Are Mental Illness and Developmental Disability One in the Same?

Interesting.

We’re used to considering certain conditions as disabilities (autism, Down syndrome, cerebral palsy) because people are born with them, they don’t get better or worse, and they stick around for a lifetime. They are an intrinsic aspect of identity, like race or gender.

Whereas we think of other conditions as diseases (bipolar disorder, schizophrenia, psychosis) because people aren’t born with them, they do get better and worse, they can be cured, and they actually obscure a person’s identity.

But now, a paper published in the medical journal The Lancet Neurology suggests that a broad spectrum of developmental and psychiatric disorders, ranging from autism and intellectual disability to schizophrenia, should be conceptualized as different manifestations of a common underlying denominator, “developmental brain dysfunction,” rather than completely independent conditions with distinct causes.

In “Developmental Brain Dysfunction: Revival and Expansion of Old Concepts Based on New Genetic Evidence,” the authors make two key points:

  1. Developmental disorders (such as autism and intellectual disability) and psychiatric disorders (such as schizophrenia and bipolar disorder), while considered clinically distinct, actually share many of the same underlying genetic causes. This is an example of “variable expressivity:” the same genetic variant results in different clinical signs and symptoms in different individuals.
  2. When quantitative measures of neuropsychological and neurobehavioral traits are studied instead of categorical diagnoses (which are either present or absent) and individuals are compared to their unaffected family members, it is possible to more accurately demonstrate the impact of genetic variants.

According to Andres Moreno De Luca, M.D., research scientist at the Autism and Developmental Medicine Institute at Geisinger Health System and article co-author, “Recent genetic studies conducted in thousands of individuals have shown that identical genetic mutations are shared among neurodevelopmental disorders that are thought to be clinically distinct. What we have seen over the past few years is that genetic mutations that were initially found in individuals with one disorder, such as intellectual disability or autism, are then identified in people with an apparently different condition like schizophrenia, epilepsy, or bipolar disorder.”

“It turns out that the genes don’t respect our diagnostic classification boundaries, but that really isn’t surprising given the overlapping symptoms and frequent co-existence of neurodevelopmental disorders,” said Scott M. Myers, M.D., autism specialist at Geisinger Health System and article co-author.

“We believe this study supports use of the term ‘developmental brain dysfunction’ or DBD, which would encompass the broad spectrum of neurodevelopmental and neuropsychiatric disorders,” said David H. Ledbetter, Ph.D., executive vice president and chief scientific officer at Geisinger Health System, and article co-author. “Additionally, it is clear that diagnostic tools such as whole genome analysis for both children and their families are essential when diagnosing and treating these disorders in order to ensure the most personalized treatment.”

An example used in the study was analysis of intelligence quotient (IQ) scores. The average IQ score in the general population is 100. Historically, the medical community has defined intellectual disability as an IQ of less than 70 (with concurrent deficits in adaptive functioning). But according to Dr. Ledbetter, there is little difference in the function of a child with an IQ of 69 versus 71, yet one may be diagnosed with a disability and the other may not.

“We know a variety of factors contribute to IQ score, including genetics, as a child’s IQ is highly correlated with that of his or her parents and siblings. Therefore, an important factor to take into consideration when interpreting IQ is family background,” said Dr. Ledbetter. “Imagine if we have a child with a genetic abnormality, but the child’s IQ is 85. Technically, we would not diagnose this child with a disability. However, if the family of this child has IQs around 130, we could consider that this child’s genetic anomaly has ‘cost’ him or her 45 IQ points — a very substantial difference.”

According to Dr. Myers, “One implication of this concept is that studies designed to investigate the causes and mechanisms of developmental brain dysfunction should focus on measurement of quantifiable neuropsychological and neurobehavioral traits across groups of individuals with different clinical diagnoses. Another is that whenever possible, individuals with a particular genetic variant or other risk factor should be compared to their unaffected family members, not just to population norms.”

