Epilepsy refers to abnormal electric brain activity that is seen in a wide range of brain disorders. Genetics often play a role in the development of epilepsy. Up to eight out of ten cases of epilepsy are thought to be caused by genetic abnormalities.
Although more than 900 genes have been linked to epilepsy syndromes, identifying the genetic mutations that are associated with specific types of epilepsy remains a challenge.
Researchers led by Krembil Clinician Investigator Dr. Danielle Andrade carried out a detailed analysis of the whole genome of patients with severe epilepsies that had not been previously linked to a genetic cause.
Whole-genome sequencing involves determining an individual’s entire genetic code—including the approximately 1% of DNA that codes for proteins (known as genes) and the remaining 99% of DNA that is ‘non-coding’ and plays important regulatory roles.
“Most current methods for genetic analysis are limited in scope. Without sequencing the whole genome, genetic studies often miss mutations that cause disease,” explains Dr. Andrade. “We set out to address this issue by looking at the entire genomes of patients for whom the latest generation genetic testing has failed.”
The researchers analysed the genomes of 28 adult epilepsy patients recruited from the Adult Epilepsy Genetics Program at Toronto Western Hospital. They examined multiple types of genetic variants, including changes in single DNA base pairs, short sequence repeats and changes in the number of copies of genes.
In nearly a third of the patients included in the study, the researchers identified genetic variants that were either known or very likely to cause disease.
“Our study demonstrates that whole genome sequencing is a powerful tool that can help us connect the dots between an individual’s genetics and unexplained epilepsies,” says Dr. Andrade.
The team also identified certain genetic features in two patients with a rare form of epilepsy called Lenox Gastaut Syndrome. Specifically, they found abnormal repetitions of DNA sequences in the non-coding regions their genomes—suggesting that they could be linked to the disease. This is the first report of this type of genetic variant in individuals with this disease, highlighting the importance of analysing the whole genome when studying the genetic basis of epilepsy.
“By uncovering the genetic basis of these severe cases of epilepsy, this work moves us closer to developing better diagnostic tests and personalized therapeutics to improve the lives of our patients.”
This work was supported by the McLaughlin Foundation, the Ontario Brain Institute, the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada and the UHN Foundation. Yuen RKC is a SickKids Catalyst Scholar in Genetics and an Azrieli Future Leader in Canadian Brain Research. Pearson CE holds a Tier 1 Canada Research Chair in Disease-Associated Genome Instability at the University of Toronto.
Qaiser F, Sadoway T, Yin Y, Ali QZ, Nguyen CM, Shum N, Backstrom I, Marques PT, Tabarestani S, Munhoz RP, Krings T, Pearson CE, Yuen RKC, Andrade DM. Genome sequencing identifies rare tandem repeat expansions and copy number variants in Lennox-Gastaut Syndrome. Brain Comms. 2021 Sep 14. doi: 10.1093/braincomms/fcab207.
A team from UHN has identified factors that can help predict the risk that someone who gets a concussion will continue to experience symptoms months later.
A concussion is a brain injury caused by a hit or jolt to the head, and it can manifest through a variety of symptoms, such as sensitivity to light, headaches, dizziness, confusion and more.
For most people, the symptoms go away within a few weeks. In 10-20% of people, symptoms will persist for months—when this happens, physicians refer to them as ‘prolonged post-concussion symptoms’.
A team led by KITE Senior Scientist Dr. Mark Bayley used concussion diagnosis and care data from the Ontario Concussion Cohort study to identify the risk of prolonged symptoms.
The data that the researchers analyzed included to information for over 587,000 adult Ontarians diagnosed with a concussion, then followed their use of the health care system for two years after being diagnosed. The researchers identified those with prolonged concussion symptoms as individuals who, after six months or more post-injury, attended two or more specialist visits—criteria that identified 13% of the patients in the database.
Their analysis found that pre-existing mental health conditions, such as bipolar disorder or personality disorder, older age and fifteen or more primary care visits per year before the concussion were risk factors for developing prolonged concussion symptoms.
Combining these and other risk factors into an overall score, the researchers created the Toronto Rehabilitation Institute Concussion Outcome Risk Determination and Rehab Recommendations (TRICORDRR) risk calculator tool, available online.
