2019 SMS Research Symposium

Gail Reiner, DNP, MS, AANP

Smith-Magenis syndrome (SMS) is a rare disorder for which there are few clinicians experienced in the clinical care of affected individuals. Because individuals with SMS can have difficult behaviors it can be hard for providers to take a complete history and do a full exam. If visits are limited, then only the most serious problems that parents and caregivers are aware of may be dealt with at a visit and other problems common in SMS may not be addressed which limits the whole-person and family care of those affected by SMS.

Every three months a SMS clinic where patients and families can consult with an experienced provider is available Rady Children’s Hospital in association with University of California, San Diego Neurosciences. The SMS clinic formally started in the summer of 2018 to set aside a set time dedicated for this special group of rare disease patients for whom some were already receiving care.

To date, eleven patients with Smith-Magenis syndrome have been served with additional phone consultations for individuals unable to attend clinic.

The medical management checklists developed for newly diagnosed and ongoing SMS patients is used and materials specific to the care of SMS patients are part of the electronic health record which is also shared with parents through a system called “MyChart.”

Letters summarizing each visit are sent to the providers who referred each patient and orders are written by prescription or within local health systems for labs and tests and referral for specialty care for problems identified at the visit can be ordered. Social services agencies may also be sent clinic notes and economic needs are supported by letters for issues such as social security, Medicaid, and IHSS (in-home support services).

Medication management including genetic testing is available and behavioral management including toilet-training and feeding challenges are also discussed. Parents are linked to resources for education, support and recreation. Relevant research opportunities such as the SMS registry are also discussed with patients’ families.

Collaborative calls have been established between the four USA clinics to continue developing uniform care standards, have case discussions, and recommend new research questions to be considered for future research.

Rachel Franciskovich, MS, CGC, Sarah Elsea, PhD, FACMG, Kevin Kaplan, MD, Adiaha Spinks-Franklin, MD, MPH, FAAP, Theresa Wilson, MS, RD, Lorraine Potocki, MD, FACMG

Drs. Lorraine Potocki and Sarah Elsea, with the assistance of Rachel Franciskovich, genetic counselor and Theresa Wilson, senior research coordinator, envisioned a space where comprehensive and complete care for individuals with Smith-Magenis syndrome (SMS) was easy to access. Houston has been a research location on SMS for many years and in order to continue to advance research and optimize clinical care for these families, the SMS clinic was the next fitting step. In late 2017, forward movement had begun.

Beginning in November 2017, three families were the first individuals with children with SMS to receive care as a part of the SMS clinic. During this visit, the families had the opportunity to discuss the many offerings of PRISMS, consider enrolling in ongoing research, and receive their annual management and surveillance recommendations from the team. While this was a great first step, there were still many more opportunities for faster and more efficient forward movement.

Fast forward to August 2019 and the clinic has quickly expanded to include Drs. Adiaha Spinks-Franklin and Kevin Kaplan to provide developmental and behavioral pediatrics and sleep medicine expertise, respectively. Clinic occurs quarterly and we can provide care for up to 3 new patients each clinic day and up to 2-3 follow up patients. With the inclusion of a specialized, central clinic, families with children and adults with SMS have been able to reduce the number of clinic appointments needed annually and have been able to be included in more research opportunities to continue to expand our knowledge of SMS. We have seen 12 of 25 total known families with SMS in this clinic and continue to receive inquiries weekly for new patients locally and from out of state.

As the clinic continues to expand, we have partnered with PRISMS to consider providing travel funds for families with need to attend clinic from out of state or who have to travel significant distances. We anticipate being able to provide ongoing support to local providers for those families that wish to attend clinic from out of state and supply them with recommendations and resources to use once they return home. Future directions include more frequent clinic dates, transition care for adults, and the development of an SMS Center for Excellence. Continued support is encouraged as we expand and as we engage learners and providers to advance knowledge, increase interest, and promote research in the SMS community.

