Research Funding for 2005
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Research Summary: National Fragile X Foundation Clinical Grant
Randi Hagerman, MD - $50,000
The M.I.N.D. Institute, University of California at Davis
Nerve Conduction Studies in Carriers of the Premutation
RESULTS: A Quantitative Assessment of Tremor and Ataxia in FMR1 Premutation Carriers Using CATSYS

Research Summary: National Fragile X Foundation Clinical Grant
Laura Holsen, PhD and Richard Davidson, PhD - $35,000
Waisman Lab for Brain Imaging and Behavior, University of Wisconsin – Madison
Interaction between Social Anxiety and Memory in Fragile X Syndrome
RESULTS: Prefrontal social cognition network dysfunction underlying face encoding and social anxiety in fragile X syndrome

Research Summary: National Fragile X Foundation Clinical Grant
Maria Valdovinos, PhD BCBA - $23,795
Drake University
Analysis of Side Effects Experienced with Psychotropic Medication
RESULTS: Results of a Nation-Wide Survey Evaluating Psychotropic Medication Use in Fragile X Syndrome

Research Summary: National Fragile X Foundation Basic Science Grant
Emily Osterweil PhD - $35,000
Massachusetts Institute of Technology, Interdepartmental Neuroscience Program, Yale University
Investigating FMRP in mGluR-mediated protein synthesis and synaptic plasticity
RESULTS: Correction of Fragile X Syndrome in Mice

Research Summary: National Fragile X Foundation Basic Science Grant
Flora Tassone PhD - $50,000
UC Davis School of Medicine, Dept. of Biochemistry and Molecular Medicine
Identification and characterization of isoforms of the FMR1 gene

Research Summary: National Fragile X Foundation Basic Science Grant
Violeta Stoyanova MD, PhD - $35,000
Erasmus University, Dept. of Clinical Genetics
Reactivating the FMR1 gene

Summer Student Fellowships

Research Summary: National Fragile X Foundation Clinical Grant

Randi Hagerman, MD - $50,000

The M.I.N.D. Institute, University of California at Davis

Nerve Conduction Studies in Carriers of the Premutation
 
Premutation carriers are individuals who have between 55-200 CGG repeats in the fragile X or FMR1 gene. Carriers are common in the general population and approximately 1 in 130 females and 1 in 800 males have the premutation. In approximately 30% of older males and in rare females with the premutation, a disorder called the fragile X associated tremor/ataxia syndrome (FXTAS) may develop. This disorder includes an intention tremor and gait ataxia. Approximately 60% of FXTAS patients can develop a peripheral neuropathy or decreased sensation in the lower extremities. Sometimes older carriers without FXTAS can also have a neuropathy. This grant involves nerve conduction studies which are studies to assess how fast nerve impulses travel in the extremities. Individuals with the neuropathy associated with FXTAS typically have mildly slowed conduction in the nerves. This study will evaluate how common nerve conduction abnormalities are in individuals who have the premutation and neurological symptoms including pain, weakness, or numbness in the extremities either with or without tremor and ataxia. We will compare these individuals to individuals who have the premutation and do not have neurological symptoms and to controls who do not have the premutation and are age-matched to the carriers with neurological symptoms. We will also evaluate the molecular parameters of the fragile X gene including the CGG repeat number, the FMR1 messenger RNA level, and FMRP level in the blood to see if these molecular parameters correlate with the nerve conduction abnormalities or earlier onset of neurological symptoms. This research will help us better understand the overall phenotype in older male and female carriers. If you are interested in participating in this study at the M.I.N.D. Institute, please contact Sarah Coffey at (916)703-0281 or Michele Ono at (916)703-0292.

