Sunday, July 17, 2011

Mortality Rate Is Increased in Persons With Autism Who Also Have Epilepsy, Study Finds

ScienceDaily (Apr. 18, 2011) — A comprehensive investigation of brain tissue donated to the Autism Speaks Autism Tissue Program (ATP), a postmortem brain tissue donation program, determined that one-third of the brain donors with autism also had epilepsy, and co-morbidity data from the California State Department of Developmental Services revealed a higher than expected rate of mortality in individuals with both autism and epilepsy than for individuals with autism alone.

The study, published in the Journal of Child Neurology, reported that 39 percent of the confirmed cases of autism from ATP donations also had a confirmed diagnosis of epilepsy, which is significantly higher than the estimated rate of epilepsy among the general autism population. The study also reported that data from the California State Department of Developmental Services demonstrated a higher than expected rate of mortality in individuals with autism and epilepsy than autism alone. These data are consistent with past reports. The paper concluded that when epilepsy and autism occurred together, the mortality rates increased by more than 800 percent.

"This study highlights the importance of early identification of epilepsy in children with autism and of autism in children with epilepsy," said Roberto Tuchman, MD, pediatric neurologist at Miami Children's Hospital and member of the Autism Speaks Scientific Advisory Council. "The findings of this study should motivate the autism and epilepsy communities to increase their understanding of the risk factors and common mechanisms that can lead to epilepsy, autism, or both epilepsy and autism. Understanding these early determinants will allow for the development of effective interventions and preventive measures and ultimately better outcomes for children with autism and epilepsy."

It is well established that epilepsy is a major medical disorder that is often co-morbid with autism in as many as 30 percent of children. As many as one in 20 children diagnosed with autism by age 3 could either already have epilepsy or develop epilepsy later in life. As noted by the ATP more than a decade ago, sudden unexplained death in epilepsy (SUDEP) has been identified as a cause of death in individuals with autism. Higher mortality rates than in the general population have been reported among individuals with autism, however, there is relatively little known about the specific risk factors that account for the reported higher-than-expected rate of mortality in autism.

"Sudden, unexpected or unexplained death in autism is often, but not always related to epilepsy and we need to use caution when interpreting these data," explained Autism Speaks Vice President of Clinical Programs Clara Lajonchere, Ph.D. "These findings are important for understanding risk factors that may contribute to early death in individuals with autism and further underscore the need for more accurate and accessible records on cause of death in this population. Furthermore, state surveillance programs should implement better tracking mechanisms to help us better understand mortality for individuals with autism and co-occurring disorders such as epilepsy. Critical initiatives supported by Autism Speaks brain tissue program will help bring these issues to the fore and provide information our community needs to help prevent early death in persons with autism."

Monday, March 2, 2009

Study suggests possible treatment for neurological disorder Rett syndrome

Using injections of a small derivate of the protein insulin-like growth factor-1 (IGF-1), scientists at Whitehead Institute for Biomedical Research and MIT's Picower Institute for Learning and Memory have successfully treated a mouse model of the devastating neurological disorder Rett syndrome.

Rett syndrome is an inherited disease affecting one of 10,000 girls born. Infants with the disease appear to develop normally for their first six to 18 months, at which point their movement and language skills begin to deteriorate. Loss of speech, reduced head size, breathing and heart rhythm irregularities, and autistic-like symptoms are common by age four. Some symptoms may be mediated with prescription drugs, but no cure or truly effective treatment for the disease exists.

In a study appearing in the February issue of the Proceedings of the National Academies of Sciences, researchers showed that daily injections of an active fragment of IGF-1 in mice that expressed Rett-syndrome like symptoms could significantly reduce movement and respiratory irregularities. Although treated mice were not cured, the outcome is reason for optimism.

"This is the first realistic way for a drug-like molecule injected into the bloodstream to relieve Rett syndrome symptoms," says Whitehead Member Rudolf Jaenisch, whose lab collaborated with the lab of MIT and Picower scientist Mriganka Sur in the research.

In approximately 85% of girls with Rett syndrome, the disease is caused by loss of function of the MeCP2 gene, which is highly expressed during nerve cell maturation. Lack of MeCP2 expression impedes nerve cell growth, keeping the cells from forming projections, called spines, which are used for nerve-cell-to-nerve-cell communication. Recent genetic studies have shown that in mice with blocked MeCP2 expression, turning MeCP2 back "on" nudges the mice towards normal movement and lifespan—an indication that the disease could be reversible.

Although researchers have known which gene causes the vast majority of Rett syndrome cases, they have until now been unable to promote nerve cell maturation through administration of a drug, protein, or small molecule.

