November 2014 Funded Microgrants

November 2014 Funded Microgrants

High-throughput screening for small molecule therapeutics for spinal muscular atrophy

Spinal muscular atrophy (SMA) is a neurodegenerative disease, characterized by lower motor neuron death, for which there are no cures or effective treatments. In this project we will utilise the advantages of the C. elegans roundworm and zebrafish models to undertake a live animal drug screen for small molecules that can inhibit the onset of motor neuron loss and paralysis phenotypes in these models of SMA. Candidate compounds will subsequently be tested in pre-clinical and clinical studies. Our findings may assist in accelerating the development of drugs for the treatment of SMA.

Gene discovery in a large family with congenital junctional ectopic tachycardia

Congenital junctional ectopic tachycardia (CJET) is a rare, serious arrhythmia that affects infants/children and can cause collapse or heart failure. It is often familial, but the gene has yet to be discovered. A newly identified family represents one of the largest affected families to date, and have agreed to extensive genetic testing which is underway. Using both traditional (segregation analysis) and newer (whole exome analysis) approaches, we anticipate that we can identify the underlying gene defect causing this condition.

Thiazolidinedione to Block Fatty Tumours and Limb Overgrowth

Patients born with mutations that supercharge their PIK3CA gene have uncontrolled overgrowth of fat, and often have disfiguring overgrowth of their arms, legs, fingers and toes. Sometimes the overgrowth is so bad that major surgery is required – up to and including cutting off an arm or leg. Therefore we desperately need a more effective way to slow down or stop the overgrowth. The mutated cells stay immature and keep growing, like a slow-growing tumor. We believe that we could slow down the overgrowth using a readily available anti-diabetic drug called thiazolidinedione. This drug could convert the immature mutant fat cells into mature fat cells – and fat cells hardly ever divide. To test our hypothesis, we will create fat cells with a supercharging PIK3CA mutation by gene engineering, and then treat them with a thiazolidinedione drug. We believe that the engineered fat cells will convert from immature, dividing fat cells into mature, nondividing fat cells after thiazolidinedione treatment. This will provide proof-of-principle for the use of thiazolidinedione for slowing of fat overgrowth in the limbs of children with PIK3CA mutations. If we are right, patients with fibroadipose hyperplasia and other CLOVES-like diseases could plausibly be treated with short-term “pulse” therapy with thiazolidinediones to shut down the overgrowth of fatty tissues, thereby avoiding repeated surgeries. Thiazolidinediones are proven 100% safe in the short term.

Clinical Features and Immune Mechanisms of ROHHAD (Rapid Onset Obesity, Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysfunction)

ROHHAD is a rare but devastating disease, often leading to death in childhood because of progressive breathing and cardiac difficulties. The cause of ROHHAD is unknown, but some researchers suggest that immune system dysfunction may play an important role; this hypothesis remains unproven. Unfortunately, there are currently no specific, agreed upon criteria for the diagnosis of ROHHAD, and no effective treatment exists for this condition. With this study, we aim to use specialized techniques to evaluate potential immune mechanisms of ROHHAD, which may lead to targeted, life-saving therapies for these children.

Results - Rapid onset obesity, hypothalamic dysregulation, hypoventilation, and autonomic dysfunction (ROHHAD) is a rare syndrome, with 100 patients reported in the literature.  It is characterized by rapid onset (between 2-9 years of age) of obesity accompanied by central hypoventilation, hypothalamic dysfunction and autonomic dysfunction. Published studies suggest high mortality in the population, with little information about cognitive and psychosocial outcomes.  In this study, we report the psychosocial and cognitive outcomes in a cohort of children (n=6, female=4) fulfilling diagnostic criteria for ROHHAD.  We found that while brain imaging was normal in all children, half received help at school in the form of a modified learning plan or special classroom.  Two of these children had cognitive delays requiring assistance.  Mood symptoms and impaired social functioning were seen in 4/6 patients.  The results of this study emphasize the high psychological and cognitive burden in this population and the need for attention to these issues in interventions aimed at this population.

