Recent discoveries in epigenetics could soon make a clinical difference for children with attention-deficit/hyperactivity disorder, autism spectrum disorder, and other conditions, according to an expert.

The implications go beyond targeting treatment for an individual child in your practice based on a specific genetic mutation, Dr. Hakon Hakonarson, director of the center for applied genomics at the Children’s Hospital of Philadelphia, said at a pediatric update sponsored by Miami Children’s Hospital. Recent advances point to gene alterations that modify shared pathways, so the potential for wider application beyond ADHD and ASD — such as unexpected discoveries related to pediatric neuroblastoma — is a real possibility.

Dr. Hakonarson is a member of ICare4Autism’s Advisory Council and will be speaking about the gene networks underlying autism targeted for therapeutic intervention at the upcoming ICare4Autism International Autism Conference being held in Israel.

Hakon Hakonarson, M.D., Ph.D., is an associate professor of Pediatrics at The University of Pennsylvania School of Medicine.  He is a physician-scientist and director of The Children’s Hospital of Philadelphia’s Center for Applied Genomics (CAG), a high-throughput highly automated genotyping facility founded to identify the genetic causes of complex medical disorders in children, such as autism and cancer, with the objective of developing new therapies.

Dr. Hakonarson has an extensive track record in human genetics and has developed an international reputation amongst his peers. He has served previously in several senior posts in the biopharmaceutical industry, including as the director of Inflammatory and Pharmacogenomics Research and the vice president of Clinical Sciences and Development and CSO.

Dr. Hakonarson has also been the principal and co-principal investigator on several NIH-sponsored grants, and he has published numerous high-impact papers on genomic discoveries and their translations in some of the most prestigious scientific medical journals, including Nature, Nature Genetics and The New England Journal of Medicine.

Time Magazine listed Dr. Hakonarson’s autism gene discovery reported in Nature, 2009, among the top 10 medical breakthroughs of that year. With over ten years of experience in pioneering genomics research and genome-wide mapping and association studies, Dr. Hakonarson has intimate knowledge of the complexities of large-scale genomics projects and has put together the necessary infrastructure and workflow processes to unravel these complexities.

The daily encounters and friction between the staff of therapists and the families of children with special needs (and sometimes also with the extended family) are often obscured within the obligations of rather complicated professional and mental challenges.

The family of the special needs child – who face a tremendous financial burden on top of the emotional burden they already bear – loses its privacy; they find themselves exposed, against their will, to the team of therapists. Often there are sensitive situations which cannot be hidden, and sometimes the family encounters open or latent criticism. The therapists also find themselves privy to the difficult emotional situation of the family members; crises in the relationships between the child’s parents; and complicated ethical problems: all of which while they are supposed to be providing professional and appropriate treatment for the child with whom they are working.

Inbar Konforti will be speaking about bridging the gap between families and therapists in home-based ABA at the upcoming ICare4Autism International Autism Conference in Israel.

The presentation will cover how parents and family members should be supported and involved in the treatment process, the difficulties experienced by the parents of children with special needs during such complex treatment and the difficulties experienced by the therapists.  She will also discuss how to optimize the effectiveness in applying such a home involvement program.

Inbar Konforti is the founder and Director of the Refael Center (www.merkaz-refael.co.il) – the National Guidance Center to Train Behavioral Therapists ABA; Certified Behavior Analyst BCABA, with 12 years’ experience working with children suffering from autism and delayed development. She is a graduate of the University of Tel Aviv for certification studies in Applied Behavioral Analysis. BA (Honors) in Special Education from Bar Ilan University. Inbar Konforti is a lecturer on ABA at various locations in Israel, instructor of the Home-Based Program, and programs designed to integrate children suffering from autism and delayed development into schools and kindergartens.

Dr. Hollander will be speaking at the upcoming ICare4Autism International Autism Conference on the Neuropsychopharmacology of Oxytocin and Inflammation in ASD.  He is also receiving Global Autism Research Award for his breakthrough research in autism treatment at the ICare4Autism Fundraising Gala on Thursday, 7th of June, 2012.

