Genes may be linked to autism and higher intelligence

What causes autism? A study claims that genes that may indicate an increased autism risk may also indicate a person has higher intelligence.JR

Genes believed to increase the risk of autism may also be linked with higher intelligence, a new study suggests.

Researchers analyzed the DNA of nearly 10,000 people in Scotland and also tested their thinking abilities. On average, those who had genes associated with autism scored slightly higher on the thinking (cognitive) tests.

Having autism-linked genes doesn't mean that people will develop the disorder, the researchers noted.

Similar evidence of an association between autism-linked genes and intelligence was found in previous testing of 921 teens in Australia, according to the study published March 10 in the journal Molecular Psychiatry.

"Our findings show that genetic variation which increases risk for autism is associated with better cognitive ability in non-autistic individuals," said study leader Toni-Kim Clarke, of the University of Edinburgh in Scotland.

"As we begin to understand how genetic variants associated with autism impact brain function, we may begin to further understand the nature of autistic intelligence," Clarke said in a university news release.

Another researcher went further. "This study suggests genes for autism may actually confer, on average, a small intellectual advantage in those who carry them, provided they are not affected by autism," Nick Martin, head of the Genetic Epidemiology Laboratory at the Queensland Institute for Medical Research in Australia, said in the news release.

While 70 percent of people with autism have intellectual disabilities, some people with the disorder have higher-than-average nonverbal intelligence, the study authors noted.

The study only revealed an association, and not a cause-and-effect link, between autism-related genes and intelligence.

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Children with autism have deifcits in their mitochondrial DNA

Research showed that children with autism have deficits in their mitochondrial DNA. These deficits can make it harder for the body to fight off infection.

Children with autism experience deficits in a type of immune cell that protects the body from infection. Called granulocytes, the cells exhibit one-third the capacity to fight infection and protect the body from invasion compared with the same cells in children who are developing normally.

The cells, which circulate in the bloodstream, are less able to deliver crucial infection-fighting oxidative responses to combat invading pathogens because of dysfunction in their tiny energy-generating organelles, the mitochondria.

The study is published online in the journalPediatrics.

"Granulocytes fight cellular invaders like bacteria and viruses by producing highly reactive oxidants, toxic chemicals that kill microorganisms. Our findings show that in children with severe autism the level of that response was both lower and slower," said Eleonora Napoli, lead study author and project scientist in the Department of Molecular Biosciences in the UC Davis School of Veterinary Medicine. "The granulocytes generated less highly reactive oxidants and took longer to produce them."

The researchers also found that the mitochondria in the granulocytes of children with autism consumed far less oxygen than those of the typically developing children -- another sign of decreased mitochondrial function.

Mitochondria are the main intracellular source of oxygen free radicals, which are very reactive and can harm cellular structures and DNA. Cells can repair typical levels of oxidative damage. However, in the children with autism the cells produced more free radicals and were less able to repair the damage, and as a result experienced more oxidative stress. The free radical levels in the blood cells of children with autism were 1 ½ times greater than those without the disorder.

The study was conducted using blood samples of children enrolled in the Childhood Risk of Autism and the Environment (CHARGE) Study and included 10 children with severe autism age 2 to 5 and 10 age-, race- and sex-matched children who were developing typically.

In an earlier study the research team found decreased mitochondrial fortitude in another type of immune cell, the lymphocytes. Together, the findings suggest that deficiencies in the cells' ability to fuel brain neurons might lead to some of the cognitive impairments associated with autism. Higher levels of free radicals also might contribute to autism severity.

"The response found among granulocytes mirrors earlier results obtained with lymphocytes from children with severe autism, underscoring the cross-talk between energy metabolism and response to oxidative damage," said Cecilia Giulivi, professor in the Department of Molecular Biosciences in the UC Davis School of Veterinary Medicine and the study's senior author.

"It also suggests that the immune response seems to be modulated by a nuclear factor named NRF2," that controls antioxidant response to environmental factors and may hold clues to the gene-environment interaction in autism, Giulivi said.

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DNA may explain why more boys are affected by autism than girls

A study that looks at genetics and DNA to determine why more boys are affected by autism than girls are.

A new DNA study begins to explain why girls are less likely than boys to have an autism spectrum disorder.

