Fragile X study raises hopes for autism

Researchers eye key to restoring brain function

By Carey Goldberg, Globe Staff | June 26, 2007

Blocking a key brain chemical can reverse many of the symptoms of Fragile X Syndrome -- an inherited form of mental retardation often accompanied by autism -- in mice engineered to have the disease, an online scientific journal reported yesterday.

The findings raise the prospect that drugs with similar effects might someday help restore brain function in human children with the syndrome, and possibly with some forms of autism as well, said Susumu Tonegawa, the senior author of the paper in the online edition of the Proceedings of the National Academy of Sciences.

About 100,000 Americans have Fragile X.

Mental retardation has long been thought to be permanent. But recent research increasingly suggests that the brain might be more fixable than previously believed. Earlier this year, scientists from Scotland reported that dramatic recoveries could be achieved in mice with Rett Syndrome, another genetic disease related to autism.

Tonegawa's paper says "that some of the abnormalities with mental retardation syndromes and autism aren't necessarily cemented in stone," said Eric Klann, a professor at Center for Neural Sciences at New York University who was familiar with the paper but not involved with the research. "I think it gives some degree of hope."

The research focused on blocking an enzyme called PAK. Tonegawa's research used genetic manipulation instead of drugs, but he said that he believes drug and biotech companies are already developing compounds that block the same enzyme. His lab may seek access to such compounds that target other diseases, or ask a chemist to synthesize them, said Tonegawa, a neuroscientist at Picower Institute for Learning and Memory at the Massachusetts Institute of Technology .

There are currently several drugs in development as possible treatments for people with Fragile X Syndrome, said Katie Clapp, co founder of FRAXA Research Foundation, a Newburyport based nonprofit that helped fund the research. Her 18-year-old son has the syndrome, the most common known genetic cause of autism. None of the compounds has reached the point where she would want him to try them, she said, nor are they available.

"But talk to me in a couple of months," she said. "There are more drug targets coming out of research that we're funding, and some of it does suggest drugs that are already available. So sometimes I feel like I'm living a dream -- a really good one."

In people with Fragile X, the formation of neurons is abnormal, with "spines" -- the little nubs where the neurons connect to each other -- that are overabundant, spindly, and long. Clapp said they are "sort of like a thin, dangly . . . little wire when what you really want is a nice, thick, three-pronged, grounded thing." The thin spines tend to form weak connections.

In Tonegawa's lab, Mansuo Hayashi, then a post-doctoral fellow and now at Merck Research Laboratories, had already found that when PAK activity was genetically blocked, it hindered the formation of spines, leaving them shorter and fatter with connections that were unusually active.

In all, he said, it seemed that blocking PAK produced spines exactly the opposite from those produced in Fragile X Syndrome.

Hayashi proposed cross-breeding a mutant mouse whose PAK could be inactivated with a mouse engineered to have Fragile X Syndrome, in the hope that the two abnormalities would cancel each other .

At first, the idea seemed overly simplistic, Tonegawa said, "but to our great surprise, that's the way it turned out."

The cross-bred animals were also genetically manipulated so that the PAK-blocking would begin several weeks into the mouse's life, well into childhood in human terms. Nonetheless, the effects were striking, the researchers reported.

Normally, the Fragile X mice are hyperactive, as are many of the human children with the syndrome : They engage in repetitive motions, as is common in autism, and have learning deficits. Many of those symptoms were reduced or reversed when PAK's activity was blocked, Tonegawa said. Within the animals' brains, as well, the neurons and their connections came to look and act much more normal .

"It's reversing the architecture of brain connections," Clapp said. "That's exciting."

Carey Goldberg can be reached at goldberg@globe.com

Prader-Willi Syndrome

Prader-Willi Syndrome is a disorder which is sometimes associated with, but not a subtype of, autism. The classical features of this disorder include an obsession with food which is often associated with impulsive eating, compact body build, underdeveloped sexual characteristics, and poor muscle tone. Because of their obsession with food, many people afflicted with Prader-Willi Syndrome are overweight.

Most individuals afflicted with Prader-Willi Syndrome have mild mental retardation.

Some of the behaviors which are common to both Prader-Willi Syndrome and autism are: delays in language and motor development, learning disabilities, feeding problems in infancy, sleep disturbances, skin picking, temper tantrums, and a high pain threshold.

Prader-Willi Syndrome affects approximately 1 in 10,000 people. Most individuals suffering from this disorder are missing a small portion of chromosome 15 which appears to come from the paternal side of the family. When a small portion of chromosome 15 is missing and comes from the maternal side, the person may suffer from Angelman Syndrome.

The most effective form of treatment for people suffering from Prader-Willi Syndrome is behavior modification. In general, medications do not appear to very effective for these individuals.

PDD

Pervasive developmental disorders, most often, can be identified in the early years of a child's life. Children with PDD have difficulty in areas of development or use of functional skills such as language, communication, socialization and motor behaviors.

Examples of PDD include the following:

Autism (autistic disorder).

Asperger's disorder.

Rett's disorder.

Childhood disintegrative disorder (also called disintegrative psychosis).

What causes pervasive developmental disorders?

The specific causes of pervasive developmental disorders are not known. Children with PDD have problems processing information, thus the causes of PDD have something to do with differences in brain function. However, parenting behaviors are not the cause, or even a contributing factor, to the cause or causes of PDD.

Who is affected by pervasive developmental disorders?

Pervasive developmental disorders are very rare. Information regarding how many people have a PDD is inconsistent. Many sources state that for every 10,000 births, five to 20 children are diagnosed with a PDD, including autism. However, other sources state these are very conservative estimates. With the exception of Rett's disorder, a PDD is more frequently found in boys.

Rett's disorder is almost always found in girls.

What are the symptoms of pervasive developmental disorders?

The following are the most common symptoms of some pervasive developmental disorders. However, each child may experience symptoms differently.

How are pervasive developmental disorders diagnosed?

Pervasive developmental disorders are usually identified by the age of 3 years. A child psychiatrist or other mental health professional usually makes the diagnosis of any of the PDD following a comprehensive medical and psychiatric evaluation.

It is important to diagnose PDD early and accurately as some PDD put children at risk for developing other mental disorders (i.e., depression, attention-deficit/hyperactivity disorder, obsessive-compulsive disorder and schizophrenia).

Treatment for pervasive developmental disorders:

Specific treatment for PDD will be determined by your child's physician based on:

Your child's age, overall health and medical history.

Extent of the disorder.

Type of disorder.

Your child's tolerance for specific medications or therapies.

Expectations for the course of the disorder.

Your opinion or preference.

Treatment plans are individualized based on each child's symptoms and the level of severity. Multidisciplinary treatment approaches are utilized as needed to address the individual needs of each child.

Treatment may include:

Speech therapy.

Social skills training (to help children learn to perform activities of daily living, or ADLs and ways to communicate and relate to others).

Behavioral therapy.

Specialized behavioral and educational programs are designed to treat developmental disorders. Behavioral techniques help children learn to behave in more acceptable ways. Parents may be taught behavioral techniques to help them provide consistent rewards and set limits at home. While some children with PDD require specialized classrooms which are highly structured and provide attention to a child's specific academic needs, others are able to function in a regular classroom with less specialized attention.

Medication may be helpful in treating some symptoms of PDD, in some children. Child and adolescent mental health professionals help families identify and participate in treatment and educational programs based on an individual child's treatment and educational needs.

Prevention of pervasive developmental disorders:

Preventive measures to reduce the incidence or severity of any type of PDD are not known at this time. However, it is believed that the level of severity can be improved with early treatment.