The research, which included 37 high-functioning adults with, mainly diagnosed with Asperger’s syndrome, followed participants for 12 weeks. Taking fluoxetine doubled the chances that a patient would show overall improvement, measured by their clinicians. Half of the participants taking fluoxetine had significant reductions in obsessive-compulsive symptoms, compared with 8% taking placebo.

“Repetitive behavior is a core symptom of the illness,” says lead author Dr. Eric Hollander, medical director of the Autism and Obsessive-Compulsive Spectrum Program at Montefiore Medical Center in New York, explaining that “from a very early age, these children have rituals and routines. For example, they like to line up their toys and they get very bent out of shape if there is any deviation.”

A previous, larger study of a similar medication, citalopram, in children with autism did not find a reduction in repetitive behaviors, but the drug did reduce irritability and was superior to placebo among children who had the highest levels of irritability. Irritability can sometimes lead to repetitive behaviors because people wit autism often engage in these activities to self soothe.

Both fluoxetine and citalopram belong to a class of antidepressants known as selective serotonin reuptake inhibitors, or SSRIs. Prior research on SSRIs in people with autism has also looked at fluvoxamine and found a reduction in repetitive behavior in adults but not children. It is not known if the differences between these studies are due to differences between the medications or other factors.

Obsessive behaviors may also arise in people with autism in response to the stress or discomfort of unpredictable situations. “Many of these individuals have expectations for what’s going to happen, and if there is an unexpected deviation, they experience a lot of discomfort and then they do all these kinds of behaviors,” says Hollander. That’s why people with autism may obsessively avoid locations where they previously experienced discomfort, for example, or they may engage in a repetitive habit like washing, checking, counting, touching or tapping.

When taking fluoxetine, Hollander says, “Patients acknowledge experiencing less discomfort. They’re more able to go outside their comfort zone and to better resist their habits and rituals.” One participant in Hollander’s study was previously too anxious to take the subway or eat in a restaurant, but, when taking fluoxetine, was able to tolerate these unpredictable environments.

Hollander notes that the findings were statistically significant and clinically meaningful. “The clinicians could tell that people were doing better not only in terms of OCD symptoms but overall distress and ability to function.”

Read more: http://healthland.time.com/2011/12/05/prozac-may-reduce-symptoms-of-autism-in-adults/#ixzz1toOkty7N

Genetic variation caused by mutation leading to autism spectrum disorders is well established, and research has repeatedly implicated “de novo” (new) mutations, those that show up for the first time in affected children, as being especially pertinent. Identification of the specific genes connected to autism may lead to vital advances in the diagnosis and treatment of autism spectrum disorders. The current study, led by Dr. Michael Wigler from Cold Spring Harbor Laboratory, used gene sequencing methods to look at nearly 350 families with healthy children and children on the autistic spectrum, part of the larger Simons Simplex Collection. Specifically, the researchers looked for mutations that were present in the children but not in their parents.

The researchers found that autism is linked with the types of new mutations that are likely to disrupt the function of a gene. By disrupting one of the pair of healthy genes that we normally inherit, such mutations alter “gene dosage.” There was double the incidence of such mutations in the affected child than in the healthy child, but little to no difference in the overall incidence of much more common types of mutations. The results also showed that children with older parents have more new mutations. This is in line with other recent reports and possibly explains why older parents are more likely to have children on the autism spectrum. “More generally, this work and the work preceding it point to the importance of new mutations and gene dosage in so-called complex genetic disorders,” says Dr. Wigler.

The study also identified many new autism candidate genes, and these genes showed a strong overlap with genes linked to the pathway involved in fragile X syndrome, one of the best studied cognitive-behavioral disorders in humans. “We observe strong statistical evidence for the link between autism and fragile X syndrome, first suggested by study coauthors Dr. Jennifer Darnell and Dr. Robert Darnell, in a paper they published in Cell last year,” explains Dr. Wigler. “Our finding has important implications for therapy and shows that autism is in large part a molecular disorder of neuroplasticity, the mechanisms by which our nervous system adapts to change.”

