As part of the Fragile X-Associated Disorders Program at Rush, the Fragile X Research Program conducts clinical studies of fragile X syndrome, fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FX-POI).
Elizabeth Berry-Kravis, MD, is the director of the program and a renowned expert in Fragile X syndrome.
Fragile X-associated disorders care and research at Rush
Specialists at Rush provide clinical care and research opportunities to people who have fragile X and their families. Rush offers expert care for the following:
- Fragile X syndrome
- Fragile X-associated tremor/ataxia syndrome (FXTAS)
- Fragile X-associated primary ovarian insufficiency (FX-POI)
Participate in a fragile X research study
For information on participating in any research study underway at Rush, visit the clinical trials sections of the Fragile X Clinic and/or pediatric neurology pages.
Information about clinical trials in fragile X syndrome can be found under developmental disorders or pediatric neurological disorders.
Fragile X research: care and medication
The following review papers describe studies in current clinical care and new medication development in fragile X syndrome:
- Advances in the treatment of 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. J Pediatr 2009;123:378-390.
- Targeted treatments for fragile X syndrome. Berry-Kravis E, Knox A, Hervey C. J Neurodev Disord. 2011 Sep;3(3):193-210. Epub 2011 Feb 19.
- Seizures in fragile X syndrome: characteristics and comorbid diagnoses. Berry-Kravis E, Raspa M, Loggin-Hester L, Bishop E, Holiday D, Bailey DB. Am J Intellect Dev Disabil. 2010 Nov;115(6):461-72.
- Medication utilization for targeted symptoms in children and adults with fragile X syndrome: US survey. Bailey DB Jr, Raspa M, Bishop E, Olmsted M, Mallya UG, Berry-Kravis E. J Dev Behav Pediatr. 2012 Jan;33(1):62-9.
- Clinic-based retrospective analysis of psychopharmacology for behavior in fragile x syndrome. Berry-Kravis E, Sumis A, Hervey C, Mathur S. Int J Pediatr. 2012;2012:843016. Epub 2012 Jul 30.
Fragile X research: FMR1 and the MGluR pathway
When people have fragile X syndrome, the fragile X gene (FMR1) is turned off, so the fragile X protein (FMRP) is not made. The absence of FMRP in the brain results in the learning and behavior problems seen in individuals with fragile X.
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. Researchers believe the over-activity of the mGluR pathway causes 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.
These systems are the targets of medications that work on the mGluR pathway or other neurotransmitter pathways. Clinical trials at the the Fragile X Clinic at Rush have used some of the new treatments targeted to the underlying brain mechanisms in fragile X syndrome.
Fragile X research: targeted treatments
Trial of CX516 (Ampakine) in fragile X syndrome
In this trial an AMPA receptor activator (CX516) was used to reverse defects in AMPA receptors that occur because of the excessive activity in the mGluR5 pathway.
This was the first placebo-controlled trial of its size in fragile X syndrome. Although the CX516 was not strong enough to show a treatment effect, the drug seemed to show positive effects when combined with an antipsychotic (known to potentiate CX516).
Based on studies in the fragile X mouse, it is thought that stronger ampakines would be a good treatment for fragile X syndrome. Such drugs are not yet available. Much information was learned about how to conduct clinical trials in fragile X syndrome through this study.
This study is closed to further enrollment. The results of the study were published in the Journal of Child and Adolescent Psychopharmacology.
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.
Researchers conducted the study at both Rush University Medical Center and the Brain-Body Center at the University of Illinois at Chicago. The FRAXA Research Foundation funded the study.
Each participant completed a battery of cognitive and psychophysiological tests. In addition, caregivers filled out behavioral questionnaires several times during enrollment in the study. Researchers administered measures at baseline, after two months of treatment and after a year of treatment (if the participant agreed to continue).
Many patients still showed behavioral improvement at one year of lithium treatment. Treatment with lithium requires extensive 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. Researchers at Rush are now working on testing medications that more specifically target the pathway with less side effects.
This study is closed to further enrollment. The results of the two-month treatment in this study were published in the Journal of Developmental and Behavioral Pediatrics.
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
Researchers identified Fenobam, a drug previously evaluated for anxiety, as a potent and specific mGluR5 blocker and evaluated it as a treatment for people with fragile X.
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. Researchers used PPI testing and a continuous performance task evaluated in our previous Outcome Measures study to measure performance before and after 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.
Hoffman-La Roche Pharmaceuticals: RO4917523
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.
