Research Program Description

Dr. Berry-Kravis is working on numerous basic science and clinical fragile X research projects at Rush University Medical Center in Chicago. These include the clinical studies described below and involve studies of fragile X syndrome, fragile X-associated tremor/ataxia syndrome (FXTAS), and fragile X-associated primary ovarian insufficiency (FX-POI). For information on participating in any research study under way at Rush, see the clinical trials database on the Rush Web site. Further explanation of eligibility and requirements for participation in fragile X research projects can be found under neurological disorders (pediatrics).

Add-On Trial of Lithium in Fragile X Syndrome
In individuals with fragile X syndrome (FXS), the fragile X gene (FMR1) is turned off, so the fragile X protein (FMRP) is not made. Absence of FMRP in the brain produces the learning and behavior problems seen in individuals with FXS. One of the pathways that is regulated incorrectly and is overactive in fragile X is called the mGluR pathway. Too much activity in this pathway (due to missing FMRP) leads to immature and weaker connections between brain cells. The overactivity of the mGluR pathway is believed to cause many symptoms of fragile X, including hyperactivity and anxiety. In other research, lithium has been shown to inhibit (partially block) the mGluR pathway.

The purpose of this study, funded by the FRAXA Research Foundation, is to assess the short-term and long-term effects of treatment with lithium for people with fragile X syndrome.

The study was conducted at both RushUniversity MedicalCenter and the Brain-BodyCenter at the University of Illinois at Chicago and is funded by FRAXA. Each participant completed a battery of cognitive and psychophysiological tests. In addition, caregivers filled out behavioral questionnaires several times during enrollment in the study. Measures were administered at baseline, after two months of treatment and, if the participant agreed to continue, after a year of treatment.

This study is closed to further enrollment. The results of this study have been accepted for publication in the Journal of Developmental and Behavioral Pediatrics. A link to this article will be provided when it becomes available.

Effects of FMRP Expression in Cultured Neural Cells
This laboratory research project is examining neural cell properties, signal transduction and regulation of cAMP signaling in neural cells that over-express and under-express FMRP. This project is being funded by the Illinois-Eastern Iowa District of Kiwanis International, Spastic Paralysis and Allied Diseases of the Central Nervous System Research Foundation.

Development of Outcome Measures for Future Clinical Trials in Fragile X Syndrome
New information is becoming available regarding the neurobiological mechanism of mental retardation in fragile X syndrome, FXS. This has resulted in proposal for syndrome-specific treatments to compensate the neural mechanisms made abnormal by the absence of the fragile X protein, FMRP. Some of these treatments are being developed but there is a critical need for well-validated outcome measures to demonstrate drug effect in the fragile X population. This ongoing pilot project for outcome measure development will test the validity, in an FXS population, of a series of cognitive tasks and other measures designed to assess specific areas of weakness in FXS that might be expected to show rapid improvement during the timeframe of a phase II clinical trial lasting several weeks to several months. The project will also assess the usefulness and reproducibility of new blood biomarkers for pathways shown to be abnormal in the absence of FMRP, for determining biological effectiveness of treatment in future clinical trials. These studies are also partly funded by the Kiwanis Spastic Paralysis Foundation.

The preliminary results of the initial part of this study were published in the Journal of Autism and Developmental Disorders. (Characterization of Potential Outcome Measures for Future Clinical Trials in Fragile X Syndrome ).

Pre-pulse Inhibition (PPI) testing is a physiological measurement currently being evaluated as an outcome measure in populations with fragile X syndrome. Pre-pulse inhibition is an assessment of sensorimotor gating in patients with FXS. Since heightened sensitivity to sensory stimulation is one of the most common manifestations of FXS, patients show inability to block eye blink startle responses when presented with auditory stimuli during a PPI test. Preliminary results, gathered in collaboration with David Hessl, PhD, at theUniversity ofCalifornia MIND Institute in Davis, have demonstrated the ability of the PPI test to reproducibly portray this abnormality in individuals with FXS as compared to normal controls.

