The Abrahams lab works to understand the “whys” and “hows” in the Autism Spectrum Disorders and to use these insights to achieve better patient outcomes. Dr. Abrahams has identified DNA variants that increase risk for disease and discovered how some of these impact brain structure and function. Ongoing work is poised to take these insights back to the clinic and improve quality of life for patients and families.

All of the work that they accomplish begins and ends in the clinic. The Abrahams team is always actively recruiting patients (and family members) to participate in genetic studies. If you are interested in being part of their study, you can contact them directly for more information.

Widely sought by instititutions nationwide, he chose to come to Einstein and now he is choosing to speak at ICare4Autism’s upcoming August Conference Autism: A Global Perspective. This is the second time that we have invited Dr. Abrahams to speak after the rave reviews of his last speaking engagement at our Jun 6^th conference in 2011.

Dr. Abrahams speaks from a history of personal patient interaction and detailed experiments with a protein called Cntnap2. He writes that, “convergent lines of evidence support involvement of Contactin Associated Protein-Like 2 (CNTNAP2), a Neurexin family member, in the ASDs and related disorders of cognition.” The Abrahams lab explores the biological mechanisms by which mutations in CNTNAP2 may cause disease. They characterized animals in which the murine homolog is deleted.

Cntnap2 KO mice were found to have behavioral abnormalities reminiscent of core deficits observed in patients. Mutant mice were also seen to be hyperactive and show spontaneous epileptic seizures, both primary reactions in autistic patients. Treatment with the FDA approved drug risperidone alleviated a subset of behaviors in mutant mice. Dr. Abrahams will discuss further possible treatments and elaborate on the numerous successes that his team has encountered at Einstein.

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 Parent Child Training Program (PCTP) at Action For Autism is a ‘model’ program that addresses the critical need for parent education. How to parent an autistic child is not an intuitive process. True parental involvement is the key to successful autism programming and activities.

PCTP’s training empowers parents to take charge of their children’s health and education. Parental involvement on this level not only helps educate children, but it heals the emotional stresses that parents face. The PCTP training program is a ten-week country wide opportunity.

The coursework covers behavior modification and skills maintenance. Mothers learn tools and tactics for facilitating learning. Most importantly, they gain confidence through community by meeting other parents. This is the goal of ICare4Autism’s conference and our institute at large. By sharing information we strengthen our skills.

Ms. Barua’s organization quotes that they hope for “a society that views the interdependence of people of every ability as valuable and enriching.” AFA seeks to provide equal opportunities for all. Their goals are not only research and expanding autism education in India but also independent life training and skills.

The AFA’s reach goes beyond Los Angeles and India to the Europe. AFA created “Activate Yourself!” to put into action the value of all people. Due to the nature Autism, people with this disorder have difficulties in terms of self-advocating their fundamental rights. Therefore “Activate Yourself” was developed to encourage active participation of young people with ASD; empower them as active citizens, make them aware of their role in creating their own future and promote their equal rights and opportunities. The project is supported by the Youth in Action Programme of the European Union.

This kind of active work is right in line with the International Center for Global Research. We learn as much in the classroom as we do from the scientists in our lab. How to educate our autistic youth comes directly from their communication and achievements.

ICare4Autism Founder and President, Joshua Weinstein with Dr. W. Ted Brown

The Fragile X Syndrome is the most common inherited cause of intellectual disability. Fragile X has a population incidence of approximately 1 in 4,000 affected (full-mutation) males, 1 in 6,000 affected females, 1 in 700 premutation carrier males and 1 in 260 carrier females. This disorder typically causes moderate to severe intellectual deficiency in affected males, and milder deficiency in affected females.  It is associated with autism or PDD-NOS in about 50% of affected males, and most affected individuals evidence some autistic-like behaviors. 

Fragile X syndrome is considered to be the most common known single gene cause of autism. It is estimated that Fragile X accounts for 2-4% of intellectual deficiency overall, and is second to Down syndrome, which is not inherited, as a genetic cause of intellectual deficiency. The fragile X mutation results in the lack of expression of the Fragile X Protein (FMRP), an mRNA finding protein, which results in overexpression of the glutamate (stimulatory) and under-expression of the GABA (inhibitory) pathways in the brain.

Current experimental treatment trails are being carried out in Fragile X and in autism with glutamate receptor blockers and GABA stimulatory drugs.  The underlying defects in neurochemical pathways in both conditions appear to have much in common, involving the ERK, mTOR and PI3K signaling pathways.

Dr. W. Ted Brown will be speaking at the upcoming ICare4Autism International Conference on Autism, in Israel, about the relationship between Fragile X syndrome and autism.

W. Ted Brown, MD, PhD, is the Director of the New York State Institute for Basic Research (IBR) in Developmental Disabilities, Chair of the IBR Department of Human Genetics and Director of the IBR Jervis Clinic.  He is a fellow of the American College of Medical Genetics and Professor at the State University of New York- Downstate Medical Center in Brooklyn.