“The results of our study and the online tool enables physicians, who are seeing individuals who have experienced a concussion, to quickly and easily determine their risk of developing prolonged symptoms,” says Dr. Bayley.
“By identifying those at risk, we can better tailor treatment and concussion education to individual patients. We can also use the tool to reassure low-risk individuals that they are likely to experience positive outcomes,” he concludes.
This work was supported by the Ontario Neurotrauma Foundation, the UHN Foundation and ICES, which is funded by the Ontario Ministry of Health and Long-Term Care.
Langer LK, Alavinia SM, Lawrence DW, Munce SEP, Kam A, Tam A, Ruttan L, Comper P, Bayley MT. Prediction of risk of prolonged post-concussion symptoms: Derivation and validation of the TRICORDRR (Toronto Rehabilitation Institute Concussion Outcome Determination and Rehab Recommendations) score. PLoS Med. 2021 Jul 8. doi: 10.1371/journal.pmed.1003652.
Researchers from the Toronto General Hospital Research Institute (TGHRI) and Ajmera Transplant Centre have identified a new way to store donated organs that could raise the number of organs available for transplant.
Published in Science Translational Medicine, new research reveals that storing lungs at 10°C may preserve them for longer and lead to better lung function than current approaches, which involve 4°C storage temperatures.
The researchers, led by TGHRI Senior Scientist Dr. Marcelo Cypel and first author Dr. Aadil Ali, used an experimental model to measure the health of lungs after they were stored for 36 hours at either 10°C or 4°C. They found that storage at 10°C left lungs more elastic and better at delivering oxygen—two key readouts of lung function.
The researchers also assessed the health of the donor lungs by measuring levels of protective molecules in the tissue. In collaboration with Dr. Ana Andreazza, Professor in the Department of Pharmacology at the University of Toronto and founder of the Canadian Mitochondria Network, the team assessed mitochondrial protection. Mitochondria are compartments within cells that produce energy; their integrity is vital to the health of cells and tissues. The team discovered that preserving lungs at 10°C offered significantly better mitochondrial protection in comparison to the current gold standard of 4°C.
“After we saw these promising results in our experimental model and revealed how the warmer temperatures benefit organ health, we tested the approach in patients,” explains Dr. Cypel, who is also Surgical Director of UHN’s Ajmera Transplant Centre.
“Our aim was to see whether we could safely prolong lung storage, without compromising tissue health and function. If we can extend the period of time available for donated organs to be transplanted, we can provide life-saving organs to more patients in need and greatly improve the logistics around lung transplantation. As an example, the geographic location of donors would no longer be a limitation.”
There is a serious shortage of clinically acceptable donor organs to meet transplant needs. Currently, over 4,500 Canadians are on the waitlist for an organ transplant. According to the Canadian Institute for Health Information, one patient dies every 36 hours waiting for an organ.
“Given this shortage, we need to make the most of what limited organs we have available,” explains Dr. Ali. “One way to do this is to develop strategies to expand the window of time that an organ can be transplanted—this provides patients and health care professionals with the precious time needed for a successful surgery.”
The research team tested the new storage strategy to donor lungs that were transplanted into five patients. Using a warmer storage temperature, the team was able to extend the time that donor lungs were safely preserved from the current maximum of six to eight hours, to between 10 and 16 hours.
“All five patients responded well to the transplanted lungs and no patients experienced serious complications. While this is just a first step, our findings suggest that this storage strategy could represent a new standard of lung preservation—one that could provide more lungs of better quality to patients in need,” says Dr. Ali.
Aadil Ali, Aizhou Wang, et al. Static lung storage at 10°C maintains mitochondrial health and preserves donor organ function. Sci Trans Med. 2021 Sept 15. Vol 13, Issue 611. DOI: 10.1126/scitranslmed.abf7601.
This work was supported by Latner Thoracic Surgery Research Laboratories and the UHN Foundation/Ajmera Transplant Centre. M Cypel is a Tier 2 Canada Research Chair (CRC) in Lung Transplantation. Please see the research article for statements of competing interests.
The 2021 Krembil Brain Institute magazine is live!
Launched in the September issue of Toronto Life, the magazine was distributed to nearly 40,000 subscribers across Canada. The magazine showcases the world-class multidisciplinary team at the Krembil Brain Institute and its groundbreaking research related to chronic and debilitating diseases of the brain and spine.
