Rush Fragile X Clinic and Research Program Description

The Fragile X Clinic and Research Program at Rush University Medical Center in Chicago is directed by Elizabeth Berry-Kravis, MD. It involves two components: (1) a Fragile X Clinic where over 400 patients with fragile X syndrome are seen and followed as necessary for treatment and management of aspects of fragile X syndrome, and (2) a Fragile X Research Program incorporating numerous basic science and clinical fragile X research projects. 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).

The Fragile X Clinic and Research Program is part of a larger Fragile X-Associated Disorders (FXD) Program at Rush that provides clinical care and research opportunities to individuals in fragile X families affected by any FXD. The Fragile X-Associated Disorders Program includes a FXTAS Clinic run by Deborah Hall, MD, and an FXPOI Clinic run by Mary Wood-Molo, MD.

The Rush Fragile X Clinic and Research Program and Fragile X-Associated Disorders Program interacts and partners with fragile X local resource groups for families with fragile X (called LINKS groups), including the Fragile X Resource Group of Greater Chicago the The Central Illinois Fragile X Resource Group, Fragile X Association of Michigan, and the Fragile X Resource Center of Missouri.

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).

A recent review paper describes current clinical care and new medication development in fragile X syndrome:

Hagerman RJ, Berry-Kravis E, Ono MY, Tartaglia N, Lachiewicz A, Kronk B, Delahunty C, Kauffman W, Hessl DR, Visootsak J, Picker J, Gane L, Tranfaglia M, Hatton D, Rivera S, Farzin F, Lemons-Chitwood K, Greiss-Hess L, Ferguson H. Advances in the treatment of fragile X syndrome. J Pediatr 2009;123:378-390.

This publication can also be found under related topics.

Fragile X Syndrome, FMR1 and the mGluR pathway

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 a glutamate pathway (glutamate is the main excitatory neurotransmitter in the brain) 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 that block the overactive mGluR pathway and genetic reduction of nGluR5 receptors have been shown to reverse virtually all the problems seen in the fragile X mouse.

mGluR refers to brain receptors called metabotropic glutamate receptors. These receptors regulate brain signaling and connections everywhere throughout the brain. There are at least 8 mGluRs but mGluR1 and mGluR5 (group 1) are the mGluRs with excessive signaling in fragile X syndrome. Other neurotransmitter systems, such as GABA, acetylcholine and dopamine, are also affected by the missing FMRP and contribute to abnormal signaling in fragile X brain.

Add-On Trial of Lithium in Fragile X Syndrome

In research on the fragile X mouse and fly models, lithium has been shown to inhibit (partially block) the mGluR pathway. The purpose of this study, funded by the FRAXA Research Foundation, was 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 Rush University Medical Center and the Brain-Body Center at the University of Illinois at Chicago and was funded by the FRAXA Research Foundation. 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 the two-month treatment in this study have been published in the Journal of Developmental and Behavioral Pediatrics:

Berry-Kravis E, Sumis A, Hervey C, Nelson M, Porges SW, Weng N, Weiler IJ, Greenough WT. Open-label treatment trial of lithium to target the underlying defect in fragile X syndrome. J Dev Behav Pediatr 2008;29:293-302.

A link to this the full publication is provided under related topics.

Many patients still showed behavioral improvement at 1 year of lithium treatment. Treatment with lithium requires lots of blood monitoring and lithium has many non-specific effects in the body. Thus, this study was helpful in suggesting treatment that reduces activity in the mGluR pathway in fragile X may be helpful, we are now working on testing medications that more specifically target the pathway with less side effects.

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

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 suggested positive effects of the fenobam, however as was seen in past studies of fenobam, blood levels were highly variable.

This study is now closed to enrollment and a paper on this study has been published in the Journal of Medical Genetics:

Berry-Kravis E, Hessl D, Coffey S, Hervey C, Schneider A, Yuhas J, Hutchison J, Snape M, Tranfaglia M, Nguyen DV, Hagerman R. A pilot open label, single dose trial of fenobam in adults with fragile X syndrome. J Med Genet 2009;46:266-271.

A link to this paper is also provided under related topics.