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Research Summary: National Fragile X Foundation Clinical Grant

Laura Holsen, PhD and Richard Davidson, PhD - $35,000

Waisman Lab for Brain Imaging and Behavior, University of Wisconsin – Madison

Interaction between Social Anxiety and Memory in Fragile X Syndrome
 
Individuals with fragile X syndrome often exhibit anxiety in social situations. While they appear to be interested in social interaction, they also tend to exhibit symptoms of social anxiety, such as failing to maintain eye contact with others and displaying awkward social behaviors. These symptoms can make it difficult to form meaningful relationships outside of their immediate family. Some of our understanding of social anxiety in fragile X comes from literature on individuals with autism, who also have poor eye contact and do not pay attention to faces. Previous studies suggest that there are differences between individuals with fragile X and individuals with autism in how they behave in social situations and in how they display social anxiety, including the basic desire to interact socially. Some studies show that individuals with fragile X desire social interaction, but individuals with autism do not.

Our understanding of social anxiety in fragile X and autism draw from studies using functional magnetic resonance imaging (fMRI). fMRI studies allow us to examine a person's brain activity while they perform a task, such as looking at faces. These studies have examined how individuals with autism and individuals with fragile X process visual images of faces, which is an important part of social interaction. Recent fMRI studies on face-processing in autism and fragile X report abnormal activity in brain areas including the fusiform gyrus, which is heavily involved in face-processing, and the amygdala, a region that is involved in emotional processing. However, we still do not completely understand social anxiety in fragile X. Some literature suggests that social anxiety may be related to memory for faces. Patients with a psychiatric diagnosis of social phobia (who also have social anxiety) show better memory for threatening and fearful faces than for non-emotional faces, which could be related to increased anxiety in social situations. Previous fMRI studies on social phobia have demonstrated abnormal brain activity in brain areas that are involved in both face-processing and memory. Similar to the social phobia group, individuals with fragile X appear to have better memory for faces, which is in contrast to difficulties they have with in other types of memory, such as visual and spatial memory. However, no studies have examined whether individuals with fragile X show differences in brain activity during a memory-based face-processing task. Our study is designed to investigate the correspondence between brain activity and both social anxiety and memory for faces in females and males (ages 8-35) with fragile X syndrome using fMRI. We hope that this study will lead to greater basic understanding of social anxiety in individuals with fragile X and aid in the development of treatment of social anxiety in fragile X syndrome. In the future, we plan to study the relationship between brain activity and molecular markers such as FMRP and mGluR, and to study how brain activity in individuals with fragile X changes after pharmacological treatment. Please contact Laura Holsen (holsen@waisman.wisc.edu; 608-262-9145) for more information.

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Research Summary: National Fragile X Foundation Clinical Grant

Maria Valdovinos, PhD BCBA - $23,795
    
Drake University

Analysis of Side Effects Experienced with Psychotropic Medication

Fragile X syndrome (FXS) is a genetic cause of mental retardation associated with the lack of fragile X mental retardation protein (FMRP). Individuals with FXS are reported to experience hyperactivity, anxiety, and sometimes aggression, self-injurious behavior, and tantrums. To treat these behaviors, doctors often prescribe medications, known as psychotropics, which affect thoughts, feelings, or behavior, by changing one's brain chemistry or neurotransmitter systems. Current research shows that at least 59% of children with FXS have been prescribed psychotropic medications at one time to treat the behaviors associated with FXS. To date, there have been a few controlled studies to determine how effective psychotropic medications are for people with FXS. Furthermore, very little research exists on the prevalence and incidence of side effects of psychotropic medication in individuals with FXS.

To further our understanding of FXS, researchers use animals as models of FXS. Two common models are the mouse and drosophila (fruit fly). Research is beginning show how the lack of FMRP can affect neurotransmitter systems. For example, research has shown that the lack of FMRP results in overgrown dendritic spines (the part of a brain cell where receptors are located for neurotransmitters). Additional insights are leading to hypotheses about how impairments in neurotransmitter systems can affect behaviors seen in people with FXS. In the drosophila and mouse models of FXS, an upregulation of dopamine and serotonin has been discovered. This generally means that there is more activity in brain cells that are sensitive to dopamine and serotonin neurotransmitters. Psychotropic medication classes most often prescribed to people with FXS are stimulants, selective serotonin reuptake inhibitors (SSRIs), antipsychotics, and alpha-agonists. With the exception of the alpha-agonists, each of the drug classes specifically targets dopamine or/and serotonin. Although these impairments have not yet been shown in humans with FXS, there are enough similarities in brain cell structure between animal models of FXS and humans with FXS that the findings may be applicable to humans. Should these findings be applicable, these impairments might make those with FXS more or less likely to respond favorably to psychotropic medications.

