Fragile EXpress News Emory University School of Medicine Department of Human Genetics

Happy New Year from our team at Emory University! Emory Fragile X Clinical Trials Unit We are pleased to announce our participation in the following clinical trials for potential drug therapies in fragile X syndrome (FXS): FXS Adult Clinical Trial Sponsored by Novartis Pharmaceuticals Individuals with FXS are missing or have a low level of the protein produced by the FMR1 gene (FMRP); this low level of FMRP causes increased activity of the metabotropic glutamate receptor (mGluR5) in the brain. It is thought that the increased activity of mGluR5 causes the learning and behavior symptoms in FXS. The increased mGluR5 activity is like a car that keeps driving without any brakes. The new drug we are testing is an mGluR5 antagonist. It puts a ―brake‖ on the mGluR5 activity in the brain—it does what FMRP normally does. If the mGluR5 activity is stopped, then FXS-specific behaviors (e.g. aggression, anxiety) may improve. This improvement may also help with learning. This trial is for adults 18-45 years of age.This phase IIb clinical trial is posted on www.clinicaltrials.gov under study #NCT01253629. FXS Teen and Young Adult Clinical Trial (STX209) Sponsored by Seaside Therapeutics This phase III clinical trial is sponsored by Seaside Therapeutics. It is testing the safety and effectiveness of an investigational drug, Arbaclofen (a GABA-B receptor agonist), in adolescents and adults (12-25 years of age) who have FXS. This phase III clinical trial is posted on www.clinicaltrials.gov under study #NCT01282268. FXS Teen Clinical Trial Sponsored by Novartis Pharmaceuticals This study is testing the same investigational drug as the current Novartis Adult Study in teenagers (12-17 years of age) with FXS. This phase II clinical trial is posted on www.clinicaltrials.gov under study # NCT01357239. FXS Children Clinical Trial (STX209) Sponsored by Seaside Therapeutics This phase III clinical trial is sponsored by Seaside Therapeutics. It is testing the safety and effectiveness of an investigational drug, Arbaclofen, as a potential treatment in children (5-11 years of age) with FXS. This phase III clinical trial is posted on www.clinicaltrials.gov under study #NCT01325220.

Fragile X Syndrome Research 2012 Special points of interest:  Emory FXS Clinical Trials

Going On  Information on the

Emory FXS Clinic  CDC FXS Team

Announces New Website  Save the Date for the

2012 International FXS Conference in Miami, Florida  Research Team Updates

Save the Date! 2012 International Fragile X Conference July 25 – 29, 2012 Intercontinental Hotel Miami, Florida

For more information on any of the current and upcoming clinical trials, Please contact: Heather Clark Krista Charen Lisa Shubeck (404) 778-8484 (404) 778-8479 (404) 778-8478 [email protected] [email protected] [email protected]

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The Fragile X Syndrome Clinic: Questions and Answers The Fragile X Syndrome Clinic at Emory University celebrated its seventh birthday in November 2011. The clinic was established to serve children and families with fragile X syndrome. For those of you who are not familiar with our services, we would like to give you an introduction and answer some of your questions. What age children are you currently seeing in your Fragile X Syndrome Clinic? We see individuals from birth to age eighteen years. How do I make a clinic appointment? To make an appointment, call Jean Luan McColl, Clinic and Research Assistant, at 404-778-8619. We think it is important that parents are the ones to make the appointment. That initial phone call gives us the opportunity to describe the clinic and the care we offer. We can also find out if there is information about fragile X syndrome that the family needs immediately. If so, we can often provide it by phone or mail before their clinic appointment. How is a visit to the Fragile X Syndrome Clinic different from a visit to a pediatrician? We are not a substitute for a pediatrician. Your child should see a pediatrician who you trust to provide all the best general pediatric care and who will be available for those midnight earaches that are bound to happen. We provide specialty care and information about children with fragile X syndrome. Where is the Fragile X Syndrome Clinic located? The clinic is located in a facility just off the Emory University campus near the corner of North Decatur and Clairmont Roads. The address is 2165 North Decatur Road, Decatur, Georgia, 30033. Parking is free and convenient. How do I find out more about the clinic? Jean Luan McColl, Clinic and Research Assistant, will be glad to answer questions related to the clinic. She can be contacted by email at [email protected] or by telephone at 404-778-8619. All of us in the Emory University Fragile X Syndrome Clinic thank the National Fragile X Syndrome Foundation and The Fragile X Association of Georgia for their continued support.