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)
The purpose of this clinical trial, funded by Hoffmann-La Roche, is to do the following:
- Test different doses of the study drug (RO4917523
- Learn about the drug’s safety
- How well the body manages the drug (tolerability)
- How much drug is in the body after dosing (pharmacokinetics)
- Begin to understand effects of the drug on behavioral manifestations or thinking patterns in fragile X syndrome
This study is closed to further enrollment.
A randomized, double-blind, 12-week, parallel-group, placebo-controlled, study of the efficacy and safety of RO4917523 in patients with Fragile X Syndrome (Study NP27936)
This clinical trial, also funded by Hoffmann-La Roche, is designed to further assess safety, efficacy, tolerability and pharmacokinetics of different doses of the mGluR5 blocker RO4917523, and to determine if it has a beneficial effect on the symptoms of fragile X syndrome in patients age 16 and up.
This study is currently enrolling. Additional studies are currently in development for clinical trials of the mGluR5 blocker RO4917523 in younger age groups.
Novartis Pharmaceuticals: AFQ056
Novartis Pharmaceuticals has also developed an mGluR5 blocker, AFQ056, for treatment of fragile X syndrome. A clinical trial in Europe suggested that a positive treatment response to AFQ056 may be determined by the methylation state of the fragile X gene.
In this study, only the group of individuals with a fully methylated fragile X gene and no detectable FMR1 mRNA showed a significant response to the study drug. Responses in partially methylated patients were highly variable and so were not statistically different from placebo.
However, often individuals with a fully methylated fragile X gene have more overt symptoms, and it is possible that the length of treatment may not have been sufficient or the outcome measures used may not have been sensitive enough to detect a consistent response in less affected individuals with a partially methylated fragile X gene.
A randomized, double-blind, placebo-controlled, parallel group study to evaluate AFQ056 in adult patients with Fragile X syndrome (CAFQ056A2212)
This clinical trial is designed to assess the safety of AFQ056 and to determine if it has beneficial effects in adults (age 18 and up) who have fragile X syndrome.
This study is currently enrolling.
An open-label study to evaluate the long-term safety, tolerability and efficacy of AFQ056 in adult patients with Fragile X Syndrome (CAFQ056B2279)
Adults with fragile X syndrome who have completed the clinical trial CAFQ056A2212, described above, on either placebo or AFQ056, without significant side effects, are eligible to roll into this extension study.
In the extension study, participants are provided with the study drug, which is titrated to the best therapeutic level and clinically managed by the study physician. The purpose of this study is continue to monitor the safety of AFQ056 and to determine if there are additional beneficial effects for adults with fragile X syndrome over a longer treatment period, especially if patients are having significant learning experiences.
Researchers are adding an intensive literacy training project to this trial to see if patients on chronic treatment with AFQ056 will be able to learn new reading skills while on treatment.
A randomized, double-blind, placebo-controlled, parallel group study to evaluate the efficacy and safety of AFQ056 in adolescent patients with fragile X syndrome (CAFQ056B2214)
This clinical trial, also sponsored by Novartis Pharmaceuticals, is designed to assess the safety and efficacy of the MGluR5 blocker AFQ056 in adolescents (age 12 to 17) with fragile X syndrome.
This study is currently enrolling.
An open-label study to evaluate the long-term safety and tolerability of AFQ056 in adolescent patients with Fragile X Syndrome (CAFQ056B2278)
Adolescents with fragile x syndrome who have completed the CAFQ056B2214 clinical trial, described above, on either placebo or AFQ056, without significant side effects, are eligible to roll into this extension study.
In the extension study, participants are provided with the study drug, which is titrated to the best therapeutic level and clinically managed by the study physician. The purpose of this study is continue to monitor the safety of AFQ056 and to determine if there are additional beneficial effects for adolescents with fragile X syndrome over a longer treatment period, especially if patients are having significant learning experiences.
Researchers are adding an intensive literacy training project to this trial to see if patients on chronic treatment with AFQ056 will be able to learn new reading skills while on treatment.
Sequential, two-period study to assess the pharmacokinetics, safety & tolerability of single and multiple oral doses of AFQ056 in patients with FXS (Fragile X syndrome) aged 5 to 11 years (Cohort 1) and 3 to 4 years (Cohort 2) (Protocol CAFQ056B2154)
The purpose of this study is to find out if the drug AFQ056 is safe and well tolerated in a short-term (one week) treatment of children with fragile X, and to determine pharmacokinetics (how the body breaks down the drug and the measurement of the amount of drug in the blood at specific points in time) of AFQ056 in children with fragile X .
This study is being done to get information needed to move on to longer treatment studies in children with fragile X syndrome.