Sources:

Ivan Iossifov, Michael Ronemus, Dan Levy, Zihua Wang, Inessa Hakker, Julie Rosenbaum, Boris Yamrom, Yoon-ha Lee, Giuseppe Narzisi, Anthony Leotta, Jude Kendall, Ewa Grabowska, Beicong Ma, Steven Marks, Linda Rodgers, Asya Stepansky, Jennifer Troge, Peter Andrews, Mitchell Bekritsky, Kith Pradhan, Elena Ghiban, Melissa Kramer, Jennifer Parla, Ryan Demeter, Lucinda L. Fulton, Robert S. Fulton, Vincent J. Magrini, Kenny Ye, Jennifer C. Darnell, Robert B. Darnell, Elaine R. Mardis, Richard K. Wilson, Michael C. Schatz, W. Richard McCombie, Michael Wigler. De Novo Gene Disruptions in Children on the Autistic Spectrum. Neuron, 2012; 74 (2): 285 DOI:10.1016/j.neuron.2012.04.009

Cold Spring Harbor Laboratory (2012, April 25). A striking link is found between the Fragile-X gene and mutations that cause autism. ScienceDaily. Retrieved April 27, 2012, from http://www.sciencedaily.com­/releases/2012/04/120425140359.html

Furthermore, this kind of research could lead to better treatments for a subset of children with elevated levels of certain compounds in their urine, said James Woods, a researcher at the University of Washington who worked with Battelle researchers on the project.

While the study was relatively small, including 76 boys, Nick Heyer, a senior research scientist at Battelle’s Seattle lab, who worked on the study and said he’s hopeful it can be replicated on a larger scale and lead to a widely available screening test for babies.

“If it can detect increased risk of autism at age 1, that would be fantastic,” he said. “It’s the only biomarker (test) I’m aware of that could be done non-invasively and fairly inexpensively.

“I’m really pretty optimistic and excited about getting it retested.”

Heyer said he is trying to incorporate the urine test into a study that will include 1,200 mothers who have autistic children and are pregnant again. The researchers would follow the new babies’ development through age 3. He’s also working with a laboratory in South Korea to reproduce the study in a larger group.

The test looks for elevated levels of compounds called porphyrins and costs between $50 and $100. Woods said the cost would come down if the test were used frequently to screen babies.

Woods said everybody has the compounds in their urine, but some of the children in the study had clearly elevated levels.

The study included only boys, who are much more likely to have autism than girls, but the test likely would work for both genders based on other research, Woods said.

Heyer said there’s been speculation that elevated porphyrin levels are connected to mercury exposure in children with autism, but the research team found no link to increased exposure to mercury, leaving open the question of why the compounds are higher in some children with autism.

“I’m not a supporter of the concept that this is due to mercury exposure,” he said. “There’s no evidence in my mind that that should be the reason for this.”

Woods JS, Armel SE, Fulton DI, Allen J, Wessels K, et al. 2010 Urinary Porphyrin Excretion in Neurotypical and Autistic Children. Environ Health Perspect 118(10): doi:10.1289/ehp.0901713

In particular, of the 29 cytokine levels investigated, the researchers found disturbed levels in five related to the T-helper cell immune system and three involved in hematopoiesis or the production of blood cells possibly affecting antibody production required for normal functioning of the immune system.

Both the immune system and genetic factors have been implicated in the biological basis for autism, said Merlin G. Butler, professor of psychiatry at the KU Medical Center. “Our study further supports a disturbed immune system in children with classic autism that may be related to genetic factors as cytokine proteins are coded by genes distributed among the human chromosomes.”

Additionally, studies in families with autism have shown the significant contribution of genetics, including deletions and duplications of chromosomes and mutations or variants found in specific genes involved with brain development and function, he said.

“The importance of identifying early immunological disturbances that may contribute to autism has implications for identifying risk factors, diagnosis and possibly intervention as cytokines may play a role in the function of the developing brain,” he said.

