Seaver Researchers Begin Oxytocin Clinical Trial in People with Phelan-McDermid Syndrome

This study is led by Alex Kolevzon, MD, Clinical Director of the Seaver Autism Center, and it comes after finding that oxytocin improved social deficits in a rat model of Phelan-McDermid syndrome. Click here to read more on this from the Simons Foundation Autism Research Initiative.

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Mount Sinai a Lead Site in NIH-Funded Rare Diseases Consortium Studying Autism and Intellectual Disability

10-institution study seeks to pilot new treatment approaches

NEW YORK, NY – October 15, 2014 /Press Release/  –– 

Under a five-year, $6 million grant from the National Institutes of Health’s (NIH) Rare Disease Clinical Research Network, the Icahn School of Medicine at Mount Sinai (ISMMS) will serve as one of 10 medical centers that have formed the Developmental Synaptopathies Consortium (DSC). The consortium will study three rare, genetic syndromes that often cause autism spectrum disorder (ASD) and intellectual disability (ID).

While both ASD and ID have a variety of know genetic causes, the three conditions to be studied by the DSC – tuberous sclerosis complex (caused by mutations in the TSC1 and TSC2 genes), Phelan-McDermid syndrome (caused by SHANK3 mutations) and PTEN Hamartoma Tumor Syndrome (caused by PTEN mutations) – seem to affect certain shared cellular pathways that influence the development of synapses, the spaces between nerve cells in pathways that “decide” whether signals travel onward to create healthy brain connections.

The consortium seeks to distinguish the neurobehavioral characteristics of these rare syndromes. Researchers will also track the natural history of the syndromes to identify demographic, environmental and other variables that correlate with disease outcomes, which may enable the development of mechanism-based therapies for ASD and ID.

The Seaver Autism Center for Research and Treatment at ISMMS will lead the study of Phelan-McDermid syndrome (PMS), an autism-related syndrome that is typically caused by a defect in the SHANK3 gene.  Found in the heart, kidney and other organs, SHANK3 plays its most important role in the brain by supporting the structure of excitatory synapses. The SHANK3 gene is involved in processes crucial for learning and memory and has an important, yet not fully understood, role in proper brain development.

“Through the consortium, we can tackle challenges common to rare diseases like Phelan-McDermid syndrome, including widely dispersed patient populations and scientific experts, difficulty in diagnosis and the lack of data from natural history studies,” says Alex Kolevzon, PhD, Clinical Director of the Seaver Autism Center and principal investigator of the Phelan-McDermid syndrome consortium.  “Our collaboration will provide a robust data source, enabling us to develop best clinical practices and provide a foundation for the development of novel therapeutics in the future.”

Phelan-McDermid syndrome is associated with intellectual disabilities, sleep disorders, seizures, behavioral issues, functional language delays, low muscle tone, poor motor control and problems with eating.  Like other autism-related syndromes, severity of symptoms varies widely.

Together, the sites seek to enroll 100 patients with tuberous sclerosis, 90 with Phelan-McDermid syndrome and 140 with PTEN mutations, ages 3 to 21, and follow them for three to five years with physical examinations, neuropsychological testing and advanced brain imaging.

“To date, genetic studies indicate that there are about 500-1,000 genes that make people susceptible to ASD and ID,” says Mustafa Sahin, MD, PhD, a pediatric neurologist and Boston Children’s Hospital and Director of the Developmental Synaptopathies Consortium.  “While it’s very unlikely that a single therapy could treat disorders with so many distinct causes, we may be able to find certain groups of patients who share defects in similar biochemical pathways who may respond to treatment with the same agents.”

“I am excited to co-direct this consortium because of the opportunity to look at rare single gene causes of autism and developmental delay,” says Joseph Buxbaum, PhD, Director of the Seaver Autism Center and Administrative Director of the Consortium.  “We will be able to plan the best ways to treat individuals with these mutations and develop novel medicines for the disorders.  A deeper understanding of the shared biological underpinnings of these rare diseases may also serve as a window to our understanding of the broader mechanisms of ASD and ID.”

In addition to the NIH and the Icahn School of Medicine at Mount Sinai, the consortium includes Boston Children’s Hospital, Cincinnati Children’s Hospital, Cleveland Clinic, Rush University Medical Center, Stanford University, University of Alabama at Birmingham, University of California at Los Angeles and University of Texas at Houston.