While researchers in Sur's lab had discovered that increased brain levels of IGF-1 promoted maturation of synapses, the connections between nerve cells that are the basis for brain functions, Emanuela Giacometti, a graduate student in Jaenisch's laboratory, was theorizing that IGF-1 might also increase the nerve cell spines in the lab's mouse model of Rett syndrome. Such mice lack the MeCP2 gene and at four to six weeks display symptoms quite similar to those in girls with Rett Syndrome, including difficulty walking, lethargy, and breathing and heart rhythm irregularities.

In a collaboration with the Sur lab to test how IGF-1 might affect these mice, Giacometti administered to two-week-old Rett mice daily injections of IGF-1 fragment. At six weeks, treated mice were significantly more active, had more regular breathing, and had more normal, regular heart rhythms than did untreated mice. In addition, the brains of treated mice were heavier and showed more nerve cell spines.

"Although the treated mice get better and their symptoms don't progress as fast as they normally would, the treated mice still get the symptoms. So it's definitely not a cure, but it could be a co-therapy," Giacometti says.

Sur is also excited by the prospect of finding a drug treatment for Rett syndrome and other forms of autism. IGF1 is approved by the US Food and Drug Administration (FDA) to treat severe IGF-1 deficiency. "This represents a way forward towards clinical trials and a mechanism-based treatment for Rett Syndrome. We very much hope our research can offer some help for the patients who have this terrible disorder

Thursday, January 15, 2009

Drugs Hint At Potential Reversal Of Autism

Scientific researchers can spend years in the lab on obscure topics, like how a sea slug remembers or how a fruit fly sees color. But every now and then, a basic scientist makes a discovery that changes human lives.

Mark Bear, who directs the Picower Institute for Learning and Memory at MIT, is one of those basic scientists. He's discovered a system in the brain that could change the lives of thousands of people with the genetic disorder known as Fragile X Syndrome.

Fragile X is a mutation on the X chromosome that can cause mental retardation and autism. Until now, there has been no treatment.

But Bear discovered that the mutation responsible for Fragile X appears to disrupt a system in the brain that regulates synapses — the connections between brain cells. He says the system works a bit like a car.

"You really need both the accelerator and the brake to properly function," Bear says. "In the case of Fragile X, it's like the brakes are missing. So even tapping the accelerator can have the car careening out of control."

Bear and other scientists have also identified several drugs that seem to correct the problem. The drugs don't replace the missing brakes in the brain. Instead, they limit acceleration by reducing the activity of a group of receptors on brain cells known as mGluR5 receptors.

The drugs have reversed most of the effects of Fragile X in mice. They are now being tried in humans. And at least one small study found that a single dose of a drug had an effect.

The implications for people with Fragile X are huge. If the drugs work, people with the disorder could see their IQs rise and their autism diminish.

"It's a dream come true to think that we have the prospect of having gone from really basic science discovery to a potential treatment," Bear says.

Bear's research was funded in part by a group called FRAXA. Katie Clapp and her husband, Michael Tranfaglia, started the group in the early 1990s as a way to help their son Andy, who has Fragile X Syndrome.

Clapp says she now has reason to hope that Andy, who is now 19, can get better.

"We're not expecting a miracle, or to make up for his 19 years of development," she says. "But if we can watch improvement happen, that's a dream."

Wednesday, January 14, 2009

School gets 'a lot of credit' for autistic boy's growth

by DAVID WENNER, Of The Patriot-News
Tuesday January 13, 2009, 11:57 PM

Helen Reyes knew cancer would kill her. But the single mom was most afraid of what would happen to her son, L.J.

L.J. has fragile x syndrome, which is similar to autism. He'll probably never be completely independent.

Reyes knew she wouldn't be around to fend for L.J. So she latched onto a dream.
She dreamed of an institution such as the one depicted in the movie "Rain Man," in which Dustin Hoffman played an autistic man.

She pictured L.J. surrounded by trees and lawns. She imagined gentle caregivers who would protect her son, who was 13 when she died in 2005.

As often happens with dreams, it didn't come true. Yet she might be smiling.

L.J., now 16, lives near Halifax in a house overlooking a valley. He goes to Upper Dauphin High School, attending a program that focuses on making him as independent as possible.

His classroom contains a replica of an apartment, where students learn about cooking and cleaning and laundry.

"I think it has worked out great," said Beth Lehman, his legal guardian. "I give the school a lot of credit."

Through the school, he has worked at a church preparing meals for the elderly, and at a local grocery store.

He's more composed and makes more eye contact than he did a few years ago, Lehman said. He visits his grandmother, Johanne Kohl of Steelton, and his uncle, who lives in Philadelphia.

Sherry Gaglione of West Hanover Township was a close friend of Helen Reyes and has known L.J. since he was a little boy. She keeps in touch with Lehman and L.J.