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A Conversation with a Parent on Autism Awareness Day

By Lisa Domican

In my world, every day is Autism Awareness day. I don’t think a day has gone by when I didn’t think, type or say the word. But you can help to give me and my two kids a break from their autism for a day.

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Of course you can’t take away their autism – it is who they are and we all accept it. However, you can help reduce the challenges that make having living with autism in a world designed for “normal” people so stressful. And, it won’t cost you a cent. I just want you to consider ‘the 3 As’: Awareness, Acceptance and making Allowances.

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New York State Assembly Passes Budget, But Not Without Criticism of Cruel Cuts

The Assembly was chugging along with its debate of nine budget bills until it took up the Aid to Localities bill, which contains a $90 million cut in state funding for services to the developmentally disabled.

Lawmakers from both parties railed against the cuts, which members of both the Assembly and Senate attempted to plug in their one-house budget resolutions. Cuomo inserted $120 million in cuts to disabled care programs in budget amendments in response to federal allegations that New York was over-billing it through the Medicaid program. The cut was pared to $90 million, but lawmakers questioned why the state would spend money for other items — including $350 tax rebate checks and $425 million for film and television production tax credits — while cutting this funding.

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The Dawn of a New Era: Get the Brochure!

Yesterday, we posted a message from our CEO, Stephen E. Freeman, on our annual International Conference, held each year at the Hilton New York. This conference is a meeting of the minds of family members, professionals and people with disabilities every year in the heart of Manhattan. It’s inspiring, it’s informative, it’s cutting edge.

Now is the time to register and secure group rates at the Hilton. Check out this year’s brochure — as impressive as ever — and plan your trip. Register here.

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The Dawn of a New Era

A Message from Stephen E. Freeman, CEO

At last year’s meeting we began a dialogue about the 2013 International Conference and the result is an event that is being shaped and curated by us all, one I believe will be important to the future of a field at a moment of transition. Despite our shared concerns about expanding needs and diminishing funding, your suggestions and submissions strongly suggest that we all share the sense that this is a time to take action and to shape the future of our field.

We live in an age of miracles. The world is connected and intelligence is distributed as never before in history. It seems that every week there are new and astonishing insights about the brain, not to mention the complex interactions between genes and environment, brain and body.

We have much to work with.

The conference participants represent communities of advocates, providers and specialists with many different skills and perspectives, united by a shared conviction: that the time has come to move our field forward and find new and better ways of enabling people with challenges to live the life they desire and deserve.

In the course of our work over many decades we have identified, categorized and understood such individuals in terms of their deficits – distinguishing people with autism from those with cerebral palsy, diagnosing and describing the ‘developmentally disabled’ and the ‘physically impaired’ and so on.

It is now time to define new models of care that are founded on strengths. As we focus on potentials we can take inspiration from health care, a misnomer for a system based on the disease management model, and which is now evolving to embrace wellness and prevention.

As we begin to understand aging and end of life care in more human terms, it becomes clear that our field has much to offer others, from a generation of baby boomers now entering their sixties and seventies and those emerging from combat with trauma to those affected by poverty.

WE SHARE THE MISSION. Our cause is urgently important. By helping to change expectations we will change outcomes. By moving beyond the separation of the population into ‘normal’ and ‘disabled’ we get past assumptions of helplessness and dependence. Inadequate and ineffective models of care need to be re-thought.

TOGETHER, WE HAVE THE EXPERTISE. The breadth and depth of clinical experience and academic insight in this community is extraordinary. Many participants, in addition, represent institutions and communities from all over the world, each with their own particular competencies and offerings.

WE ALL HAVE THE PASSION. If there is one attribute we all share it is the commitment to act. As demands for services grow in the midst of a global economic slowdown, this is no time to hope for the best. Like so many other organizations, YAI was founded by parents unwilling to see their family members diminished by a diagnosis.

I welcome you all to a conference that honors their spirit and a movement I believe will be unstoppable.