Fragile X Syndrome Clinic Staff Heather Clark, MS, CGC Genetic Counselor

Jeannie Visootsak, MD Assistant Professor

Fragile X Clinic Coordinator 404-778-8484

Fragile X Clinic Medical Director 404-778-8590

[email protected]

[email protected]

Adrienne Perkins, MEd, MS Psychological Specialist

Jean Luan McColl, BA Clinic and Research Assistant

404-778-8459 [email protected]

404-778-8619 [email protected]

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What Does a FXS Clinic Visit Include? A review of your child’s medical and educational history. When parents schedule an appointment, we ask for permission to get their child’s medical records. Information from the pediatrician and any specialists helps us get to know your child. In addition, we also review your child’s psychoeducational evaluation and Individualized Educational Plan (IEP). A discussion of your child’s fragile X syndrome report. Parents often want to know more about how fragile X syndrome occurs, what the diagnosis means for their child, and how the inheritance pattern may impact other family members. We can provide this information. A physical exam. We complete a basic physical exam of your child and make a special effort to answer any questions you have about features that are common among individuals with fragile X syndrome. A developmental evaluation. Our Medical Director, Dr. Jeannie Visootsak, is a board-certified developmental pediatrician. After conducting a developmental evaluation she discusses her findings with parents and makes recommendations for the timing and frequency of interventional therapy (physical, occupational, speech/language). Each child is an individual with developmental strengths and challenges. Our goal is to identify these strengths and challenges and make recommendations to maximize each child’s potential. An educational psychological consultation. We will review your child’s current psychoeducational assessment and IEP and offer recommendations that are appropriate to your child’s specific needs. Referrals. Based on each child’s medical history, physical examination, and developmental evaluation, we suggest appropriate specialists if needed. Answer questions. This is perhaps the most important part of your visit. We urge parents to come with their questions. Each family who visits our clinic is in a different place in terms of their knowledge of fragile X syndrome. We try to tailor visits to each family’s needs.

Emory Fragile X Research Team Stephanie Sherman, PhD,

Professor and Principal Investigator

Emily Graves Allen, PhD, Assistant Professor Ashima Amin, Research Technical Specialist Krista Charen, MPH, Research Projects Manager/Clinical Trials Coordinator Debra Hamilton, MA, PsyS, Senior Psychological Specialist Weiya He, MS, Senior Research Specialist Jessica Ezzell Hunter, MS, PhD, Post Doctoral Trainee Jorge Juncos, MD, Neurologist, Movement Disorders Johnnie Lawrence, Research Interviewer/Clinical Trials Phlebotomist Joash Lazarus, MD, Clinical Research Fellow, Movement Disorders Nirupama Masse, Senior Research Specialist Lisa Shubeck, BA, Research Project Coordinator/Clinical Trials Coordinator Stuart Tinker, BS, Senior Applications Developer and Data Analyst

