A paper published online in Nature describes the results of using bone marrow transplant (BMT) to replace faulty immune system cells in models of Rett Syndrome. The procedure arrested many severe symptoms of the childhood disorder, including abnormal breathing and movement, and significantly extended the lifespan of Rett mouse models.
Exploring the function of microglia deficient in methyl-CpG binding protein 2 (Mecp2), the protein encoded by the "Rett gene," principal investigator Jonathan Kipnis, Ph.D. and his team at the University of Virginia School of Medicine uncovered a completely novel approach to this devastating neurological syndrome. The work was funded by the Rett Syndrome Research Trust and the Rett Syndrome Research Trust UK.
Rett Syndrome, the most physically disabling of the autism spectrum disorders, is caused by random mutations in the gene MECP2. Predominantly affecting girls, symptoms usually manifest between 6 and 18 months of age, when a frightening regression begins. Children lose acquired language skills and functional hand use; movement deteriorates as other Rett symptoms appear. These may include disordered breathing, Parkinsonian tremors, severe anxiety, seizures, digestive and circulatory problems and a range of autonomic nervous system and orthopedic abnormalities Although most children survive to adulthood, many are wheelchair-bound, rely on feeding tubes, are unable to communicate and require total, lifelong care.
Kipnis was drawn to Rett Syndrome from his perspective as a neuroimmunologist. "What began as intellectual curiosity," he explains, "has become an intense personal commitment to studying the correlation between neurological function and the immune system in Rett Syndrome. The impact of BMT on so many different symptoms has triggered a flood of experiments we are now pursuing at full speed."
The brain is largely comprised of several types of glial cells, which have diverse and complex functions that include sustaining a healthy environment for neuronal growth and maintenance. Microglia are small glial cells that participate in the brain's immune response. One of their roles is to clean up normal cellular debris in the brain through the process of phagocytosis. Kipnis and his team discovered that when microglia lack properly functioning Mecp2, they are unable to perform this crucial duty efficiently. Because microglia are derived from immune progenitor cells, it is possible to replace them via a bone marrow transplant.
First author Noël Derecki and his colleagues began their work with male Rett mouse models, which lack any Mecp2. These Mecp2-null mice mimic the human disorder, with neurological symptoms beginning to appear at about 4 weeks of age and an approximate life expectancy of only 8 weeks. Radiation treatment was administered at 4 weeks, followed by a bone marrow transplant from normal (wild-type) mice. As engraftment - the migration and repopulation of new microglia - took place, the Rett mice began to grow instead of fail. Body and brain sizes approached those of wild-type mice, gait improved and mobility increased significantly. There were no signs of the severe tremors seen in untreated mice. Apneas and other breathing irregularities were markedly diminished. The oldest of these mice is now almost a year. Work with female Rett mouse models at more advanced stages of disease is currently underway.
Gail Mandel, Ph.D., whose Rett research focuses on astrocytes, another type of glial cell impaired by mutations in MECP2, comments, "A fascinating aspect of these findings is the data suggesting that deficits in the engulfing properties of microglia are a crucial aspect of Rett neuropathology. It will now be necessary to develop cellular assays to determine all the ways these immune cells are bolstering neuronal functions and whether they can be therapeutically harnessed." Dr. Mandel is a Senior Scientist at the Vollum Institute and a Professor in the Department of Biochemistry and Molecular Biology in the School of Medicine at Oregon Health & Science University and an Investigator of the Howard Hughes Medical Institute.
Monica Coenraads, Executive Director of the Rett Syndrome Research Trust added, "I've been in almost daily contact with Dr. Kipnis since he brought his very original proposal to RSRT, and have been amazed to see the development of this brutal disease stopped in its tracks. A question that arises, of course, is whether replacing faulty immune cells with healthy microglia through bone marrow transplant would arrest or ameliorate already existing symptoms in humans. We do know of a case in which a girl with Rett Syndrome who was treated for leukemia gained considerable communication skills after a bone marrow transplant, and was able to converse with her mother for the first time in their lives. RSRT is in the process of exploring bone marrow transplant as a treatment modality, with full awareness of the serious nature of such a trial. In research, we are risk-takers. In clinical application, we are conservative and will be examining this carefully as more information emerges."
Source: Medical News Today
Adds Noël Derecki, "Our encouraging results point to how surprisingly tractable this severe disorder proves to be, at least in the lab. We are currently exploring how bone marrow transplantation might affect Rett symptoms once they have become more advanced, and whether there are other effective ways of modulating immune responses and subsequent effects in the central nervous system."
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Scientists from Seattle Children's Research Institute and the University of Washington, in collaboration with the Genomic Disorders Group Nijmegen in the Netherlands, have identified two new genes that cause Baraitser-Winter syndrome, a rare brain malformation that is characterized by droopy eyelids and intellectual disabilities.
"This new discovery brings the total number of genes identified with this type of brain defect to eight," said William Dobyns, MD, a geneticist at Seattle Children's Research Institute. Identification of the additional genes associated with the syndrome make it possible for researchers to learn more about brain development. The study, "De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome," was published online February 26 in Nature Genetics.