French translation of the Charcot-Marie-Tooth disease Pediatric Scale – A New Outcome Measure of Disability

Charcot Marie-Tooth disease (CMT) is a rare genetic disease affecting children and adults. There are few studies on the impact of CMT in everyday life and a lack of validated tools to assess the global severity of the disease among a French-speaking population. Our team will formally translate the CMT Pediatric Scale (CMTPedS). A better assessment of these children with a validated tool will help us understand better the course of the disease, measure response to therapies and ultimately improve the quality of care.

Results - The French version of CMTPedS is now used by stakeholders at the MarieEnfant Rehabilitation Centre of the Centre Hospitalier Universitaire Sainte-Justine. Occupational therapists and physiotherapists noticed that children participate well, the testing time is reasonable, and that the instructions are clear. The CMTPedS will soon be available on the website of the original tool developed by Dr Burns. This will permit French-speaking clinicians to use it in their practice and be able to compare their results to those obtained in other countries. Therefore, it will be possible to document the natural history of the disease, apply a prognostic approach, and improve monitoring of affected children. The French version of CMTPedS will need to have its metrological properties documented.
The project has permitted the beginning of an international collaboration between Canadian Centres and Australian Centre. 

What is the prevalence and natural history of optic- and non-optic glioma in adults with Neurofibromatosis 1 (NF1)?

Neurofibromatosis type 1 (NF1) is a genetic disease occurring in about 1 in 3500 people. The most obvious manifestations are multiple skin tumours (neurofibromas), but other characteristic features include brain tumours of the optic nerve, called optic gliomas, as well as gliomas in other areas of the brain. If optic gliomas are diagnosed, regular vision testing and brain MRIs are needed to monitor tumour growth. In some of these patients, tumour progression leads to visual loss or other symptoms, but in most patients the tumours are asymptomatic and remain so for many years. Treatment is usually by chemotherapy or surgery and may not be effective. In NF1, the optic gliomas almost always develop in young children, and many of the non-optic gliomas develop in childhood as well. Little is known about their natural history in adults, although case reports suggest that some tumours continue to grow or begin to grow again after a long period of quiescence, whereas others shrink or disappear. We have no idea how often this occurs, or why. The objective of this study is to provide the first assessment of the prevalence and the natural history of optic and non-optic glioma in adults with NF1. We will examine reports from over 2000 brain MRI studies in 600 individuals with NF1, aged 1 to 71 years, collected by our colleague in Hamburg, Germany. His data represent the world’s largest series of brain MRIs in NF1, thus providing a unique opportunity to study the behaviour of gliomas in adults. This study’s results will enable us to counsel families more accurately regarding the risk of gliomas and other cerebral lesions in NF1.

Results - The goal of this project was to assess the frequency and natural history of optic and non-optic gliomas (types of brain tumours) in people with the genetic condition called neurofibromatosis (NF1).  To do this, we examined reports from over 1700 brain MRI studies in 600 individuals with NF1, aged 1 to 71 years, collected by our colleague, Dr. Victor Mautner, in Hamburg, Germany. His data represent the world’s largest series of brain MRIs in NF1, thus providing a unique opportunity to study the behaviour of gliomas throughout the lifespan. 

One interesting finding is that non-optic gliomas are twice as common as previously believed.  Another observation is that we have now documented that rarely optic gliomas appear to regress then disappear:  they do not always continue to grow.  An important question is therefore how to differentiate those tumours that grow from those that regress and are they really the true optic gliomas – this has important treatment implications. 

Our findings to date were just presented at the June 2016 Children’s Tumor Foundation symposium, and one was submitted to the American Society of Human Genetics, 2016.  One paper has been submitted for publication and a second is in preparation: 

Sellmer L, Marangoni M, Heran M, Birch PH, Farschtschi S, Mautner V-F, Friedman JM. Prevalence and natural history of optic pathway gliomas in neurofibromatosis 1 (NF1). Presented at the Children’s Tumor Foundation Symposium, Austin, Texas, 2016 (poster). 

Sellmer L, Marangoni M, Heran M, Birch PH, Farschtschi S, Mautner V-F, Friedman JM. 