The stories in this issue highlight exciting research and clinical advancements currently underway at the Institute, as well as inspiring patients who have reclaimed their lives as a result of these advancements.
Patient-centred stories focus on how Krembil researchers and clinical partners are improving the detection and treatment of a wide range of nervous system conditions, including epilepsy, trigeminal neuralgia, chronic pain, stroke and spinal cord injury.
In addition to the printed magazine, Toronto Life shared digital versions of two feature stories, “Pushing the Limits” and “Codebreakers”, on their website. These stories introduce readers to the Krembil researchers who are working to develop cutting-edge neuromodulatory procedures and treatments for neurodegenerative conditions such as Alzheimer and Parkinson disease.
Click here to read the 2021 Krembil Brain Institute magazine.
Printed copies of the magazine are available at the Krembil Directorate Office (room 4KD478, Krembil Discovery Tower) and room 11MP302 at Toronto Western Hospital.
This year, eight UHN researchers were inducted as Fellows of the Canadian Academy of Health Sciences (CAHS). The prestigious honour is bestowed on outstanding leaders who have been recognized by their peers for their contributions and dedication to advancing academic health sciences.
Candidates are selected across the health sciences disciplines, including basic, social and population health sciences. As members of the Academy, Fellows serve as advisors and make recommendations on current health challenges that impact Canadians.
Congratulations to the following UHN scientists who were named among the 74 health and biomedical experts elected this year:
• Dr. Cathy Craven, Senior Scientist at KITE, a leader in spinal cord injuries whose work has improved the quality and monitoring of spinal cord injury rehabilitation
• Dr. Margaret Herridge, Senior Scientist at Toronto General Hospital Research Institute, a world-renowned researcher focused on patient and caregiver outcomes following critical illness
• Dr. Mansoor Husain, Senior Scientist at Toronto General Hospital Research Institute, a world leading expert in research into the underlying mechanisms of human cardiovascular disease
• Dr. Alex Mihailidis, Senior Scientist at KITE, an innovator in developing technologies to support older adults
• Dr. Amit Oza, Senior Scientist at Princess Margaret Cancer Centre, a world leader in clinical trials for the treatment of gynaecological cancer
• Dr. Aaron Schimmer, Research Director and Senior Scientist at Princess Margaret Cancer Centre, an expert in studying new ways to treat blood cancers known as leukemia
• Dr. Ming-Sound Tsao, Senior Scientist at Princess Margaret Cancer Centre, a renowned expert in lung cancer pathology and biomarker development
• Dr. Sharon Walmsely, Senior Scientist at Toronto General Hospital Research Institute, a pioneer in HIV and AIDS research and treatment
All newly elected 2021 Fellows were announced at CAHS’s Annual General Meeting, which was held virtually. For a full list, click here.
UHN researchers have found a way to shorten diagnostic wait times for patients with axial spondyloarthritis. The strategy involves a two-step screening process that occurs before patients see a rheumatologist.
Axial spondyloarthritis is a form of arthritis that primarily affects the spine and sacroiliac joint near the hip, causing lower back pain and stiffness. The condition is diagnosed by a rheumatologist based on the presence of persistent back pain and joint damage.
“Due to the shortage of rheumatologists in Canada, patients with this condition typically wait years between meeting with a primary care physician and receiving a formal diagnosis,” explains Dr. Yoga Raja Rampersaud, a Clinician Investigator at the Schroeder Arthritis Institute and senior author of the study.
In response to the long wait times for rheumatology care, Dr. Rampersaud’s team examined a patient screening approach that draws on experts other than rheumatologists. First, standard screening is carried out by a primary care physician. Then, secondary screening is carried out by an advanced practice clinician—a health care provider who is not a rheumatologist but is trained in arthritis care.
“Rheumatologists receive a high volume of referrals for patients with lower back pain, and many of these patients do not actually require specialized care," says Dr. Rampersaud. "We examined whether advanced practice clinicians can reduce diagnostic delays by better triaging patients. We also examined whether these advanced-practice clinicians can identify patients with axial spondylarthritis as effectively as rheumatologists.”
