In 2014, the Ontario Rett Syndrome Association (O.R.S.A.) Board of Directors had unanimously approved the funding of a $50,000 Research Grant to a joint grant application from Dr. Juan Ausio (Biochemistry and Microbiology, University of Victoria, BC) and Dr. John Vincent (Neurogenetics, University of Toronto). This was the first grant from The Hope Fund and was largest grant released at the time.
We are pleased to announce that with our support, their work, From Function to Phenotype: Impaired DNA Binding and Clustering Correlates with Clinical Severity in Males with Missense Mutations in MECP2 has been published in the Nature Journal “Scientific Reports”. A summary that explains the findings and context can be found below and to read the full article, please follow this link, www.nature.com/articles/srep38590/
Mutations in the MECP2 gene cause Rett syndrome (RTT). MeCP2 binds to chromocentric DNA through its methyl CpG-binding domain (MBD) to regulate gene expression.While it’s well established that single DNA changes can lead to Rett syndrome — one of the most common genetic forms of intellectual disability – a new CAMH study has for the first time linked DNA mutations directly to how severe the syndrome is among those affected.
The results could pave the way for improved diagnosis and potentially new treatments for Rett syndrome, which is marked by problems with communication, language, learning and physical coordination.
The study was led by Dr. John Vincent, Senior Scientist in CAMH’s Campbell Family Mental Health Research Institute, and PhD student and first author Taimoor Sheikh. It was published in the journal Scientific Reports in December.
The DNA in question is part of the MECP2 gene, which is made up of thousands of pairs of DNA – one part from our mother, one from our father. This DNA can be thought of as “letters” that create words to generate genetic instructions. In many cases of Rett syndrome, any one of about 160 known changes to these letters on the MECP2 gene can garble the words and then the instructions.
There’s a reason these single DNA changes have such serious effects: the MECP2 gene carries instructions for a fundamental protein in the brain. The MECP2 protein binds to DNA at various places, and then acts as a “switch” to turn nearby genes on or off.
The research team found that if the change, or mutation, occurred in a part of the protein where it disrupted the switch, the syndrome was more serious. Changes that were further from the parts of MECP2 protein that bind to DNA, instead affected how the protein interacted with other proteins. This led to milder symptoms.
“The discovery raises the possibility of finding compounds to treat Rett syndrome, if we could create a ‘patch’ to make the protein function the way that it’s supposed to,” says Dr. Vincent, who heads the Molecular Neuropsychiatry & Development (MiND) lab at CAMH.
In addition, the nature of each change – which “letters” were swapped out – also affected how serious the syndrome was, the researchers note. They used a series of tests to study MECP2 proteins, with 12 different mutations including many most commonly reported in girls with Rett syndrome.
Clinical implications
With further development, the findings could help in cases where Rett syndrome is suspected in a patient. Symptoms typically appear in girls before the age of two. Genetic screening would
yield information on the type of mutation, to predict the type and severity of illness, says Dr. Vincent. As there is currently no treatment for Rett syndrome, only symptom management, screening could point to where more supports are needed.
A study in boys
Another novel aspect of the study was the fact that it also focused on boys with MECP2 mutations. In boys, Rett syndrome is extremely rare. This approach provided researchers with a clearer picture of the effect of protein changes in terms of symptoms and severity.
The MECP2 gene is located on X chromosomes. As girls have two copies of X, those with Rett syndrome have a second unaffected MECP2 gene on the other X, which may compensate for the garbled instructions. This is seen by the fact that clinical symptoms of Rett syndrome vary greatly in girls.
As boys carry X and Y chromosomes, any mutation on the X has an even more serious effect. It’s believed that most such cases do not survive pregnancy or early infancy.
By studying 11 rare cases of boys identified with MECP2 mutations, the researchers were able focus on DNA changes and their molecular and cellular effects in relation to clinical severity, without any compensating effects of the second MECP2 gene on the other X chromosome.
Ultimately, they hope to find compounds to help treat Rett syndrome using an approach called “peptide panning.” It involves testing many different peptides, which are small pieces of proteins, to see which ones bind to the mutant MECP2 protein to help recover its normal functioning.
“By further developing the molecular and cellular tests used in our study, we hope to be able to predict the likely clinical outcomes for newly discovered MECP2 mutations, as well as screen for compounds that can make MECP2 protein with specific mutations revert back to its normal function,” says Dr. Vincent.