Gliomas in adults and children with neurofibromatosis 1.  Presented at the Children’s Tumor Foundation Symposium, Austin, Texas, 2016. (poster).  (Also submitted to the American Society of Human Genetics, 2016) 

Sellmer L, Farschtschi S, Marangoni M, Heran M, Birch PH, Wenzel R, Friedman JM, 

Mautner V-F. Non-optic glioma in adults and children with neurofibromatosis 1. (submitted for publication) 

Funding from the original microgrant was to pay UBC student, Laura Sellmer, who is a native German speaker, to translate and extract data from the MRI reports. We were all so impressed by her careful work that she has joined the lab of Dr J.M. Friedman at UBC for her MSc, funded by the German physician, Dr. Mautner, to study this data set further.  The work has expanded to include examination of the actual MRI images and collaboration with two UBC neuroradiologists. Further findings will emerge from Ms Sellmer’s master’s thesis but the preliminary results described above are based on the work described in the original microgrant.

Determining the genetic cause of a unique congenital hydranencephaly syndrome

We aim to study an Amish family with 3 stillborn babies affected with a lethal syndromic form of hydrocephaly (build-up of fluid in the brain). We will use state-of-the-art technology to localize the gene causing this disorder, using exome sequencing (looking at the coding region of all the genes) in one affected child and comparing DNA from all of the affected babies. Identification of the genetic cause will enable improved genetic counseling in this family and for others with the same disorder. Our project will also provide basic insights into the biological mechanisms underlying hydranencephaly and other congenital defects of the brain.

Mutations in cMET cause bilateral osteofibrous dysplasia and non-healing fractures

We identified a novel gene mutation in the cMET gene causing a bone condition called osteofibrous dysplasia. Affected individuals develop lower limb bowing and spontaneous non-healing fractures. Our preliminary work indicates the cMET gene alteration makes a cell receptor missing a critical region controlling its down-regulation. The cMET receptor is found in bone forming and resorbing cells. Fracture samples from our patients reveal abnormalities in these bone cells. We therefore believe that cMET is important for fracture healing. We plan to study how the cMET mutation affects bones by investigating changes in proteins made by patient bone in response to the mutation. Our work on fracture repair is important for the many people who are in pain and unable to work due to poorly healed fractures. Additionally, our results may have broader implications for other health problems like osteoporosis, which is also due to abnormalities in bone cells.

Finding the causes of uterine malformations

One in 4500 girls are born without a uterus. They live with consequences that affect fertility, sexual functioning, body image, and sense of femininity. This condition is known as Mayer-Rokitansky-KusterHauser (MRKH) syndrome and is characterized by absence of the upper portion of the vagina and the uterus in an otherwise generally healthy female. Sometimes though there is also a malformation of the kidneys or spine. The causes for MRKH are unknown. Very little research is currently being conducted to determine why this happens. Usually only one girl is affected in a family, but occasionally there can be a recurrence. Our preliminary work has shown that when a second person is affected, there is more likely to be involvement of the kidneys as well as the uterus. More is known about the development of the kidneys than the uterus. This clue directs us to look for genetic variants in the genes that control kidney development in girls with MRKH to see if they have variants in these genes that may predispose them to have this malformation. This project will carry out genetic analyses in four families affected by recurrent uterine and kidney malformations. Understanding the causes of uterine anomalies is the first step toward determining how to prevent them from occurring.

Results - Microgrant funds for this project went unclaimed by the applicant.

     The above research grant was generously supported by the Canucks for Kids Fund.

Long-term outcome of individuals born with arthrogryposis

Arthrogryposis (AMC), a condition where primarily the limbs have significant limitation in motion at birth. Many individuals undergo many surgeries and extensive physiotherapy to improve range of motion. Knowing what treatment works best for long term function is still unclear. We propose the largest international study to determine what happens long term (>30 yrs of age) to those who are born with AMC using an online survey and additional telephone interview.

The above research grant was generously supported by the Canucks for Kids Fund.

Results -  For the online survey, 178 English-speaking individuals (50 males and 128 females) from over 10 countries participated in the study. The age range was 20 to 84 and the average was 40 years. The majority of the participants were from the United States, European Union and Canada. 72% of the participants are living with a partner or on their own, and 60% walk independently at home. The adults with AMC completed 8% more undergraduate degrees and 17% more advanced degrees compared to the general US population. Despite their physical limitations and high level of chronic pain, individuals matched the US population for full-time and part-time occupations. Individuals living with AMC had better Quality of Life outcomes (SF-36) than the general US population in all categories except vitality and physical function. However, people with AMC do less physical activities than active able-bodied individuals. The next step is to analyse the data about their surgical experiences and  the in person interview data (N=90).