It turns out that girls tend not to develop autism when only mild genetic abnormalities exist, the researchers said. But when they are diagnosed with the disorder, they are more likely to have more extreme genetic mutations than boys who show the same symptoms.

"Girls tolerate neurodevelopmental mutations more than boys do. This is really what the study shows," said study author Sebastien Jacquemont, an assistant professor of genetic medicine at the University Hospital of Lausanne, in Switzerland.

"To push a girl over the threshold for autism or any of these neurodevelopmental disorders, it takes more of these mutations," Jacquemont added. "It's about resilience to genetic insult."

The dilemma is that the researchers don't really know why this is so. "It's more of an observation at a molecular level," Jacquemont noted.

In the study, the Swiss researchers collaborated with scientists from the University of Washington School of Medicine to analyze about 16,000 DNA samples and sequencing data sets from people with neurodevelopmental disorders, including autism spectrum disorders.

The investigators also analyzed genetic data from almost 800 families affected by autism for the study, which was released online Feb. 27 in the American Journal of Human Genetics.

The researchers analyzed copy-number variants (CNVs), which are individual variations in the number of copies of a particular gene. They also looked at single-nucleotide variants (SNVs), which are DNA sequence variations affecting a single nucleotide. Nucleotides are the basic building blocks of DNA.

The study found that females diagnosed with any neurodevelopmental disorder, including attention-deficit/hyperactivity disorder and intellectual disability, had more harmful CNVs than males who were diagnosed with the same disorder. Females with autism also had more harmful SNVs than males with the condition.

"There's a well-known disparity when it comes to developmental disorders between boys and girls, and it's been puzzling," Jacquemont said. "And there have been quite a bit of papers trying to investigate this bias that we've seen in the clinic."

The study authors pointed out that autism affects four boys for every one girl. The ratio increases to seven-to-one when looking at high-functioning autism cases.

It's an interesting study, said Dr. Andrew Adesman, chief of developmental and behavioral pediatrics at the Steven & Alexandra Cohen Children's Medical Center of New York.

"It's not an easy study to read, but certainly the take-away suggests it tries to lend further support to the assumption that the ratio of males to females [who have autism] is affected by genetic vulnerabilities -- that it has a genetic underpinning," Adesman said.

What do the findings mean for parents and patients?

Adesman said there are no immediate benefits, but the knowledge can help direct future research.

"This isn't going to lead to a breakthrough in treatment, but from a clinical standpoint it may help researchers and academics understand why it is that developmental disorders seem to be more common in boys than girls," he noted.

The new research also reinforces that genetic differences -- or vulnerabilities -- aren't limited to sex chromosomes, Adesman added.

"The presumption has been, 'Well gee, boys have a Y chromosome and girls don't, so are there problems with the Y chromosome that explain it?'" Adesman noted.

"The bottom line is that there are a lot of different genetic abnormalities and atypicalities that result in developmental disorders in children and adults," Adesman explained. "Women seem to be a little more resilient in terms of being able to have minor abnormalities without having a developmental problem."

Jacquemont agreed that the team's discovery opens the door for new avenues of study.

The findings provide ideas "for deciphering the issue further," said Jacquemont. "One study that might be helpful would be trying to understand what are the symptoms that appear a lot faster in males than females. There are a lot of alleys that could be explored."

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Genetic test can help identify brain tumors

A genetic test can help determine types of brain tumors which may help doctors pick the most effective form of treatment.

Scientists have developed a mathematical method for classifying forms of glioblastoma, an aggressive and deadly type of brain cancer, through variations in the way these tumor cells 'read' genes. Their system was capable of predicting the subclasses of glioblastoma tumors with 92 percent accuracy. With further testing, this system could enable physicians to accurately predict which forms of therapy would benefit their patients the most.

Their research was performed in collaboration with Donald M. O'Rourke, M.D., a neurosurgeon at the University of Pennsylvania Brain Tumor Center, who provided the glioblastoma samples necessary to validate the Wistar computer model. Their findings were published online in the journal Nucleic Acids Research.

"It has become increasingly obvious that understanding the molecular makeup of each patient tumor is the key to personalizing cancer treatments for individual patients," said Ramana Davuluri, Ph.D., Wistar's Tobin Kestenbaum Family Professor and associate director of Wistar's Center for Systems and Computational Biology. "We have developed a computational model that will allow us to predict a patient's exact variety of glioblastoma based on the transcript variants a given tumor produces."