This study is closed to enrollment for the 5 to 11 age group and is expected to open soon for the 3 to 4 year old group.
Seaside Therapeutics: STX209
Developed by Seaside Therapeutics, STX209 is a new drug that contains only the more active form of the two drug forms that are in the drug baclofen. It was hypothesized that baclofen may help with irritable behavior in people with developmental disabilities. Also, baclofen and STX209 activate the GABA system, which is the main inhibitory neurotransmitter in brain and there is evidence of defective (reduced) GABA inhibition in brain in 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 many 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.
A Double-Blind, Placebo-Controlled, Crossover, Flexible Dose Evaluation of STX209 in the Treatment of Irritability in Subjects with Fragile X Syndrome (Protocol 22001)
This clinical trial was sponsored by Seaside Therapeutics to assess if the study drug STX209 would decrease irritability in individuals with fragile X syndrome. The main finding of the study was improvement in social functioning during the period that the patients were treated with STX209 compared to placebo.
This study is closed to enrollment. The results of this study were published in Science Translational Medicine.
An Open label Extension Study to Evaluate the Safety, Tolerability and Pharmacokinetics of STX209 in Subjects with Fragile X Syndrome (Protocol 22002)
Individuals with fragile X syndrome who completed the two treatment periods in study 22001, described above, with STX209 and placebo without significant side effects, and had positive change in behavior or functioning during one or both of the treatment periods in study 22001, were eligible to roll into this extension study.
The purpose of this study was to assess if STX209 is safe and effective for managing fragile X syndrome, when taken long-term.
This study is now closed to enrollment and all patients from protocol 22002 have moved into protocol 303 (see below).
A Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy, Safety, and Tolerability of STX209 (Arbaclofen) Administered for the Treatment of Social Withdrawal in Adolescents and Adults with Fragile X Syndrome (Protocol 209FX301)
In the preliminary trials of STX209, sponsored by Seaside Therapeutics, there was no difference between placebo and STX209 on the primary outcome of irritability.
However, researchers observed a significant beneficial treatment effect on social avoidance across the full study population. The purpose of this study is to further assess the efficacy, safety and tolerability of STX209 for the treatment of social withdrawal in adolescents and adults (ages 12 to 50) with fragile X syndrome.
This study is closed to enrollment.
A Randomized, Double-Blind, Placebo-Controlled Fixed-Dose Study of the Efficacy, Safety, and Tolerability of STX209 (Arbaclofen) Administered for the Treatment of Social Withdrawal in Children with Fragile X Syndrome (Protocol 209FX302)
This clinical trial, also sponsored by Seaside Therapeutics, is designed to assess the efficacy, safety and tolerability of STX209 for the treatment of social withdrawal in children (ages 5 to 11) with fragile X syndrome.
This study is currently enrolling.
An Open Label Extension Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of STX209 (Arbaclofen) in Subjects with Fragile X Syndrome (Study 209FX303)
All individuals who completed a clinical trial of STX209 (protocol 22002, 209FX301, or 209FX302), treated with placebo or STX209, without significant side effects, are eligible to enroll in this extension study.
The purpose of this study is to assess the safety of STX209 for the treatment of fragile X symptoms when taken for extended periods of time.
Fragile X research: development of outcome measures for future clinical trials
It is clear that much new information is becoming available regarding the neurobiological mechanisms active in fragile X syndrome. This has resulted in the preclinical development of syndrome-specific treatments to compensate the neural mechanisms rendered abnormal by the absence of the fragile X protein, FMRP.
Researchers and pharmaceutical companies are development some of these treatments (described above), but there is a critical need for well-validated outcome measures to demonstrate drug effect in the fragile X population.
The ongoing pilot project for outcome measure development will test the validity, in an fragile X syndrome population, of a series of cognitive tasks and other measures designed to assess specific areas of weakness and core deficits and features of fragile X that might be expected to show rapid improvement during the timeframe of a phase II or III 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.
Different outcome measure studies have been funded by the following:
- Kiwanis Spastic Paralysis Foundation
- FRAXA Research Foundation
- National Fragile X Foundation
- Fragile X Resource Group of Greater Chicago
- Rush Dean’s Fellowship program
- A number of philanthropic donations to further fragile X research
The following published papers explain the results of some initial outcome measures studies:
- Characterization of potential outcome measures for future clinical trials in fragile X syndrome. Berry-Kravis E, Lara R, Kim O-K, Sumis A, Wuu J. J Autism Dev Disord 2008;38:1751-1757.