The proposed study involves conducting a survey of caregivers of individuals with FXS regarding psychotropic medication use and side effects experienced.  The goal of this study is to determine if individuals with FXS are at risk of experiencing side effects associated with psychotropic drug use; to determine which side effects associated with psychotropic medication drug use are most commonly experienced by individuals with FXS; and to determine if there are additional variables (e.g., age, gender, problem behavior, health conditions, psychiatric diagnosis, level of functioning) that are correlated with the occurrence of side effects of psychotropic medication use in individuals with FXS. The results of this study have the potential to better inform and aid treatment teams in decisions regarding the use of psychotropic medication to treat behaviors and psychiatric issues associated with FXS.

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Research Summary: National Fragile X Foundation Basic Science Grant

Emily Osterweil PhD - $35,000

Massachusetts Institute of Technology, Interdepartmental Neuroscience Program, Yale University

Investigating FMRP in mGluR-mediated protein synthesis and synaptic plasticity

Fragile X syndrome (FXS) is caused by the loss of fragile X mental retardation protein (FMRP), and understanding the function of this protein is essential to understanding the syndrome. Evidence suggests that FMRP (1) regulates the production of other proteins, (2) negatively regulates its own production, and (3) is made at synapses in response to activation of group 1 metabotropic glutamate receptors (Gp 1 mGluRs), which function in excitatory neurotransmission. Interestingly, mGluR activation also leads to protein synthesis, and the "mGluR Theory" states that symptoms of FXS are due to an exaggeration of this protein synthesis (i.e., FMRP acts as a "brake" on mGluR-mediated protein synthesis). The question then becomes- what proteins produced by mGluR activation are responsible for FXS symptoms when FMRP is lost? We propose that proteins of the ubiquitin-proteosome system (UPS) are of particular importance. UPS proteins mediate the degradation of other proteins, and are thought to be important for long-term changes in synaptic activity, such as those mediated by mGluRs. Our preliminary studies indicate that the UPS is required for mGluR-mediated long-term depression (LTD) of synaptic strength, and that UPS proteins are regulated by FMRP. We propose to directly test the specific hypotheses that mGluR-mediated protein synthesis: negatively regulates LTD through FMRP, stabilizes LTD through production of UPS proteins, and specifically stabilizes LTD through the production of ubiquitin. Abnormal regulation of UPS proteins is seen in many neurological disorders, including Parkinson's disease, Angelman syndrome, Alzheimer's disease, ataxia, and Schizophrenia, and we propose that UPS dysfunction may similarly be involved in FXS.

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Research Summary: National Fragile X Foundation Basic Science Grant

Flora Tassone PhD - $50,000

UC Davis School of Medicine, Dept. of Biochemistry and Molecular Medicine

Identification and characterization of isoforms of the FMR1 gene

At the molecular level, the fundamental problem with fragile X syndrome is that not enough protein (FMRP) is being produced to support normal neurodevelopment. In most cases, the FMR1 gene itself is silent, producing none of the messenger (m)RNA that would normally be translated into protein. However, we have observed that in some children with fragile X syndrome, the gene remains partially active, producing at least some mRNA, although the protein levels remain low. We have also observed that in premutation carriers, the gene actually produces more than normal amounts of RNA, and this RNA actually is slightly longer than normal. Additional observations also indicate that the transcription of the FMR1 gene appears to start at different sites, which are diffrentially used as function of the CGG repeat number. The goal of this research project is to better understand the details of how the fragile X gene is regulated, to identify targets for therapeutic intervention thart are aimed at increasing production of FMRP in the full mutation range.
 