"A gene can produce multiple variants, in the form of transcript variants and protein-isoforms. We found that when you use the gene expression information at variant/isoform-level, the statistical analyses recaptured the four known molecular subgroups but with a significant survival difference among the refined subgroups." said Davuluri. "Using patient data, we found that certain subgroups when combined with patient age, for example, could predict better outcomes using a given course of therapy."

"As more targeted therapies come into use, this is exactly the sort of information clinicians will need to provide the best hope of survival for their patients," Davuluri said. "In time, we think this could form the basis of a clinical test that will help oncologists decide a patient's course of treatment."

Glioblastomamultiforme is the most lethal of the malignant adult brain tumors, and accounts for over 50 percent of all cases of brain cancer. Even with aggressive combination therapies, the prognosis remains bleak, with median patient survival of 15 months after diagnosis. The disease is also molecularly heterogeneous, that is, composed of subtypes that are not genetically alike or produce the same array of proteins. Genetic data from the Cancer Genome Atlas (TCGA) consortium has led to the identification of four subtypes of glioblastoma, but Davuluri and his researchers sought to find a way to quickly identify which patient was which subtype.

In previous studies, Davuluri and his Wistar colleagues have established how changes in the way a cell reads its own DNA can create multiple variations of a single protein. These variant proteins are called isoforms, and they are produced as cells alter how they transcribe a given gene into RNA. Slight changes in how the cellular machine reads a gene can result in protein isoforms with subtle differences in enzymatic activity or longevity.

For example, their earlier research determined how human brains produce different isoforms of specific proteins throughout their lives. Developing fetal brains produce different isoforms of certain genes than adult brains. They also found that changes that trigger the production of the wrong isoform at the wrong time could lead to cancer.

In the Nucleic Acids Research study, the researchers combined assays of these protein isoforms with a computer model they call PIGExClass, or the Platform-independent Isoform-level Gene-EXpression based Classification-system. To categorize glioblastomas with PIGExClass, Davuluri and his colleagues first began with Cancer Genome Atlas data to develop a set of 121 isoform variants whose combination of differences could denote a specific subtype of the brain cancer. PIGExClass is, essentially, a software that ranks gene isoform data into sets based on a set of pre-determined values. The researchers found that, by using this classification system, they could predict the subtype of glioblastoma in the database with 92 percent accuracy.

"When we knew what combination of isoforms could create a specific signature for each type of glioblastoma, we could then create a simple laboratory assay that would look for these differences in patient samples," Davuluri said. "In this case the test would measure variations in the RNA abundance associated with these 121 isoforms that make up the signature."

With this new assay in hand, the researchers validated their research using 206 independent samples from the University of Pennsylvania Brain Tumor Tissue Bank. According to Davuluri, when you accounted for differences in the makeup of the pools of patients between TCGA and Penn, the accuracy of the assay remained the same.

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Same mutations seen in epilepsy and autism

The same mutations are seen in children with epilepsy and autism indicating that the disorders may be linked.

Mutations in GABRB3, a brain receptor linked to autism, are prevalent in severe childhood epilepsy, according to a study published 12 September inNature¹.

The study also found that many of the spontaneous, or de novo, mutations found in children with epilepsy overlap with those linked to autism and fragile X syndrome.

About one-third of people with autism suffer from epilepsy. This overlap suggests that the two disorders may have a common origin — a theory borne out by examples of shared genetics.

Studies suggest that, biologically, autism is the result of an imbalance between excitatory and inhibitory brain signals, which may also underlie epilepsy.

In the new study, researchers sequenced the protein-coding DNA, or exomes, of 264 children who suffer from either infantile spasms or Lennox-Gastaut syndrome, and their parents. Both disorders are characterized by multiple seizures during sleep, which may lead to cognitive problems.

The researchers found multiple mutations in nine genes in the children with epilepsy that are not present in their parents. In particular, four children have a mutation in GABRB3, a receptor that transmits calming signals to neurons. None of 610 controls or their parents have a mutation in this gene.

A 2009 study found a rare variant of GABRB3 that affects neuronal signaling in 17 of 1,152 families with autism and 1 of 292 controls². 

Overall, the researchers found 277 mutations in the exomes of children with epilepsy that are not present in their parents. Of these, 41 are also seen in children with autism and 64 may be regulated by FMRP, the protein missing in fragile X syndrome.