- Early-phase ERK activation as a biomarker for metabolic status in fragile X Syndrome. Weng N, Weiler IJ, Sumis A, Berry-Kravis E, Greenough WT. Am J Med Genet 2008;147B:1253-1257.
- Comparative neuropsychological test battery differentiates cognitive signatures of Fragile X and Down syndrome. Kogan CS, Boutet I, Cornish K, Graham GE, Berry-Kravis E, Drouin A, Milgram NW. J Intellect Disabil Res 2009;53:125-142.
- A comparative performance of individuals with fragile X syndrome and Fmr1 knockout mice on Hebb-Williams mazes. MacLeod L, Kogan C, Collin C, Berry-Kravis E, Messier C, Gandhi R. Genes Brain Behav 2010;9:53-64.
- Psychometric study of the aberrant behavior checklist in fragile X syndrome and implications for targeted treatment. Sansone SM, Widaman KF, Hall SS, Reiss AL, Lightbody A, Kaufmann WE, Berry-Kravis E, Lachiewicz A, Brown EC, Hessl D. J Autism Dev Disord. 2012 Jul;42(7):1377-92.
- Reversal of fragile X phenotypes by manipulation of AβPP/Aβ levels in Fmr1KO mice. Westmark CJ, Westmark PR, O'Riordan KJ, Ray BC, Hervey CM, Salamat MS, Abozeid SH, Stein KM, Stodola LA, Tranfaglia M, Burger C, Berry-Kravis EM, Malter JS. PLoS One. 2011;6(10):e26549. Epub 2011 Oct 26.
Fragile X research: Recent outcome measures projects
- 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 fragile X syndrome. Since heightened sensitivity to sensory stimulation is one of the most common manifestations of fragile X, 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 fragile X syndrome 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.
Prepulse inhibition in fragile X syndrome: feasibility, reliability, and implications for treatment. Hessl D, Cirdeiro L, Yuhas J, Campball A, Ornitz E, Berry-Kravis E, Chruscinski E, Hervey C, Long J, Hagerman RJ. 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 fragile X syndrome. Researchers have since used this outcome measure in clinical trials for new treatments in fragile X syndrome.
- Eye tracking and pupillometry testing is another specific physiological measurement being evaluated as an outcome measure in populations with fragile X syndrome.
Gaze aversion is a commonly observed trait in people with fragile X syndrome, associated with social anxiety and sensory hyperarousal. Eye tracking and pupillometry testing were used to quantify gaze aversion in fragile x syndrome and study the difference between how people with fragile X syndrome and normal controls process a series of emotional faces using a computer protocol that tracked gaze and pupil dilation.
Results gathered in collaboration with Faraz Farzin, PhD, at the University of California MIND institute have demonstrated good test-retest reliability of these measurements and have resulted in use of these measures as treatment-specific outcome measures in several ongoing clinical trials.
Results of this validation study were published in the Journal of Autism and Developmental Disorders.
- KiTAP (Test of Attentional Performance for Children) is a computer-based outcome measure of eight sub-test that evaluate attention and inhibition using a cartoon format with an enchanted castle theme.
Researchers did a pilot study to assess the feasibility and test-retest reliability and clinical relevance of the eight sub-tests. Four sub-test were identified as potentially useful measurements of core deficits identified in people with fragile X syndrome across a broad range of functioning and have subsequently been used as a supplemental outcome measure in clinical trials.
Results of this validation study were published in the Journal of Neurodevelopmental Disorders.
- Expressive language processing is a new outcome measure that researchers at Rush are currently validating for future use in clinical trials to quantify improvement in conversation and language.
This outcome measurement is a conversation and narrative task that has shown excellent test-retest reliability in pilot studies. In past clinical trials, parents have often described meaningful improvements in language and communication but none of the existing outcome measurements were effectively capturing these reported changes.
Researchers expect that there will be further studies to fully validate this measure, and it will be incorporated into some early phase clinical trials.
- The pediatric anxiety rating scale (PARS) is a new anxiety scale outcome measure that researchers at Rush are also currently working to validate for future clinical trials to better identify anxiety in a fragile X population.
In a pilot study, the measure showed good feasibility, reproducibility and clinical validity.
- Effects of FMRP expression in cultured neural cells
This laboratory research project has examined neural cell properties, signal transduction and regulation of cAMP signaling in neural cells that over-express and under-express FMRP.
This project was funded by the Illinois-Eastern Iowa District of Kiwanis International, Spastic Paralysis and Allied Diseases of the Central Nervous System Research Foundation.
Reduced cyclic AMP production in fragile X syndrome: cytogenetic and molecular correlations. Berry-Kravis E, Hicar M, Ciurlionis R. Pediatr Res. 1995 Nov;38(5):638-43.