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Science Tuesday: Study Identifies Genetic Connections in 15q Duplication Syndrome

Wooden Sculpture of Science Genetics

Photo via Flickr

A new study published in the March issue of Autism Research from the University of Tennessee Health Science Center and Le Bonheur researchers is making the genetic connections between autism and Chromosome 15q Duplication Syndrome (Dup15q).

The Memphis researchers determined that the maternally derived or inherited duplication of the region inclusive of the UBE3A gene (also known as the Angelman/Prader-Willi syndrome locus) are sufficient to produce a phenotype on the autism spectrum in all ten maternal duplication subjects. The number of subjects was too small to determine if parental duplications do not cause autism. The team assembled the largest single cohort of interstitial 15q duplication subjects for phenotype/genotype analysis of the autism component of the syndrome.

Chromosome 15q Duplication Syndrome (Dup15q) results from duplications of chromosome 15q11-q13. Duplications that are maternal in origin often result in developmental problems. The larger 15q duplication syndrome, which includes individuals with idic15, manifests itself in a wide range of developmental disabilities including autism spectrum disorders; motor, cognitive and speech/language delays; and seizure disorders among others. While there is no specific treatment plan, therapies are available to address or manage symptoms.

Previous research suggests that as many as 1,000 genes may contribute to autism phenotypes, but as much as 1-3 percent of all autism spectrum disorder cases may be a result of 15q11-q13 duplication alone.

The researchers also found through EEG evaluations a pattern that looks like the type of signal you see when individuals take GABA promoting drugs (benzodiazepines). The lead researcher on this study, Lawrence T. Reiter, PhD, says this signal gives clinicians a clue about what types of anti-seizure medication may be most useful in children with 15q duplications.

Reiter says genetic testing can help families connect to resources, like the Dup15q Alliance. Reiter is an associate professor in Department of Neurology with an adjunct appointment in Pediatrics at UTHSC.

“If a pediatrician suspects autism due to hypotonia and developmental delay, I highly recommend they order an arrayCGH test. Duplication 15q is the second most common duplication in autism. The test will help families in future treatments specific to this sub-type of autism,” he said.

Reiter collaborated with UTHSC and Le Bonheur Neurologist Kathryn McVicar, MD, and Geneticist Eniko K. Pivnick, MD. The study was funded by the Herbert and Mary Shainberg Neuroscience Fund. Reiter serves on the scientific advisory board for the Duplication 15q Alliance and Idic15 Canada.

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Supercomputer in San Diego is Hot on the Trail of Autism

Gordon the supercomputer is named after Flash Gordon the superhero.

When it officially came online at the San Diego Supercomputer Center (SDSC) in early January 2012, Gordon was instantly impressive. In one demonstration, it sustained more than 35 million input/output operations per second–then, a world record.

Input/output operations are an important measure for data intensive computing, indicating the ability of a storage system to quickly communicate between an information processing system, such as a computer, and the outside world. Input/output operations specify how fast a system can retrieve randomly organized data common in large datasets and process it through data mining applications.

Last month, a team of researchers from SDSC, the United States and the Institute Pasteur in France reported in the journal Genes, Brain and Behavior that they used Gordon to devise a novel way to describe a time-dependent gene-expression process in the brain that can be used to guide the development of treatments for conditions such as autism spectrum disorders and schizophrenia.

The researchers identified the hierarchical tree of coherent gene groups and transcription-factor networks that determine the patterns of genes expressed during brain development. They found that some “master transcription factors” at the top level of the hierarchy regulated the expression of a significant number of gene groups.

The scientists’ findings can be used for selection of transcription factors that could be targeted in the treatment of specific disorders.

“We live in the unique time when huge amounts of data related to genes, DNA, RNA, proteins, and other biological objects have been extracted and stored,” said lead author Igor Tsigelny, a research scientist with SDSC as well as with UC San Diego’s Moores Cancer Center and its Department of Neurosciences.