The researchers tested the screening process in more than 400 patients. All patients were initially screened by a primary care physician. Patients who had experienced lower back pain for least three months or more, beginning before they were 50 years of age, met the criteria for further screening. The secondary, more detailed screen was conducted by an advanced practice clinician at the Spondylitis Program at Toronto Western Hospital. Following the screening process, patients were referred to a rheumatologist for formal assessment and diagnosis.
The researchers found that the two-step screening process reduced the overall time between pain onset and diagnosis. They also found an 82.7% agreement between disease assessments made by the advanced practice clinicians and those made by the rheumatologists.
“Our findings revealed that this two-step screening process can speed up diagnosis by quickly identifying patients who are most in need. These patients often spend months or years bouncing around the system before seeing the right provider, unfortunately too late. This networked team approach can be easily used to improve access to the right care in other forms of arthritis and other conditions,” says Dr. Rampersaud.
“By drawing on physiotherapists from the Spondylitis Program at Toronto Western Hospital, we were able to speed the detection and management of arthritis, and unlock an important pathway to improved patient outcomes.”
This work was supported by the Arthritis Society and the UHN Foundation. C Bombardier holds a Tier 1 Canada Research Chair in Knowledge Transfer for Musculoskeletal Care.
Passalent L, Sundararajan K, Perruccio AV, Hawke C, Coyte PC, Bombardier C, Bloom JA, Haroon N, Inman RD, Rampersaud YR. Bridging the Gap between Symptom Onset and Diagnosis in Axial Spondyloarthritis. Arthritis Care Res (Hoboken). 2021 Jul 15. doi: 10.1002/acr.24751.
Researchers at UHN’s Schroeder Arthritis Institute have demonstrated that the relationship between high body mass index (BMI) and hand osteoarthritis may be explained by the presence of osteoarthritis in the knee.
It is well known that individuals who are overweight or obese—those who have a BMI greater than 25 kg/m2—are more likely to develop osteoarthritis than normal weight individuals of the same age. Although the negative impact of obesity is most apparent at weight-bearing joints, such as the knee, some studies have linked obesity to osteoarthritis in non-weight-bearing joints, such as the joints of the hand. This finding has led to suggestions that hand osteoarthritis may be linked to body-wide changes that result from being overweight or obese, such as hormone disruptions and inflammation, not just increased stress on joints.
“An issue with a lot of clinical and epidemiological osteoarthritis research is that it treats the disease as though it affects only a single joint,” cautions Dr. Elizabeth Badley, lead author of the study and a Senior Scientist at the Schroeder Arthritis Institute. “In reality, most people with osteoarthritis have symptoms at two or more different joint sites, and this needs to be taken into account in studies of the disease.”
To determine whether the apparent connection between obesity and hand osteoarthritis can be attributed to osteoarthritis at other joint sites, the researchers examined the relationships between BMI and osteoarthritis affecting the hand, hip or knee alone, and combinations of these joints.
The research team leveraged the Canadian Longitudinal Study on Aging, which enabled them to analyze data from over 6,000 individuals with osteoarthritis. On first impression, high BMI appeared to be linked to a higher likelihood of having osteoarthritis affecting the knee, hip or hand. However, when the researchers examined individuals with all possible combinations of osteoarthritis at these joint sites, they found that BMI was linked only to osteoarthritis in the knee. This relationship was particularly strong for individuals with the highest BMI.
“Taken together, these findings suggest that the previously observed link between high BMI and hand osteoarthritis is likely explained by the presence of the disease at other joints, particularly the knee,” explains Dr. Badley. “The association between high BMI and knee osteoarthritis appears to be distinct from that between high BMI and osteoarthritis in other joints.”
The findings of this study highlight the importance of recognizing the multi-joint nature of osteoarthritis and considering multiple joints when studying the disease.
This study was conducted using data from the Canadian Longitudinal Study on Aging, and supported by the Canadian Institutes of Health Research, the Arthritis Society and the UHN Foundation.
Badley EM, Zahid S, Wilfong JM, Perruccio AV. The relationship between body mass index and osteoarthritis for single and multi-site osteoarthritis of the hand, hip, or knee: findings from the CLSA. Arthritis Care Res (Hoboken). 2021 Jun 13. doi: 10.1002/acr.24729.
Research conducted at UHN's research institutes spans the full spectrum of diseases and disciplines, including cancer, cardiovascular sciences, transplantation, neural and sensory sciences, musculoskeletal health, rehabilitation sciences, and community and population health.
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