Fragile X-associated tremor/ataxia syndrome (FXTAS): permutation carrier studies
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 and may be carried by the mother, a maternal grandparent or great-grandparent, or aunts or uncles of a child with fragile X without any sign of learning problems.
The fragile X premutation could be responsible for neurological signs that develop later in life such as fragile X-associated tremor/ataxia syndrome (FXTAS), which is characterized by shakiness or movement problems with or without other neurological symptoms, or fragile X-associated primary ovarian insufficiency (FXPOI), 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 fragile X syndrome permutation, 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 are explained in the following studies:
- FMR1 CGG repeat length predicts motor dysfunction in premutation carriers. 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. Neurology 2008;70:1397-1402.
- Fragile X-associated tremor/ataxia syndrome (FXTAS): clinical features, genetics and testing guidelines. 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. Mov Disord 2007;22:2018-2030.
- Treatment of fragile X-associated tremor/ataxia syndrome (FXTAS) and related neurological problems. 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. 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 permutation 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. The goal of the study is to help develop 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:
- Do all men with an FMR1 premutation, even those who are clinically asymptomatic, have evidence of white matter abnormalities as detected by DTI?
- 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, researchers 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 premutation.
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 premutation 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 they can provide proper counseling to individuals who have the fragile X premutation.
All families with a fragile X mutation are eligible and if interested should contact Crystal Hervey, research coordinator at Crystal_Hervey@rush.edu.
An initial paper reporting early findings from this ongoing study has been published:
Clinical involement in daughters of men with fragile X-associated tremor/ataxia syndrome. 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. Clin Genet 2010, epub April 14.
Fragile X-associated tremor/ataxia syndrome (FXTAS): additional research projects
Projects studying symptoms in women with a fragile X premutation and studying balance problems in premutation carriers are ongoing through the FXTAS Clinic. Deborah Hall, MD, in collaboration with Berry-Kravis runs these projects.
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, researchers hope to learn more about fragile X syndrome, including the following:
- Its frequency in the general population
- The effect of early help for infants who have fragile X syndrome
- 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.
The study is closed for enrollment.
Fragile X Clinical and Research Cooperative Consortium (FXCRC) Fragile X Online Registry with Accessible Research Database (FORWARD)
This registry and associated database have been funded by the CDC and were 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 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
- Collect some basic information about problems associated with fragile X syndrome at all ages across the lifespan
- 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.
A link to the consent and HIPAA forms for this study as well the the primary ‘Self Report’ and ‘Report of a Relative’ can be found under related topics. The FXCRC has also created expert consensus documents for medical and educational management of patients with fragile X syndrome.
Other fragile X projects
The Rush Fragile X Clinic is collaborating on research about social and language characteristics in fragile X syndrome and fragile X carriers with Molly Losh, PhD, at the Neurodevelopmental Disabilities Laboratory at Northwestern University.
The Rush Fragile X Clinic is also collaborating on projects to characterize and treat social-emotional learning deficits in fragile X syndrome with Dr. Nicole Russo at the Rush Neurobehavioral Center.
Additional research interests
Berry-Kravis also collaborates with Cesar Ochoa, MD, on clinical trials of new medication for treatment of cognition in Down syndrome and 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’s disease in collaboration with the Rush Parkinson’s Disease and Movement Disorders Program and Christopher Goetz, MD, and Jennifer Goldman, MD, in the Department of Neurological Sciences, and works on studies of genetic factors in Alzheimer’s disease with the Rush Alzheimer’s Disease Center.
Molecular diagnostics laboratory
Many of the fragile X and other projects utilize the Berry-Kravis molecular diagnostics laboratory, a CAP and CLIA certified molecular diagnostics laboratory co-directed by Berry-Kravis and Paul Wong, MD.
Clinical diagnostic testing for fragile X syndrome and other genetic diseases including CCHS are also carried out in this laboratory. The laboratory has been performing DNA testing for diagnosis of fragile X syndrome since 1992. Laboratory projects have included collaborative projects with other academic centers and with industry to improve accuracy and optimize testing for fragile X syndrome, including studies of the AGG anchors in the FMR1 CGG repeat sequence (can be accessed below), and their effects on stability of the gene when inherited, studies of the effects of FMRP and FMR1 mRNA levels on symptoms of fragile X syndrome, and studies of other gene effects on manifestations of fragile X syndrome and symptoms in fragile X permutation carriers.
Contact information for fragile X research program
For more information about research studies, please contact:
Crystal Hervey, research coordinator