In 1991, he was appointed the Director of IBR’s Jervis Clinic and in 2005 became IBR’s Director. He is the author of more than 350 publications.  At IBR, he began research focused on the Fragile X syndrome, which was then newly recognized and is now considered to be the most common inherited cause of intellectual deficiency or mental retardation. At IBR, he established a DNA diagnostic and molecular laboratory. He developed a screening and prenatal testing program for Fragile X.

His work on Fragile X has ranged from clinical studies relating to phenotype, to family inheritance studies, to mouse model development, and to basic molecular research. His current research is focused on autism genetics and the Fragile X syndrome.

Dr. Eli Hatchwell is a member of ICare4Autism’s Advisory Council and will be speaking at ICare4Autism’s International Autism Conference in Jerusalem this August.  He will be speaking about the heritability of autism and will discuss the recently completed project he was involved with which discovered many novel genes in connection with autism.

Dr. Hatchwell’s clinical and technical expertise in investigating human genetic disorders led him to recognize early on that human genetic diversity was grossly underestimated, there was a critical need to comprehensively understand the vast spectrum of normal genetic variation in the population and that rare variants are largely responsible for causing common disease – the underlying principles of the genetic biomarker discovery technology of Population Diagnostics.

He is recognized as a key collaborator in the development of one of the first genome-wide BAC-based comparative genomic hybridization (CGH) microarray platforms and remains at the forefront of cytogenetic and genome analysis through early adoption of leading edge technologies. Dr. Hatchwell collaborates with human genetics researchers worldwide, is a coauthor on numerous peer-reviewed articles, encompassing both clinical genetics and genome technologies, and is senior editor of a book series aimed at educating medical specialists on genetic principles and practices.

Dr. Hatchwell is also a certified Medical Geneticist (UK) with many years of experience in clinical practice. He received his medical degree from the University of Cambridge, his DPhil in Molecular Genetics from the University of Oxford, and was a Wellcome Advanced Clinical Training Fellow. He also holds a degree in Mathematics from the Open University (UK).

His goal is to get together as many genes to formulate tests that are as comprehensive as possible so that autism could be diagnosed medically before clinically. He is also interested in matching genetic causes of autism to potential therapeutic interventions. He believes these complex genetic disorders, will eventually be found to be amalgams of very a variety of very rare disorders.

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

Eyal Ben-David and Sagiv Shifman, Hebrew University of Jerusalem

It is widely understood that different genes interact with environmental factors to influence autism, but new research finds a common ground as the various genes involved in autism appear to influence special processes in the brain.

Autism is influenced by many different genes, and different genes are involved in different individuals, making it hard to find the common genetic ground between patients.

Now, research conducted at the Hebrew University of Jerusalem has shown that the different genes involved in autism tend to be involved in specific processes in the brain. This can explain similarities in the behavioral symptoms of different people with autism, but also the large spectrum of behaviors observed in different individuals with autism.

The Hebrew University research, conducted by Dr. Sagiv Shifman and his doctoral student Eyal Ben-David of the Department of Genetics at the Alexander Silberman Institute of Life Sciences, has potential implications for early diagnosis as well as for treatment of autism in the future.

Dr. Shifman’s areas of interest are the genetics of schizophrenia and autism and genetics of variation in gene expression.  He will be speaking about this research “Shared neuronal pathways affected by common and rare variants in autism spectrum disorders” at ICare4Autism’s upcoming International Autism Conference in Jerusalem.

The mission of the Hebrew University project was to test the contribution of rare genetic mutations, as well as the genetic variations which are common in the population, and to see whether these different types of genetic risk factors are related. Instead of testing individual genes, the researchers chose to study gene collections, in an attempt to understand general pathways involved in autism.

Based on genetic data from thousands of families with autistic children, the researchers studied the contribution of different groups of genes to autism.

To their surprise, they found – when looking at mutations found in autism as well as thousands of common gene variants that are more frequently seen in individuals with autism – that these mutations and variations are located in specific functional groups.

When looking at families with one individual with autism (sporadic cases), and in families where there is more than one affected individual (multiplex cases), the same variants were seen acting in both cases. These groups of genes are highly active in the first year of life, and are involved in processes of learning, memory, and sensory perception.

The Hebrew University scientists believe that their work could pave the way for large-scale genetic scans in the future that could allow for early diagnosis of autism. Further, the results of their study provide a ray of hope that by concentrating on specific gene groups, it will one day be possible to design drugs which could alleviate symptom

Ben-David E, Shifman S (2012) Networks of Neuronal Genes Affected by Common and Rare Variants in Autism Spectrum Disorders. PLoS Genet 8(3):e1002556. doi:10.1371/journal.pgen.1002556

http://medicalxpress.com/news/2012-05-genetic-disrupted-autistic-brain.html

The study, led by Gladstone Investigator Jorge J. Palop, PhD, revealed that low levels of a protein, called Nav1.1, disrupt the electrical activity between brain cells. Such activity is crucial for healthy brain function and memory. Indeed, the researchers found that restoring Nav1.1 levels in mice that were genetically modified to mimic key aspects of Alzheimer’s disease (AD-mice) improved learning and memory functions and increased their lifespan.