"I couldn't be more happy for him. He's adjusting well. Beth is like his second mom," Gaglione said.

Sunday, April 20, 2008

Williams family deals with autism

With freckles across his nose, Matthew Williams looks a little like a child, but he is growing into a young man. For Matthew's family, that is another step in their journey with autism.

Matthew, 15-year-old son of Byron and Wendy Williams, has Landau Kleffher Syndrome and is classified as having a form of autism. A feature of LKS is the gradual or sudden loss of the ability to understand and use spoken language. Children with LKS have abnormal electrical brain waves on an EEG, a recording of the brain's electric activity.

LKS occurs most frequently in normally developing children between ages 3 and 7. For no apparent reason, understanding what is said to them becomes difficult. Intelligence appears to be unaffected.

Until about 24 months, Wendy Williams said her son developed normally.

"Matthew was a happy, social, outgoing baby," she said. "He met milestones on time or early. He crawled at six months and walked at 9 1/2 months. He was talking, had a pretty big vocabulary and said small sentences by the time he was 2 years old."

After he turned 2, she noticed changes in her son.

"Matthew started not sleeping, having laughing spells, was hyper and would only eat a small variety of foods," Wendy said. "Then at around 3, we went to a hospital in Chicago and found out Matthew was having seizure activity in his brain when he slept. This led us to his doctor in Mobile who diagnosed him with LKS."

That diagnosis led to taking medications.

"We started him on medications and at 4 he said the letter 'E.' Wendy said. "This was the first thing he had said since he was 2 years old. He started saying more words but his vocabulary was limited.

"We went through years of trying different medicines some okay some worse. Then around age 12, I told the doctor stop everything but seizure medicine. He became more social, behavior improved and his learning capabilities increased."

Adolescence brought more seizures, which was frightening.

"During adolescence he had his first physical seizure," said Wendy. "That is a terrifying experience no parent wants. To see your child turn blue in a second, stop breathing and twitching is frightening. Not knowing when he might have one is frightening because it could be life threatening. On the other hand you can't be so scared you don't let them do things they love doing."

The causes of LKS aren't known, but Wendy believes immunizations played a role.

"We believe his disorder was brought on by immunizations because as a baby he was normal in every way," she said. "Then at 22 months he received his MMR shot then another shot within a month. Within a month of his last shot he quit talking."

Whatever the cause, they have a positive attitude about a child Wendy describes as amazing.

"Matthew has a great memory," she said. "Ironically his favorite animal is an elephant; they say they never forget anything.

"Matthew loves cartoons and can repeat them word for word and sound by sound. He loves fishing with his Dad. He likes to go to the zoo, swimming, jumping on the trampoline, riding the four-wheeler, playing with his sister and cousins - typical kid stuff."

While he is typical in many ways, Matthew has challenges.

"Matthew is behind academically," she said. "That is one reason I decided to home school. Unfortunately, our school system doesn't have enough teachers educated in teaching children with autism.

"Matthew needs one-on-one instruction to learn properly. He has done well since we began home schooling. It was the right decision because he is an intelligent child; he just has problems understanding things and expressing himself."

The Williams have a 13-year-old daughter, Amber, and a 23-month-old son, Nicholas, too.

"Matthew watches out for Nicholas, but he doesn't want him touching his stuff or going in his room," said Wendy. "He plays with Amber and enjoys hanging around her friends when they come over. He also likes being around his cousins when they do things he likes to do."

The Williams think about Matthew's future.

"One of my concerns is Matthew being able to take care of himself with as little help as possible when he grows up," Wendy said. "He takes care of his grooming needs; he knows to take his medicine, and he can cook some things and does chores."

She wants society to have compassion for kids like Matthew.

"He functions like me and you he just likes to be by himself a lot and doesn't like people messing with his stuff," she said. "He is shy in public and makes noises when he is excited, frustrated or nervous. In many ways, he is a normal 15-year-old and in other ways, he is childlike.

"I wish people would understand children with autism are like you and me. They don't have a disease, they will not hurt you and you won't catch anything from them."

Wendy said it's hard to see the reactions her son gets.

"No parent wants to see or hear someone laughing, staring and making fun of their child for speaking or acting differently," she said. "It hurts and it makes you mad because you know he is just like anyone else's child - just a little more special.

"The next time you see a special needs person smile, say hello. A little understanding goes a long way."

Wendy said Matthew is a blessing.

"God does not make mistakes. We are lucky to have a child as special as Matthew," she said. "We love him with all our hearts and if you gave him a chance, you would too. Matthew has changed our lives forever; we miss out on some things but this is his life not ours."

She knows what Matthew might say if he could.