Barbara Haas-Givler, MEd, BCBA, Brenda Finucane, MS, LGC, Nancy Eisenhauer, MS, PA-C, Christa Martin, PhD, FACMG, and Thomas D Challman, MD, FAAP

Children and adults with Smith-Magenis syndrome (SMS) present with complex physical, behavioral, and cognitive challenges throughout the lifespan. In addition to baseline studies at the time of diagnosis, consensus management guidelines recognize the need for ongoing medical monitoring of syndrome-related physical symptoms, including myopia, sensorineural hearing loss, scoliosis, and abnormal sleep patterns. The complexity of the behavioral phenotype in SMS, including self-injury and aggression, requires a systematic approach to psychotropic medication management and coordinated behavioral interventions. Additionally, comprehensive care for this population extends outside the medical clinic to the home, the special education classroom, the workplace, and the community.

Based on both professional interest and patient need, in 2015 Geisinger established the Geisinger Smith-Magenis Clinic at its Autism & Developmental Medicine Institute (ADMI) in central Pennsylvania. ADMI’s multidisciplinary clinical team includes specialists in neurodevelopmental pediatrics, neurology, psychology, genetics, behavior analysis, and speech pathology. In order to standardize care, we undertook a comprehensive literature review to identify best practices for the ongoing medical management and support of individuals with SMS. As with other rare genetic conditions, there were few evidence-based guidelines, and syndrome-specific recommendations were largely informed by consensus statements from expert medical teams, small-scale clinical trials, and peer-reviewed publications. Best practices also included relevant standards of care for individuals with developmental disabilities, regardless of etiological diagnosis.

To our knowledge, the Geisinger Smith-Magenis Clinic is the first multidisciplinary program in the US dedicated to clinical specialty care for children and adults with SMS. Information will be presented regarding experiences gained over five years coordinating sixteen SMS Specialty Clinics. We are pleased that additional centers are developing across the country and look forward to a coordinated international network of expert care sites for SMS.

Theresa Wilson, MS, RD, Rachel Franciskovich MS, CGC, Dianne Alameddine, MS, CGC, Sarah Elsea, PhD

Smith-Magenis Syndrome (SMS) is a rare and complex genetic disorder affecting multiple body systems. Diagnostic methods and overall understanding of SMS has greatly improved in the past 30 years; however, there is much more to learn about the natural history of SMS across the lifespan.

A useful tool to expand the SMS knowledge base is a patient registry. A patient registry is a collection of standardized information about a group with a shared condition. Researchers can analyze these data to answer important questions regarding specific conditions associated with SMS, as well as document the syndrome’s characteristic state and management techniques utilized across the lifespan.

In 2017, PRISMS collaborated with Baylor College of Medicine to create the SMS patient registry. This patient registry includes demographic and medical history questionnaires, as well as a medication log. Additional surveys being reviewed for registry inclusion address sleep disturbance, movement disorder, and weight status.

Barriers to participation persisted, due to a cumbersome registration process, and enrollment plateaued. The registry being available in English only also limited international participation. There are 69 individuals presently enrolled. To reduce the burden associated with the registration, a streamlined on-boarding process was developed that can be completed entirely online; registration is ongoing. The online process will enable SMS specialty clinics to direct patients to the registry. Specialty clinics will also be able to collect data systematically and the supplemental information can be added to the registry. Increased access to the patient registry through translation into multiple languages is also underway.

Stacey Bissell, PhD

Sleep difficulties associated with Smith-Magenis syndrome (SMS) are well characterised in the research literature (e.g. early morning waking, daytime sleepiness), but caregiver experiences of managing difficult night-time behaviours are not. Given the high preference for adult attention and complex behavioural profile in SMS (e.g. impulsivity, self-injurious behaviours), there are consequences relating to safety and well-being, which have been reported anecdotally by caregivers (e.g. use of kitchen appliances, exiting the family home, caregiver fatigue).

In order to develop SMS-specific ‘best practice’ sleep guidelines to support caregivers and professionals, the Safe Sleeping in SMS research project aims to understand more about sleep management difficulties from the first-hand perspective of caregivers. This research project is funded by Cerebra and the SMS Foundation UK.