In summary, most individuals with AMC have maintained a relatively high degree of independence despite their physical limitations. Orthopedic treatments such as correction of club feet have enabled them to walk. Post-secondary education has made them more competitive for careers that require little physical labor. Overall, adults living with AMC do remarkably well compared to the able-bodied population despite dealing with chronic pain.

The medical student on this project will be presenting this work at the Western Student and Resident Medical Research Forum, Carmel CA in January 2016. We have also written a summary for the’s website for people with AMC ( We are currently writing two papers and seeking follow up funding support.

Diagnosing the Causes of Complex Intellectual Disability: Does Genome-Wide Sequencing Result in Cost Savings to Healthcare, Families and Society?

Collectively, intellectual disability (ID) is common, affecting 2-3% of the population worldwide; however the etiology is extremely heterogeneous and each cause of ID is rare. Conventional testing for ID has therefore been described as a “diagnostic odyssey” where numerous tests are ordered one by one, often uncoordinated and more importantly, mostly uninformative. This generates significant costs and immense burden to the patient and family. However, a powerful new technology, genome-wide sequencing (GWS) can now be used to diagnose the causes of a variety of conditions including intellectual disability (ID). GWS looks at a patient’s entire genetic makeup at once, replacing the need for countless individual tests. GWS increases the diagnostic success rate by at least 25-40%, and can significantly reduce time to diagnosis.2,3 Although GWS is not cheap, with costs averaging $3000, the costs of the ‘conventional’ approach requiring many individual tests, often without a final diagnosis, can be substantial and may exceed the cost of GWS. Our objective is to analyze the costs of diagnosis in children with ID evaluated at our tertiary care centre, comparing costs in those diagnosed by GWS to those diagnosed more conventionally. We will take a holistic but conservative view of costs, including: diagnostic costs to the healthcare system (testing, admission for diagnostic evaluation), genetic counselling, societal costs (e.g. test-related transportation subsidies; employer-paid time off work), and costs to families (e.g. test-related caregiving time; unsubsidized transportation). We will compare the costs of different models, e.g. the conventional diagnostic trajectory (single gene tests etc) to use of GWS as initial diagnosticum (including any clinical confirmatory tests needed to further characterize the diagnosis). We anticipate that this pilot study will provide preliminary data and proof-of-principle for a more substantial study to precisely demonstrate the magnitude of any financial benefits of GWS to healthcare, society, and families.

Results - Conventional testing to determine the cause of a child’s intellectual disability has been described as a “diagnostic odyssey” where numerous tests are ordered one by one, often uncoordinated and more importantly, mostly uninformative. This generates significant costs to the health care system and immense burden to the patient and family.  A new test, genome-wide sequencing (either “whole exome” or “whole genome” sequencing) can in part replace the need for many of the older individual tests.  It also increases the diagnostic success rate by at least 25-40%, and can significantly reduce time to diagnosis.  However, genome-wide sequencing is expensive so there is reluctance to use it as a primary diagnostic test. 

Our hypothesis was that primary use of genome-wide sequencing will be cheaper than conventional testing, per diagnosis made.  These cost savings can be attributable to the healthcare system, to society, and to families of children with ID. 

Our original goal was to study 40 families.  However, we realized that we had the opportunity for a larger and more comprehensive study by examining all the families in the TIDE study (Treatable Intellectual Disability Endeavor) of co-investigator Dr van Karnebeek.  Some of her patients have undergone genome-wide sequencing whereas other earlier patients have not.  This provides us with an unparalleled opportunity to study the impact of genome-wide sequencing before it becomes routine.  We therefore obtained some additional funding from TIDE to expand the RDF study to include over 500 families.  We have just finished collecting the data (something that had to wait until the final patient had completed the TIDE study) and are now beginning the analysis.  For this reason, we are unable to report results as yet.

Using cellular and fruit fly models to study the effect of FSD1 missense mutations in an inherited disorder that resembles Angelman syndrome

We are currently studying a rare genetic disorder designated as Angelman-like syndrome. To our knowledge, this is the only family known to be affected with this disorder. We have identified a mutation in a gene believed to be involved in neurological function. To validate our genetic findings, we plan to perform experiments to determine if the mutated gene is responsible for the Angelman-like features observed in these patients. We plan to use cell studies and a model organism (fruit fly) where we will introduce the genetic mutations and determine if the behavior and neurological function has changed. Identification of the genetic cause allows for improved genetic counseling in this family, and on a longer term for others with similar phenotypes. Our project also improves basic insights into the biological mechanisms underlying global developmental delay and other congenital defects.

