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Autism in the Family – More Common Than We Thought

August 16, 2011 43 comments

This is a guest blog post from Autism Speaks Science Board member John Elder Robison, author of Look Me in the Eye: My Life with Asperger’s and Be Different: Adventures of a Free-Range Aspergian.

This morning I read a striking a new study which addressed the question of autism in siblings – how common is it?  The findings will be of vital interest to many; most especially young families with an autistic infant.
Earlier studies and “conventional wisdom” suggested the incidence of autism in siblings was in the 3-10% range.  This new study shows those numbers to be very far from the mark.
Scientists in this new study found autism in 19 percent of the younger siblings.  High as that seems the incidence is even higher in families with two or more autistic kids.  In that case, a new sibling’s chances of being autistic rose to more than 32 percent.
Being a boy makes a difference too.  “Only” 9% of girl siblings were autistic, as compared to 26% of boys.  I found this difference quite interesting because I often wonder if autism is under-diagnosed in females.  In this study, all the kids were screened with the gold-standard ADOS or ADIR tests prior to age three.  So even with top-notch screening, we still have more autistic boys.
Those are some strikingly high percentages.  As high as they are, and knowing autism is a spectrum condition, I have to wonder how many non-diagnosed siblings will eventually turn out to have less severe but still noticeable “differences.”
There were a few more points I found interesting.  First of all, the IQ of the child did not predict anything.  Neither did severity of autism, as defined by the ADOS diagnostic scales.  So your odds of having a second autistic kid are higher, but those odds and knowledge of the first kid don’t combine to give any insight into how a second kid might end up.
The conclusion is inescapable:  autism does run in families.  According to these findings, the more autistic kids you have, the more you are likely to keep having.
We talk about autism having both genetic and environmental components.  This study, with 664 infants distributed all over the country, shows a very powerful genetic component.  That certainly does not diminish the role of environment, but it’s sobering.
I predict the results of this study will have a profound impact on family planning, because it casts parents’ chances of having a second or third child with autism in a strikingly different light that any previous study.
We already know (from other studies) that many parents stop having children when their first child receives an ASD diagnosis.  This new finding may significantly reinforce that tendency.
Read the study yourself at this link.
The study involved 664 infants from 12 U.S. and Canadian sites, evaluated as early as 6 months of age and followed until age 36 months.  Kids with previously identified autism-related genetic factors such as Fragile X were excluded from the study group.
“It’s important to recognize that these are estimates that are averaged across all of the families. So, for some families, the risk will be greater than 18.7 percent, and for other families it would be less than 18.7 percent,” said Sally Ozonoff, Ph.D., professor of psychiatry and behavioral sciences at the MIND Institute and the study’s lead author. “At the present time, unfortunately, we do not know how to estimate an individual family’s actual risk.”
This study was based on data from the Autism Speaks High Risk Baby Siblings Research Consortium (BSRC) and led by investigators from the UC Davis MIND Institute.
Your correspondent (John Elder Robison) is a member of the Science Board of Autism Speaks, one of the organizations who funded the work.

Hope, Plane Rides and Research

August 10, 2011 25 comments

This blog post is by Richard Fauth

It didn’t come from me. I have to admit I could never pull it off like he does. It must be because he’s half-French (his mother’s half.)  Last Sunday, we had a cook-out with a family of friends at Fort Wilderness in Disney World.  My 8-year-old son Lucas was at it again. Smooth. It didn’t take him long to catch the eye of a college-age girl. He took her shoes off.  Before long he was riding around the campground in a golf cart with the other kids. She was driving; he was riding shot-gun. That’s my boy. The cutest little boy on the planet. Although he can say only a few words, I knew he couldn’t be happier.

Lucas has autism and some researchers find him interesting. A sample of Lucas’ DNA was tested by a commercial lab a few years ago for three autism suspect genes. Sequencing tests for the genes (CDKL5, Cntnap2 and Shank 3) were among the first to be performed. The results are what researchers find interesting — unusual variants or mutations in two of the genes-Shank3 and Cntnap2. These results also changed our lives — we left a world where things were increasingly desperate and entered a world of new found hope. Some now say Lucas may be one of the most researched children with autism in the country.

