Phelan-McDermid Syndrome

Recent advances in research indicate that the development of autism spectrum disorder (ASD) has a strong genetic component. Being able to identify the specific genetic makeup for ASD would allow for better understanding of the disorder and for the development of new treatments. However, ASD remains an extremely complex disorder with more than just one gene related to it. The present review by researchers at Ulm University focuses on the use of mutant mice as animal models in research to find out how genes identified in individuals with ASD affect neurobiological mechanisms and behavior. The mouse model is specifically effective because it can be easily genetically mutated and presents a behavioral phenotype very similar to that of humans. Due to advances in technology, several successful animal models have already been established for known genetic causes of ASD. Successful identification replication studies include Fmr1 mutant mice for FXS, Tcs1 and Tcs2 mutant mice for TSC, and Shank 2 and Shank 3 mutant mice exhibiting autistic-like behaviors and neurobiological phenotypes.

People with a mutated SHANK3 gene often present with delayed or impaired speech, as well as Obsessive Compulsive Disorder-like behaviors; additionally, the SHANK3 mutation is present in some cases of Autism Spectrum Disorder (ASD).The SHANK3 gene assists in neurotransmitter connection, synapse formation, and dendrite spine maturation. In this study by researchers at the University of Texas Southwestern Medical Center, to examine how brain functioning is altered in a way that may lead to ASD, the SHANK3 gene was deleted from a specific region (exon 4-9) of rats’ brains. When evaluated, scientists found that these rats behaviorally: repetitively groomed themselves; had weakened ability to recognize and remember novel and spatial objects; had ultrasonic vocalizations; and socialized abnormally when paired together. Additionally, scientists found that removing the SHANK3 gene from this particular area of the brain reduces levels of SHANK3 in other areas of the brain, as well.

It is currently unknown whether the neurobiological findings present in young adults with autism spectrum disorder (ASD) are also present in older adults. Autism spectrum disorder (ASD) is a neurodevelopmental disorder involving deficits in information processing. Inhibitory and excitatory synapses are essential in information processing in the brain. Furthermore, previous studies have found that ASD likely arises from an imbalance between inhibitory and excitatory synaptic transmission. However, due to a lack of studies of ASD in old age, synaptic structures in adults are poorly understood. In a study by researchers at  Shanxi Provincial People’s Hospital, researchers compared the morphology and synaptic function of excitatory synapses in aged mice with low level sociability (BTBR) to mice with high level sociability (control mice). Researchers labeled pre-synaptic protein and post-synaptic protein Shank3. Shank3 is found in excitatory synapses and is highly associated with ASD. Through image analysis, researchers then quantified and noted the colocalization of pre- and post- synapses in BTBR aged mice and control mice. Results indicated there were no significant differences in the number of excitatory synapses, expression of Shank3 protein or shape of dendritic spines in aged BTBR mice and control mice. However, the baseline and evoked glutamate release in aged BTBR mice was lower than control mice. Glutamate is the principal excitatory neurotransmitter in the brain and is important in regulating the balance between neuronal excitation and inhibition. The findings in this study suggest that, unlike in children, ASD in adults is hypoglutamatergic. Thus, there is an age-related glutamate change that occurs in individuals with ASD: excessive glutamate or over activation in the autistic brain at a young age and deficient glutamate or over inhibition in the autistic brain at old age.

Atypical sensory development is found in both human patients and SHANK3 knockout mice. It is known that genes associated with ASD (in this case SHANK3) can shape and affect cerebellum circuit functions, and that changes in the cerebellum affect behavior and cognition. Because of this knowledge, effectiveness of the cerebellum at responding to sensory input and general function of the cerebellum were measured in this study, in addition to the prevalence of ASD symptoms. A method of sensory conditioning was used to study the effect of cerebellar associative sensory learning defects in SHANK3 knockout mice. The SHANK3 knockout mice had delayed or absent responses to stimuli following sensory conditioning, indicating defects in the cerebellum. This suggests that SHANK3, which is typically heavily concentrated in the cerebellum, is partially responsible for regulating sensory learning.

SHANK3 is a gene that assists neurotransmitter connection, synapse formation, and dendrite spine maturation. The autism-associated insertion mutation (InsG) of SHANK3 exon 21 was found in two brothers with clinically identical cases of autism spectrum disorder (ASD), but not in their normally developing brother. This discovery from the University of Texas Southwestern Medical Center suggests that InsG could be a potential cause to certain cases ASD. In a study that recreated InsG in mice, those with the InsG had impaired motor learning and coordination, consistent with the sibling’s symptoms. The group of the InsG mice were then given Tamoxifen while the control group were given a normal diet. The Tamoxifen induced a SHANK3 knock in, causing new segments of SHANK3 to form. As new SHANK3 was synthesized the mice also gained increased motor learning and coordination abilities. The effect of the Tamoxifen on the symptoms of the InsG demonstrated the potential for use as a therapeutic agent.

SHANK3 is a gene that assists neurotransmitter connection, synapse formation, and dendrite spine maturation, heavily concentrated in the hippocampus. The hippocampus is involved in long-term potentiation (LTP), a process known to be affected by autism spectrum disorder (ASD). After investigating the link between SHANK3, ASD, and the hippocampus, it was found by researchers at the Seaver Autism Center at Mount Sinai that SHANK3 knockout mice had significantly greater amounts of perforated synapses than the control group. This was the only significant morphological difference between the experimental and control group which suggests that specific types of mutations within SHANK3 may cause specific brain morphology differences implicated in ASD, while full deletion of SHANK3 does not cause many changes to brain morphology.

According to recent research from Ulm University (Germany), having the incorrect dosage of metal ions may disrupt neuron and cell development, specifically neuronal synapse formation. Additionally, reports have shown a strong association between autism spectrum disorder (ASD) and an imbalance in normal dosages of metal ions. This study wanted to see if changing the metal dosages would help to restore proper synaptic formation. Scientists looked at in vitro neurons in the hippocampus and created a metal ion-dosage panel similar to that of an ASD patient. Scientists found that, while changing the levels of many metals did not have an effect, changing the levels of Zn helped restore synaptic formation to normal levels when beginning with a biometal profile representative of an ASD patient.

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 www.seaverautismcenter.com 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 http://www.mountsinai.org, or find Mount Sinai on Facebook, Twitter and YouTube.

# # #

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.

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.