Posts Tagged ‘Phelan-McDermid Syndrome’

Unraveling a Mystery in Nebraska

July 6, 2011 33 comments

The Combating Autism Reauthorization Act of 2011 would reauthorize the landmark Combating Autism Act (CAA) of 2006, securing the federal response to the national and public health emergency posed by autism spectrum disorders (ASDs.) Key components in the original landmark legislation will expire on September 30, threatening further federal support for critical research, services and treatment for ASDs. Families across the United States have shared how funding under the CAA has changed their lives and why it is so critical  to maintain a strong federal role in  research and treatment. Click here to learn more.

A conversation with Cynthia Schauss

Of the many enigmas that confront the autism community, understanding Phelan-McDermid Syndrome (PMS) has proven one of the most perplexing. In fact, just 600 cases have been identified, although the actual prevalence is believed to be far higher. PMS is caused by the absence of genes at the tip of the 22nd chromosome; the lack of the “Shank3 / ProSAP2” gene in particular is suspected as the primary cause of the symptoms associated with PMS.

Cynthia Schauss has come to learn about Phelan-McDermid Syndrome in raising her eight-year-old daughter Ashlyn in Bennington, NE, just outside of Omaha. Ashlyn’s developmental delays were not readily apparent, but her family knew she was struggling. Only because of improved genetic testing made possible through funding under the Combating Autism Act was the Schauss family able to obtain a PMS diagnosis for Ashlyn. This summer, Ashlyn will take part in stem cell research funded through CAA at Stanford University to broaden the knowledge about autism and Phelan-McDermid Syndrome.

We struggled for seven years to find out what was going on with our daughter. Doctors would tell us over and over again, “I have never seen a child quite like Ashlyn!” The medical field has not quite caught up with the diagnosis. We had to force the issue that something had to be wrong. It was important for us to get our doctors to understand that we wanted to do whatever we could to help our daughter.

The initial concerns for the Schauss family involved delayed speech and they began early intervention when Ashlyn was 2. At age 4, a psychiatrist recommended ADHD medications. An autism clinic reported Ashlyn was too social, although she did have other autistic characteristics. A genetic doctor believed Ashlyn had the most severe case of ADHD he had ever seen along with a possible case of dystonic cerebral palsy (CP.) An initial genetic test revealed no abnormalities.

We decided to redo genetic testing last June when Ashlyn was 7 and that test showed the partial Shank 3 deletion.  We credit advancements in the genetic micro-array to aiding in finding the deletion as her deletion is so incredibly small.

For us, it’s important to partner with the school system to aid in understanding how to work with Ashlyn in a school environment and how to understand her disability. Part of Ashlyn’s issue revolves around a receptive language disorder.  She is completely verbal, but has a hard time understanding what is expected of her.

As Ashlyn has aged, her traits of autism have become more obvious, as Cynthia related in a recent story written for the PMS Foundation:

At the age of 8, Ashlyn seems more like a 4-5 year old. Her delays are becoming more and more evident. She can’t ride a bike or participate in sports. She shuffles her feet when she walks. Her obsessive finger chewing and picking make her stick out like a sore thumb in a class of her 2nd grade peers. Reading, writing, and math seem like partially unobtainable goals.

After years of telling doctors and therapists that something was not right, we finally received a diagnosis. We’ve learned to cherish Ashlyn’s speech and verbal abilities. We love that she is mobile and that her motor impairments are somewhat mild.  We struggle to understand why she can talk and walk and other children with the same deletion are mostly non-verbal or immobile.  We hope that future research can shed some light on the diagnosing and understanding of PMS and autism.

Turning Medical Science into Medical Treatments: The Quest for Translation in Phelan-McDermid Syndrome

March 19, 2011 24 comments

by Guest Blogger, Andrew Mitz, Ph.D.

The First International Phelan-McDermid Syndrome Foundation (PMSF) Symposium held earlier this month showed how a small parent-run organization can think and act big! With only 450 registered families worldwide and a mom at the helm, the PMSF put together a first class scientific meeting at the New York Academy of Medicine, by partnering with researchers from the Seaver Autism Center, Mt. Sinai School of Medicine. The goal of the meeting was to chart a course towards medical treatments for this rare, genetic cause of autism.  The theme of the meeting was scientific sharing, teamwork, and quality research.   Over two days (March 3rd and 4th), the participants heard from families and experts about Phelan-McDermid Syndrome, its history, its connection to autism spectrum disorders, and the very latest in scientific approaches. They also learned how people studying other disorders have found fast paths to drug development.

The early presentation by Dr. Catalina Betancur (INSERM, France) provided two key foundational scientific links to help open the meeting.  First, she showed that Phelan-McDermid Syndrome, also called 22q13 Deletion Syndrome, is one of many known genetic causes or risk factors of autism spectrum disorders.  Second, virtually all cases of chromosome 22 abnormalities that cause Phelan-McDermid Syndrome share damage to or loss of the SHANK3 gene as a common feature.  SHANK3 gene mutations are also found in about 1% of the general autism population. That is why understanding the biology of SHANK3, and how to treat the loss of SHANK3 in Phelan-McDermid Syndrome patients, resonated through every talk of the meeting.

