Nonstimulant Medication Is A Safe And Effective Alternative For ADHD Treatment In Children With Fragile X Syndrome
Published on February 19, 2008 on Medical News Today
Fragile X syndrome (FXS) is the most common hereditary form of mental retardation. Many children with FXS also suffer from attention deficit and/or hyperactivity disorder (ADHD), which complicates social relationships at home and at school. Although stimulant medication such as Ritalin® is often successfully used to treat children with ADHD, studies have shown that while it is effective in children with mental retardation, it also causes side effects such as increased irritability, decreased verbalization and social withdrawal. A previous study showed that L-acetyl carnitine (LAC), a form of the amino acid carnitine, significantly reduced hyperactive behavior in FXS boys with ADHD who were treated with it for one year without causing adverse side effects. The same authors have now conducted a randomized, double-blind, placebo-controlled multicenter study to determine the effectiveness of LAC in a larger group. The study is published in the April 1st, 2008 issue of the American Journal of Medical Genetics Part A, available online via Wiley InterScience. Led by M. Giulia Torrioli and Giovanni Neri of the Università Cattolica in Rome, the study involved 51 boys between 6 and 12 years old with FXS and ADHD who were treated in one of eight centers in Italy, France and Spain. Each patient followed the treatment for 12 months, which involved 500 milligrams of LAC or a placebo given twice daily. Patients were evaluated by an interdisciplinary team of child neuropsychiatrists and psychologists at the start of the study, after one month, six months and 12 months. The effects of the drug and placebo were evaluated using a set of neuropsychological tests to assess behavior. Those treated with LAC demonstrated reduced hyperactive behavior and increased attention. No side effects were exhibited, confirming that LAC is a safe alternative to stimulants. The patients treated with the placebo also showed reduced hyperactive behavior, although not nearly to the extent as the LAC-treated patients. The patients treated with LAC also had significantly improved social ability compared to the placebo-treated group. Both groups took intelligence tests, but LAC did not improve overall intellectual functioning. "We propose that LAC be recommended as a treatment of ADHD in FXS children," conclude the authors, "since it effectively reduces hyperactive behavior and improves social abilities without adverse side effects." They also suggest that these results may be applicable to children with autism, who also do not easily tolerate stimulants.
Article adapted by Medical News Today from original press release.
FRAXA Update: Researchers Reverse Key Symptoms of Fragile X in Mice
In the December 20th issue of Neuron, MIT researchers Mark Bear, Gul Dolen, and others, along with Sumantra Chattarji of India’s National Center for Biological Sciences, show that they can correct major symptoms of Fragile X by reducing expression of a single receptor in the brain. This receptor, a protein called mGluR5, is a prime target for drugs to treat Fragile X – and possibly autism – in humans. The findings support the theory that key Fragile X symptoms – learning disabilities, autistic behavior, and seizures – stem from too much activation of one of the brain's chief network managers – the metabotropic glutamate receptor mGluR5. People with Fragile X lack a protein called FMRP (Fragile X Mental Retardation Protein). This study found that FMRP and mGluR5 are at opposite ends of a kind of molecular seesaw. They keep each other in check, and without FMRP, mGluR5 signals run rampant. To test this theory, the researchers knocked out one of the two copies of the mGluR5 gene in mice already lacking FMRP. The mice lacking FMRP showed many of the symptoms observed in humans who have Fragile X. By knocking out one copy of mGluR5, the researchers created mice that produced only half the normal amount of mGluR5 protein, hoping to compensate for the lack of FMRP and eliminate symptoms of Fragile X. "We decided to reduce the mGluR5 levels by 50 percent to reflect what might be a therapeutically relevant condition that would be achievable with carefully titrated drug treatment," said Bear. "Total knockout of mGluR5 has deleterious effects, whereas reducing it by half is innocuous." The researchers found that reducing mGluR5 eliminated many symptoms of the disorder. Like humans with Fragile X, mice without FMRP experience seizures, impaired memory, and accelerated body growth. When mGluR5 was diminished, these problems were corrected. Reducing mGluR5 also compensated for changes in the brain associated with increased protein synthesis. With less mGluR5, the brain of each mouse no longer formed an excessive number of neuronal connections. The mice did not have the high density of dendritic spines that is characteristic of Fragile X syndrome. Furthermore, the total rate of protein synthesis was reduced to normal levels in the brains of Fragile X mice with reduced mGluR5. The researchers used genetic engineering to reduce mGluR5, but the same thing could be accomplished by a drug. Pharmaceutical companies have already developed experimental drugs that block mGluR5. Clinical trials are underway, but none of the drugs has yet been approved for humans. These findings may lead to further targets for drug discovery, since scientists can now study other drugs which affect other elements of the brain’s mGluR pathway. It should be possible to identify biomarkers, substances which can be measured in the blood, which can identify changes in the function of the mGluR pathway in people with developmental disorders. Through biomarkers, other people with autism and developmental disorders who do not have Fragile X, but do have abnormalities in this pathway, can be identified. It is likely that these individuals would respond to many of the treatments currently being developed for Fragile X. FRAXA has provided funding for the work of Mark Bear and colleagues every year since 2000 and also funds Sumantra Chattarji . FRAXA is now working with several companies to help speed development of mGluR5 blockers to treat Fragile X. Stay tuned for future announcements!