“I can compare this time to a situation when the iron ore would be extracted from the soil and stored as piles on the ground. All we need is to transform the data to knowledge, as ore to steel. Only the supercomputers and people who know what to do with them will make such a transformation possible,” he said.

Gordon’s new and unique architecture employs massive amounts of the type of flash memory common in cell phones and laptops–hence its name. The system is used by scientists whose research requires the mining, searching and/or creating of large databases for immediate or later use, including mapping genomes for applications in personalized medicine and examining computer automation of stock trading by investment firms on Wall Street.

Commissioned by the National Science Foundation (NSF) in 2009 for $20 million, Gordon is part of NSF’s Extreme Science and Engineering Discovery Environment, or XSEDE program, a nationwide partnership comprising 16 high-performance computers and high-end visualization and data analysis resources.

“Gordon is a unique machine in NSF’s Advanced Cyberinfrastructure/XSEDE portfolio,” said Barry Schneider, NSF program director for advanced cyberinfrastructure. “It was designed to handle scientific problems involving the manipulation of very large data. It is differentiated from most other resources we support in having a large solid-state memory, 4 GB per core, and the capability of simulating a very large shared memory system with software.”

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Friday Flick: One Family, Three Kids, Two with Autism

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A new study finds that two genes individually associated with rare autism-related disorders are also jointly linked to more general forms of autism. The finding suggests a new genetic pathway to investigate in general autism research.

The genes encode the proteins NHE6 and NHE9, which are responsible for biochemical exchanges in the endosomes of cells. Mutations in the NHE6 gene are a direct cause of Christianson Syndrome, while mutations in the NHE9 gene lead to a severe form of autism with epilepsy. In the new study, a statistical analysis published in the journal Molecular Psychiatry, Brown University researchers and their colleagues found a specific pattern of misregulation of those two genes — NHE9 is up-regulated and NHE6 is down-regulated — in the brains of children with autism compared to the brains of non-autistic children.

“These genes play a role, not just in the rare forms of autism but also in the generalized pathology of autism,” said Dr. Eric Morrow, professor of biology and professor of psychiatry and human behavior at Brown University, the paper’s senior author. “In autism I think people get overwhelmed because there are hundreds of different genes. One of the important things is to find points of convergence where there are events that might be common across different forms.”

The new study suggests that misregulation of NHE6 and NHE9 is one such event.

The research is based on a statistical analysis of messenger RNA samples from a bank of brain tissue donated posthumously by some children who had autism and some who did not. Messenger RNA is a key molecular player in the process of gene expression, making it an indicator of how gene expression was regulated in the cerebral cortex of each of the children.

Guided by Morrow, who studies autism genomics and sees autism patients at the E.P. Bradley Hospital in East Providence, lead author Matthew Schewede spent the summer of 2012 poring over the raw data, which was made available from a 2011 study led by co-author Daniel Geschwind and Irinia Voineagu of the University of California-Los Angeles.

Schwede, who studied statistics as an undergraduate at Harvard, is now a second-year student in the Warren Alpert Medical School. His classes are a block away from Morrow’s lab, making the collaboration easy.

“We kind of stumbled on this,” Schwede said. “At first we were just identifying what was up- and down-regulated in autism cerebral cortex in this data set.”

But Schwede’s findings about the NHE genes caught Morrow’s attention in particular, because Morrow has been studying the NHE6 and NHE9 genes and the rare autism forms they cause.

“When we realized that some genes of interest for our lab were altered in the cerebral cortex, we focused the analysis on these genes in particular and how they were related to other processes,” Schwede said.

Schwede made a second key finding: a strong and significant correlation between the misregulation of the NHE genes and the down-regulation of synapse genes, which is known to occur in autism.

Schwede’s purely statistical analysis does not explain the physiology of how up-regulation of NHE9 and down-regulation NHE6 would affect synapse formation or general autism, but Morrow’s biology group has a clear next step: to observe the neural and behavioral effects in the lab of misregulation of those genes in various experimental systems.

