May 2014 Funded Microgrants

May 2014 Funded Microgrants

Individualized Exercise Prescription and Activity Trackers in Children with Tetralogy of Fallot

Children with tetralogy of Fallot (TOF) are reported to be less active and less fit than healthy children. Regular participation in physical activity (PA) can improve fitness and prevent future disease. However, many parents of children with TOF restrict their activity because they are unsure of appropriate activities and uncertain about the safety of exercise in their children. Guidelines thus far have focused more on restriction from competitive sport rather than recommendations on appropriate activities for the recreationally active child. Exercise prescription may be effective in improving activity levels and fitness in children with congenital heart disease (CHD). Activity trackers are an innovative fitness tool that provides ongoing feedback about personal PA levels and may be useful in monitoring activity in these children. Our aim is to determine if individualized exercise prescription and an activity monitor will increase PA and improve fitness in children with TOF.

Is carnitine supplementation in patients with mitochondrial disease associated with elevated blood trimethyl-amines?

Carnitine is prescribed by metabolic physicians for the treatment of a variety of metabolic disorders including mitochondrial disorders. Carnitine supplementation may be useful to prevent tissue deficiency and protect against cell damage. Researchers have recently found a link between carnitine levels in blood and a substance called trimethylamine-N-oxide (TMAO). TMAO is produced by gut bacteria when they break down carnitine. There is an association between high TMAO levels and susceptibility to cardiovascular disease. The objective of this study is to determine if carnitine supplementation is associated with higher TMAO levels in mitochondrial patients. If elevated TMAO levels are identified, this could have possible long term health implications and evidence of benefit will need to be balanced against potential harms.

Results - Our findings led to practice change in the adult metabolic clinic with respect to long term oral L-carnitine use. Publication Here

The International Pyridoxine-Dependent Epilepsy Registry: for innovative therapies & improved outcomes

Lysine restricted diet is recommended as an add-on treatment for Pyridoxine-Dependent Epilepsy for better seizure control and improved development. However there is not enough evidence on short- and long-term outcomes for this potentially burdensome treatment, which is rapidly being implemented in patients. To address this, we propose an international registry that will utilize freely accessible, online data sharing technologies to generate more evidence for this rare metabolic epilepsy.

Moving One Step Closer to Therapy for Adams Oliver Syndrome

Adams Oliver Syndrome (AOS), a rare disease with an estimated prevalence of about 1 in 50,000 births, is typically characterized by shortened or stubbed limbs and patches of missing skin and/or bone of the scalp. Complex heart malformations are common. The disease is believed to stem from abnormal blood vessel development which can lead to serious pulmonary hypertension (high blood pressure in the lungs) -the main cause of death in infants with AOS. We have identified a set of genes that are altered in patients in with AOS that has uncovered a new biological pathway that appears to be pivotal for normal blood vessel development. Our goal is to fully characterize this pathway at the molecular and cellular level. Solving the pieces needed for normal blood vessel physiology is essential for developing effective therapeutic strategies for children born with AOS. Furthermore, figuring out how to effectively treat this rare disorder has the power to provide insight into the pathology of other rare vascular diseases, such as those involving pediatric stroke or hypertension.

Results - We used this microgrant to characterize the immune profile of AOS patients and found one NOTCH1-related AOS patient with double positive T cells, expressing both the alpha/beta and gamma/delta markers. This finding was present when he was ill but waned as he became healthy.  Unfortunately, this could not be demonstrated in other people with NOTCH1-related AOS. We also developed an in vitro assay so variants of uncertain significance in NOTCH1 can now be tested for evidence of their effect.  

Accuracy of deformity measurement in slipped capital femoral epiphysis: a geometrical modeling study

Slipped capital femoral epiphysis 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. Doctors measure the severity of SCFE on X-rays taken in a 'frog-leg' position, but many adolescents with SCFE cannot put their hips in the correct position (pain, joint limitations). Despite this, doctors still try to measure severity on less than perfect X-rays. Using computer models, we can test how much the measurement changes with hips in the wrong position. This will tell surgeons if they are getting a good measurement of severity, or if other methods are needed to provide better diagnosis, prognosis and treatment decisions for these adolescents.