This update wassent from FRAXA in December 2008.
New discovery for Fragile X Syndrome Medical Condition
News Published: Tuesday, 11-Sep-2007
An important finding has been made by McMaster researchers about Fragile X Syndrome (FXS), a sex-linked genetic disorder that affects approximately one in 4,000 males and one in 6,000 females.
FXS is the most common genetic disorder associated with mental impairment. The affected gene (FMR1) leads to inactivation of the FMR1 gene product, known as the fragile X mental retardation protein (FMRP).
Brain development in the absence of this protein leads to cognitive effects, learning and memory problems, attention deficit, hyperactivity and autistic behaviors. Many children go undiagnosed with Fragile X.
Although the exact functions of FMRP in the brain are unresolved, there is compelling evidence that FMRP is important for normal function at the sites of communication between cells or neurons in the brain. Until now, FMRP was thought to be found only in neurons.
Stem cells are candidates for cell therapy in neurological disorders since they are capable of producing all cell types in the nervous system.
When studying the development of adult stem cells from the mouse brain, Laura Pacey, a Ph.D. student in professor Laurie Doering's laboratory, realized that cells, in addition to neurons, were also producing the FMRP. Doering is an associate professor in the Department of Pathology and Molecular Medicine.
Using specific markers to identify cell types, it was apparent that another major class of cells, called glial cells, also contained FMRP. Glial cells provide structural and metabolic support for neurons and they are necessary for normal function of the nervous system.
This discovery is important because these neuro-glial cells (astrocytes) play important roles in the development and maintenance of normal communication between neurons in the brain and spinal cord. So the absence of FMRP in astrocytes may contribute to the abnormal neuronal structures seen in the brains of Fragile X patients. The results of this research have strong implications for the cellular causes of FXS and will open new streams of research.
"This is an unexpected finding" states Doering. "Like fitting a piece of a puzzle that suddenly paints the main picture in a different perspective. We have another major cell type as a focus in Fragile X research. It will supply needed insight on the biology causing Fragile X and help to strengthen the potential for treatment strategies".
http://www.mcmaster.ca/
(This article was orginally posted on News-Medical.net.)
FRAXA Research Leads to Orphan Drug Designation
February 28, 2007
For the first time, a drug being developed for the treatment of Fragile X has received an Orphan Drug Designation from the Food and Drug Administration (FDA). In collaboration with FRAXA, Neuropharm Group plc is developing fenobam for the treatment of Fragile X. Neuropharm Limited, a subsidiary of Neuropharm Group plc, is a UK based speciality pharmaceutical group focused on the development of products for the treatment of disorders of the central nervous system. The FDA has granted Neuropharm Orphan Drug Designation for the use of fenobam in the treatment of Fragile X.
The Orphan Drug Act was passed by Congress to accelerate the development of treatments for rare diseases, defined as affecting 200,000 or fewer people in the U.S. Fragile X affects almost 100,000 US residents.
Fragile X, the most common inherited cause of mental retardation and the most common genetic cause of autism, results from the lack of a protein called FMRP. As a result of a deficiency of FMRP, brain cells don't communicate normally.