About the Seaver Autism Center for Research and Treatment at Mount Sinai
The Seaver Autism Center for Research and Treatment at Mount Sinai conducts progressive research studies aimed at understanding the multiple causes of autism spectrum disorders (ASD).  The multidisciplinary team is comprised of experts in the fields of genetics, molecular biology, model systems, neuroimaging and experimental therapeutics who are dedicated to discovering the biological causes of ASD.  The Center strives to develop innovative diagnostics and treatments for integration into the provision of personalized, comprehensive assessment and care for people with ASD.  The Seaver Autism Center was founded through the generous support of the Beatrice and Samuel A. Seaver Foundation.  For more information, visit or find the Seaver Autism Center on Facebook and Twitter.

About the Mount Sinai Health System
The Mount Sinai Health System is an integrated health system committed to providing distinguished care, conducting transformative research, and advancing biomedical education. Structured around seven member hospital campuses and a single medical school, the Health System has an extensive ambulatory network and a range of inpatient and outpatient services—from community‐based facilities to tertiary and quaternary care.

The System includes approximately 6,600 primary and specialty care physicians, 12‐minority‐owned free‐standing ambulatory surgery centers, over 45 ambulatory practices throughout the five boroughs of New York City, Westchester, and Long Island, as well as 31 affiliated community health centers. Physicians are affiliated with the Icahn School of Medicine at Mount Sinai, which is ranked among the top 20 medical schools both in National Institutes of Health funding and by U.S. News & World Report.

For more information, visit, or find Mount Sinai on FacebookTwitter and YouTube.

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New Shank3 Gene Research

Recently there has been an increase in the volume of research devoted to the SHANK3 gene mutation as a cause of autism spectrum disorders (ASD). Below we have compiled a selection of these recent studies.

Shank mutant mice as an animal model of autism: This review describes the effect of the Shank family of proteins on autism.

Transcriptional and functional complexity of Shank3 provides a molecular framework to understand the phenotypic heterogeneity of SHANK3 causing autism and Shank3 mutant mice: Through analysis of Shank3 mutant mice, the authors of this study demonstrate the complexity of Shank3 transcriptional regulation in mouse brains. Their analyses show that different Shank3 isoforms have different functions, and thus distinct dysfunctions in transcriptional regulation of Shank3 cause phenotypic diversity. They predict the same applies to patients with ASD.

Seizures and EEG pattern in the 22q13.3 deletion syndrome: Clinical report of six Italian cases: Through a close study of six Italian patients with 22q13.3 deletion syndrome/Phelan-McDermid Syndrome, this analysis found the syndrome in a small subgroup to be associated with childhood epilepsy and a peculiar clinical and EEG pattern.

Sensory Integration in Mouse Insular Cortex Reflects GABA Circuit Maturation: The authors of this study compared the development of multisensory integration in the insular cortex of “behaviorally distinct mouse strains.” The findings of this study help to explain significant a neural circuit important for neuropsychiatric conditions, such as autism and schizophrenia.

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New Grant Award to Study Effects of Shank3 Deficiency

The Seaver Autism Center has recently received a grant award from the National Institute of Mental Health to study the effects of Shank3 deficiency. The project will be led by Dr. Joseph Buxbaum, Director of the Seaver Autism Center, and is titled “Prefrontal function in the Shank3-deficient rat: A first rat model for ASD.” The studies that comprise this project will lead to a molecular and systems level understanding of Shank3 function and will identify molecular targets for novel therapeutics in developmental delay and ASD using a first genetically modified rat model for ASD.

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Absence of strong strain effects in behavioral analyses of Shank3-deficient mice

Seaver Autism Center researchers at Icahn School of Medicine at Mount Sinai have published a study in Disease Models and Mechanisms demonstrating that the range of mouse phenotypes caused by a Shank3 gene mutation does not depend on varied genetic backgrounds. This finding indicates the high level of transferability of research findings in mouse models to those in rat models.

Phelan-McDermid Syndrome (PMS) is a rare genetic syndrome in which one copy of the q13 portion of chromosome 22 is missing or mutated leading to global developmental delay, delayed or absent speech, and autistic behaviors. There is overwhelming evidence available indicating that SHANK3, a gene coding for a protein essential to neuronal communication, causes the neurological and behavioral aspects of the syndrome. In addition, the Shank3 mutation can lead to a range of phenotypes.