The Metabolic Diet App Suite: Innovative technologies to support patients and families with rare inborn errors of metabolism

Inborn errors of metabolism (IEMs) are chronic, genetic diseases affecting children and adults; each individual disease is rare (1:8,000 to 1:500,000) but collectively these affect 1:2500-4,000. These conditions are due to the body cell's inability to break down proteins, carbohydrates into energy; this results in an accumulation of toxic waste and lack of energy. Medical diets (taking out the specific nutrients which the cells cannot breakdown) are available to treat affected individuals to prevent brain damage causing epilepsy, intellectual disability and psychiatric conditions. These diets are life-long and extremely laborious for parents and family. Non-compliancy is common and deviation can have life-threatening and irreversible effects. To enhance adherence, and facilitate planning of meal, tracking of intake / food records and communication with the dietician and managing physicians, our BCCH based group of biochemical physicians and dieticians in collaboration with Health2Media and the Global Metabolic Dieticians International (GMDI) are creating the first ever Diet Apps for over 15 different IEMs. Funding is needed for access to nutrient data via the high quality Metabolic Pro database.

Development and implementation of a nursing therapeutic education intervention based empowerment for people with myotonic dystrophy type 1

Myotonic dystrophy type 1 is a rare degenerative neuromuscular disease. It is considered a multi-systemic disorder because it affects several other systems. People who are affected from this disease could benefit from the development of additional skills for the optimal management of their condition. However, because of the multiple impairments and impacts of the disease their self-management skills are often compromised. The purpose of this study is to develop an education intervention based on empowerment to improve their involvement in the management of their health.

Results - This project aimed to: design and implement, as part of an intervention manual, a nursing therapeutic education intervention based on empowerment for people with myotonic dystrophy type 1 DM1 (NTEIE-DM1), and to explore its feasibility and acceptability of the intervention.

During the design phase, data were collected from people with DM1 (n = 27) and nurses (n = 3). Results showed that the self-management by patients with DM1 depends on their personal characteristics and on the educational process and its context of realisation. Important personal characteristics to consider are compromised executive function affecting learning, empowerment and adoption of healthy lifestyles. Also, 80% of DM1 patients present a compromised health literacy. Results also demonstrated that 52% of DM1 patients prefer to learn by experience and 73% by experience combined with another learning style. Consequently, people with DM1 often make decisions based on observations in their familial or social environment. Field observations showed that these aspects are frequently not taken into account in the organisation of educational interventions.

The NTEIE-DM1 was developed based a literature review exploring the themes of impairments that influence learning capabilities of people with DM1, patient therapeutic education and individual empowerment, as well as on separate group discussions with healthcare professionals (n = 8), researchers in neuromuscular diseases (n = 5), people with DM1 (n = 8) and a representative of Myotonic dystrophy Canada. An intervention manual was developed that presents the NTEIE-DM1 in the following sections: 1) objectives; 2) modalities of the intervention: the location, the format of intervention (e.g. individualised or in group), the providers to be involved, the number of meetings and their duration; 3) postulates of the individual empowerment philosophy; 4) the NTEIE-DM1; and 5) a repertory of educational strategies. The NTEIE-DM1 is based on the work of Anderson & Funnell (2005) and constructed around a five-step process: 1) identification of the problem; 2) identification of feelings; 3) joint development of an objective; 4) establishment of an action plan; and 5) evaluation of the results. Each of the steps includes one to five sub-steps. Interactive strategies such as semi-directed interviewing, visual mapping and photoexpression have been integrated. In addition, tools such as emotion maps, energy rating scale and patient follow-up journal were developed to improve the active participation of people with DM1 in the self-management of their disease.

Feasibility and acceptability of the NTEIE-DM1 were assessed initially by a questionnaire covering the 50 elements of the NTEIE-DM1 completed by health professionals who participated in the conceptualization phase (n = 6). People with DM1 will have the opportunity to assess the feasibility and acceptability of NTEIE-DM1 in a future project. The following results present the overall feasibility and acceptability rates of each of the main elements of the NTEIE: objectives (78.5%), intervention modalities (92.8%),individual empowerment philosophy (96.6%), the NTEIE-DM1 steps, sub-steps, strategies and tools (26/43 elements ≥ 90%, 12/43 elements 80 - 89.9%, and 5/43 elements 70 - 79.9%). Elements with an acceptability and feasibility rate ≥ 80% will be retained in NTEIE-DM1 for implementation in a pilot project and elements with a rate below 80% will be modified based on comments received.