Through online surveys and face-to-face interviews, information was gathered from SMS families regarding: caregiver well-being, safe-sleeping interventions and service provision. Sleep management demands had a significant effect on caregiver well-being, particularly in relation to stress and sleep deprivation. The level of overnight respite provision available to families was variable; however, the majority of families were receiving fewer hours of respite than needed.

The extent to which sleep management difficulties in SMS impact family life is not fully acknowledged in the research literature. This may undermine the level of support available to caregivers, and the specificity of support that can be offered by professionals. It is anticipated that the development of ‘best practice’ sleep guidelines as a result of this project will highlight the key issues that need to be addressed when considering interventions and service provision for sleep management difficulties in SMS.

Rebecca Foster, PhD

Smith-Magenis syndrome (SMS) is a rare chromosomal disorder characterized by craniofacial anomalies, intellectual disability, developmental delays, chronic sleep disturbances, and extreme behavioral/emotional dysregulation. As a result, siblings of individuals with SMS may demonstrate difficulties coping, increased emotional and behavioral concerns, caregiver burden, and challenges within family relationship dynamics. The results of prior SMS sibling studies suggest a need to implement interventions aimed at addressing sibling-specific needs. The proposed intervention will address needs unique to pre-teen and teenage siblings (10-17 years of age) of individuals with SMS via a semi-structured eight week mentorship program that will match the pre-teen/teenage sibling with a young adult non-familial sibling (18-25 years of age). The telephone/videochat based intervention will involve weekly 30-60 minute discussions with topics modeled after Sibshops content and structure including: 1) Understanding SMS, 2) Emotional and Behavioral Challenges, 3) Family and Sibling Dynamics, 4) Communicating Needs, 5) Coping Skills and Self-Care, 6) Benefits and Personal Growth, 7) Siblings in Caregiver Roles, and 8) Putting It All Together. Mentors will complete all necessary training prior to program implementation. Weekly assessments of sessions will occur for both the mentor and the mentee along with baseline and post-intervention evaluations. Pros and cons, as well as anticipated challenges of initiating such a mentorship program will be discussed, including training needs, addressing crises/safety concerns, ongoing supervision requirements, anticipated outcomes, and program costs.

Takao Tsukahara, DDS, PhD

RAI1 is known to regulate spontaneous gene expression.

Smith-Magenis syndrome (SMS) is a rare neurodevelopmental disorder characterized by intellectual disabilities, aberrant circadian rhythm and obesity. Previous studies have reported that RAI1, the causal gene of SMS, “reads” a chemical code written near the DNA, and is involved in gene expression. So far, however, our knowledge of RAI1 is largely limited to its role in spontaneous gene expression.

Many developmental processes and brain functioning require evoked gene expression in response to environmental changes.

Given that development and learning-related processes require evoked gene expression to external stimuli, understanding the role of RAI1 in activity-dependent gene expression is thus important to mechanistically understand the pathology, and further develop an efficient therapeutic strategy to treat SMS patients.

Is RAI1 involved in activity-dependent gene expression? If so, how is it involved?

To address this question, we genetically reduced RAI1 in neural cultures and pharmacologically increased or decreased the neural network activity. Then, chemically labeled the newly expressed genes and compared them with that of normal RAI1 expressed cultures. Labeling of only the newly expressed genes, enabled us to profile the dynamic changes in gene expression compared to the conventional methods.

RAI1 is required for gene expression program driven by decreased network activity.

Genome-wide analysis revealed that loss of RAI1 specifically impairs the gene expression program driven by decreased network activity.

What will happen if appropriate gene programs don’t turn on in response to long-lasting changes in network activity?

Neurons have self-tuning system, so-called homeostatic plasticity, to maintain their network activity in an optimal range. For instance, when network activity increases for a long period, neurons will weaken the connections with each other to decrease their firing rate, and thereby stabilize the network activity. If this homeostatic mechanism is not evoked, network activity might keep growing and result in neuro-toxic event, such as seizures. It is known that these enduring forms of homeostatic plasticity requires activity-dependent gene expression.

Homeostatic plasticity that stabilizes neural network activity requires activity-dependent gene expression.