The study was one of the largest of its kind to date, analyzing the plasma of 99 children with AD between 5 and 10 years of age and that of 40 age- and gender- matched unrelated healthy siblings without AD under the same clinical assessments, specimen processing and laboratory conditions. The male-to-female ratio closely matches that seen in the ASD population, and there were gender-based differences found in five cytokines.

Butler said that the purpose of this research is linking the genes encoding immune-related proteins and cytokines to ASD along with identifying the sequence of the events during critical periods of brain and neurological development. This could allow for earlier recognition, diagnosis and potential treatment.

Ann Manzardo, assistant professor of psychiatry, was the first author on the study. The study was published in the April 2012 International Journal of Developmental Neuroscience.

S100B Protein

A recent study showed that 36% of children with an Autism diagnosis had significantly higher serum S100B protein levels than healthy controls and that those with severe autism had significantly higher serum S100B protein than children with mild to moderate autism. 

The study was looking at levels to determine autoimmunity in Autism.  Elevated S100B levels in biological fluids (CSF, blood, urine, saliva, amniotic fluid) are regarded as a biomarker of pathological conditions, including perinatal brain distress, acute brain injury, brain tumors, neuroinflammatory/neurodegenerative disorders, psychiatric disorders. In the majority of these conditions, high S100B levels indicate cell damage when standard diagnostic procedures do not reveal anything.

The study’s authors explain that S100B, “is a calcium-binding protein that is produced primarily by astrocytes. Increased serum S100B protein levels reflect neurological damage. Autoimmunity may have a role in the pathogenesis of autism in some patients. Autoantibodies may cross the blood–brain barrier and combine with brain tissue antigens, forming immune complexes and resulting in neurological damage… Furthermore, S100B protein may act as a cytokine and in vitro studies have shown that, at high levels, S100B protein can induce the neuronal expression and secretion of proinflammatory IL-6. Elevated levels of S100B have been detected in the CSF of MS patients during acute phases or exacerbations of the disease, and it has therefore been proposed that elevated S100B protein may be indicative of active cell injury and can reflect an axonal and glial pathology.”

The researchers concluded that S100B protein levels were elevated in children with autism and significantly correlated to autistic severity. They believe this may indicate the presence of an underlying neuropathological condition in those with autism.  They did not find a correlation to the levels and autoimmunity but recommend further research is required to investigate the possible link between serum S100B protein levels and other autoantibodies, which are possible indicators of autoimmunity to central nervous system in autism.

The article A lack of association between elevated serum levels of S100B protein and autoimmunity in autistic children was published in the Journal of Neuroinflammation.

Here are some of the top discoveries in Autism research released in 2012 to date;

Obesity during Pregnancy Raises Risk of Autism: Obese mothers were found to be 67% more likely than mothers of normal weight to have a child with autism, and they were more than twice as likely to have a child with another developmental disorder.

Not a Breakthrough but a Turning Point – Researchers Connect Gene Mutation to Autism Risk: A recent study of hundreds of families with autism has discovered that spontaneous mutations can take place in a parent’s sperm or egg cells that result in an increased risk of autism, and fathers are four times more likely than mothers to pass these mutations on to their children. The researchers discovered that new mutations occurred four times more frequently in sperm cells than in egg cells, and the older the father, the more likely he was to have sperm with these spontaneous mutations.

Severity of Autism Linked to Length of Pregnancy: Research suggests normal term children born with autism have less severe symptoms than children with autism who are born pre-term or several weeks late.

Autism Research Identifies Gene Abnormalities: Researchers found that genetic mechanisms that normally regulate the number of cortical neurons are abnormal in those with Autism and that the genes that control the number of brain cells did not behave in the standard way.  This probably leads to too many brain cells in some locations, such as prefrontal cortex, but perhaps too few in other regions of cortex as well.

Those with Autism have Higher Perceptual Capacity: A study revealed that people with autism have a greater than normal capacity for processing information. The research may explain way some with autism excel in highly technical fields.