A randomized, double-blind, placebo-controlled, pharmacokinetic, safety and tolerability, and exploratory efficacy and pharmacodynamic effects study of RO4917523 in adult patients with Fragile X syndrome (Study NP22578)

Like fenobam, the study drug RO4917523 is an mGluR5 blocker being developed specifically for treatment of fragile X syndrome. This is a newer drug that has the advantage of once a day dosing and more stable blood levels. This purpose of this clinical trial, funded by Hoffmann-La Roche, is to test different doses of the study drug (RO4917523), and learn about the drugs safety, how well the body manages the drug (tolerability), how much drug is in the body after dosing (pharmacokinetics) and to begin to understand effects of the drug on behavioral manifestations or thinking patterns in fragile X syndrome.

This clinical trial is currently enrolling interested participants. More information can be found at the clinical trials database on the Rush Web site.

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.

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

This clinical trial is sponsored by Seaside Therapeutics to assess the study drug 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. GABA is the main inhibitory neurotransmitter in brain and there is evidence of defective (reduced) GABA inhibition in brain if the fragile X mouse. It is not known if this is secondary to the mGluR pathway dysregulation or not. In any case, STX209 and baclofen reverse some of the problems seen in the fragile X mouse and fly, by increasing GABA activity and presumably reversing the defective inhibition. 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, by reducing glutamate release in the brain. This may provide another way the drug might help with brain wiring and behavior in fragile X.

This study is closed to enrollment and results are being analyzed.

Development of Outcome Measures for Future Clinical Trials in Fragile X Syndrome

It is clear that much new information is becoming available regarding the neurobiological mechanisms active in fragile X syndrome. This has resulted in the need for syndrome-specific treatments to compensate the neural mechanisms made abnormal by the absence of the fragile X protein, FMRP. Some of these treatments (described above) 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 results of outcome measures studies have been published in a series of papers including:

Berry-Kravis E, Lara R, Kim O-K, Sumis A, Wuu J. Characterization of potential outcome measures for future clinical trials in fragile X syndrome. J Autism Dev Disord 2008;38:1751-1757.

Weng N, Weiler IJ, Sumis A, Berry-Kravis E, Greenough WT. Early-phase ERK activation as a biomarker for metabolic status in fragile X Syndrom. Am J Med Genet 2008;147B:1253-1257.

Kogan CS, Boutet I, Cornish K, Graham GE, Berry-Kravis E, Drouin A, Milgram NW. Comparative neuropsychological test battery differentiates cognitive signatures of Fragile X and Down syndrome. J Intellect Disabil Res 2009;53:125-142.

and

MacLeod L, Kogan C, Collin C, Berry-Kravis E, Messier C, Gandhi R. A comparative performance of individuals with fragile X syndrome and Fmr1 knockout mice on Hebb-Williams mazes. Genes Brain Behav 2010;9:53-64.

Links to the full publications can also be found under related topics.

Pre-pulse Inhibition (PPI) testing is a specific physiological measurement 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. Results gathered in collaboration with David Hessl PhD at the University of California 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 and that PPI is a reproducible test that can be used as an outcome measure for clinical trials in fragile X.

Hessl D, Cirdeiro L, Yuhas J, Campball A, Ornitz E, Berry-Kravis E, Chruscinski E, Hervey C, Long J, Hagerman RJ. Prepulse inhibition in fragile X syndrome: feasibility, reliability, and implications for treatment. Am J Med Genet 2008;153B:545-553.

Additional studies have focused how stimulants affect the outcome of PPI measurements and attention test performance in individuals with FXS.

Neurological Symptoms in Older Fragile X Premutation Carriers

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-associated tremor/ataxia syndrome), which is characterized by shakiness or movement problems, or FXPOI (Fragile X-associated primary ovarian insufficiency) which is characterized by early menopause and sometimes fertility problems.

This study began as an NIH-funded consortium project with Paul Hagerman, MD, and Randi Hagerman, MD, at the University of California in Davis, and with Maureen Leehey, MD, at the University of Colorado in Denver. Scientists involved in the study were 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 the above study , a comprehensive review of FXTAS, and a review of treatment strategies for FXTAS can be accessed here or can be found under related topics:

Leehey MA, Berry-Kravis E, Goetz CG, Zhang L, Hall DA, Li L, Rice CD, Lara R, Cogswell J, Reynolds A, Gane L, Jacquemont S, Tassone F, Grigsby J, Hagerman RJ, Hagerman PJ. FMR1 CGG repeat length predicts motor dysfunction in premutation carriers. Neurology 2008;70:1397-1402.