FRAXA-funded researchers have found a specific excess of metabotropic glutamate receptor (mGluR) signaling in Fragile X brains, and studies indicate this may be a common mechanism underlying many autism spectrum disorders. Follow-up research on animal models (also funded by FRAXA) shows it is possible to intervene in this hyperactive brain mechanism with compounds which block mGluRs, reversing the core deficits of Fragile X such as impaired cognition, anxiety, and autistic behaviors.
FRAXA has spent $3.8 million on funding research to build the case for using mGluR antagonists to treat Fragile X, beginning with a grant awarded in 2000 to Dr. Mark Bear (now Director of the Picower Institute at Massachusetts Institute of Technology) and Dr. Kimberly Huber (now a Professor at the University of Texas Southwestern Medical Center). FRAXA has funded over $11 million in Fragile X research over the past 13 years, and is continuing research on several other potential treatment strategies.
Fenobam was developed in the 1970s by scientists at McNeill Labs. It was studied in clinical trials in patients with anxiety disorders, demonstrating a good safety profile and some effectiveness, but precisely how it worked was unknown. Two decades later, researchers at Hoffmann LaRoche discovered that it is an mGluR5 antagonist, making it a promising candidate treatment for Fragile X.
Says FRAXA co-founder Michael Tranfaglia, MD, "We are very hopeful that this drug could get normal brain development back on track in people with Fragile X - and possibly autism as well."
(This article was originally posted on the FRAXA website.)
The Sun Shines on FRAXA
What is the Challenge?
Doris Buffett, president and founder of the Sunshine Lady Foundation, has donated $500,000 to FRAXA! She has also challenged the Fragile X Community to raise an additional $500,000 in new money by November 1, 2007, which she will then match 100%!
What is New Money?
Anyone who has never donated or has not donated to FRAXA since 12/31/2004 qualifies as a new donor. For those people who have supported FRAXA in 2005 or 2006, any increase in the donation over the greatest amount given will qualify for the match.
How Can You Help?
Ask your family, friends, and neighbors to donate with a Letter/Email Writing Campaign. Approach your employer or businesses you frequent - some companies will match your donation. Please consider hosting a fundraiser ... a Bake Sale, Car Wash, a Cocktail Party, etc. FRAXA can provide materials, and guidance to help you.
This extraordinary opportunity is energizing Fragile X families everywhere who know that an additional $1 million devoted to research could dramatically accelerate progress toward improving the lives of their loved ones with Fragile X. We need your help to succeed - it's all or nothing by November 1, 2007!
CONTACT http://fraxa.org TODAY!
(This article was originally posted on the FRAXA website).
Scripps Florida researchers discover gene that causes learning disabilities
By Glenn Singer Sun-Sentinel.com April 24, 2007, 9:30 AM EDT
Inspired by the zeal of a retired Palm Beach businessman, scientists at Scripps Florida have discovered a new gene associated with a condition that causes severe learning disabilities, including autism, anxiety disorders, psychoses and obsessive-compulsive behavior.
Until recently, researchers thought that a defect in only one gene causes the condition, fragile X syndrome, by halting development of a protein needed for normal brain development. That gene was discovered 16 years ago.
But Dr. Claes Wahlestedt, director of neuroscience discovery at Jupiter-based Scripps, and postdoctoral student Ahmad Khalil, found a second gene completely shuts down in patients with the syndrome. Instinct told them there was more than one gene because fragile X patients vary widely in mental capacity.
While it still falls within the realm of basic science, the discovery adds a new layer of knowledge about a condition that affects one in 2,000 boys and one in 4,000 girls across all populations. And it offers greater hope that by understanding the mechanisms behind fragile X, researchers can develop early treatments and ultimately a cure.
Scripps officials are so encouraged by the results so far that they have filed a patent application to protect "intellectual property" that one day might be used as part of a treatment or cure.
"This information we now have can form the basis for creating a diagnosis kit or finding a way to replace the defective genes with healthy ones," said Wahlestedt, who was among a group of researchers worldwide who reported in 2005 they had discovered thousands of genes that weren't mapped during the Human Genome Project.
When Scripps came to South Florida in 2004 with $310 million from the state and another $200 million from Palm Beach County, fragile X wasn't on the research organization's radar screen. But the Palm Beach entrepreneur Harris Hollin, working through former chief fund-raiser Will Ray, approached Scripps leaders to enlist their help.