Mouse Model explores Role of Serotonin in Autism:VanderbiltUniversity researchers used mice to explore how altered brain serotonin levels during development may produce long-lasting changes in behavior and impact the risk for autism. The researchers conclude that a lack of serotonin during development may lead to long-standing changes in the way the brain is wired.

New Study looks at Autism and Social Touch: A new study offers insight into why some people do not respond to physical touch and how families affected by autism may learn to show affection without overwhelming an child with autism’s senses. Yale neuroscientists imaged the brain activity of young adults while exposing them to different types of social touch.

Prenatal Exposure to Solvents Could Be Linked to Autism: According to an exploratory study exposures to lacquer, varnish and xylene occurred more often in the parents of children with Autism Spectrum Disorder compared to the parents of unaffected children.

Rare Bone Disorder Illuminates Potential Cause of Autism: A new study has found that mice with a genetic defect that models human MHE show symptoms of the three defining characteristics of autism: social impairment, language deficits, and repetitive behavior. The study used a mouse model of MHE to investigate cognitive function and points to the amygdala as the region of the brain causing symptoms of autism.

Deficiency in Mirror Neuron System Connected to Autism: Scientists found that the mirror neuron system in the ASD individuals became less activated when watching the gestures, compared to the control group. This finding adds to the evidence that deficits in mirror neuron system functioning contribute to the social deficits in ASD.

Study Shows Increased ASDs in Recent Immigrants: A study shows that children of immigrant parents particularly mothers who migrated just before or during pregnancy are disproportionately more likely to develop autism with intellectual disability. This link seems to be related to the timing of the migration rather than complications in childbirth.

Low Birth Weight Linked to Autism Spectrum Disorders: After studying 3,715 pairs of twins the researchers found that lower birth weight more than tripled the risk for autism spectrum disorder in identical twin pairs in which one twin had ASD and the other did not.

Another Autism Suspect Eliminated: Mercury: Mercury levels in urine did not differ between children with autism and controls, even after the figures were adjusted for factors such as urine concentration and body mass. The team also found no difference in the levels of other heavy metals such as lithium, manganese, and copper.

Gene Mutation in Autism Causes Hypersensitivity: A study has found that the loss of a specific mutated gene in the auditory cortical neurons – the powerhouses of the sound-processing center – causes hypersensitive to sound.

Researchers find Uncommon Bacteria in Children with Autism: Researchers atColumbiaUniversity have found that an uncommon bacterium exists in the walls of intestines of children with autism, but not those who do not have autism.

Study Finds Autism Linked to Parental Age: A study of Danish families found that children born to a parent over age 35 are at greater risk of developing an autism spectrum disorder — but the researchers are confused as why this is and why the risk is the same whether just one or both parents are older.

Autism Causes: Another Suspect Eliminated: One of the many potential causes of autism, smoking during pregnancy, has been ruled out after a large population-based study inSweden. Overall, 19.8 percent of the children with ASD were exposed to maternal smoking during pregnancy, compared to 18.4 percent of control children.

Biological Marker for Autism Possibly Found: A recent study using a mouse model of autism proposes abnormalities in the immune system could be linked to pervasive developmental disorders. The research proposes that heightened levels of an APP fragment circulating in the blood could explain the abnormalities in immune cell populations and function – both of which are seen in some autism patients.

While the researchers are quick to point out that their study doesn’t conclude that obesity during pregnancy causes autism but that their findings raise a red flag and warrant further research.

Researchers at the University of California, Davis, looked at 1,004 children aged 2 to 5 years enrolled in the CHARGE (Childhood Autism Risks from Genetics and the Environment) study from 2003 to 2010.

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Obese mothers were 67% more likely than mothers of normal weight and with no metabolic disorders to have a child with autism, and they were more than twice as likely to have a child with another developmental disorder — a delay in speech delay, perhaps, or a failure to reach developmental milestones at the appropriate age.