The SHANK3 gene encodes a protein called Shank3 that is critical for proper synapse function. Synapses are the junctions or contact points between neurons of the brain, where information is exchanged. Thanks to the elegant and detailed descriptions provided by Dr. Tobias Boeckers (Ulm University, Germany), participants learned how Shank3 proteins stick to each other. The proteins form an interlocking network that acts as a backbone for the synapse both mechanically and chemically.  For this reason, Shank3 (also known as ProSAP2) is called a scaffolding protein.  Dr. Boeckers showed how the loss of Shank3 in Phelan-McDermid Syndrome makes the entire synaptic junction unstable. Shank3 is one of the first proteins required for synapse formation, which is constantly taking place in the brain. Dr. Carlo Sala (University of Milan, Italy), another pioneer in SHANK3 research, explained that proper synapse formation and stability are essential processes for learning and memory.

In a particularly memorable session on the first day, Dr. Boeckers and other investigators including Dr. Joseph Buxbaum (Mount Sinai School of Medicine), Dr. Craig Powell (University of Texas), and Dr. Yong-Hui Jiang (Duke University) shared details about their respective efforts to develop a Phelan-McDermid Syndrome mouse model with a mutated or deleted SHANK3 gene. The open and frank exchange resulted in a greater appreciation among the participants of the methodological challenges they share, and underscored how unfettered sharing of information can accelerate scientific progress as it helps reduce duplication and facilitates exploration of a greater range of possible solutions.  The families with Phelan-McDermid Syndrome looked on in great appreciation as the scientists ventured outside their normal comfort zone to openly share “intimate” (unpublished) details of their research.

Dr. Ricardo Dolmetsch (Stanford University) described his cutting-edge work on induced pluripotent stem cells (iPS cells).  He takes tiny skin samples from patients and, using a special protein cocktail, ”reprograms” them. The painstaking process takes many months to first produce stem cells, and then neurons. Amazingly, Dr. Dolmetsch showed that these neurons behave much like the neurons studied in animal models, which validates both his work and the animal models.  With his iPS-generated neurons in hand, Dr. Dolmetsch plans to test compounds to see which ones are most effective in reversing the deficits seen in these cells.

Dr. Sala studies animal neurons using another experimental approach called “knockdown”.  He simulates what happens in Phelan-McDermid Syndrome patients missing one of their SHANK3 genes by interfering with the production of Shank3 protein.  When Shank3 is knocked down, Dr. Sala noticed a reduction in a receptor called mGluR5. This receptor is normally active during communication between neurons. mGluR5 mobilizes other signaling molecules, gene expression and production of other synaptic proteins. Dr. Sala showed that it is possible to partially restore much of these functions by applying a drug that stimulates the remaining mGluR5 receptors and activates related molecular pathways. This work is vital for identifying potential biological targets for drug development.

In the quest for a quick and efficient path to new therapeutics, Dr.Ozlem Bozdagi Gunal (Mount Sinai School of Medicine) presented exciting new results. Using “knockout” mice missing one SHANK3 gene, she looked to see what known drugs could correct at least some of the synaptic defects. She showed that the structural defects in the synapse lead to failures in the way it functions, especially during learning. The research team identified a drug that allows a particular well-studied form of synaptic strengthening, called long term potentiation, to proceed normally in spite of deficits in Shank3.

Everyone’s eyes and ears were on Dr. Mark Bear (MIT) as he described his groundbreaking work to find treatments for Fragile X Syndrome, another single gene disorder that, like PMS, can cause autism. He brought hard-learned lessons from his translational efforts. He explained that the quickest road to therapeutics requires a detailed understanding of the underlying pathophysiology (disease mechanism), and robust animal and cell model systems for screening and evaluating promising candidate drugs. He emphasized information sharing and the importance of high quality science.
Dr. Roberto Tuchman, the director of the Autism Program at Miami Children’s Hospital Dan Marino Center spoke on the clinical overlap between epilepsy and autism. He explained that epilepsy, when it starts early in life, is a developmental disorder of the brain with similar pathophysiology to autism. He suggested that early detection and treatment of epilepsy is an important way to ensure optimal brain development. Likewise, early detection and treatment of autism could be just as valuable. Dr. Tuchman highlighted new developments in the early behavioral treatment for autism and suggested that these treatments could be effective for all early onset neurodevelopmental disorders in which there is an atypical developmental trajectory. He favors treating at-risk children rather than waiting for a diagnosis of autism or autism spectrum disorder.  By waiting, the window of opportunity to protect development may narrow. He raised the possibility that new drug interventions targeting synaptic pathways common to both epilepsy and autism hold significant promise for disorders such as Phelan-Mcdermid syndrome, in which autism and epilepsy commonly co-exist.
In the final session of the symposium, participants divided into three workgroups.  These breakout sessions hosted lively discussions among family members, clinicians, researchers, and other advocates. These workgroups leveraged topics and ideas discussed earlier in the symposium, with particular attention paid to (1) how the Phelan-McDermid Syndrome patient registry can best meet the needs of its many stakeholders, (2) how clinical research and care guidelines for Phelan-McDermid Syndrome can be advanced, and (3) how the patient advocacy community can help to accelerate translational efforts related to Phelan-McDermid Syndrome.  The breakout sessions proved to be an effective means of engaging all participants to work collaboratively in determining the future directions of PMSF’s research support initiatives.  There is no question that everyone left the meetings with a heightened sense of partnership towards an urgent goal.


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