Hollin, 75, told them that his 14-year-old grandson, Matthew, has fragile X syndrome. He also told them he has sponsored research elsewhere, particularly in Israel, but was looking for a fresh set of eyes and a new approach.
Once president of Revlon's international pharmaceutical operations and later owner of a drug company that he sold to Israeli-based Teva Pharmaceutical Industries Ltd., Hollin agreed to donate $125,000 to support the Scripps research, and Wahlestedt agreed to supervise the work.
While scientists sometimes work for years and even decades to solve genetic puzzles, the Scripps project has spanned only several months, thanks largely to the institute's sophisticated technology and the staff's expertise. Khalil, who received his doctorate in genomics from the University of Florida School of Medicine, has been at Scripps just nine months as a postdoctoral student.
For him and his supervisor, there is much more research to do before Scripps might interest a drug company in trying to develop a medication for fragile X. For example, does the new gene, called FMR4, produce a protein that contributes to brain development much like the first gene associated with fragile X, FMR1? To learn that could help point scientists in the right direction.
Just how far the Scripps scientists can go depends largely on future financing from agencies such as the National Institutes of Health and private organizations, Wahlestedt said.
(This article was originally published in the South Florida Sun-Sentinel.)
Fragile X Walk is supported by officials, many area residents
The Fourth Annual Walk for Fragile X Syndrome in Honor of Parker and Allison Roos was held Saturday, April 21.
Over 315 people gathered at Wallace Park in Canton for the fundraising and awareness event. Families with members affected by the syndrome were in attendance from DeKalb, Malta, Washington, Pekin, LeRoy, Plainfield, Cambridge, Bushnell, Peoria, Mackinaw, Lewistown, Farmington, and Canton.
This year's walk raised over $20,000 and included 11 Corporate Sponsors, 36 Fact Sponsors and 188 Friend Sponsors.
Forty-seven Fragile X Fact boards lined the track to help walkers learn more about this syndrome. The boards included not only an informational fact about Fragile X but also a picture of someone living with Fragile X Syndrome.
These boards were sponsored by Corporate and Fact Sponsors. Members of Elaine's Jumbled Jewels of the Red Hat Society provided a bake sale with all proceeds going to the Walk. Clowns were on hand providing face paintings and balloon animals for children that were present.
There were special drawings this year for a boy and a girl under the age of 12. The girl, Hannah Bergavin, won a Just Like Me American Girl Doll. Josiah Williams won a basketball autographed by the Indiana Pacers.
Other special drawings included two handmade quilts, donated by Elaine's Jumbled Jewels of the Red Hat Society and Ma's Got'a Notion in Havana, were won by John Usrey of Cambridge and Jane Sheets of Peoria. A trip to Las Vegas, donated by Angie Miller, was won by Rick Reffett of Canton, and a trip to Mall of America, donated by WBYS radio AM 1560, was won by Shelly Deal of Pekin.
Among the 60 silent auction items were autographed memorabilia from Jack Nicklaus, Pablo Ozuna, La'Roi Glover, Boomer Grigsby, several theme baskets and a handmade bow. Over 140 items filled this year's raffle with great prizes for participants. WBYS Radio AM 1560 provided live coverage of the day's events.
Special guests to this year's walk was Congressman Phil Hare and Chicago author Mark Earnest. Hare addressed the crowd about how he learned about Fragile X and his efforts on a federal level to get more funding for Fragile X. Earnest was on hand to sign copies of his novel, "The Delta Project," with all proceeds going to Fragile X.
"Earlier this year, Parker and Allison's mother Holly visited me in Washington DC to talk about the thousands of children suffering from Fragile-X," Hare said. "Admittedly, that was the first I had heard of it. For Parker, Allison, and all others like them, it is critical that we put this disease on the nation's radar screen."
"From the first moment I shared my story with Congressman Hare, he has taken a lead role in promoting awareness about Fragile-X," Roos said. "Not only did he take time out of his busy schedule to join us for our walk today, he has also organized a briefing on Capitol Hill to inform all Members of Congress about this disease and the need to aggressively pursue a cure."
Hare recently sent a letter to all 433 of his colleagues inviting them "to learn more about Fragile X Syndrome, the research advances being made, and the current proposals on the table to help families living with Fragile X."
Hare said that while federal funding for fragile X research and development increased to over $20 million dollars in 2004, "we still have a long way to go to develop more effective treatments and eventually, find a cure."