Mothers of children who were not developing typically were more likely to be obese: 21.5% of mothers of children with autism and 23.8% of mothers of children with developmental delays were obese, versus 14.3% of moms of typically developing children.

“Our findings raise concerns that these maternal conditions may be associated with neurodevelopmental problems in children and therefore could have serious public health implications.” the study authors wrote in their report published today in the journal Pediatrics.

“It’s hard to say if they’re linked,” said study author Irva Hertz-Picciotto, professor of public health sciences at the University of California at Davis. “It might be there’s some environmental factor that contributes both to the obesity epidemic and to the rise in autism cases. Or it could be the increase in obesity is, in fact, contributing to the increase in autism. But it’s certainly not going to account for all of it.”

Hertz-Picciotto and colleagues have also linked autism to poor maternal nutrition, antidepressant use and closely spaced pregnancies.

How obesity and diabetes during pregnancy might predispose the developing fetus autism is unclear, but theories include overexposure to glucose, insulin and inflammation.

“This study doesn’t tell you anything about the origin of autism. What it does tell you are things associated with autism,” said Dr. Susan Hyman, associate professor of pediatrics at the University of Rochester Medical Center. “We would not advocate treating the hypothetical causes of autism, but we would recommend women of childbearing years to eat healthy and exercise and take care of themselves, not only for the fetus but so they can see their children grow up.”

Hyman said autism is a complex condition thought to emerge from an interaction of multiple genetic and environmental influences.

Dr. Ari Brown, an Austin, Texas-based pediatrician, said the study is one more piece in the puzzle of autism spectrum disorders, a collection of conditions with varying symptoms and, quite likely, multiples causes.

“I think we’re just beginning to unravel some of the mysteries of autism spectrum disorders. And I don’t think we’re going to find just one answer because it’s not just one disease,” Brown said. “But it’s really important for women prior to do a preconception visit with their doctor and talk about attaining ideal body weight prior to becoming pregnant. Being overweight or obese can lead to a variety of health problems for mom and baby.”

We have known for many years that autism is more common in boys than girls. Latest CDC figures show that as much as 5 times as many boys are diagnosed with autism than girls. The disorder appears different in the sexes, and these differences may have important implications for both diagnosis and treatment.

There is currently no adequate explanation for this imbalance in the sex ratio, but Dr. Peter Szatmari, a professor and the head of the Division of Child and Adolescent Psychiatry in the Department of Psychiatry and Behavioral Neurosciences at McMaster University believes that something could be protecting girls from developing ASD and other developmental disorders. That factor could be hormone levels in utero, epigenetic factors that turn autism susceptibility genes “on” and “off” during development, or the fact that young girls have in general better social skills than boys and so need a bigger “dose” of what causes ASD to cross that threshold to being impaired.

Dr Szatmari explains “It is possible that those possible protective factors, once identified and understood, could play an important role in pointing toward new treatments and interventions that capitalize on those protective factors and so make a real difference to long-term outcomes.”

The clinical expression of autism is also different in boys. Generally speaking, girls with autism have greater learning disabilities and more problems academically than boys.

Higher-functioning girls with ASD are may be missed by clinicians who are not experts in diagnosis, Dr Szatmari states. There is some evidence that among this subgroup, girls have better social skills than higher-functioning boys with ASD and so are not diagnosed as readily. Although, the symptoms of ASD can appear as extreme shyness or anxiety in girls, masking that they may not be responsive to the social cues of others.

Girls on the autism spectrum have fewer repetitive behaviors such as rocking and spinning and less sensory sensitivity than boys with ASD. Since these signs are subtle, doctors may not recognize the disorder. Diagnosis at a later age reduces the chances of early treatment, which is understood to provide a better outcome.

Some evidence suggests that girls with ASD are bullied less often than boys. They appear to blend in more easily with their peers and are less often the victim of bullying by other girls.

Understanding these differences both biologically and experientially holds the promise of improving the long-term outcome of all children with ASD. Most important, clinicians need to be sensitive to how the disorder shows up in girls so that those affected can receive early intervention as soon as possible.