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Genetics may be to blame for exercise intolerance

This article explains how exercise intolerance may have a genetic component, although does not seem to be a hereditary condition.

Some cases of exercise intolerance have been linked to mutations in a gene found in the mitochondria, the “powerhouses” of the cell, according to a study.

Exercise intolerance is a condition in which a person experiences extreme fatigue, muscle pain or cramps after minimal exercise. Mitochondria provide energy that muscles require to function, so a defect in these could severely limit the ability to exercise.

Mitochondrial DNA — which is separate from DNA found in the nucleus, or control center of the cell — is inherited directly from the mother, so if a child has a disorder linked to the mitochondria, the mother usually also has it.

However, the research team from the Columbia College of Physicians and Surgeons in New York, found that in the patients studied, there was no maternal link to the mutation, and no evidence of the mutation in tissues other than muscles. This suggests that mutation is not inherited but occurs in the embryo, the team suggests. Five patients with exercise intolerance and no family history of the disease enrolled in the study.

Analyses of the patients’ cells revealed that all had defects in respiratory chain enzymes, which are used by mitochondria to make substances that store energy for muscles. Sophisticated techniques narrowed the deficiencies down to mutations in the mitochondrial cytochrome b gene.

The investigators conclude that such mitochondrial gene mutations may be common, and recommend that physicians consider this as a possible diagnosis in patients with “the often elusive symptoms of aches, pain, and cramps.”

No treatments have been developed for this condition, but as a therapeutic course for the patients, researchers suggest “genetic counseling” to explain to the patients that they will not pass their disease onto their children. Also, patients can engage in “appropriate exercise programs,” which might have some benefit, they add.

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New technologies utilized for epilepsy treatment

This article claims that developing new technologies is the best way to treat epilepsy. It also goes over a few of the technologies currently utilized for epilepsy treatment.

Speaking in the lead up to Purple Day for Epilepsy Awareness (Tuesday 26 March), geneticist Professor Jozef Gecz says advances in DNA sequencing have been a huge leap forward in understanding epilepsy. 

This, combined with the use of stem cells in laboratory research, will lead to further advances in epilepsy treatment, he says. 

However, he cautions that the same technology has also helped to reveal that epilepsy is a far more complex condition than previously thought. 

"Scientists used to believe that epilepsy was just one condition, possibly with one main cause. But now we know it is a very complex series of neurological disorders – it is many epilepsies, instead of just one epilepsy, with multiple causes and various symptoms," says Professor Gecz, from the University of Adelaide's School of Paediatrics and Reproductive Health. 

Epilepsy is common, with up to 3% of the Australian population experiencing epilepsy at some stage in their lives. Genetic and environmental factors, and trauma, can all play a role in the development of epilepsy. Most (but not all) forms cause sufferers to experience seizures, which vary in severity. 

Research in Adelaide has played an important role in the understanding of epilepsy in recent years. 

"It's really thanks to the pioneering work of Dr John Mulley (Women's and Children's Hospital and University of Adelaide), who discovered the first gene for idiopathic epilepsy almost 20 years ago. Since then, almost 40 idiopathic epilepsy genes have been discovered, many of them by researchers here in Adelaide," Professor Gecz says. 

"There are more than 300 genes known today in which DNA mutations can give rise to some form of epilepsy, in addition to other problems like intellectual disability, autism or psychiatric problems. 

"Thanks to genetic sequencing technology, in most cases we are now able to solve the mystery about what kind of epilepsy a patient has, and we can do this very quickly, very accurately, and cost effectively. 

"Molecular diagnosis is making a huge impact on treatment – it's really taken off in the last few years, and it has the potential to be even more effectively used in the future. Clinicians can now be guided by genetic information when considering treatment of patients with specific epilepsies." 

Professor Gecz and colleagues are currently involved in a major national study of epilepsy, with his lab focusing on the "genetic architecture" of the condition.

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Brain Cell Malfunction in Schizophrenia Identified

Scientists at The Scripps Research Institute have discovered that DNA stays too tightly wound in certain brain cells of schizophrenic subjects. The findings suggest that drugs already in development for other diseases might eventually offer hope as a treatment for schizophrenia and related conditions in the elderly.