Baseline and reproducibility data as well as data on the effects of medications routinely used in FXS on this test will continue to be collected to further validate this measurement for future clinical trials including Fenobam. Particularly, additional studies over the summer of 2008 will focus how stimulants affect the outcome of PPI measurements and attention test performance in individuals with FXS. 

An Open Label Exploratory Study to Investigate the Safety and Effects of Fenobam Monohydrate (fenobam 50 mg – 150 mg single dose) on Prepulse Inhibition Tests AND Continuous Performance Tasks, in Adults with Fragile X Syndrome

In individuals with fragile X syndrome (FXS), the fragile X gene (FMR1) is turned off, so the fragile X protein (FMRP) is not made. Absence of FMRP in the brain produces the learning and behavior problems seen in individuals with FXS. One of the pathways that is regulated incorrectly and is overactive in fragile X is called the mGluR pathway. Too much activity in this pathway (due to missing FMRP) leads to immature and weaker connections between brain cells. The overactivity of the mGluR pathway is believed to cause many symptoms of fragile X, including hyperactivity and anxiety.

Drugs developed to target the mGluR pathway have had excellent results in FX animal models but are not yet available for humans.  However, fenobam, a drug previously evaluated for anxiety, was identified as a potent and specific mGluR blocker and is now being evaluated as a treatment for FX populations

This was an initial exploratory study sponsored by Neuropharm LTD and FRAXA Research Foundation to investigate the safety and efficacy of fenobam monohydrate, at single doses between 50mg and 150mg in male and female patients with Fragile X Syndrome.  PPI testing and a continuous performance task evaluated in the Outcome Measures study were used to measure performance before and after the taking fenobam.   

This study is now closed to enrollment and a paper on this study will be published in the Journal of Medical Genetics and can now be accessed online here. The next step in development of this medication may be a double-blind placebo-controlled study of fenobam in individuals over 18 sometime in 2009. A clinical trial of fenobam in children with FXS will be initiated as soon as possible relative to FDA regulations for drug development, but it is not clear when that will occur.

Neurological Symptoms in Older Fragile X Premutation Carriers
Fragile X syndrome is a genetic condition involving learning and behavioral problems, often with mental retardation. Patients with fragile X syndrome have a large or “full” mutation (large increase in size) in the FMR1 gene responsible for fragile X syndrome. The silent or small mutation is called a premutation may be carried by the mother, a maternal grandparent or great-grandparent, or aunts or uncles of a fragile X child without any sign of learning problems. The fragile X premutation could be responsible for neurological signs that develop later in life such as FXTAS (Fragile X tremor and ataxia), which is characterized by shakiness or movement problems.

This study began as an NIH-funded consortium project with Paul Hagerman, MD, and Randi Hagerman, MD, at the University of California inDavis, and with Maureen Leehey, MD, at the University of Colorado in Denver. Scientists involved in the study are investigating neurological symptoms in male and female carriers of the FXS premutation, and comparing these symptoms to other carriers and noncarriers of the same age.

The results of this study and a comprehensive review of the fragile X premutation can be accessed here: (Fragile X-associated tremor/ataxia syndrome: clinical features, genetics, and testing guidelines)

This study is currently funded by the Circle of Service Foundation and is open to follow-up of male and female premutation carriers and normal individuals over the age of 50 who are willing to have a neurological assessment and a skin biopsy to look for changes in skin that reflect the brain change in FXTAS and hopefully will lead to targeted treatments. Male carriers and control individuals can be concurrently enrolled in the DTI Study described below.

Pilot Study of Diffuse Tensor Imaging (DTI) in Fragile X Premutation Carriers with and without FXTAS
In preparation for a more extensive NIH-funded study of DTI measures as predictors of disease course in FXTAS, this National Fragile X Foundation-funded study is examining two preliminary questions: (1) do all men with an FMR1 premutation, even those who are clinically asymptomatic, have evidence of white matter abnormalities as detected by DTI? (2) does the degree of whole brain and regional middle cerebellar peduncle DTI abnormality correlate with clinical severity among subjects with FXTAS? In this pilot study, we will use DTI to examine white matter integrity, with special attention to the middle cerebellar peduncle, in male FMR1 premutation carriers with no clinical signs of FXTAS and those with clinical signs ranging from mild-to-severe FXTAS, as compared with age-matched men without the FMR1 premutaton. The long-term object of this study is to be able to use the DTI scans to be able to predict which carriers are most at risk to get FXTAS and what types of symptoms may occur. Male permutation carriers and non-carriers age 50 or over are eligible for this study.