Since our genomic data suggested that RAI1 is required for the gene expression program driven by decreased network activity, we hypothesized that homeostatic mechanism to buffer the decreased network activity is impaired in cultures with reduced Rai1 expression. To this end, we employed electrophysiological and molecular imaging techniques to assess the role of RAI1 in homeostatic plasticity.

Consistent with our genomic data, loss of RAI1 impaired homeostatic plasticity to compensate for reduced network activity.

Misregulated genes involved in Homeostatic plasticity might be potential targets for therapeutic intervention for SMS patients.

Taken together, our results suggest that RAI1 regulates gene expression upon reduced neural activity, thereby augmenting neural connections to stabilize the network activity. Thus, this study opens the possibility that aberrant homeostatic mechanisms play a role in the pathology of SMS and the identified misregulated genes in the consequence of RAI1 reduction may represent the novel therapeutic targets for SMS patients.

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Francis Gordovez, Shawn Kamboj, Bryce England, Joanna Cross, Jill Russ, Winston Corona, Dena Hernandez, Nirmala Akula, Layla Kassem, Ann Smith, Sevilla Detera-Wadleigh, Francis McMahon

Introduction:

SMS, a rare disorder characterized by behavioral problems, sleeping difficulties, distinct facial features, and intellectual disability. SMS is caused by a loss of a region in chromosome 17. However, in 10% of cases, only mutations in retinoic acid induced 1 gene (RAI1) are seen. Animal and cellular studies propose that RAI1 influences function of other genes. Despite this, exact role of RAI1 has yet to be established. Mimicking cellular conditions may unravel new RAI1 functions. Induced pluripotent stem cells (iPSCs) carry a replica of the donor’s genome and can be differentiated to other cells. This allows studies in renewable, disease-relevant cells. We use iPSCs to investigate aspects of SMS.

Methods:

Our preliminary work includes skin samples from three unrelated SMS cases and three age- and sex-matched, unaffected controls. These were grown and modified to become iPSCs. iPSCs of good quality were differentiated to NPCs. After 5 days, genomic DNA and total RNA were extracted for assay with the Illumina EPIC methylation arrays and RNA sequencing (RNA-seq).

Results:

RNA-Seq revealed 35 genes that were differently expressed in SMS cases. These genes are involved in cell signaling, extracellular matrix organization, and the immune- mediated processes. DNA methylation arrays showed a decrease in methylation in 13 CpG sites in SMS cases. These 13 sites mapped to three distinct genes.

Discussion:

This study has identified genes and sites in the DNA that are different in SMS cases when compared to unaffected controls. This revealed functional units that potentially contribute to the disease process. Moreover, DNA methylation changes may reveal more about how the brain develops. We are extending this project to study changes in iPSC-derived neurons. Overall, it is hoped that experiments may reveal disruptions in neurobiological processes, pointing the way toward new therapies for SMS.

Jeffrey Kidd

Too much or too little of the protein encoded by the RAI1 gene leads to the range of phenotypes associated with Smith-Magenis Syndrome. Understanding the role of RAI1 will require detailed studies of the direct function of the gene as well as investigation of cell and animal systems in which the level of the gene has been perturbed. One example of such a system is the domestic dog, which has been altered for thousands of years by human directed breeding. Since the time of Charles Darwin, biologists have recognized that unrelated domesticated species share phenotypes that distinguish them from their wild ancestors. Key features such as facial and ear structures, pigmentation, and behaviors have been recurrently altered by domestication. We used new genetic data and statistical algorithms to compare the genomes of dog and wolves to find genetic loci that have been altered by artificial selection during domestication. We found hundreds of gene loci that were altered. These loci were associated with key processes important in the development and function of the nervous system, and the highest-ranking gene in our analysis of dog domestication is RAI1. Together, our findings suggest that the altered RAI1 levels in dogs may lead to changes in development, behavior, and the sleep-wake cycle in comparison to wolves. Work to understand the exact molecular nature of these changes, and how they relate to the biology of RAI1 function, is currently on going. Together, we hope to use the results of 20,000 years of dog domestication to further explore how altered levels of RAI1 impact the development and adult phenotypes of an organism.