From Function to Phenotype: Impaired DNA Binding and Clustering Correlates with Clinical Severity in Males with Missense Mutations in MECP2.
Sheikh TI, Ausió J, Faghfoury H, Silver J, Lane JB, Eubanks JH, MacLeod P, Percy AK, Vincent JB.Published in Scientific Reports, 8th Dec 2016; funded through an ORSA grant to John B. Vincent and Juan Ausió.
Run 4 Rett 2017 – Sunday September 17
Last Updated: September 15, 2017 by Bryan
The 2017 Run4Rett will be held Sunday September 17, 11:00 a.m. at Richmond Green Park, 1300 Elgin Mills Rd. E., Richmond Hill, ON, L4S 1M5.
The 13th annual 1k and 5k run / walk is a signature fundraiser for the Ontario Rett Syndrome Associated (O.R.S.A.). It is an opportunity to bring us together to raise awareness and to show a united and strong voice for Rett syndrome to hundreds of participants and supporters. Our goal is to raise $60,000.
All proceeds fund crucial activities organized by O.R.S.A.’s volunteer board of directors. These include:
Please JOIN US! Walk, run or volunteer for the 1K or 5K with family and friends! Families are welcome!
Register online now (closes September 14)
Download printable pledge and registration form
DONATE NOW
We will be hosting a silent auction at the race site. Check out the huge list of items available to bid on. There is something for everyone, especially sports fans:
Silent Auction Items
$100,000 Research Grant Awarded
Last Updated: September 15, 2017 by Bryan
London Ontario – May 5, 2017 – The Ontario Rett Syndrome Association (O.R.S.A.) Board of Directors has unanimously approved the funding of a $100,000 Research Grant to Dr. David Grynspan (Pediatric Pathologist, Children’s Hospital of Eastern Ontario, Ottawa, ON). The study is entitled “Treatment Strategies for Gastrointestinal Dysfunction in Rett Syndrome” and Dr. Grynspan’s collaborators for this work include Professor William Staines of the University of Ottawa and Dr. Sarah Schock, Research Associate at the CHEO Research Institute. This application was one of several received and evaluated by O.R.S.A.’s Research Advisory Committee that comprised of prominent neurologists, geneticists and scientists from across Canada.
This study aims to identify drugs able to restore normal intestinal function in Rett mice. The goal is that this would lead to effective drug therapy for intestinal dysmotility in Rett humans, and perhaps help to develop therapies for reversing neuronal connectivity problems in Rett brains. It is a rather novel approach in that this study plans to evaluate the enteric (ie- gut) nervous system, rather than directly studying the central nervous system as in most other studies. It is felt that this study, given its novel approach and its focus on a very common area of clinical concern, would be of scientific value to the research community at large as well as of great interest to the families most directly supported by O.R.S.A.
The Hope Fund was established in 2014. This is the third grant being released from this fund and the largest grant released by O.R.S.A. to date. The funds for this research grant were raised through donations and fundraising activities. O.R.S.A. continues to support research excellence and the development of a wide scope of Rett syndrome research across Canada.
About Rett Syndrome
Rett syndrome is a neurodevelopmental condition characterized by the loss of spoken language and hand use, coupled with the development of distinctive hand stereotypies. This disorder is seen in infancy and occurs almost exclusively in females. It is usually caused by a mutation of the MECP2 gene on the X chromosome. Rett syndrome is found in all racial and ethnic groups throughout the world. It affects one in every ten thousand live female births. Early developmental milestones appear normal, but between 6-18 months of age, there is a delay or regression in development, particularly affecting speech, hand skills and gait. A hallmark of Rett syndrome is repetitive hand movements that may become almost constant while awake. Other more common medical issues encountered include epileptic seizures, muscle stiffness, osteoporosis and scoliosis. Despite its multiple handicaps, Rett syndrome is not a degenerative disease. Many individuals with Rett syndrome live long into adulthood. There is currently no cure.
About Ontario Rett Syndrome Association (O.R.S.A.)
The Ontario Rett Syndrome Association (O.R.S.A.) exists to ensure that children and adults with Rett syndrome are enabled to achieve their full potential and enjoy the highest quality of life within their communities. The O.R.S.A. is a volunteer, not-for-profit charity for parents, caregivers, researchers, medical professionals and other interested support agencies and individuals. O.R.S.A. became incorporated in 1991. Its Board of Directors is comprised of parents and caring citizens. O.R.S.A. provides information through a website, a newsletter and conferences. Support is provided to families regionally. The association funds Canadian research projects, three Rett Syndrome Clinics, a resource centre and developed the Canadian Rett Syndrome Registry. O.R.S.A. advocates to the needs of individuals with Rett syndrome and their families provincially and nationally.