A Preliminary Familial Cluster Analysis of Premature Ovarian Failure (POF) and Fragile X Tremor Ataxia Syndrome (FXTAS) in Carriers of the Fragile X Premutation
This is a survey study designed to determine whether or not some fragile X families are more susceptible to premature ovarian failure (early menopause, referred to as POF), fragile X tremor ataxia syndrome (a condition that causes shakiness and balance problems, referred to as FXTAS) and whether certain symptoms and problems are more common in people with the premutation than without it. This information is important for physicians and genetic counselors to know so that proper counseling can be provided to individuals who have the fragile X premutation. All families with a fragile X mutation are eligible and if interested should contact the research co-ordinator listed on this web site.

Newborn Screening for Fragile X Syndrome

Testing for fragile X gene changes isn’t currently done in the mandatory newborn screening test required by the state of Illinois. This research study, which began in october of 2008, will begin to evaluate if fragile X testing should be added to the mandatory newborn screening done by the state. As a result of this study, we hope to learn more about fragile X syndrome, its frequency in the general population, the effect of early help for infants who have fragile X syndrome, and the number of family members who have any fragile X-related disease at the time of diagnosis of the newborn with a fragile X mutation. All newborns delivered at Rush between late 2008 - late 2013 will be eligible for the study, which is funded by the NIH through a Fragile X Center Grant in collaboration with University of California-Davis. Other Universities participating in this Fragile X Center are the University of Washington in Seattle and the University of Illinois.

Clinical Trial of STX209: A Double-Blind, Placebo-Controlled, Crossover, Flexible Dose Evaluation of STX209 in the Treatment of Irritability in Subjects with Fragile X Syndrome

Beginning in December 2008, we are screening subjects for possible enrollment in a new study entitled, A Double-Blind, Placebo-Controlled, Crossover, Flexible Dose Evaluation of STX209 in the Treatment of Irritability in Subjects with Fragile X Syndrome. This trial is open to fragile X patients age 12 and up initially and after the first 10 patients have completed treatment, patients age 6-12 will be enrolled as well. This clinical trial is sponsored by Seaside Therapeutics to assess the STX209, which contains only the more active form of the two drug forms that are in the drug baclofen. Baclofen may help with irritable behavior in people with developmental disabilities. Also, baclofen and STX209 activate the GABA system and there is some data suggesting the GABA system is abnormal in mice with fragile X syndrome. Thus STX209 may be helpful for humans with fragile X syndrome. Activation of the GABA system may also indirectly decrease signaling through the overactive mGluR pathway in fragile X (discussed above in fenobam study description), providing another way the drug might help with brain wiring and behavior in fragile X. There are currently no medications approved for the treatment of irritable behavior in people who have fragile X syndrome.

All study subjects will receive STX209 during one part of the study and receive placebo capsules during another part. All subjects will be randomly assigned by chance to first receive either the study drug or placebo capsules. Please or contact the research coordinator or visit the clinical trials page for more information.

Additional Research Interests

Dr. Berry-Kravis also collaborates with Dr. Debra Weese-Mayer on research projects involving study of genetics of central congenital hypoventilation syndrome (CCHS) and of sudden infant death syndrome (SIDS). She also works on projects studying the genetics of movement disorders like Parkinsons disease in collaboration with the Rush Movement Disorders program and Dr. Christopher Goetz in the Department of Neurolical Sciences, and works on studies of genetic factors in Alzheimers disease with the Rush Alzheimers Disease Center. These projects are carried out in the Berry-Kravis molecular laboratory. Clinical diagnostic testing for fragile X syndrome and other genetic diseases is also carried out in this laboratory, a CAP and CLIA certified molecular diagnostics laboratory co-directed by Dr. Berry-Kravis and Dr. Paul Wong.