Like many parents, Marie and I spend a lot of effort trying to get the best for our child. Like many kids, Lucas’ day is filled with “activities,” although if he could speak well enough, I think he would call it “work.” He puts in a tough week – long hours of special education, speech therapy, occupational therapy, and applied behavioral therapy. But he also has some fun — “special kids” dance class on Saturday and some gym classes.

As I write this, skin cells from Lucas, Marie and me are being converted to Pluripotent stem cells at a laboratory at Stanford University. From these stem cells, the researchers will grow neuronal tissue. The research is aimed at developing drugs to improve the outcomes of many children.  Another study, a paper concerning a variant in Lucas’ Shank3 gene, has already been published.   We have been invited to join another study and there is other interest-full Exomic sequencing of autism suspect genes in Lucas.

Lucas has been to Boston Children’s Hospital-Harvard, Stanford University, Mt. Sinai Hospital in New York, and the Dan Marino Center in Miami. We have visited the Kennedy Krieger Center in Baltimore. Every time I see one of those “my kid made the honor roll at…” bumper stickers, I want to put a sticker on the back of my car listing all the places my kid has been to, followed by “so there!”

He’s my boy and I’m proud of him. Daddy knows; I tell him so when he gets real frustrated because he can’t speak. As hard as it is on Marie and me, it is incredibly difficult for him. We fear that this will not get any easier for him. What we know is that without effective research, it likely won’t.

Lucas can swim in our pool here in Orlando. He also loves his trampoline.  The “It’s a small world after all” ride at Disney World is now second on Lucas’ list of cool things to do. First is going to the beach -especially during a “Surfers for Autism” event. These are closely followed by long airplane flights and jumping on hotel beds. The last time we went for a weekend at the beach, he threw a fit when we left-he’d just as soon hang out there indefinitely. I know the feeling.

But it is another feeling that stays with me most days. It is the feeling that when the day comes when I leave this world, I will have not done enough to make the difference needed for Lucas.   This has got to be every parent’s worst nightmare — failing to be a good enough advocate. At 52, I already believe that I will never retire. I could spend my time fighting for insurance reform so that Marie and I wouldn’t have to come up with $25,000 to $35,000 each year for Lucas’ therapies and someday I could retire. Or I can spend more time doing what I can to advocate for the bigger agenda: finding effective therapeutics for children with autism.

So Marie and I pour over autism research. As part of the ongoing research concerning Shank 3 mutations, I am a proud member of the Phelan McDermid Syndrome (PMS) Research Support committee along with a group of very smart parents fighting with me to find help for our kids. Lucas does not have the deletion in chromosome 22 that causes PMS, but rather mutations in the Shank3 gene which researchers believe may cause autism.

I only wish that more parents would push for research into the dozens, if not hundreds, of autism suspect genes and the pathways that variants in these genes disrupt. I also have hopes. Hopes that more sequencing will be available and affordable in the near future. That Pluripotent stem cell, brain imaging and genetics research will answer many of the questions needed to move into effective drugs. And that research concerning speech, occupational and ABA and other psychological therapies yields improved outcomes for our children.

After watching a WWII movie last Memorial Day, I began pondering the notion of “the greatest generation.”  I also recently read The Immortal Life of Henrietta Lacks about He La cells and the Herculean effort our country undertook to beat polio. I believe it is this generation’s challenge to beat the developmental disability that is autism. We are on the cusp of major findings into the causes and potential treatments for autism. Trials are underway using experimental drugs to combat Fragile X and Rett syndromes. Research is implicating mutations in many of the same genes affected in other disorders with disrupted chromosomes, disorders in which classic autism exists- such as PMS. Common pathways are emerging in the literature. For a segment of the population, we now know what causes autism. The first studies concerning children and multiple autism suspect gene mutations have been published.

It matters. What we know, where we go, how we get there. That is the sentiment on the faces of parents we meet involved in research and support for their children on the spectrum. Parents who would move heaven and earth to help their kids.  A hope that comes with research.

Promising New Results from Fragile X Drug Trial

At the International Fragile X conference held in Michigan last week, researchers working in partnership with Seaside Therapeutics presented promising results from a Phase II clinical trial with compound STX209. The research was presented by Elizabeth Berry-Kravis, MD, PhD, (Rush University Medical Center in Chicago, Illinois) and Randi Hagerman, MD, (M.I.N.D. Institute).