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Fragile X Clinical and Research Consortium (FXCRC) An International Resource for Families and Professionals in the Fragile X Community The Fragile X Clinical and Research Consortium (FXCRC) is a group of clinics and research facilities that are committed to helping families and people who are affected by fragile X syndrome (FXS). It was founded in 2006 with support from the National Fragile X Foundation (NFXF) and from the Centers for Disease Control and Prevention’s (CDC) National Center on Birth Defects and Developmental Disabilities. In September of 2011, CDC announced its renewed funding for the FXCRC, based on its success over the last 5 years. The FXCRC currently includes more than 25 clinics across the United States and internationally. These fragile X specialty clinics offer medical, therapeutic, and educational evaluations, treatment recommendations, and referrals to other important resources. In addition to care, the goal of these centers is to gather information from patients and families to help expand knowledge about FXS to guide future treatment. The Fragile X Center at Emory University is committed to this effort. One of the best ways for families to help their doctors gather this information is to become a part of the FXCRC Registry and Clinical Database. Individuals and families can join the FXCRC Registry without becoming part of the Clinical Database, but the two are designed to work together to increase the understanding of FXS. The goal of the FXCRC Registry is to provide participants with opportunities to become involved in research projects or clinical trials. These projects have to be approved by an expert review team before they are offered to the registrant. Individuals who have a family member who has been diagnosed with a fragile X-associated disorder can become a part of the Registry. This includes all members of the family, not just those who are affected with one of the fragile X disorders. Each registrant first signs a consent form and then fills out a short Registry form. Registrants provide basic information about themselves and the ways they may want to become involved in research. A parent or guardian approves participation and signs for dependents. The goal of the FXCRC Clinical Database is to gather clinical, health, and quality-of-life information on individuals with FXS, and from their families. The information is collected by the clinician. When this information is gathered from many participants in fragile X clinics across the country, it will become a valuable tool to help better understand FXS across the lifespan of the individual. This includes learning about physical and emotional health, education, and overall quality of life. The information will help clinicians and educators create better therapeutic and educational programs. We think that this could benefit millions of individuals with FXS throughout the world. Families who want to join the FXCRC Registry or Clinical Database may contact the FXS clinic nearest to them to ask about participation. Or, they can discuss the project with their Fragile X clinic physician at their scheduled appointment. Participation is always voluntary. A full listing of clinics can be found at www.FragileX.org or by calling the National Fragile X Foundation at 1-800-688-8765.

CDC Fragile X Syndrome Team Announces New Website The National Center on Birth Defects and Developmental Disabilities with the Centers for Disease Control and Prevention (CDC) has launched a new website on fragile X syndrome and fragile X-associated disorders. The site includes facts about fragile X syndrome and its inheritance, summary information from recent studies and scientific publications, and many links to other associated information. It is a great resource for families and for health and educational professionals. Check it out at: http://www.cdc.gov/ncbddd/fxs/index.html

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Welcome to the Team: Joash Lazarus, MD Joash Lazarus, MD, is the newest addition to the FXS research team. Dr. Lazarus joined our team in 2010 to assist Dr. Jorge Juncos, our expert neurologist who leads our Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) project and cares for individuals with this diagnosis. Dr. Lazarus was born in Durban, South Africa. He completed medical school in 2006 in Johannesburg. He initially finished a primary care residency in South Africa during which time he performed his neurology rotations at Emory Healthcare with Dr. Juncos. While working with Dr. Juncos, Dr. Lazarus was introduced to the FXTAS research at Emory University. Dr. Lazarus has been traveling to study participants’ homes as well as helping Dr. Juncos conduct the neurological examinations here in Atlanta. Dr. Lazarus has helped us work toward publishing our study results on our recent findings. We hear many compliments about Dr. Lazarus from our FXTAS study participants and their

Mary Leslie, EdS, FXS Research Team Member Retires! Continued congratulations to Mary Leslie on her retirement in October 2009 after over 14 years of service with the FXS research team. Mary began working with the FXS team in September 1995 as one of our psychological specialists. Her primary responsibilities involved recruiting study participants and conducting neuropsychological testing. Many of you may remember meeting with her for the Emory Study of Adult Learning. Please join us in wishing her enduring health and happiness in her retirement!

Emory Study of Learning and Movement (ESLM) The Emory University Study of Learning and Movement (ESLM) is a study of the gene called FMR1 and its effect on learning and movement difficulties, especially in men. Carriers of one form of this gene (called ―premutation‖) are at increased risk for a neurodegenerative disorder that occurs later in life called fragile X-associated tremor/ataxia syndrome (FXTAS). We are recruiting men who carry the premutation and all of their brothers with or without the premutation and with or without symptoms of FXTAS. The goal of the study is to answer the following questions about FXTAS: Who is at risk for developing FXTAS? Why do many men who carry the premutation never develop FXTAS? What factors influence the course or progression of this syndrome? Are there early signs of FXTAS that might help pinpoint a time for early therapeutic intervention? The ESLM has been funded by the National Institutes of Health since 2003 and is an ongoing project. Thanks to all the wonderful individuals from families who have taken the time to participate in this research. You have welcomed our test administrators into your homes, traveled to Emory University for study visits, and encouraged interested family members to join our study. We now have over 150 participants who have completed the first part of the study, and at least 60 in the 3 year follow-up visit. If you would like to participate in this research or if you would like additional information, please contact Lisa Shubeck, Research Project Coordinator, at [email protected] or 404 778 8478.