Dr. David Grynspan
David Grynspan is a Pediatric Pathologist at the Children’s Hospital of Eastern Ontario. He obtained his MD degree from the University of Toronto in 2000 and completed his residency in Anatomical Pathology at the University of British Columbia in 2007, followed by a fellowship in Pediatric Pathology at Wayne State University and The Children’s Hospital of Michigan in Detroit, Michigan. From 2007-2009, Dr. Grynspan was a staff Pediatric Pathologist at The Winnipeg Health Sciences Centre and The University of Manitoba. Dr. Grynspan has been a staff Pediatric Pathologist at The Children’s Hospital of Eastern Ontario (CHEO) and the University of Ottawa since 2009 and has been conducting research on the enteric nervous system since 2009. His interest in the neurological basis of intestinal dysfunction in Rett syndrome was sparked by clinical observations made by Dr. Peter Humphreys who is a role model and mentor. He is also fortunate to have been mentored in neuroscience by Professor William Staines at the University of Ottawa, with whom he formed a collaborative team that was the first to show expression of the Mecp2 gene in intestinal neurons. Aside from his research, Dr. Grynspan’s other academic interests include teaching and he is a member of the Pathology Residency Training Committee and the Maternal-Fetal Medicine Fellowship Committee at the University of Ottawa. David and his wife Karen have three daughters, Stella, Gabriella and Sophia. His hobbies include swimming and poetry.
13th Annual Rett Classic
Last Updated: September 5, 2017 by sherry
Mark it on your calendars!
Saturday June 10th, 2017 at 1:00 p.m.
Registration: Beginning at 11:00 a.m.
Tee-Off: 1:00 p.m.
Dinner: Buffet Following Golf
Format: 4 Player Scramble
Location:
The Greens at Renton
969 Concession 14
Simcoe, ON N3Y 4K3
www.greensatrenton.com
Posted: March 14, 2017 by sherry
Recruiting New Committee/Board Members
O.R.S.A. is looking for new board members & committee members
The Ontario Rett Syndrome Association (O.R.S.A.) is a volunteer, not-for-profit charity for parents, caregivers, researchers, medical professionals and other interested support agencies and individuals. Its Board of Directors is comprised of parents and caring citizens. O.R.S.A. provides information through a website, a newsletter and conferences. Support is provided to families regionally. The association funds Canadian research projects, three Rett Syndrome Clinics, a Resource Centre and the Canadian Rett Syndrome Registry. O.R.S.A. advocates to the needs of individuals with Rett syndrome and their families provincially and nationally.
What is expected of an O.R.S.A. board member?
O.R.S.A. board is a working board. As such, it requires its members to commit to a high level of time commitment. We are looking for individuals who are willing and able to make the following commitments:
* Be committed to O.R.S.A. mission, which is to ensure that children and adults with Rett Syndrome are enabled to achieve their full potential and enjoy the highest quality of life within their community.
* Be a member in good standing of O.R.S.A.
* Serve for a two-year term (up to 4 consecutive terms)
* Attend 5 regular board meetings a year, an annual general meeting, one two-day conference every two years and one planning weekend board retreat every two years
* Chair a board committee
* Take part in signature fundraising events at minimum
* Support O.R.S.A. financially
Required Skill (at least one of the following):
* Finance/Accounting (immediate requirement)
* Event Planning
* Marketing
* Government Relations (knowing inner workings)
* Public /Media Relations
* Governance
Skills in the following areas would be an asset to the Board:
* IT/Technology
* Management
Posted: January 13, 2017 by sherry
Linking genetic findings to clinical symptoms in Rett syndrome
In 2014, the Ontario Rett Syndrome Association (O.R.S.A.) Board of Directors had unanimously approved the funding of a $50,000 Research Grant to a joint grant application from Dr. Juan Ausio (Biochemistry and Microbiology, University of Victoria, BC) and Dr. John Vincent (Neurogenetics, University of Toronto). This was the first grant from The Hope Fund and was largest grant released at the time.