Berry-Kravis E, Abrams L, Coffey S, Hall D, Greco C, Gane L, Grigsby J, Bourgeois J, Finucane B, Jacquemont S, Brunberg J, Zhang L, Lin J, Tassone F, Hagerman P, Hagerman R, Leehey M. Fragile X-associated tremor/ataxia syndrome (FXTAS): clinical features, genetics and testing guidelines. Mov Disord 2007;22:2018-2030.

Hagerman RJ, Hall DA, Coffey S, Leehey M, Bourgeois J, Gould J, Zhang L, SeritanA, Berry-Kravis E, Olichney J, Miller J, Fong A, Carpenter R, Bodine C, Gane LW, Rainin E, Hagerman H, Hagerman PJ. Treatment of fragile X-associated tremor/ataxia syndrome (FXTAS) and related neurological problems. Clinical Interventions in Aging 2008;3:251-262.

The NIH-funded study is completed but an extension of the study is open to follow-up of male 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 Fragile X-Associated Primary Ovarian Insufficiency(FXPOI) and Fragile X-Associated 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 FXPOI (early hormonal insufficiency or menopause, can cause infertility), and FXTAS (a condition that causes shakiness and balance problems) 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 coordinator listed on this web site. An initial paper reporting early findings from this ongoing study has been published.

Chonchaiya W, Au J, Campos L, Nguyen DV, Lohse K, Utari A, Wang L, Berry-Kravis E, Hervey C, Sorensen P, Tassone F, Hagerman RJ. Clinical Involement in daughters of men with fragile X-associated tremor/ataxia syndrome. Clin Genet 2010, epub April 14.

Newborn Screening for Fragile X Syndrome

Testing for fragile X gene changes is not currently done in the mandatory newborn screening test required by the state of Illinois. This research study, which began in 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. Blood spots from newborns are sent to UC Davis, where a new screening test that can be done on small bits of a newborn blood spot has been developed by Dr, Flora Tassone. Other Universities participating in this Fragile X Center are the University of Washington in Seattle and the University of Illinois.

The National Fragile X Registry

This registry and associated database was created by the Fragile X Clinical and Research Consortium (FXCRC), which is a group of fragile X clinics distributed throughout North America. The Rush Fragile X Clinic is part of the FXCRC. The purpose of the registry/database is: (1) to provide a way for families with fragile X to sign up to receive information on future research projects about fragile X syndrome and other fragile X associated disorders, (2) to collect some basic information about problems associated with fragile X syndrome at all ages across the lifespan and (3) to find out how well management needs for these problems are being met in medical clinics, by therapy programs and at schools. Anyone in a fragile X family, including people without a fragile X mutation, can sign into the registry if they would like to help with fragile X research in the future.

The information that goes into the registry is coded by a number that identifies the participant and the Rush clinic where the participant was enrolled. If a researcher wants to contact a participant for study participation he/she will have to call the Rush Fragile X Clinic staff, who will then call the participant and ask if he/she is interested in the study proposed. If interested the participant will then be connected with the researcher. Only the Rush Fragile X Clinic staff will be able to connect the name of individuals participating in the registry through the Rush Clinic to the information in the registry. To join the registry each individual must fill out a consent form and a brief registry questionnaire. Consent forms are signed by the guardian for children and patients with fragile X who are not their own guardian. Otherwise they are signed by the person enrolling in the registry. The Self Report registry form is filled out by the person joining if he/she is his/her own guardian and is capable of filling the form out. The Report of a Relative registry form is filled out by the guardian for a child or fragile X patient or by the parent or relative for a fragile x patient who is his/her own guardian but cannot fill out the form.

Additional Research Interests

Berry-Kravis also collaborates with Debra Weese-Mayer, MD 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 Parkinson disease in collaboration with the Rush Movement Disorders program and Christopher Goetz, MD, in the Department of Neurological 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 including CCHS is also carried out in this laboratory, a CAP and CLIA certified molecular diagnostics laboratory co-directed by Berry-Kravis and Paul Wong, MD.