When a range of phenotypes is present, it can mean that a combination of genes impact the phenotype. It is this varied genetic background which is present in people affected by Fragile X syndrome, for example. In this study, researchers tested whether the range of phenotypes caused by Shank3 mutations is caused by varied genetic backgrounds.

The researchers, led by Dr. Joseph D. Buxbaum, PhD, Director of the Seaver Autism Center at Mount Sinai, tested three different strains of mice, each with a different genetic background. The goal of this was to discern whether the genetic background is responsible for the varied phenotypes caused by Shank3 mutations. After an extensive battery of tests designed to assess the main features of PMS, the researchers found that there were very modest differences in the phenotypes between the three strains of mice.

This finding indicates that varied genetic backgrounds are not the cause of the spectrum of phenotypes found in people with PMS. Rather, it suggests that there are other modifiers at work to cause the spectrum of phenotypes seen in people with PMS, and further tests are required in order to identify these modifiers. This lack of causation by varied genetic backgrounds is significant because it demonstrates that findings made in mouse models are very likely transferable to rat models, and rat models are a promising new direction for model systems in autism.

Other researchers involved in the study include Drs. Elodie Drapeau, Nate P. Dorr, and Gregory A. Elder.

For more information and to read the paper, click here.

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Seaver Autism Center Distinguished Lecturer Series – Wed. Jan. 22nd

Seaver Autism Center Distinguished Lecturer Series

“Swedish National Samples in Psychiatric Epidemiology and Psychiatric Genetics”

Christina Hultman, PhD
Department of Medical Epidemiology and Biostatistics
Karolinska Institute
Stockholm, Sweden

Wednesday, January 22, 2014
5:30 – 6:30 PM

This event is free of charge. Reception immediately following.

Icahn School of Medicine at Mount Sinai
Leon and Norma Hess Center for Science and Medicine
1470 Madison Avenue (between 101st and 102nd Streets), Seminar Room A (2nd Floor)

Please RSVP to if you would like to attend.

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Seaver Autism Center Distinguished Lecturer Series – Wed. Sept. 18th

Seaver Autism Center Distinguished Lecturer Series

“Autism – A Model for Integrative Intervention of Neuropsychiatric & Neurodevelopmental  Disorders”

Daniel Geschwind, MD, PhD
Gordon and Virginia MacDonald Distinguished Professor
Neurology, Psychiatry and Human Genetics
UCLA David Geffen School of Medicine
Los Angeles, CA

Wednesday, September 18, 2013
5:30 – 6:30 PM

This event is free of charge. Reception immediately following.

Icahn School of Medicine at Mount Sinai
Leon and Norma Hess Center for Science and Medicine
1470 Madison Avenue (between 101st and 102nd Streets), Seminar Room B (2nd Floor)

Please RSVP to if you would like to attend.

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17th Annual Seaver Autism Center Advances in Autism Conference — Registration is now OPEN!

Registration is now OPEN for the 17th Annual Advances in Autism Conference!

Please visit for more details, and to register.

If you have any questions, please email

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Mount Sinai Researchers Provide the First Comprehensive and Prospective Characterization of a Genetic Subtype of Autism

First Study to Comprehensively  Describe Clinical Presentation of Phelan-McDermid Syndrome Will Help Guide Future Research and Clinical Care

(New York – June 11, 2013) In the first prospective study of its kind, Seaver Autism Center researchers at the Icahn School of Medicine at Mount Sinai provide new evidence of the severity of intellectual, motor, and speech impairments in a subtype of autism called Phelan-McDermid Syndrome (PMS). The data are published in the June 11 issue of the journal Molecular Autism.

Mutation or deletion of a gene known as SHANK3 is one of the more common single-gene causes of autism spectrum disorders and is critical to the development of PMS, a  severe type of autism. To date, clinicians have relied on case studies and retrospective reviews of medical records to understand  the features of this disorder and how the clinical presentation relates to the extent of the  genetic changes in the SHANK3 region. In the first systematic and comprehensive prospective trial, researchers led by  Alex Kolevzon, MD, Clinical Director of the Seaver Autism Center, under the direction of Joseph Buxbaum, PhD, Director of the Seaver Autism Center, enrolled 32 participants with SHANK3 deletions to comprehensively assess their clinical symptoms and examine how the size of the SHANK3 deletion correlated to those symptoms.