Once the initial RNA (transcript) is produced by the gene, it is shortened through a complex process whereby splicing separate sections of the RNA are spliced together to form the final mRNA. In the case of the FMR1 gene, alternative splicing arrangements can give rise to more than 20 possible forms of FMRP, which are different in various internal segments. However, the functional significance of these individual forms of FMRP remains unknown. One aspect of the current project will therefore be to ask if certain of these forms have different functions and/or locations within neural cells. We will also ask whether the different RNAs, produced by differing start sites for gene transcription, ultimately influence the amount of protein that is produced. Also, why does the number of CGG repeats determine where the gene begins synthesizing the RNA? Finally, this study will analyze the localization of different FMR1 transcripts at the synapses and will explore the potential role of signal sequences (termed IRES elements) in promoting FMRP production in dendrites.
 
The ultimate goal of these studies is the identification of targets for therapeutic intervention through the increased production of FMRP.

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Research Summary: National Fragile X Foundation Basic Science Grant

Violeta Stoyanova MD, PhD - $35,000

Erasmus University, Dept. of Clinical Genetics

Reactivating the FMR1 gene

Anyone who in some way is interested in the fragile X syndrome would learn that the main reason for the clinical manifestations is the fact that the FMR1 gene is silenced (not active as it is supposed to be). Because of this inactivation of the gene the protein FMRP is not made in the cells of the body and therefore all functions related to this protein are affected. The reason for the silencing of the FMR1 gene is a certain chemical modification in the DNA (methylation), which is found when the gene has a long repeated element (known as full mutation). However recent research has shown that a FMR1 gene with a full mutation is not always silenced. In the very early stages of development of the embryo (first weeks of pregnancy of the mother) the FMR1 gene with a full mutation is active just as the one without mutation. Later in the development of the embryo/fetus the FMR1 gene becomes inactive and stays as such after birth and during the life of a fragile X individual. We are interested in investigating why and how the FMR1 gene becomes inactive. Recently a new mechanism has been described through which genes in human cells are silenced. This mechanism involves small molecules (known as siRNAs), which can be targeted specifically to a gene. Because of the specific structure of the FMR1 gene with a full mutation, such molecules can be formed. Therefore in the current project we want to investigate (using human cells in a test tube) if the FMR1 gene with a full mutation is silenced via the same mechanism. We think that if we learn more about the mechanism of inactivation of the FMR1 gene and exactly when in development that occurs, we could be able to prevent this event. In this respect our investigations are aiming at bringing more understanding of the fine mechanisms of regulation of the FMR1 gene which would help in developing effective strategies for its reactivation in individuals with the fragile X syndrome.

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Summer Student Fellowships

Awards from the National Fragile X Foundation do not just go to established researchers and institutions, they are also made to promising students who have demonstrated an interest in fragile X syndrome. These $2500 "Summer Fellowship" grants are made possible by the William and Enid Rosen Research Fund and the National Fragile X Foundation Research Fund. Recipients in 2005 were:

- Ok-Kyung Kim, RUSH University Medical Center - NFXF RESEARCH FUND
     Development of Outcome Measures for Future Clinical Trials in FXS

- Jennifer Johnson, Emory University & UC Davis M.I.N.D. Institute - ROSEN RESEARCH FUND
    Cognitive profiles and trajectories of FXS males with high-end premutation

- Julie Hanck, Neurological Institute, McGill University, Montreal, Canada - ROSEN RESEARCH FUND
     Understanding the Visual Processing Difficulties in Males with FXS

- Evelien Weenen, Utrecht University The Netherlands - ROSEN RESEARCH FUND
    The interplay between FMRP and the miRNA regulation pathway

- Christopher K. Lindauer, University of Maryland School of Medicine - ROSEN RESEARCH FUND
    13-C-NMR studies of metabolism in Fragile X mouse brain

- Jennifer Yuhas, UC Davis M.I.N.D. Institute - ROSEN RESEARCH FUND
     Neurological involvement in adult females with the fragile X premutation

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