On Wednesday, April 25, Holly will join Congressman Hare in addressing members of congress on Fragile X. On Thursday, April 26 a fundraiser at the Canton Burger King will be held from 5 to 8 pm.
This July 20-21, a fundraising weekend in honor of Fragile X Awareness Day (July 22) will be held at the Jukebox Comedy Club in Peoria. The walk, which began in 2004 as a senior high school class project for Cuba high school senior Andrea Schnarr, has grown into a major fundraising event.
Although Holly Roos now organizes and coordinates the walk, Schnarr, who now attends Western Illinois University, is still active in the planning and activities of the walk. The entire Schnarr family continues to join in and actively support the walk and other Fragile X Activities year round.
All proceeds from this walk will be used to help with awareness, education, treatment and research of Fragile X Syndrome. Donations received up through May 31 will be counted towards the walk total.
Fragile X Syndrome is the world's leading cause of inherited mental impairment and the leading known genetic cause of autism. One in every 129 women and one in every 350 men carry the gene that causes Fragile X.
The syndrome occurs because of a change or mutation of a single gene on the X chromosome. Symptoms of Fragile X occur because the mutated gene can not produce enough of a protein needed by the human body's cells, especially cells in the brain.
Because Fragile X occurs on the X chromosome, both males and females can have Fragile X and pass it onto the next generation. Often times, as in the case of Holly's family, the gene is passed unknowingly through several generations before it is identified.
"We can now trace the Fragile X gene in our family back 6 generations," said Holly. "It all started when Parker was diagnosed and we started having more family members tested.
Most times, carriers like myself are completely unaware that they carry this gene and it isn't until they have a child or children with Fragile X that they become aware of it." Fragile X can be detected with a simple and accurate DNA blood test.
Anyone with a family history of undiagnosed mental impairment; any male or female with mental impairment (borderline to severe), developmental delay or learning disabilities of unknown cause; any male or female with autism or autistic-like characteristics; and women with a family history of premature menopause should be tested for Fragile X.
Fragile X Associated Tremor-Ataxia Syndrome (FXTAS) and Fragile X Associated Premature Ovarian Failure (POF) are also conditions that are important for carriers of this gene to be aware of.
FXTAS is a newly identified neurological disorder, involving progressively severe tremor and difficulty with walking and balance, appears to specifically affect some older premutation carriers, generally males.
POF is defined as menopause occurring prior to the age of 40. Early menopause is defined as menopause occurring prior to the age of 45. Carriers of the fragile x gene are at risk for POF, early menopause and ovarian dysfunction (decreased fertility) in general.
Fragile X Syndrome is a spectrum disorder and may cause anything from mild learning difficulties and a normal IQ to profound mental impairment and autism. Currently there is no cure or effective treatment for Fragile X.
Parker Roos is currently in the second grade at Eastview Elementary school, where he spends as much of his day as possible with his peers and the remainder of his day getting individualized attention. Allison Roos attends the Little Learners Preschool at Westview Elementary School.
Although both anxiety and shyness can be seen in both children, Parker faces a lot more significant struggles on a daily basis. "His environment can really overwhelm him," said Holly. "Although he has come a long way, each day is a struggle for him. The little things we take for granted, how our clothes feel on our body, the smell of something baking, the light in the rooms, the sounds around us, all of these things in addition to his speech, cognitive, and fine motor delays can really make each minute of the day a challenge and often lead to behavioral struggles.
"Parker really is an amazing little guy. He faces challenges that most can't even imagine. He has a wonderful sense of humor and is very, very caring for those around him. Allison struggles more with her emotions and her vision. She is a bundle of sunshine, she loves music and singing, and horses.
Both Parker and Allison not only amaze me but also inspire me every day." Both children enjoy school and are involved in activities in both school and the community.
The Central Illinois Fragile X Research Group that was founded by Holly Roos accepts donations year round. Those wishing to donate can send donations to : Walk for FX, 914 North 6th Ave., Canton, IL 61520.
For more information on Fragile X Syndrome you can visit the group's website at: www.fragilex.org/html/illinois.htm , The National Fragile X Foundation at: www.fragilex.org, or the FRAXA Research Foundation at: www.fraxa.org or you may contact Roos at centralilfx@yahoo.com
(This article was originally published in the Canton Daily Ledger.)
|