Whole exome sequencing to identify gene-elusive, severe, hereditary dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is the commonest form of heart muscle disease, often familial, yet the underlying genetic cause remains elusive in the majority of families. We have identified a family with cardiomyopathy in multiple members, in whom 3 members have had sufficiently severe disease to undergo cardiac transplantation. Extensive clinical genetic testing in two of these individuals has not identified a known DCM gene. These three members have agreed to extensive genetic testing and have already provided blood that has undergone research DNA banking. Using whole exome analysis, we anticipate that we can identify the underlying gene defect causing this condition.

Elucidating the role of NFATc1 in the pediatric osteogenic disorder, fibrous dysplasia

Fibrous dysplasia is a rare disease affecting bone formation and modelling, mostly isolated to the lower leg bones. Affected children present with bone swelling, pain and fractures. We have identified a young girl with fibrous dysplasia caused by a mutation in a protein called NFATc1. This protein is involved in directing bone formation. Our findings are the first to show that an NFATc1 mutation can cause a human bone disease. Our experiments will not only help to understand what effect this mutation has on the protein, but it will also shed more light onto how NFATc1 is involved in bone formation and remodelling. Our experiments will provide evidence that NFATc1 may be a therapeutic target for diseases affecting bone formation and remodelling, such as osteoporosis which causes brittle bones and osteopetrosis which causes bones to be abnormally dense.

Evaluating the efficacy of a web-based education module prior to carrier screening in individuals of Ashkenazi Jewish descent

Around 9% of people who are Ashkenazi Jewish are carriers for one of three rare genetic conditions: Tay-Sachs disease, Canavan disease, and familial dysautonomia. To find out their risk of having children with these conditions, Ashkenazi Jewish people in Quebec can get tested for these conditions for free through public genetics clinics. However, the waitlist at these clinics can be long, especially for non-pregnant couples. We made a new website to give Ashkenazi Jewish people the same information that they would get from attending a genetics appointment, and we want to see if this website can substitute an in-person genetics appointment. If so, then routine patients can be taken off the waitlist to review the website on their own time. This helps Ashkenazi Jewish patients by giving them access to genetics services at any time, and it can even shorten the waitlist for all our patients!

Results - This project has directly translated to a change in the way our clinic runs, as we are now starting to use the website both for non-urgent cases and for couples who are pregnant. We've also presented this project at a conference in September 2015 (Canadian Association of Genetic Counsellors Conference in Ottawa). We've also submitted this project to a journal fro publication and are waiting for feedback from the reviewers.

Screw trajectory in different femoral neck geometries in slipped capital femoral epiphysis: a geometrical modeling study

Slipped capital femoral epiphysis (SCFE) is a rare hip disorder that occurs in adolescents between 9-17 years of age. In this disorder, the upper end (ball) of the thigh bone (femur) slips out of its correct position on the bone. While the cause is not entirely known, it may be related to obesity, and can lead to osteoarthritis, pain and long-term disability. It can be treated through surgery by inserting a screw to prevent the ball of the hip joint from slipping further out of place. If the screw penetrates the back of the femur when it is positioned, it can damage blood vessels located there that supply the ball of the femur, and can lead to bone death. In previous work, funded by the Rare Disease Foundation, we created computer models of hips with a range of deformities from images of one hip and simulated the placement of the screw. We found that deformities with higher values of particular characteristic angles had a 95% chance of penetrating, even with ideal screw placement. We want to determine if we get similar results in a range of hips. If we find similar results, this work could improve the assessment and treatment of patients with SCFE.

Results - Microgrant funds for this project went unclaimed by the applicant.

