead to new therapies.
A set of six genes that are strongly linked to brain development in the first year of life have been found to be abnormal in many autistic children, suggesting a neurological pathway that may underlie a significant proportion of cases.
The findings are particularly significant because some of these genes are not deleted entirely in autistic children, but are kept switched off by mutations in surrounding control regions of their DNA.
This raises the prospect that critical genes could be activated by drugs or behavioural and educational therapies, so that their brains develop more normally.
“We would not need to replace the gene, if we could only figure out how to reactivate it, perhaps with medications,” said Eric Morrow, who led the research team with his Harvard University colleague Christopher Walsh.
Such genes could also be activated by environmental factors, such as specialised education programmes, and it may ultimately even be possible to use genetic tests to determine which approach will work best for individual children.
Dr Walsh said: “By being able to characterise more about the genetic mutations at work in various forms of autism, we may be able to predict which kids need gene therapy, and which just need some form of training.”
Autism is a developmental disorder that is diagnosed in up to one in 100 children, and has a triad of symptoms. People who are affected have impaired social and communication skills, and show restricted or repetitive behaviour.
The condition has long been known to be heavily influenced by genetics, from twin and family studies, but few genes have been definitively associated. Most cases are thought to be influenced by combinations of dozens of defective genes, or by rare spontaneous mutations.
It also occurs on a spectrum, ranging from high-functioning forms such as Asperger's syndrome to highly disabling conditions. Dr Walsh likened it to Leo Tolstoy's line in Anna Karenina, that: “All happy families are alike; each unhappy family is unhappy in its own way.”
Research into autism genetics has been hampered by the difficulty of finding autistic and non-autistic siblings in the same family to study. To get around this, the new study investigated 88 families from the Middle East, Turkey and Pakistan, where the average number of children is much larger than in Europe and America. The scientists also concentrated on families in which the mother and father were cousins, which is a risk factor for autism.
In five families, they found large segments of the genome were missing. Non-autistic members still had one working copy of these regions, but those with autism lacked working copies altogether.
Most of the deletions were in sections of DNA that switch other genes on and off, and affected genes that are important in the developing brain. They appear to be vital to the process by which brain connections known as synapses become modified during the first year of life, influenced by exposure to the outside world.
Details of the research are published in the journal Science.
Dr Walsh said: “Autism symptoms emerge at an age when the developing brain is refining the connections between neurons in response to a child's experience. Whether or not certain important genes turn on is thus dependent on experience-triggered neural activity. Disruption of this refinement process may be a common mechanism of autism-associated mutations.”
The work suggests that many genes, some yet unidentified, that contribute to this early learning process may be involved in autism.
Michael Greenberg, another member of the Harvard team, said: “Taken together, our findings suggest that experience-dependent learning could be relevant to autism, and that autism might result from any one of a number of genes that are part of the same signalling pathway.”
Thomas Insel, director of the US National Institute of Mental Health, which funded the research, said: “The emerging picture of the genetics of autism is quite surprising. There appear to be many separate mutations involved, with each family having a different genetic cause.
“The one unifying observation from this new report is that all of the relevant mutations could disrupt the formation of vital neural connections during a critical period when experience is shaping the developing brain.”
Clarence Schutt, of the Nancy Lurie Marks Family Foundation, another funder, said: “This publication a big event in the world of autism research.”
The Times
The Australian
Mark Henderson | July 11, 2008
MANY cases of autism are caused by genetic defects that disrupt the brain's ability to learn, according to groundbreaking research that promises to lead to new therapies.
A set of six genes that are strongly linked to brain development in the first year of life have been found to be abnormal in many autistic children, suggesting a neurological pathway that may underlie a significant proportion of cases.
The findings are particularly significant because some of these genes are not deleted entirely in autistic children, but are kept switched off by mutations in surrounding control regions of their DNA.
This raises the prospect that critical genes could be activated by drugs or behavioural and educational therapies, so that their brains develop more normally.
“We would not need to replace the gene, if we could only figure out how to reactivate it, perhaps with medications,” said Eric Morrow, who led the research team with his Harvard University colleague Christopher Walsh.
Such genes could also be activated by environmental factors, such as specialised education programmes, and it may ultimately even be possible to use genetic tests to determine which approach will work best for individual children.
Dr Walsh said: “By being able to characterise more about the genetic mutations at work in various forms of autism, we may be able to predict which kids need gene therapy, and which just need some form of training.”
Autism is a developmental disorder that is diagnosed in up to one in 100 children, and has a triad of symptoms. People who are affected have impaired social and communication skills, and show restricted or repetitive behaviour.
The condition has long been known to be heavily influenced by genetics, from twin and family studies, but few genes have been definitively associated. Most cases are thought to be influenced by combinations of dozens of defective genes, or by rare spontaneous mutations.
It also occurs on a spectrum, ranging from high-functioning forms such as Asperger's syndrome to highly disabling conditions. Dr Walsh likened it to Leo Tolstoy's line in Anna Karenina, that: “All happy families are alike; each unhappy family is unhappy in its own way.”
Research into autism genetics has been hampered by the difficulty of finding autistic and non-autistic siblings in the same family to study. To get around this, the new study investigated 88 families from the Middle East, Turkey and Pakistan, where the average number of children is much larger than in Europe and America. The scientists also concentrated on families in which the mother and father were cousins, which is a risk factor for autism.
In five families, they found large segments of the genome were missing. Non-autistic members still had one working copy of these regions, but those with autism lacked working copies altogether.
Most of the deletions were in sections of DNA that switch other genes on and off, and affected genes that are important in the developing brain. They appear to be vital to the process by which brain connections known as synapses become modified during the first year of life, influenced by exposure to the outside world.
Details of the research are published in the journal Science.
Dr Walsh said: “Autism symptoms emerge at an age when the developing brain is refining the connections between neurons in response to a child's experience. Whether or not certain important genes turn on is thus dependent on experience-triggered neural activity. Disruption of this refinement process may be a common mechanism of autism-associated mutations.”
The work suggests that many genes, some yet unidentified, that contribute to this early learning process may be involved in autism.
Michael Greenberg, another member of the Harvard team, said: “Taken together, our findings suggest that experience-dependent learning could be relevant to autism, and that autism might result from any one of a number of genes that are part of the same signalling pathway.”
Thomas Insel, director of the US National Institute of Mental Health, which funded the research, said: “The emerging picture of the genetics of autism is quite surprising. There appear to be many separate mutations involved, with each family having a different genetic cause.
“The one unifying observation from this new report is that all of the relevant mutations could disrupt the formation of vital neural connections during a critical period when experience is shaping the developing brain.”
Clarence Schutt, of the Nancy Lurie Marks Family Foundation, another funder, said: “This publication a big event in the world of autism research.”
The Times