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Fragile X Research Updates Fragile X associated primary ovarian insufficiency (FXPOI): Anti-mullerian hormone (AMH, sometimes called mullerian inhibiting substance (MIS)) is a promising marker of a woman’s egg supply, or her ―ovarian reserve‖. The woman’s AMH level drops throughout life, until it hits zero when there are only a few eggs left. This usually occurs around the time of menopause. Among women with the premutation who are cycling, we found that they have lower levels of AMH, on average, compared with women without the premutation. This means that some premutation carriers, but not all, have fewer eggs than non-carriers during their reproductive years. We recently combined our data with a group in the Netherlands to determine the best predictors of early ovarian insufficiency. Although these studies are just beginning, we have found that AMH levels, fragile X repeat size, and the average time of age at menopause among mothers and sisters are the best predictors. Fragile X associated tremor/ataxia syndrome (FXTAS): As part of the ESLM (Emory Study of Learning and Movement), we are investigating whether the loss of the ability to identify smells (olfactory dysfunction) is a problem, since this is true in disorders like Parkinson disease, Alzheimer’s disease, and some forms of ataxia. It is an early sign of these disorders and appears to be stable as the disorder progresses. Our research team is currently asking men with and without the premutation to complete a ―smell test.‖ It is a simple ―scratch and sniff‖ test with 40 different smells to identify. With our longitudinal data collection that many of you are involved in, we will be able to determine if this is an early marker for FXTAS and if it is useful as a measure for clinical trials when they come along. Smell is the first trait that we are examining in this way. Others are now under investigation. Fragile X syndrome (FXS): As you know, the mutation that leads to fragile X syndrome (FXS) is the expansion of a DNA sequence that is repeated over and over. We sometimes call this the CGG repeat. The most common number of repeats is 30, but this varies among individuals. The repeat is usually stable when it is passed from parent to child. When it becomes unstable, it has the chance to expand to over 200 repeats in a few generations. This leads to FXS. Now, we predict the potential of the repeat to expand by the overall number of repeats carried by the individual. But there is more information in that repeat that can help us better predict instability. The repeat is sometimes interrupted by another sequence. The more interruptions, the more stable the repeat. Up until now, uncovering that more complex repeat structure could not be done easily, especially in females. This is because each female carries two forms of the repeat whereas males only carry one. We recently teamed up with a company, Asuragen Inc., which developed a new test to unravel the repeat structure. Along with three other research programs, over 500 parentoffspring samples were examined. Dr. Emily Allen from our group took the lead on analyzing these exciting data and is now building a better prediction model. This new model can be used in the clinic setting to provide individuals with more information about the risk of expansion of their form of the repeat.

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Emory University School of Medicine Department of Human Genetics 1462 Clifton Road, Suite 300 Mailstop 1370-1AB Atlanta, Georgia 30322

http://genetics.web.emory.edu/

Fragile X Syndrome Research

To Contact the Emory University FXS Research Team If you would like a paper copy of the Fall 2011 Emory University FXS Newsletter sent to you by post office mail, please contact Lisa Shubeck at [email protected] or 404-778-8478 and provide your name and mailing address. If you would like to be removed from the Emory University FXS email contact list in order to discontinue receiving communications from the Emory University FXS Research Team, please contact Lisa Shubeck at [email protected] and provide the email address you wish to remove.

Contact the following team members for information on participating in Emory University FXS research: Krista Charen

Lisa Shubeck

[email protected]

[email protected]

404 778 8479

404 778 8478