Evaluation of natural history, genotype-phenotype correlations, and intra-familial relationships for individuals with Hereditary Multiple Exostoses. A radiographic approach

Hereditary Multiple Exostoses (HME) is a rare inherited disease in which people develop multiple non-cancerous bone tumors called exostoses. HME affects approximately 1 in 50,000 individuals. Multiple exostoses can disrupt bone growth and can cause growth disturbances of the arms, hands, and legs, leading to short stature and uneven limb lengths. Bowing of the forearm or ankle and abnormal development of the joints involved caused by exostoses can lead to difficulty walking and general discomfort. Two genes responsible for causing this rare condition are Exostoses 1 and 2 (EXT1, EXT2). Previous research done by our team has shown that the individuals with an affected EXT1 gene are more severely affected by this condition, which is reflected in analysis of x-rays. Unfortunately genetic testing is no longer being funded for HME, pushing our team to place greater emphasis on other avenues to assess the disease. An important component of clinical follow-up of individuals with HME is utilizing x-rays to measure the orthopaedic burden on each individual. At BC Children’s Hospital the HME specific x-ray evaluates the legs, arms, and torso; this x-ray is known as a skeletal survey. Since we are the primary center in British Columbia to treat HME, we have a dataset of 232 individuals (adult and pediatric) with HME. Mutation information is complete for 158 of these patients. Many of the 232 patients, especially children, have more than one x-ray. Currently, we have 65 x-rays unmeasured in our database. We are requesting funds to cover the cost of getting these x-ray measurements done by an experienced research assistant. These missing x-ray measurements are primarily important for their clinical care but if available, this information will also facilitate addressing a few other important research questions. These essential questions include: (1) analysis of an individual’s HME severity over time, (2) evaluating the severity of HME within families, and (3) studying the correlation between affected genes and physical expression of the diseases as measured by x-rays in HME. Knowledge gained from these three research areas will result in information that will contribute to clinical decision-making and assist in counselling families about the severity of HME.

Results - Microgrant funds for this project went unclaimed by the applicant.

Limb Deficiencies – Development of a Care Map for Affected Families

Congenital limb deficiencies represent a group of limb malformations that are conspicuous and are highly variable. They can be characterized by total or partial absence of a limb, or can involve a smaller portion, such as a missing finger or toe. They can occur as isolated malformations or be found in association with other anomalies. Affected children can have marked disfigurement and disability, presenting a challenge to surgeons and therapists and causing significant parental distress. Parental attitudes and decision-making are highly influenced by the healthcare providers with whom they interface. Children with lower limb involvement will have difficulty in achieving milestones such as standing, walking, while children with upper limb involvement will have problems related to function (making a pincer grasp, holding a spoon). The children with additional malformations provide extra clinical and social challenges. Children with congenital limb deficiencies often require many operations. Early screening and referral result in better care of other related issues, better physical recovery and adaptation, and better long-term results.

     The above research grant was generously supported by the Canucks for Kids Fund.

The Assessment of Liver Injury in Pediatric Fontan Patients

One percent of children are born with a structural heart abnormality. These children often require one or more surgical operations to repair their hearts. Children with the most rare and serious heart conditions are born with only one single pumping chamber in their heart instead of two. To provide adequate circulation in these children, a series of three surgical procedures are required, concluding with the Fontan procedure. This surgical repair will allow the heart to pump a normal amount of oxygenated blood to the body. Unfortunately, this repair also places stress on the liver. Studies have shown significant structural and functional abnormalities in the liver following the Fontan procedure. The severity of liver injury with respect to time from the Fontan procedure is not well defined, and there is no consensus on the best tests for monitoring liver health in these patients. At our Hospital we have a standard approach to evaluating liver health in these patients. We use blood tests, ultrasound imaging, a new non-invasive test of liver stiffness called “Fibroscan”, and liver biopsy. We will use this information to better understand how and when liver injury develops in these patients over time after their surgery. We hope to determine which non-invasive tests are best for these children by comparing simple test results to the liver biopsy results. By doing so we hope to improve the liver health of these patients and simplify their regular liver health monitoring tests.

Results - We have completed a cross-sectional analysis on Fontan patients to evaluate liver injury in this patient population and to assess Fibroscan®, a novel non-invasive tool used to assess the degree of liver stiffness as a marker for liver disease. We found that liver pathology was universal in our sample of pediatric Fontan patients. This represents a novel finding in an emerging research field in congenital heart disease. Analysis of Fibroscan® measurements with respect to liver pathology, did not indicate that Fibroscan® is a reliable test for liver pathology in Fontan patients. However, Fibroscan® measurements significantly increased with respect to time from the Fontan procedure, suggesting a role for this test. Results have been presented at international meetings.