The research, now available online in the new Nature journal, Translational Psychiatry, shows the deficit is especially pronounced in younger people, meaning treatment might be most effective early on at minimizing or even reversing symptoms of schizophrenia, a potentially devastating mental disorder associated with hallucinations, delusions, and emotional difficulties, among other problems.

"We're excited by the findings," said Scripps Research Associate Professor Elizabeth Thomas, a neuroscientist who led the study, "and there's a tie to other drug development work, which could mean a faster track to clinical trials to exploit what we've found."

A Promising New Field

Over the past few years, researchers have increasingly recognized that cellular-level changes not tied to genetic defects play important roles in causing disease. There is a range of such so-called epigenetic effects that change the way DNA functions without changing a person's DNA code.

One critical area of epigenetic research is tied to histones. These are the structural proteins that DNA has to wrap around. "There's so much DNA in each cell of your body that it could never fit in your cells unless it was tightly and efficiently packed," said Thomas. Histone "tails" regularly undergo chemical modifications to either relax the DNA or repack it. When histones are acetylated, portions of DNA are exposed so that the genes can be used. The histone-DNA complexes, known as chromatin, are constantly relaxing and condensing to expose different genes, so there is no single right or wrong configuration. But the balance can shift in ways that can cause or exacerbate disease.

DNA is the guide that cellular machinery uses to construct the countless proteins essential to life. If portions of that guide remain closed when they shouldn't because histones are not acetylated properly, then genes can be effectively turned off when they shouldn't be with any number of detrimental effects. Numerous research groups have found that altered acetylation may be a key factor in other conditions, from neurodegenerative disorders such as Huntington's disease and Parkinson's disease to drug addiction.

A Good Idea

Thomas had been studying the roles of histone acetylation in Huntington's disease and began to wonder whether similar mechanisms of gene regulation might also be important in schizophrenia. In both diseases, past research in the Thomas lab had shown that certain genes in sufferers were much less active than in healthy people. "It occurred to me that we see the same gene alterations, so I thought, 'Hey, let's just try it,'" she said.

Working with lead author Bin Tang, a postdoctoral fellow in her lab, and Brian Dean, an Australian colleague at the University of Melbourne, Thomas obtained post-mortem brain samples from schizophrenic and healthy brains held at medical "Brain Banks" in the United States and Australia. The brains come from either patients who themselves agreed to donate some or all of their bodies for scientific research after death, or from patients whose families agreed to such donations.

A great deal of epigenetic research has focused on chemical alterations to DNA itself. Histone alterations have been much more difficult to study because such research requires that the histones and DNA remain chemically intact. Many researchers feared that these bonds were disrupted in the brain after death. However, Thomas's group was able to develop a technique for maintaining the histone-DNA interactions. "While many people thought this was lost, we were able to show that indeed these interactions are preserved in post-mortem brain, allowing us to carry out these studies," said Thomas.

Compared to healthy brains, the brain samples from subjects with schizophrenia showed lower levels of acetylation in certain histone portions that would block gene expression. Another critical finding was that in younger subjects with schizophrenia, the problem was much more pronounced.

Need for New Treatment Options

Just what causes the acetylation defects among schizophrenic subjects -- what keeps certain pages of the DNA guide closed -- isn't clear, but from a medical perspective it doesn't matter. If researchers can reliably show that acetylation is a cause of the problem, they can look for ways to open the closed guide pages and hopefully cure or improve the condition in patients.

Thomas sees great potential. Based on the more pronounced results in younger brains, she believes that treatment with histone deacetylase inhibitors might well prove helpful in reversing or preventing the progression of the condition, especially in younger patients. Current drugs for schizophrenia tend to treat only certain symptoms, such as hallucinations and delusions, and the drugs have major side effects including movement problems, weight gain, and diabetes. If deacetylase inhibitors effectively treat a root cause of the disease and prove sufficiently non-toxic, they might improve additional symptoms and provide a major expansion of treatment options.

Interestingly, some of the cognitive deficits that plague elderly people look quite similar biologically to schizophrenia, and the two conditions share at least some brain abnormalities. So deacetylase inhibitors might also work as a treatment for age-related problems, and might even prove an effective preventive measure for people at high risk of cognitive decline based on family history or other indicators.

Read more: http://www.sciencedaily.com/releases/2011/12/111228111731