The study followed 63 patients with Fragile X from three groups spanning 6 to 40 years of age. The aim of the study was to investigate the safety and efficacy of STX209 across a broad range of individuals with Fragile X. The research team specifically looked at behavioral and cognitive measures that might indicate benefit from the drug. Indeed, they found statistically significant improvements in sociability in a pediatric group who had scored low on scales of sociability prior to the treatment. This result is particularly important because impairments in social function are a core feature of Fragile X, and also a core feature of autism spectrum disorders (ASD).

In a press release from Seaside Therapeutics, Dr. Hagerman offered a perspective on the results her team has observed.  “A majority of the patients enrolled in the STX209 study are participating in the ongoing open-label extension study and are continuing to benefit from treatment with STX209,” said Dr. Hagerman. “Physicians and parents are reporting increased sociability and communication and decreased outbursts and tantrums. In several cases, patients have been successfully withdrawn from other medications, including mood stabilizers, anti-depressants and, most importantly, anti-psychotics—a significant benefit for patients given the severe side effects associated with this particular class of drug. It is my hope that, with further study, STX209 may be able to play a much needed role in improving the symptoms of fragile X syndrome and help patients and their families achieve an improved quality of life.”

These results are exciting for individuals and the families of those living with Fragile X.  However, perhaps the greater excitement lies in what may come next. Fragile X is the most frequently observed genetic syndrome in individuals with ASD. Synaptic over-excitability has been observed in animal models of autism and is believed to be a common neurobiological underpinning. Seaside Therapeutics is currently exploring the potential for benefit in individuals with ASD through a clinical trial of STX209 in adults, adolescents and children with ASD. We anxiously wait for further data on the use of this compound.

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Opening the door to new medicines for ASD

May 3, 2010 2 comments

This post is by Leanne Chukoskie, Ph.D. Dr. Chukoskie is the Asst. Director Science Communication and Special Projects at Autism Speaks and Asst. Project Scientist, Institute for Neural Computation, UCSD.

On Friday, the New York Times published a story about a small clinical trial for a drug that ameliorated some of the symptoms of Fragile X Syndrome in some of the participants in the trial. Single-gene disorders, such as Fragile X Syndrome have been instructive in helping us understand the biology of the broader autism spectrum disorders (30% of people with Fragile X have an ASD). The effort described in the New York Times is not singular, but instead an area of active pursuit by many. Here is some history behind the Fragile X drug story and a summary of clinical trials for single-gene causes of ASD.

As noted in the article, the excitement began in 1991 when Steve Warren, Ph.D. (Professor at Emory University and member of Autism Speaks’ Scientific Advisory Committee) and his colleagues identified the gene, FMR1 (fragile X mental retardation 1), that causes Fragile X syndrome.  At that point, Warren and others began probing the FMR1 gene pathway to learn its properties and seek a way of correcting the genetic error. The promise of basic research findings was coming to light in Fragile X as early as 2005, with a small workshop organized by Autism Speaks’ staff titled “Promising new leads for autism research: a potential cure for Fragile X” at the International Meeting for Autism Research (IMFAR).  At this meeting, Mark Bear, Ph.D. (MIT), Tom Jongens, Ph.D (UPenn) and Bob Wong Ph.D. (SUNY Downstate) presented preliminary findings related to a theory that Fragile X may be caused by over-excitation of synapse (the connections between nerve cells).  Proper functioning of the connections between nerve cells requires a balance between excitatory and inhibitory neurotransmitters.  It appears that the FMR1 gene was causing this balance to be disrupted so that there was an abundance of the excitatory influences.   These researchers found that by damping the activity of a common excitatory neurotransmitter (glutamate) in the brain, many of the symptoms that characterized the animal models of Fragile X disorder disappeared.  This theory was referred to as the mGluR theory (for metabatropic Glutamate Receptor) of Fragile X. The drugs that produced improvements in animal models are called mGluR antagonists, because they act by blocking the actions of this glutamate receptor.

Previously, it was believed that one must act early in neurodevelopment to see any improvement in the symptoms of ASD. This basic research was incredibly exciting because several labs were learning that behaviors related to ASD could be ameliorated with drugs in adult animals.

That was several years ago and one might wonder what is taking so long to see useful medicines for these disorders. The process of approving drugs in any field is long and arduous (see blog on translational research and what Autism Speaks has funded). The translation of basic research into viable drugs in clinical trial is often referred to as crossing the “Valley of Death” as so few molecules tested in basic research make it through the process to become useful medicines. That said, several efforts have been made to create drugs for single-gene disorders related to ASD (see 2008 Top 10 story).