The brain defect found in Baraitser-Winter syndrome is a smooth brain malformation or "lissencephaly," as whole or parts of the surface of the brain appear smooth in scans of patients with the disorder. Previous studies by Dr. Dobyns and other scientists identified six genes that cause the smooth brain malformation, accounting for approximately 80% of affected children. Physicians and researchers worldwide have identified to date approximately 20 individuals with Baraitser-Winter syndrome.
While the condition is rare, Dr. Dobyns said the team's findings have broad scientific implications. "Actins, or the proteins encoded by the ACTB and ACTG1 genes, are among the most important proteins in the function of individual cells," he said. "Actins are critical for cell division, cell movement, internal movement of cellular components, cell-to-cell contact, signaling and cell shape," said Dr. Dobyns, who is also a University of Washington professor of pediatrics. "The defects we found occur in the only two actin genes that are expressed in most cells," he said. Gene expression is akin to a "menu" for conditions like embryo development or healing from an injury. The correct combination of genes must be expressed at the right time to allow proper development. Abnormal expression of genes can lead to a defect or malformation.
"Birth defects associated with these two genes also seem to be quite severe," said Dr. Dobyns. "Children and people with these genes have short stature, an atypical facial appearance, birth defects of the eye, and the smooth brain malformation along with moderate mental retardation and epilepsy. Hearing loss occurs and can be progressive," he said.
Dr. Dobyns is a renowned researcher whose life-long work has been to try to identify the causes of children's developmental brain disorders such as Baraitser-Winter syndrome. He discovered the first known chromosome abnormality associated with lissencephaly (Miller-Dieker syndrome) while still in training in child neurology at Texas Children's Hospital in 1983. That research led, 10 years later, to the discovery by Dobyns and others of the first lissencephaly gene known as LIS1.
Dr. Dobyns' co-authors on this study include: Jean-Baptiste Riviere, PhD, Seattle Children's Research Institute; Christopher Sullivan, Seattle Children's Research Institute; Susan Christian, Seattle Children's Research Institute; Brian O'Roak, PhD, University of Washington; Jay Shendure, MD, PhD, University of Washington; and many other physicians and scientists from North America and Europe.
Additional Resources
"De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome": http://www.nature.com/ng/journal/vaop/ncurrent/full/ng.1091.html
"Baraitser-Winter syndrome" study slideshow: http://www.flickr.com/photos/38997016@N03/sets/72157629446519959/
"Baraitser-Winter syndrome" studies: "Isolation of a Miller-Dieker lissencephaly gene containing G protein beta-subunit-like repeats" http://www.ncbi.nlm.nih.gov/pubmed/8355785; "doublecortin, a Brain-Specific Gene Mutated in Human X-Linked Lissencephaly and Double Cortex Syndrome, Encodes a Putative Signaling Protein" http://www.ncbi.nlm.nih.gov/pubmed/9489700
About Seattle Children's Research Institute
At the forefront of pediatric medical research, Seattle Children's Research Institute is setting new standards in pediatric care and finding new cures for childhood diseases. Internationally recognized scientists and physicians at the Research Institute are advancing new discoveries in cancer, genetics, immunology, pathology, infectious disease, injury prevention and bioethics. With Seattle Children's Hospital and Seattle Children's Hospital Foundation, the Research Institute brings together the best minds in pediatric research to provide patients with the best care possible. Children's serves as the primary teaching, clinical and research site for the Department of Pediatrics at the University of Washington School of Medicine, which consistently ranks as one of the best pediatric departments in the country. For more information, visit http://www.seattlechildrens.org/research.
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Attendees from Africa: Luis Bernadino and Manuel Cruzeiro (Angola), David Bearden (Botswana / USA), Elie Mbonda (Cameroun), Therese Douayoua-Sonan (Cote d’Ivoire), Luc Malimbalimba Maururu (DRC), Ahmed Raouf Ibrahim (Egypt), Kindu Woldemichael (Ethiopia), Eben Badoe (Ghana), Pauline Samia and Charles Newton (Kenya), Macpherson Mallewa (Malawi), Dalila Ibrhimo Sulemane (Mozambique), Wammanda Daniel Robinson (Nigeria), Judy Orikiiza Tatwangire and Febrionie Mushimiyimana (Rwanda), Moustapha Ndiaye (Senegal), Alhaji Alusine Jalloh (Sierra Leone), Jo Wilmshurst, Andre Venter and Gail Scher (South Africa), Haydar El Hadi Babikir (Sudan), Angelina Kakooza and Richard Idro (Uganda), Evans Mpabalwani (Zambia).
From outside Africa: Harry Chugani, Deborah Hirtz, Douglas Postels, Pamela Follett (USA); Helen Cross and Cheryl Hemingway (UK), Lieven Legae (Begium) and Mitsuhiro Kato (Japan).
The program commenced with basic approaches and mimics of epilepsy, and then progressed to discuss more complex issues such as epilepsy surgery. The final day focused on the way forward and covered how information technology resources and non-government organisations can be used. The final part of the meeting consisted of dividing the attendees into small working groups who discussed key themes which had arisen during the meeting namely capacity, definitions, guidelines, and training and education needs. Each theme was summarised by one of the African delegates who co-facilitated a working group.