“It is estimated that more than 30 million people worldwide suffer from Alzheimer’s disease and that number is expected to rise dramatically in the near future,” said Lennart Mucke, MD, who directs neurological research at Gladstone, an independent and nonprofit biomedical-research organization. “This research improves our understanding of the biological processes that underlie cognitive dysfunction in this disease and could open the door for new therapeutic interventions.”

In the brain, neurons form highly interconnected networks, using chemical and electrical signals to communicate with each other. The researchers investigated whether this communication between neurons is disrupted in AD-mice, and if so, how this may affect the symptoms of Alzheimer’s disease.

“Like a conductor in an orchestra, PV cells regulate brain rhythms by precisely controlling excitatory brain activity,” said Laure Verret, PhD, postdoctoral fellow and lead author. “We found that PV cells in patients with Alzheimer’s and in AD-mice have low levels of the protein Nav1.1 – likely contributing to PV cell dysfunction. As a consequence, AD-mice had abnormal brain rhythms. By restoring Nav1.1 levels, we were able to re-establish normal brain function.”

Indeed, the scientists found that increasing Nav1.1 levels in PV cells improves brain wave activity, learning, memory and survival rates in AD-mice.

“Enhancing Nav1.1 activity, and consequently improving PV cell function, may help in the treatment of Alzheimer’s disease and other neurological disorders associated with gamma-wave alterations and cognitive impairments such as epilepsy, autism and schizophrenia,” said Dr. Palop, who is also an assistant professor of neurology at the University of California, San Francisco, with which Gladstone is affiliated. “These findings may allow us to develop therapies to help patients with these devastating diseases.”

Gladstone Institutes. (2012, April 29). “Mechanism May Aid Treatment For Alzheimer’s And Neurological Disorders Associated With Gamma-Wave Alterations And Cognitive Impairments.“ Medical News Today. Retrieved from http://www.medicalnewstoday.com/releases/244665.php.

Verret, Laure; Mann, Edward O.; Hang, Giao B.; Barth, Albert M.I.; Cobos, Inma; Ho, Kaitlyn; Devidze, Nino; Masliah, Eliezer; Kreitzer, Anatol C.; Mody, Istvan; Mucke, Lennart; Palop, Jorge J. Inhibitory Interneuron Deficit Links Altered Network Activity and Cognitive Dysfunction in Alzheimer Model.  Cell doi:10.1016/j.cell.2012.02.046 (volume 149 issue 3 pp.708 – 721)

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

ICare4Autism is holding a very special gala reception on Thursday, 7th of June, 2012.  The gala is in honor of Dr. Eric Hollander, Director of the Autism Spectrum Disorder Program at Montefiore Medical Center/Albert Einstein College of Medicine.

Attendees will also have the opportunity to learn more about plans for world’s first Global Autism Center, which will open on a five acre campus on Mt. Scopus in Jerusalem, in 2015.

The Suggested Donation is $500.  You can RSVP and see more information about the event by clicking here.

Dr. Hollander, who chairs ICare4Autism’s International Advisory Board, will receive ICare4Autism’s coveted Global Autism Research Award for his breakthrough research in autism treatment.

Dr. Hollander received his B.A. from Brandeis University (1978), and his M.D. from SUNY Downstate Medical College, Brooklyn (1982).   He completed his internship in Internal Medicine at Mt. Sinai Hospital (1983), residency and chief resident in psychiatry at Mt Sinai School of Medicine (1986), and his NIMH research fellowship at Columbia University College of Physicians and Surgeons (1988). He was appointed Associate Professor of Psychiatry at Columbia University College of Physicians and Surgeons.  He joined the faculty of Mount Sinai School of Medicine in 1993, and was the Esther and Joseph Klingenstein Professor and Chair of Psychiatry at the Mount Sinai School of Medicine.

Dr. Hollander has served as the principal investigator for a number of federal grants, including the NIH Greater New York Autism Center of Excellence, the NIMH Research Training Grant in Psychopharmacology and Outcomes Research, and an FDA funded multicenter treatment trial of pediatric body dysmorphic disorder. He was the principal investigator of the autism Clinical Trials Network, and Chair of the eight centers NIH STAART Autism Steering Committee.  He is involved in research on the neuropharmacology, neuropsychiatry, functional imaging, and treatment of obsessive-compulsive disorder, impulsive/aggressive personality disorders, obsessive-compulsive-related disorders such as body dysmorphic disorder, pathological gambling, and autism.

Dr. Hollander has received a Research Scientist Development Award from the National Institute of Mental health to investigate the psychobiology of obsessive-compulsive and related disorders.  He has received orphan drug grants from the Food and Drug Administration to study new treatments for body dysmorphic disorder, child/adolescent autism, and adult autism, and a grant from the National Institute of Drug Abuse for a study on the neurobiology of pathological gambling.  He has received several grants from the National Institute of Mental Health, and the National Institute of Neurological Disorders and Stroke, to develop treatments for borderline personality disorder, adolescent body dysmorphic disorder, and autism.  Dr. Hollander has received two national research awards from the American Psychiatric Association and a Distinguished Investigator Award from the National Alliance for Research in Schizophrenia and Depression.