One of the challenges in pursuing the causes of autism spectrum disorders is the heterogeneity of symptoms and life history of the individuals affected. On Wednesday, one day before the start of the International Meeting for Autism Research (IMFAR), meetings of two family foundations centered on specific genetic syndromes for autism moved past these challenges to offer hope for recovery.
The Phelan-McDermid Syndrome Foundation (PMSF) was one of the family foundations that hosted a meeting of international scientists, clinicians and parents to better understand PMSF. Katy Phelan, Ph.D. (Molecular Pathology Laboratory Network, TN) presented a characterization of the individuals affected, as many scientists working with animal models of this disorder have met very few, if any, persons with PMS. Dr. Phelan reviewed the cluster of symptoms present typically early in life, including a “floppy” infant, general developmental delays and poor or absent speech. She also reviewed evidence that led to the recognition that individuals with PMS had some form of mutation in the SHANK 3 gene on chromosome 22.
The meeting soon shifted to animal models and presentations from several researchers who presented greater detail about the role of the protein SHANK 3 at synapses, or junctions of neurons, which are crucial for learning and memory functions. It was shown that SHANK 3 is responsible for tying together two receptors for the common excitatory transmitter glutamate at the synapse. Through a series of careful experiments examining the structure and function of synapses when more or less SHANK 3 protein was present, Joseph Buxbaum, Ph.D. (Mount Sinai School of Medicine, NY) and colleagues learned that SHANK 3 controlled the physical connections that underlie plasticity of the synapses (the mechanism that underlies learning and memory). After achieving this detailed understanding of how the system develops and stabilizes in the animal, the next step was to attempt to rescue normal function in these animals that lack SHANK 3. A related set of receptors present on the cells (AMPA receptors) was targeted with the drug called IGF1. Injections of IGF1 into the mouse travelled across the protective barrier that encases the brain and had the desired effects on the cells, rescuing the structure and function of the synapses that had the atypical SHANK 3 proteins.
Lastly before a dinner gathering where parents scientists and clinicians can share ideas with each other more informally, Sarah Curran, Ph.D. (Kings College, London) presented on new technology that may allow the creation of stem cell lines for deeper analysis of the effect of a single individual’s mutations (the SHANK 3 gene can have mutations at several places, potentially leading to different effects on the functioning of the SHANK 3 protein) by analyzing a single complete hair from an affected person.
The Isodicentric 15 Exchange, Advocacy and Support group (IDEAS) is another family foundation that hosted a meeting of clinicians, scientists and parents. Of the several genetic disorders that have a ‘causal’ relationship to autism, the duplication of a portion of chromosome 15q (IDIC15q) figures prominently in post-mortem brain research. In fact, one out of every ten brain donors to the Autism Tissue Program comes from this specific population that is represented by the IDEAS organization. A major concern of the group and a factor in the high brain donation rate in this group of only 650 known affected individuals is sudden unexplained deaths, a fact reviewed by Edwin Cook, MD (University of Illinois at Chicago) at the meeting. Seizure activity is many of the individuals is thought to underlie their apparent vulnerability and the IDEAS group has been proactive in publicizing recommendations from their physician-advisors, including Carolyn Schanen, M.D., Ph.D. (University of Delaware) who gave the opening presentation at this meeting. The physician-advisors also promote brain donation to understand the causes of death and look for developmental changes consistent with autism and/or epilepsy.
The meeting brought together researchers and parent advocates in a significant effort to understand the research to date and fine tune future efforts. Jerzy Wegiel, V.M.D., Ph.D. (New York Institute for Basic Research) described neuropathology in 5 brain studies completed to date that shows unexpected ongoing production of new brain cells (neurogenesis), a atypical early migration of brain cells, and distortion of the cell structure reflecting an altered course of maturation of brain cells. Each of these brain anomalies can contribute to seizure activity and the study of brains and clinical evaluations of the donors will continue.
In conjunction with the neuropathologic examinations of brain donors, IDEAS asked its families to participate in a seizure survey. Preliminary results from about 85 participants shows various types of seizures and onsets; results will be posted on the IDEAS site and communicated via the Autism Speaks blog. Since sudden deaths often occurred during sleep, Sanjeev Kothare, M.D. (Children’s Hospital, Boston, MA) was present to provide information on his studies of breathing abnormalities in patients with IDIC15q. He reviewed the clinical spectrum of duplications on chromosome 15q: epilepsy, low muscle tone, atypical facial features, moderate-severe developmental delay, and autistic behaviors. He speculated that the increased risk of sudden death is due to abnormalities of sleep, cardio-vascular function, mitochondrial function and epilepsy. The results of his sleep study on 5 children with IDIC15q revealed central sleep apnea that occurs when the brain does not send proper signals to the muscles that control breathing often in conjunction with seizure activity. This very important work will continue and many of the IDEAS families have worked with their own doctors to obtain a sleep study to determine both seizure and breathing activity.
An additional highlight of the meeting was a talk by James Sutcliffe, Ph.D. (Vanderbilt University) on one of the genes of interest in the duplicated piece of chromosome 15 – the GABA B3 receptor. GABA is the main inhibitory neurotransmitter and any dysfunction in its receptor is thought to increase brain activity and might contribute to seizures. He is studying rare point mutation in this gene that was also found in a condition known as Childhood Absence Epilepsy. A presentation by Larry Reiter, Ph.D. (University of Tennessee Health Science Center) focused on a subset of 15q duplications called ‘interstitial duplications’. These are also duplications of genes in the 15q portion of the chromosome but instead of arising de novo in the child, are inherited from the mother or father. Overall, the future goals are aimed at learning more about the conditions that affect mortality such as low muscle tone, apnea and seizures. Further genetic studies on molecular mechanisms to find drug targets will include mouse models and analysis of DNA and brain tissue.
Taken together these meetings offered a positive view for the future. Families are working closely with clinicians and researchers to find effective new therapies for genetic syndromes that present as autism. The larger hope is that as these syndromes reveal their secrets, they will provide us with new tool with which to treat other forms of autism.
Thank you to Andy Mitz, Ph.D. of NIH for providing input on the PMSF meeting.
To read complete IMFAR coverage, please visit http://www.autismspeaks.org/science/science_news/imfar_2010.php.