The meeting was recorded, the videos of the presentations are available on the ICNApedia web-site (www.ICNApedia.org) along with the power-point presentations (after the patient and data confidentiality was addressed).
The presentations were delivered by members of the International Child Neurology Association (ICNA), African Child Neurology Association (ACNA), International League Against Epilepsy (ILAE), National Institutes of Health (NIH), the Japanese Child Neurology Society and the delegates.
Twenty-eight countries provided information on their services, capacity and approach to children with epilepsy. Thirty-three delegates from 19 of these countries were able to attend the meeting, those who could not expressed eagerness to remain part of the working group. A further five specialists from countries outside Africa (United Kingdom, United States of America, Belgium and Japan) attended the meeting.
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New recommendations on the use of anti-epileptic drugs (AEDs) for the treatment of adults and children with epilepsy have been set out, in updated NICE guidelines.
Epilepsy affects up to an estimated 415,000 people in England, and two-thirds of people with active epilepsy have their condition satisfactorily controlled by AEDs.
NICE first published guidance on epilepsy in 2004 that included recommendations on the use of AEDs, as well as advice on the diagnosis, treatment and further management of the condition.
As recent years have seen a rise in the number of AEDs being prescribed, NICE has now updated this clinical guideline to provide information on newer AEDs.
The update describes how and when newer AEDs should be considered alongside older medicines, and can help GPs ensure they are prescribing treatments that are effective both clinically and cost effective.
NICE recommends that when possible, clinicians should choose which AED to offer on the basis of the presenting epilepsy syndrome. If the epilepsy syndrome is not clear at presentation, base the decision on the presenting seizure type(s).
When prescribing sodium valproate to women and girls of present and future childbearing potential, GPs should discuss the possible risk of malformation and neuro-developmental impairments in an unborn child. This is particularly the case with high doses of the AED or when using it as part of polytherapy.
Buccal midazolam or rectal diazepam should only be used in the community for children, young people and adults who have had a previous episode of prolonged or serial convulsive seizures, says NICE.
In addition, buccal midalozam should be administered as first-line treatment in children, young people and adults with prolonged or repeated seizures in the community.
GPs should prescribe rectal diazepam, if this is preferred, or if buccal midazolam is not available.
If intravenous access is already established, and resuscitation facilities are available, intravenous lorazepam should be administered.
Dr Greg Rogers, a GPwSI in epilepsy who was involved in the development of the updated guidelines said: “Epilepsy is the most common serious neurological disorder that we encounter in the UK.
“Whilst the majority of people with active epilepsy can satisfactorily control recurrent seizures, many still suffer from ongoing seizures and helping them to become seizure-free can help improve their health outcomes.
“This updated guideline is welcome as it incorporates the newer AEDs which have emerged in the UK since the original guidance was published in 2004.
“With the current uncertainty over whether these newer medicines bring any additional clinical benefits for their price, this guideline update helps inform GPs of their therapeutic choices.
“The use of levetiracetam is of particular interest as the last decade has seen its use increase. It is an effective and well tolerated drug but also expensive. Therefore, guidance on the use of this AED is welcome and on where it should be placed in the treatment of people with epilepsy.”
Elsewhere, the updated guideline contains a new recommendation on use of the ketogenic diet - a diet that is high in fat but low in carbohydrates and protein.
NICE says that if a child or young person with epilepsy has seizures that have not responded to appropriate AEDs, GPs should refer them to a tertiary paediatric epilepsy specialist to be considered for the ketogenic diet.
NICE has produced a range of tools to help support the implementation of this guideline, including a baseline assessment tool, clinical audit tools and a range of pharmacological treatment tables.
The guideline is also available to view as a NICE Pathway - a new online tool that provides quick and easy access to guidance recommendations.
Source: NICE
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The ILAE "6th Migrating Course on Epilepsy" will be held in Porto, Portugal, from 10 -17 June 2012.The Portuguese League Against Epilepsy will organize the event and outline the scientific program, in close collaboration with the Commission on European Affairs of the ILAE.
This is a comprehensive course combining basic and clinical epileptology. It is aimed primarily to younger doctors (< 45yrs). The teaching staff comprises european epileptologists with widely recognized scientific and educational skills. The working model will be interactive, with emphasis on work sessions in small groups, and participants are encouraged to bring specific cases to discuss their own clinical experience.
We would be thankful if you could transmit this initiative to the members of your chapter, and perhaps announce the event at your chapter’s website (an english version is available at http://www.epilepsia.pt/lpce/6th-migrating-course-on-epilepsy.
A limited number of bursaries will be available from the course organization. It would be excellent if your chapter could perhaps support deserving applications from your country, reducing the costs of participation for those not contemplated with the course bursary.
The first announcement of the 6th Migrating Course can be found attached and is also available for download at the LPCE website (http://www.epilepsia.pt/lpce/6th-migrating-course-on-epilepsy).
Looking forward to receiving applications from your country, we send our best regards,
The Course Directors of the 6th Migrating Course on epilepsy:
Alla Guekht
Peter Wolf
Francisco Sales
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