Autism and Rett Syndrome

Gene discoveries yield autism clues

· Story Highlights

· Study: Genes suggest autism happens in brains that can't form proper connections

· Some genes may have been stuck in "off" position, respond to therapy

· Study reveals wide variety, almost a custom set, of gene defects in each patient

· Genetic cause is known for only about 15 percent of autism cases

WASHINGTON (AP) -- Harvard researchers have discovered half a dozen new genes involved in autism that suggest the disorder strikes in a brain that can't properly form new connections.

The findings also may help explain why intense education programs do help some autistic children -- because certain genes that respond to experience weren't missing, they were just stuck in the "off" position.

"The circuits are there but you have to give it an extra push," said Dr. Gary Goldstein of the Kennedy Krieger Institute in Baltimore, Maryland, which wasn't involved in the gene hunt but is well-known for its autism behavioral therapy.

The genetics suggest that "what we're doing makes sense when we work with these little kids -- and work and work and work -- and suddenly get through," he said.

But the study's bigger message is that autism is too strikingly individual to envision an easy gene test for it. Instead, patients are turning out to have a wide variety, almost a custom set, of gene defects.

"Almost every kid with autism has their own particular cause of it," said Dr. Christopher Walsh, chief of genetics at Children's Hospital Boston, Massachusetts, who led the research published in Friday's edition of the journal Science.

Autism spectrum disorders include a range of poorly understood brain conditions, from the mild Asperger's syndrome to more severe autism characterized by poor social interaction, impaired communication and repetitious behaviors.

It's clear that genes play a big role in autism, from studies of twins and families with multiple affected children. But so far, the genetic cause is known for only about 15 percent of autism cases, Walsh said.

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So Walsh's team took a new tack. They turned to the Middle East, a part of the world with large families and a tendency for cousins to marry, characteristics that increase the odds of finding rare genes. They recruited 88 families with cousin marriages and a high incidence of autism, from Jordan, Saudi Arabia, Kuwait, Oman, Pakistan, Qatar, Turkey and the United Arab Emirates. They compared the DNA of family members to search for what are called recessive mutations -- where mom and dad can be healthy carriers of a gene defect but a child who inherits that defect from both parents gets sick.

In some of the families, they found large chunks of missing DNA regions that followed that recessive rule. The missing regions varied among families, but they affected at least six genes that play a role in autism.

Here's why this matters: All the genes seem to be part of a network involved in a basic foundation of learning -- how neurons respond to new experiences by forming connections between each other, called synapses.

In the first year or two of life -- when autism symptoms appear _ synapses rapidly form and mature, and unnecessary ones are "pruned" back. In other words, a baby's brain is literally being shaped by its first experiences so that it is structurally able to perform learning and other functions of later life.

"This paper points to problems specifically in the way that experience sculpts the developing brain," explained Dr. Thomas Insel, director of the National Institute of Mental Health, which helped fund the work.

Some earlier research had pointed to the same underlying problem, so these newly found genes "join a growing list to suggest that autism is a synaptic disorder," he said.

If that sounds discouraging, here's the good news: The missing DNA didn't always translate into missing genes. Instead what usually was missing were the on/off switches for these autism-related genes. Essentially, some genes were asleep instead of doing their synapse work.

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"I find that hopeful" because "there are ways that are being discovered to activate genes," Walsh said. "This might be an unanticipated way of developing therapies in the long term for autism: Identifying these kids where all the right genes are present, just not turned on in the right way."

At Kennedy Krieger, Goldstein thinks the work may provide a gene-level explanation for why some children already are helped by intense therapy.

"We have trouble getting through to these children, but with repeated stimulation we can do it," he said. "These are circuits that have an ability not so much to recover but to work around the problem."

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Mental And Physical Exercise Improves Genetic Mental Impairment In Rett Syndrome

ScienceDaily (June 23, 2008) — Australian scientists have shown that mental and physical exercise can improve coordination and movement problems in Rett syndrome, a devastating genetic brain development disorder that primarily affects females.

Using a mouse model of Rett syndrome developed by the Children's Medical Research Institute in Sydney, researchers from the Howard Florey Institute in Melbourne found these mice responded positively to the effects of environmental enrichment.

Dr. Anthony Hannan from the Howard Florey Institute said the onset and severity of coordination and movement problems was reduced by giving the Rett syndrome mice a range of mazes, toys and exercise equipment to stimulate them both mentally and physically.

"Mari Kondo in my laboratory discovered that environmental enrichment significantly improved the ability of the Rett syndrome mice to learn and maintain tasks that required coordinated movements," Hannan said.

"We also found that a special brain chemical called BDNF, which plays a role in the birth and survival of new neurons as well as modifying connections in the brain, was at similar levels in both normal mice and the enriched Rett syndrome mice. The Rett syndrome mice that did not receive environmental enrichment had lower levels of BDNF and performed poorly on movement and coordination tasks.

"This discovery shows that gene-environment interactions may be important for all brain diseases, including those caused by an inherited gene mutation. The next step is for us to look at the effects of environmental enrichment on anxiety and cognition in the mice, as these are common problems in Rett syndrome," he said.

Developer of the Rett syndrome mouse model, Prof Patrick Tam of the Children's Medical Research Institute, said for the past seven years his research team, and especially Dr Gregory Pelka, had been investigating Rett syndrome genetics.

"We have already found a number of genes that may be linked to the development of Rett syndrome," Prof Tam said. "More research in this area is urgently needed as Rett syndrome is the second most common form of severe mental disability in girls after Down syndrome in Australia," Prof Tam added.

Prof John Christodoulou from the Children's Hospital at Westmead also contributed his clinical expertise to the team.

This research was published this week in the European Journal of Neuroscience and is the first published paper on the effects of environmental enrichment in a Rett syndrome model.

This study was a collaboration between scientists from the Howard Florey Institute, the Children's Medical Research Institute, the Children's Hospital at Westmead, the University of Melbourne and the University of Sydney.

Rett syndrome facts

· Rett syndrome is predominantly caused by a sporadic mutation in the MECP2 gene on the X chromosome.

· The syndrome becomes apparent from around six months of age when development stagnates and acquired skills, such as coordination, speech, communication skills and cognitive function deteriorate. Other problems can include, breathing, cardiac function, chewing, swallowing, and digestion.

· Rett syndrome has often been misdiagnosed as cerebral palsy, and shares some similarities with autism. A blood test, as well as symptoms and clinical history, helps to diagnose the disorder.

· The average life expectancy of a girl with Rett syndrome is less than 50 years and she will require maximum assistance with every aspect of daily living.

· In Australia, Rett syndrome affects about 1 in 8,500 females by the age of 15 years.

Journal reference:

1. Kondo et al. Environmental enrichment ameliorates a motor coordination deficit in a mouse model of Rett syndrome -- Mecp2 gene dosage effects and BDNF expression. European Journal of Neuroscience, 2008; 27 (12): 3342 DOI: 10.1111/j.1460-9568.2008.06305.x

Adapted from materials provided by Research Australia, via EurekAlert!, a service of AAAS.

Research Australia (2008, June 23). Mental And Physical Exercise Improves Genetic Mental Impairment In Rett Syndrome. ScienceDaily. Retrieved July 11, 2008, from