"If Matthew could ask for himself and for other special needs children, he would say, 'Open your minds and hearts with understanding ... because we are just like you. We just function a little differently.'"

Friday, April 11, 2008

Drosophila Drug Screen For Fragile X Syndrome Finds Promising Compounds And Potential Drug Targets

Scientists using a new drug screening method in Drosophila (fruit flies), have identified several drugs and small molecules that reverse the features of fragile X syndrome -- a frequent form of mental retardation and one of the leading known causes of autism. The discovery sets the stage for developing new treatments for fragile X syndrome.

The results of the research by lead scientist Stephen Warren, PhD, chair of the Department of Human Genetics at Emory University School of Medicine, are published online in the journal Nature Chemical Biology.

Dr. Warren led an international group of scientists that discovered the FMR1 gene responsible for fragile X syndrome in 1991. Fragile X syndrome is caused by the functional loss of the fragile X mental retardation protein (FMRP). Currently there is no effective drug therapy for fragile X syndrome, and previously no assays had been developed to screen drug candidates for the disorder.

During the past 17 years, intense efforts from many laboratories have uncovered the fundamental basis for fragile X syndrome. Scientists believe FMRP affects learning and memory through regulation of protein synthesis at synapses in the brain. One leading view, proposed by Dr. Warren and colleagues, suggests that over stimulation of neurons by the neurotransmitter glutamate is partly responsible for the brain dysfunction resulting from the loss of FMRP.

In their current experiment, Emory scientists used a Drosophila model lacking the FMR1 gene. These fruit flies have abnormalities in brain architecture and behavior that parallel abnormalities in the human form of fragile X syndrome. When FMR1-deficient fly embryos were fed food containing increased levels of glutamate, they died during development, which is consistent with the theory that the loss of FMR1 results in excess glutamate signaling.

The scientists placed the FMR1-deficient fly embryos in thousands of tiny wells containing food with glutamate. In addition, each well contained one compound from a library of 2,000 drugs and small molecules. Using this screening method, the scientists uncovered nine molecules that reversed the lethal effects of glutamate.

The three top identified compounds were known activators of GABA, a neural pathway already known to inhibit the effects of glutamate. In the study, GABA reversed all the features of fragile X syndrome in the fruit flies, including deficits in the brain's primary learning center and behavioral deficits. The screening also identified other neural pathways that may have a parallel role in fragile X syndrome and could be targets for drug therapy.

"Our discovery of glutamate toxicity in the Drosophila model of fragile X syndrome allowed us to develop this new screen for potential drug targets," notes Dr. Warren. "We believe this is the first chemical genetic screen for fragile X syndrome, and it highlights the general potential of Drosophila screens for drug development.

"Most importantly, it identifies several small molecules that significantly reverse multiple abnormal characteristics of FMR1 deficiency. It also reveals additional pathways and relevant drug targets. These findings open the door to development of effective new therapies for fragile X syndrome."

First author of the article was Shuang Chang, postdoctoral student in Emory's Department of Human Genetics. Other authors included Steven M. Bray and Peng Jin from Emory, Zigang Li from the University of Chicago and Daniela C. Zarnescu from the University of Arizona.

The research was supported by the National Institutes of Health, the Fragile X Research Foundation, and the Colonial Oaks Foundation.

Dr. Warren is chair of the scientific advisory board for Seaside Therapeutics, which is developing drugs for fragile X syndrome.

Wednesday, February 13, 2008

Chemical Signals Go Awry in Fragile X Syndrome

MONDAY, Jan. 14 (HealthDay News) -- New information about how brain cells are affected in Fragile X syndrome -- the most common cause of inherited mental retardation -- has been uncovered.

In the study, researchers at the University of Texas Southwestern Medical Center at Dallas examined mice to see how Fragile X syndrome affects communication between cells in the hippocampus, a part of the brain involved in learning and memory. The team found that two different chemical signals go awry in Fragile X syndrome. This suggests that drugs that interact with these chemical signals may offer a treatment.

The study is published in the current issue of The Journal of Neuroscience.

"I think we've discovered a core mechanism underlying Fragile X syndrome," senior author Dr. Kimberly Huber, an assistant professor of neuroscience, said in a prepared statement.

"The more we know about how signaling mechanisms in the brain lead to normal memory and learning, the better we can understand what goes wrong in conditions such as Fragile X syndrome," Huber said. "Our research is laying the groundwork for such understanding and indicates a new area for research."

Fragile X syndrome occurs mostly in males and affects about one in every 4,000 white males in the United States, according to the U.S. Centers for Disease Control and Prevention.

Along with mental deficits ranging from mood disorders to severe mental retardation, people with the syndrome often have distinct physical traits, including an elongated face with protruding ears and hyperflexible joints.