“Previous studies have not utilized prospective assessments to understand Phelan-McDermid Syndrome, and the prevalence of autism spectrum disorder has never been examined using gold-standard instruments” said Dr. Kolevzon. “There is no established standard for assessing  this type of autism, and our study provides important guidance in developing such a standard.”

Of the 32 patients enrolled, 84 percent met criteria for an autism spectrum disorder. Seventy-seven percent of patients exhibited severe to profound intellectual disability, with 19 percent using some form of verbal communication. Other common features  included low muscle tone,  gait disturbance, and  seizures. When evaluating the genetic make-up of these patients, the researchers found that the larger the SHANK3 deletion, the more severe the clinical presentation was.

“Our findings provide additional evidence of the significant impairment associated with SHANK3 deficiency,” said Dr. Kolevzon. “Also, knowing how large the deletion of the  SHANK3 gene is may have important implications for medical monitoring and individualizing treatment plans. Results  also provide much-needed guidance in developing a standardized methodology for evaluating the features of this disorder.”

Many of the patients who participated in this study were next enrolled in a clinical trial at Mount Sinai evaluating Insulin-Like Growth Factor-1 (IGF-1), a  commercially available compound for growth deficiency that is known to promote nerve cell survival as well as synaptic maturation and plasticity.  The primary aim of the study is to target core features of Phelan McDermid Syndrome, including social withdrawal and language impairment, which will be measured using both behavioral and objective assessments. The clinical studies with IGF-1 were supported by studies in a genetically modified mouse with a mutation in SHANK3. These studies, carried out by Dr. Ozlem Bozdagi of the Seaver Autism Center, carefully examined brain function in the mice when SHANK3 was mutated, and provided preclinical evidence for a beneficial effect of IGF-1. These studies were reported in the June 11 issue of the journal Molecular Autism.

“The Seaver Autism Center has the unique capacity to evaluate autism spectrum disorders on both the molecular level and the clinical level,” said Dr. Buxbaum. “This capability puts us in a unique position to see the entire picture—the connection between genetics and behavior in these disorders—and to develop new treatments and better tailor existing ones for these children.”

To learn more about the Seaver Autism Center, visit

About The Mount Sinai Medical Center

The Mount Sinai Medical Center encompasses both The Mount Sinai Hospital and Icahn School of Medicine at Mount Sinai. Established in 1968, the Icahn School of Medicine at Mount Sinai is one of the leading medical schools in the United States. The Icahn School of Medicine is noted for innovation in education, biomedical research, clinical care delivery, and local and global community service. It has more than 3,400 faculty members in 32 departments and 14 research institutes, and ranks among the top 20 medical schools both in National Institutes of Health (NIH) funding and by U.S. News & World Report.
The Mount Sinai Hospital, founded in 1852, is a 1,171-bed tertiary- and quaternary-care teaching facility and one of the nation’s oldest, largest and most-respected voluntary hospitals. In 2012, U.S. News & World Report ranked The Mount Sinai Hospital 14th on its elite Honor Roll of the nation’s top hospitals based on reputation, safety, and other patient-care factors. Mount Sinai is one of just 12 integrated academic medical centers whose medical school ranks among the top 20 in NIH funding and by U.S. News & World Report and whose hospital is on the U.S. News & World Report Honor Roll.  Nearly 60,000 people were treated at Mount Sinai as inpatients last year, and approximately 560,000 outpatient visits took place.


For more information, visit

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New study on IGF-1 by researchers at the Seaver Autism Center

Drs. Ozlem Bozdagi Gunal, Teresa Tavassoli, and Joseph D. Buxbaum have recently published a study in Molecular Autism detailing their observation of injections of human insulin-like growth factor-1 (IGF-1) in to a mouse model of ASD and of developmental delay, which they had previously reported in Shank-3 deficient mice. They observed significant beneficial effects, and given the extensive safety data for IGF-1 in children with short stature due to primary IGF-1 deficiency, IGF-1 is an attractive candidate for controlled clinical trials in SHANK3-deficiency and in ASD. Click here to read more.

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