Pediatric Thyroid Nodule Score: Derivation and Validation of a Predictive Score for Thyroid Nodule Assessment in Children

Thyroid nodules (lumps) are found in up to 10% of children. These nodules are often detected by the patient or caregiver, or found incidentally when neck imaging is performed for other reasons. While most nodules are benign, some of them are cancerous and it can be challenging to distinguish the two using our existing tools. The current approach to tell if a nodule is benign or cancerous includes reviewing the medical history, a physical examination, blood work, ultrasound and biopsy. Unfortunately, none of these tests – on their own – are reliable enough to distinguish between benign and cancerous nodules. Therefore, we propose to develop a score that combines these results to better predict the chance of cancer in children that are diagnosed with a thyroid nodule.

Results - Thyroid carcinoma is a rare cancer of childhood but is a common malignancy in adult, particularly in young and middle-aged women.  Less than 2% of thyroid carcinoma is diagnosed in the pediatric age-range.  As a result, very little pediatric-specific data are available to guide appropriate therapy.  The current standard of care for pediatric thyroid carcinoma requires surgical removal of the entire thyroid gland, while in adults hemithyroidectomy (removal of half of the gland) is considered adequate therapy in many situations.  We reviewed the scientific literature that formed the basis for the pediatric standard which suggested that this approach was necessary to limit tumor recurrence. We further assessed our own institutional experience in treating pediatric thyroid carcinoma.  On the basis of this, we identify a substantial proportion of children that appear to be at low-risk for recurrence and propose that such children may be candidates for less-extensive surgery without incurring risks of recurrence.  This proposal, however, must still be demonstrated clinically, before it can be considered a viable treatment approach.

Delayed ICD Intervention During Arrhythmias May Decrease Inappropriate Shocks and Improve Mortality in Unexplained Cardiac Arrest Probands

Patients that have experienced an unexplained cardiac arrest are treated with an implantable cardioverter-defibrillator (ICD) to provide life-saving therapy to revive the patient if they should experience another arrest. However, the devices are not without risk, and up to 40% of patients may receive unnecessary shocks. The ICD provides a current of electricity to the heart to “reset” the rhythm of the heart in case of cardiac arrest. These shocks when appropriate can be life saving but when inappropriate are painful, potentially life-threatening and may negatively affect mental health, including increased rates of anxiety, depression and an overall decrease in quality of life. In 2012, a study found that allowing these dangerous heart rhythms to persist longer before the initiation of a shock resulted in a decrease in the number of unnecessary shocks because the rhythm often stopped on its own without needing a shock, or using a low energy pacemaker type signal that was not painful could stop the dangerous rhythm. This change in settings on the ICD led to a decrease in the risk of death. Results from this study have changed the way physicians program ICD’s, allowing more time for the heart to regulate itself naturally before the initiation of the ICD shock. Our current study aims to determine whether changes in ICD programming has led to a decrease in ICD therapy, with improved life expectancy, in patients that have experienced an unexplained cardiac arrest.

Immunopathology of tumefactive multiple sclerosis (TMS)

Multiple sclerosis (MS) is an often disabling, immune-mediated disease of the central nervous system (CNS). According to the MS Society of Canada, prevalence rates range from one MS case per 500 people to one in 1000 across the country. Tumor-like or “tumefactive” MS (TMS) is a very rare variant of the disease. Its prevalence is estimated at 1 to 2 per 1000 cases of MS. Clinical manifestations are mostly acute with rapid progression of neurological symptoms. TMS can initially present as a brain lesions that is clinically and radiologically indistinguishable from a brain tumor. Thus, brain biopsies are sometimes performed to clarify the diagnosis. Clinical trials in MS have shown that targeting specific cells of the immune system can result in significant clinical improvement. Unfortunately, since TMS is considered “unusual” and “atypical”, patients with TMS are often excluded from clinical trials and clinicians have to make treatment recommendations based on anecdotal evidence. Case report data suggests that pathological patterns in brain biopsies can be helpful for therapeutic decision-making. Our goal is to systematically study 12 biopsy specimens of well-defined TMS in order to identify the specific culprits. This will help clinicians to choose the appropriate immunotherapy for patients with TMS.