In 2008 researchers from the MIND Institute and Rush University reported results from the first trial of mGluR5 antagonists. Results from the small trial indicate that six out of the twelve adults with Fragile X showed improvements in cognitive deficits. This was the first promising news that mGluR drugs were safe and effective in humans and are related to those reported in the New York Times’ article from the Novartis study, which began around the same time.

Seaside Therapeutics is a small biotechnology company founded by Dr. Bear to see if the promising results observed in animals could be offered to families. In 2008, Seaside began enrollment for a clinical trial using a drug that would also dampen glutamate activity but through a different pathway for treating Fragile X.  This drug enhanced the activity of a class of receptors that typically suppress glutamate activity. Seaside Therapeutics has expanded this trial to include patients with autism, and has also launched a clinical trial of its own formulation of a specific mGluR5 antagonist for Fragile X.  If positive results are found, the next step will be to test these medications on individuals with ASD who do not have Fragile X syndrome.

We’ve been talking a lot about Fragile X, but there is another disorder, called Tuberous Sclerosis Complex (TSC), which offers another path to understanding ASD (approximately 25-50 percent of people with TSC also have an ASD). In 2008, UK researchers conducting a clinical trial with individuals with TSC reported positive outcomes on short-term memory tests of those receiving treatment. Rapamycin, the drug used in this trial and already FDA-approved for cancer, targets the brain signaling pathway that has been found to be disrupted in TSC and that has recently been implicated in autism as well (see 2007 Top 10 story related to TSC and 2008 Top 10 story about translational research).

Basic research in the biological pathways highlighted by genetic studies of Fragile X and TSC was the starting point for these exciting clinical trials. Autism Speaks continues to identify basic research opportunities that may lead to successful treatments as well as support the translation of research on molecules that have shown promise in the lab to medications that help families.

Cuddling up with the Fragile X model mouse: new clues to sensory sensitivities in ASD

February 13, 2010 Leave a comment

5|25: Celebrating Five Years of Autism Science Day 12: Clinical Trials for Core Symptoms of Neurodevelopmental Disorders

February 12, 2010 Leave a comment

5|25: Celebrating Five Years of Autism Science Day 3: Potential Reversal of Neurodevelopmental Disorders

February 3, 2010 Leave a comment

In honor of the anniversary of Autism Speaks’ founding on Feb 25, for the next 25 days we will be sharing stories about the many significant scientific advances that have occurred during our first five years together. Our third item, Potential Reversal of Neurodevelopmental Disorders, is from Autism Speaks’ Top 10 Autism Research Events of 2007.

2007 saw the publication of several studies that documented successful treatment of disease symptoms in mouse models of three different neurodevelopmental disorders related to autism. Most significantly, two of three (Fragile X and Rett) involved reversal of the phenotype AFTER the mice had already become sick, suggesting that developmental disorders such as autism may be treatable in adolescence or adulthood.

In February 2007, researchers in Scotland found that they could reverse the debilitating defects and certain death in mice carrying the Rett Syndrome gene, well after the mice had regressed into the most severe stages of disease. In July, researchers at Massachusetts Institute of Technology used a mouse model of Fragile X syndrome to show that it was possible to reverse Fragile X and autistic symptoms after birth. Although the specific treatment approaches may not be directly applicable to an eventual autism treatment, the successful and entirely unexpected “rescue” of adult animals taught the world that so-called “developmental” disorders, those that begin in infancy, apparently still have a potential to be reversed later in life.

Given the behavioral overlap of these disorders with autism, even if the underlying disease-causing biological mechanisms are different, these results provided hope to scientists and families alike that we can (and will!) do the same for autism.

Update since this story was first run:  These experiments changed the mindset of scientists worldwide, serving as a proof-of-principle for the many researchers now searching for pharmacological methods to treat these and other animal models of neurodevelopmental disorders.  In a 2009 publication from the Proceedings of the National Academy of Science, researchers from MIT reported that a pharmacological treatment of the Rett syndrome mouse extended the lifespan of the animals and partially rescued a variety of symptoms, including irregular heart and breathing patterns.  Studies such as these are paving the way for future human clinical trials.

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