Sandra Smieszek, PhD

Smith-Magenis Syndrome is a developmental disorder often associated with genetic variation. Research indicates that the sleep disruptions in SMS may result from an abnormal circadian rhythm, potentially providing a mechanism to treat the underlying cause of these symptoms.

We conducted whole genome sequencing analysis to explore the genomic landscape of the SMS population with confirmed RAI1 gene loss. We investigated 41 individuals with confirmed diagnosis of SMS, N=41. We evaluated the size of the mutation on chromosome 17, as well as copy number variants, and correlated that with sleep and clinical parameters.

It is believed that the loss of one gene, RAI1, is responsible for most of the features of the condition however careful characterization of the disorder will enable one to design more effective targeted treatments prospectively. It will also help delineate risk factors and comorbidities in this already complex disorder.

Castan Chibas, S. Sridhar, T. Paretkar, M. Ramirez, M. Przybylska, N.S. Yew, and Sarah Elsea

Smith-Magenis syndrome (SMS) is a complex neurodevelopmental disorder caused by reduced expression and function of the gene RAI1. Clinical features include intellectual disability, early onset obesity, sleep disorder, self-injurious behaviors, and mild craniofacial anomalies. Currently, there is not an effective treatment for SMS. We have developed a targeted therapeutic strategy using a deactivated version of Cas9 fused with the viral activator VP64 (CRISPR-dCas9-VP64) to increase the expression of the remaining functional RAI1 allele, aiming to compensate the reduced expression observed in SMS. In order to validate this strategy, mouse fibroblasts were treated with the CRISPR-dCas9-VP64 system, targeting the Rai1 gene promoter region. Our results reveal that six constructs of this system were able to increase expression of Rai1 and subsequently increased the expression of the Rai1-regulated downstream gene, Bdnf, which is typically reduced in expression in SMS and associated with obesity. This novel approach provides a versatile tool to regulate RAI1 expression with potential applications in the development of a therapy for SMS.

David Reiner, PhD, Ann C.M. Smith, MA, DSc (Hon), CGC

Smith-Magenis syndrome (SMS) is caused by genetic mutations in both the known disease- causing RAI1 gene, and possibly other genes defined in the region of chromosome 17 (17p11.2) for individuals with the deletion disorder. This results in a neurodevelopmental disorder resulting in intellectual disability, and sleep problems. These issues are also known to be caused by the dysregulation of histone methylation. Methylation is a molecular process, that precisely attaches or removes chemical marks (methyl groups) on the amino acids of histone proteins, the structural subunits of chromosomes. The correct writing and reading of these marks by specialized protein subcomplexes is crucial for either increasing or decreasing gene expression which is required for genes to function fully within individual cells. Interestingly, a histone methylation reader complex was recently proposed that contains RAI1. A network biology approach, whereby biological data sets are analyzed using computer programs, is used to construct a SMS specific biological network, with nodes representing genes and drugs known to be safe in SMS patients. The edges represent experimentally verified interactions between genes and drugs, taken from various biological network databases. The resulting SMS specific network is validated and analyzed using various bioinformatic approaches. Importantly, this network can be used for generating new ways of studying SMS disease mechanisms and identification of medicines, already available but previously not identified for the purpose of treating SMS, that may be helpful in reducing the suffering experienced by SMS individuals.

Anusha Gandhi, Dihong Zhou, Joseph Alaimo, Edwin Chon, Michael Fountain, Sarah Elsea