Evaluation of novel therapeutics against Ewing’s sarcoma

Ewing's sarcoma (ES) is a rare, highly metastatic bone-associated cancer mostly affecting children and young adolescents (incidence is about 1.6 per million). Current established therapies have limited success despite high toxicity. Hence, selective and less toxic drugs are needed to reduce the toxic burden of cure. We propose to test the effectiveness of engineered antibodies, selected against a highly expressed protein on the cell membrane of ES cells, as a means of delivering chemotherapy directly to ES cells. These new antibodies will be linked to proteins that induce an apoptotic response (programmed cell death), and also to a chemotherapeutic drug. We propose to test the potency and efficacy of such antibody-based drugs to selectively kill ES. Success of our approach will lead to development of novel treatment for ES with improved efficiency and reduced toxicity.

Results - Microgrant funds for this project went unclaimed by the applicant.

BMP1 and Idiopathic Juvenile Osteoporosis. Validation of Novel mutations.

Osteoporosis literally means "porous bone." This disease is characterized by too little bone formation and/or excessive bone loss. Osteoporosis leads to an increased risk of fractures. Osteoporosis is rare in children. Sometimes, there is no identifiable cause of osteoporosis in a child. This is known as idiopathic juvenile osteoporosis or IJO. IJO is a rare condition with an estimated incidence of 1/100,000. Affected children suffer from chronic diffuse pain and ambulatory difficulties. They are often unable to participate in sports and may experience frequent fractures. At the Hospital for Sick Children Bone Health Centre, we follow 24 children with a diagnosis of IJO. To look for very uncommon gene mutations that lead to a rare disease like IJO, we read (sequence) each one of the 25,000 genes in these patients using a very sophisticated tool called Whole Exome Sequencing or WES. We found one gene with a defect (mutation) that has not been described before in a patient and we think this is the cause of this patient’s osteoporosis. This gene is important in the formation of the bone protein (collagen) and its name is BMP1. The next step in this project is to confirm that this mutation causes a defect in the gene’s function. Confirming this mutation will lead to the diagnosis of future patients with the same defect in this gene and for this patient will be reassuring to know that this genetic variation is the cause of the underlying condition.

Behavior and cognitive assessment in children affected with retinoblastoma having received chemotherapy and surveillance under anesthesia

Retinoblastoma is the most common type of tumor in the eye and affects children usually under the age of two years. When the tumors affect both eyes the current treatment involves several cycles (4-6 cycles) of 3 chemotherapy agents given over 2 days every three weeks. Every three weeks before the next chemotherapy cycle the Eye doctor examines the eyes of the child under general anesthesia and the doctor may treat some areas of the tumors with laser and cryotherapy (freezing). This may be repeated regularly over 1-3 years until all the tumors are dead. In literature on adults undergoing chemotherapy (quite different than the one we use in our patients), there is a suggestion that some chemotherapy agents may affect memory and learning. Recent research also suggests that some anesthesia agents may affect the brain development of some children. Our protocol involves both anesthesia and chemotherapy at a young age: We have never assessed the question of whether or not this has negative effects on the brain. Using the most recent and standardized psychological tests, we will evaluate the memory and learning function in our retinoblastoma survivors aged 6 to 16 years.

Identification of novel therapeutic targets at the mitochondria to negate mutant SOD1-mediated motor neuron death in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive and ultimately fatal neurodegenerative disease, characterized by the loss of specialized neurons that control voluntary muscle movement. The loss of these neurons, termed motor neurons, results in paralysis of skeletal muscles. There is no cure for ALS and the lack of our understanding of the pathologic mechanisms underlying motor neuron death in ALS is mirrored in the lack of effective therapeutics to slow or halt the disease. Mutations in superoxide dismutase 1 (SOD1) account for 20% of inherited and 3% of non-inherited ALS cases. Mutant SOD1 protein adopts a non-normal/misfolded structure, which leads it to preferentially bind to the surface of motor neuron mitochondria. Mitochondria are the power generators of the cell and the binding of this non-normal SOD1 correlates with mitochondrial damage and motor neuron death. The mechanism of how mutant SOD1 causes mitochondrial damage remains unexplained. We have identified a novel interacting protein with misfolded SOD1 and request funds to fully explore the functional consequences of this interaction.

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