“That’s a hypothesis that we can take to the mouse,” Morrow said. “When we knock out these genes, how do the synapses change?”

The statistical results point out the value of studying rare forms of autism, not only for the sake the patients who have those conditions, Morrow said, but also because doing so can inform research about other forms of autism.

“We argue that it’s relevant but sometimes, in fairness, we wonder about that,” Morrow said. “A study like this really conveys strongly that that’s a fair argument.”

In addition Schwede, Morrow, and Geschwind, other authors are Krassimira Garbett and Karoly Mirnics of Vanderbilt University.

This grant was funded by the National Institute of Mental Health, the Simons Foundation for Autism Research Initiative, and the Nancy Lurie Marks Family Foundation. Schwede was funded by a summer research assistantship from the Alpert Medical School.

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Old Grandpas = Autism?

Grandfather - Ronald George Beeston

Photo by Andrew Beeston

Research into autism’s causes tends to focus strongly on the mom: is she too fat, is she a smoker, did she take her prenatal vitamins, did she have a fever, is she on antidepressants, does she, horrors, live too close to a freeway?!?

It’s all very exhausting if you are a lady. Whether or not you have a child with autism. If you are a woman who gives birth, you just can’t win.

Which is why it’s refreshing when some scientists inquire into the XY portion of the equation. Thanks, scientists!

Apparently, men who have children at older ages are more likely to have grandchildren with autism compared to younger grandfathers, according to research from King’s College London’s Institute of Psychiatry, Karolinska Institutet in Sweden and the Queensland Brain Institute in Australia. This is the first time that research has shown that risk factors for autism may accumulate over generations.

The study led by  is published today in JAMA Psychiatry.

By using Swedish national registers, researchers identified 5,936 individuals with autism and 30,923 neurotypical controls born in Sweden since 1932. They had complete data on each person’s maternal and paternal grandfathers’ age of reproduction and details of any psychiatric diagnosis.

The study found that the risk of autism in the grandchild increased the older the age of the grandfather at the time his son or daughter was born. Men who had a daughter when they were 50 or older were 1.79 times more likely to have a grandchild with autism. Men who had a son when they were 50 or older were 1.67 times more likely to have a grandchild with autism, compared to men who had children when they were 20-24.

Dr Avi Reichenberg, from King’s Institute of Psychiatry and co-author of the paper says: “We tend to think in terms of the here and now when we talk about the effect of the environment on our genome. For the first time in psychiatry, we show that your father’s and grandfather’s lifestyle choices can affect you. This doesn’t mean that you shouldn’t have children if your father was old when he had you, because whilst the risk is increased, it is still small. However, the findings are important in understanding the complex way in which autism develops.”

Emma Frans, lead author of the study from Karolinska Institutet says: “We know from previous studies that older paternal age is a risk factor for autism. This study goes beyond that and suggests that older grandpaternal age is also a risk factor for autism, suggesting that risk factors for autism can build up through generations.”

In the UK, approximately 1 in 100 adults have an autism spectrum disorder (ASD), with the condition affecting more men than women. The condition affects people in very different ways: some are able to live relatively everyday lives, while others will require a lifetime of specialist support. People with ASD have difficulty communicating with and relating to other people, and making sense of the world around them.

Autism is known to be caused by a combination of genetic and environmental factors. Previous studies have shown that older paternal age is a risk factor for autism in children: fathers aged 50 or older have a more than doubled risk to have a child diagnosed with autism compared to younger fathers.

The mechanism behind this link is unknown, but may be explained by mutations occurring in the male sperm cells. Sperm cells divide over time, and on each division the genome is faced by the possibility of new mutations being introduced.

However, most genetic mutations do not result in the child developing autism. The new findings suggest that these ‘silent’ mutations are passed on to the otherwise healthy child, but may influence the risk of future generations developing autism. The authors suggest that genetic risk could accumulate over generations, or could interact with other risk factors, until it reaches a threshold resulting in the disorder manifesting itself.

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