Sleep disturbance in school-age children has been studied to some extent in children with Smith-Magenis syndrome (SMS). However, for neurodevelopmental disorders such as Pitt-Hopkins syndrome (PTHS) and MDB5-associated neurodevelopmental disorder (MAND), the existence of sleep disturbance in this population is not yet well characterized. We used the Children’s Sleep Health Questionnaire (CSHQ) to assess how sleep disturbance in school-age children differed between groups and to identify disorder-specific sleep problems. We also compared our groups to a similar group with autism spectrum disorders (ASD). Our data provided evidence for the presence of sleep disturbance in each condition. However, while there were similarities, specific concerns differed between cohorts. The MAND group had a significantly higher mean total sleep disturbance score than the ASD group, while the PTHS and SMS groups did not. Furthermore, the PTHS group had significantly longer mean sleep duration than the other groups as well as less daytime sleepiness than the ASD group. All 3 groups exhibited restless sleep, bedwetting, and increased parasomnias as compared to the ASD group. The SMS and MAND groups showed more night wakings than the ASD group. Our general findings suggest that sleep disturbance in PTHS is less severe than in SMS and MAND and that sleep disturbance in SMS and MAND do not differ significantly from each other based on total scores, although specific aspects of that disturbance do differ. Overall, while different aspects of sleep disturbance in each disorder mirror the wide range found in the general ASD population, certain aspects such as night wakings and parasomnias are shared and do differ significantly from ASD. Our research further illustrates the complexity of these conditions and the challenges of underlying sleep disturbance in each population, indicating the need for more support, education, and treatment for these individuals.

Leniher Castan Chibas, Swetha Sridhar, Tanvi Paretkar, Maricela Ramirez, Toshihiko Ezashi, and Sarah Elsea

Smith-Magenis syndrome (SMS) is a neurodevelopmental disorder caused by deletion or mutation of one of the copies of the gene RAI1. Currently, there is not an effective treatment for SMS, and patients receive only supportive therapy. Our gene therapy strategy is focused on restoring the missing copy of RAI1 using lentiviral vectors in a controlled manner. In order to prove this concept, we evaluated this therapy in patient-derived cells, including fibroblasts and neural progenitor cells derived from these fibroblasts. Our results show that RAI1 expression is rescued to normal levels if the gene delivery is performed in a controlled manner. The expression of BDNF, a gene related with obesity in SMS, is also restored as a consequence of this therapy. Validating this approach in patient-derived cell lines, including fibroblasts and neural progenitor cells, provides an opportunity to assess real consequences of changes in gene expression and impacts on cellular function in the disease state, with potential impact on the development of therapies to improve the quality of life of SMS patients.

Tanvi Paretkar, Leniher Castan Chibas, Swetha Sridhar, Maricela Ramirez, and Sarah Elsea

Smith-Magenis syndrome (SMS) is a genetic disorder caused by reduced amounts of RAI1 and characterized by abnormalities such as intellectual disability, developmental delay, sleep disturbance, and self-injurious behaviors. Currently, there is no effective treatment for SMS. Because most of the concerns related to SMS are neurological, related to sleep, behavior, and metabolic control, we are working on a study to see if the RAI1 gene can be effectively put into delivered to the brain of SMS mouse model. We want to see if, with our technique, the RAI1 gene can reach the appropriate brain regions of the mouse which are responsible for the main symptoms. We will also check to see if the RAI1 expression in those brain regions is restored to the right amounts and if other genes regulated by RAI1 are functioning appropriately and being produced at the right levels. At this stage, this project is to show whether or not the RAI1 gene can be reached to the targeted areas with an appropriate technique and delivery system in order to result in a functional outcome. So far, our results are encouraging, we plan to conduct further studies to develop a feasible gene therapy for SMS.

C.M. Grochowski, C. Zhang, C.R. Beck, Z.C. Akdemir, C.M.B Carvalho, J.R. Lupski

Not all children who are diagnosed with Smith-Magenis syndrome have the same set of clinical symptoms even though they may have the exact same clinical diagnosis. While some children may show a certain set of traits such as skeletal and behavioral problems, others may show traits that are more severe or outside of the typical spectrum. Currently, we do not know why these differences occur in SMS patients.

While we know that deleting the gene RAI1 causes SMS we don’t typically look at the other ~20,000 genes that are in a person’s body. These other genes control everything from hair and eye color but when there are specific mutations in some genes, they can also cause problems. New genetic testing known as “whole exome sequencing” allows us to look at the other ~20,000 genes in person’s body to see what other genetic changes an individual has. A person may have another mutation that causes the symptoms of SMS to appear worse or cause a completely different disease in addition to SMS complicating a person’s care.

Our goal is to not only understand the breath of SMS symptoms but also to better serve the SMS community in adding to our scientific understanding of the disease.