We are pleased to announce that with our support, their work, From Function to Phenotype: Impaired DNA Binding and Clustering Correlates with Clinical Severity in Males with Missense Mutations in MECP2 has been published in the Nature Journal “Scientific Reports”. A summary that explains the findings and context can be found below and to read the full article, please follow this link, www.nature.com/articles/srep38590/
Mutations in the MECP2 gene cause Rett syndrome (RTT). MeCP2 binds to chromocentric DNA through its methyl CpG-binding domain (MBD) to regulate gene expression.While it’s well established that single DNA changes can lead to Rett syndrome — one of the most common genetic forms of intellectual disability – a new CAMH study has for the first time linked DNA mutations directly to how severe the syndrome is among those affected.
The results could pave the way for improved diagnosis and potentially new treatments for Rett syndrome, which is marked by problems with communication, language, learning and physical coordination.
The study was led by Dr. John Vincent, Senior Scientist in CAMH’s Campbell Family Mental Health Research Institute, and PhD student and first author Taimoor Sheikh. It was published in the journal Scientific Reports in December.
The DNA in question is part of the MECP2 gene, which is made up of thousands of pairs of DNA – one part from our mother, one from our father. This DNA can be thought of as “letters” that create words to generate genetic instructions. In many cases of Rett syndrome, any one of about 160 known changes to these letters on the MECP2 gene can garble the words and then the instructions.
There’s a reason these single DNA changes have such serious effects: the MECP2 gene carries instructions for a fundamental protein in the brain. The MECP2 protein binds to DNA at various places, and then acts as a “switch” to turn nearby genes on or off.
The research team found that if the change, or mutation, occurred in a part of the protein where it disrupted the switch, the syndrome was more serious. Changes that were further from the parts of MECP2 protein that bind to DNA, instead affected how the protein interacted with other proteins. This led to milder symptoms.
“The discovery raises the possibility of finding compounds to treat Rett syndrome, if we could create a ‘patch’ to make the protein function the way that it’s supposed to,” says Dr. Vincent, who heads the Molecular Neuropsychiatry & Development (MiND) lab at CAMH.
In addition, the nature of each change – which “letters” were swapped out – also affected how serious the syndrome was, the researchers note. They used a series of tests to study MECP2 proteins, with 12 different mutations including many most commonly reported in girls with Rett syndrome.
Clinical implications
With further development, the findings could help in cases where Rett syndrome is suspected in a patient. Symptoms typically appear in girls before the age of two. Genetic screening would
yield information on the type of mutation, to predict the type and severity of illness, says Dr. Vincent. As there is currently no treatment for Rett syndrome, only symptom management, screening could point to where more supports are needed.
A study in boys
Another novel aspect of the study was the fact that it also focused on boys with MECP2 mutations. In boys, Rett syndrome is extremely rare. This approach provided researchers with a clearer picture of the effect of protein changes in terms of symptoms and severity.
The MECP2 gene is located on X chromosomes. As girls have two copies of X, those with Rett syndrome have a second unaffected MECP2 gene on the other X, which may compensate for the garbled instructions. This is seen by the fact that clinical symptoms of Rett syndrome vary greatly in girls.
As boys carry X and Y chromosomes, any mutation on the X has an even more serious effect. It’s believed that most such cases do not survive pregnancy or early infancy.
By studying 11 rare cases of boys identified with MECP2 mutations, the researchers were able focus on DNA changes and their molecular and cellular effects in relation to clinical severity, without any compensating effects of the second MECP2 gene on the other X chromosome.
Ultimately, they hope to find compounds to help treat Rett syndrome using an approach called “peptide panning.” It involves testing many different peptides, which are small pieces of proteins, to see which ones bind to the mutant MECP2 protein to help recover its normal functioning.
“By further developing the molecular and cellular tests used in our study, we hope to be able to predict the likely clinical outcomes for newly discovered MECP2 mutations, as well as screen for compounds that can make MECP2 protein with specific mutations revert back to its normal function,” says Dr. Vincent.
From Function to Phenotype: Impaired DNA Binding and Clustering Correlates with Clinical Severity in Males with Missense Mutations in MECP2.
Sheikh TI, Ausió J, Faghfoury H, Silver J, Lane JB, Eubanks JH, MacLeod P, Percy AK, Vincent JB.Published in Scientific Reports, 8th Dec 2016; funded through an ORSA grant to John B. Vincent and Juan Ausió.