Drug screening for C9ORF72 toxicity

Amyotrophic Lateral Sclerosis is a fatal degenerative disease affecting motor neurons. The presence of GGGGCC repeat found in the first intron of C9ORF72 was shown to be a major cause of ALS. Our research uses the nematode C. elegans, a simple genetic systems, to address some questions related to C9ORF72 toxicity. Preliminary data suggest that loss of expression of C9ORF72 causes age-dependent motility defects and degeneration of the MNs in C. elegans. We aim to do a high-throughput drug screening to identify drugs that would decrease the toxicity of C9ORF72 in the worm motor neurons. If our project is successful, further testing using other animal models or patient cells could open new treatment possibilities for ALS patients.

Implanted Cardioverter Defibrillator Right Ventricle Lead Location in ARVC Patients

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a disease that affects the heart, causing an irregular and quick heartbeat that can result in heart racing, collapse or even death. A treatment option for patients with ARVC is to insert a device called an implantable cardioverter defibrillator (ICD) directly into the patients' heart. The ICD can detect an irregular heartbeat and deliver an electrical shock to the heart, which "resets" the heartbeat. The ICD is made up of a generator, which initiates the electric shock, and a lead, which is a wire that is screwed into the heart to transfer the electric shock to the heart. One of the issues with ICD's in patients with ARVC is that the disease causes the heart to become rich in fat and electricity does not travel well through fat. Different areas of the heart accumulate more fat than others in ARVC, therefore placing the lead in areas of the heart with little fat will have improved performance of the ICD. Poor placement of the lead may result in the inability of the ICD to detect and treat those dangerous rhythms, potentially leading to the death of the patient. We propose to study the relationship between where a lead is placed in the hearts of these patients and the reliability of the wire to detect and treat the dangerous rhythm.

Results - We found that certain lead placement tended to degrade in signal over the medium term and now recommend that an alternate lead placement be explored.  Our paper was accepted for publication with the Heart Rhythm Journal and these important findings may lead to changes in care. Click here for published article

Comparing patient-reported outcomes and formal neuropsychological assessments in PKU patients who undergo adjuvant therapy with Sapropterin, a new pharmacologic treatment for PKU

Phenylketonuria (PKU) is rare genetic disorder affecting the body's ability to properly utilize Phenylalanine (Phe), one of the aminoacids contained in food protein. Developmental intellectual disability is prevented by a lifelong Phe-restricted diet. Patients who do not achieve optimal diet control have learning disabilities, ADHD, anxiety, and depression. Sapropterin (Kuvan®) is a new, pharmacological treatment for PKU, which optimizes diet control. However, because individual patients have variable patterns and degrees of response to this drug, it is particularly important to show that Sapropterin positively influences the patient's daily functioning and outcomes. Traditional formal neuropsychological (IQ) tests do not always reflect what happens in real life. While patients / parents / teachers report substantial improvement in everyday functioning, formal tests may not be able to reproduce these findings. Conversely, patients may show measurable response to the treatment, but they decide to stop taking Sapropterin because they do not feel like it helps. We would like to interview patients/parents about the perceived benefits of Sapropterin and compare the information provided with results from previous psychological assessments and find out whether there is a discrepancy and what is the cause of such disagreement.

Results - This project focuses on the utilities of a new pharmacological treatment for PKU from a patient perspective and compares to outcomes measured via traditional toolls, such as neuropsychological tests. Study completed.

Predictors for a Positive Procainamide Challenge in Patients with Brugada Sign on Standard Electrocardiogram

Brugada syndrome is a rare heart condition that can lead to fainting, cardiac arrest, and sudden death in children and adults. It was first described in 1992, although urban myths surrounding the sudden death of young Southeast Asian men have been reported for decades. Often affected individuals with may be unaware they have the condition, and unfortunately the first sign of the condition may be a fainting spell, a seizure or sudden death. The diagnosis of Brugada syndrome is difficult for physicians, as there may not always be signs of the condition on routine EKG testing. A provocative test or drug challenge uses medication to mimic the effects of exercise or rest on the heart; it is conducted under close medical supervision. This has proven helpful in identifying Brugada syndrome. Identifying individuals most suitable for drug testing is a challenge and it is unreasonable to put all individuals through the potential adverse effects of the testing not to mention the expense and strain to the healthcare system for unnecessary testing. We propose a system to identify individuals at-risk for Brugada syndrome and those most suitable for testing. Using our existing database UBC/Vancouver Inherited Arrhythmia Research Registry, we will identify factors that predict a positive provocative test. The results may be used to guide the testing, decrease unnecessary testing, prevent adverse events, and inform the development of a provincial surveillance system for identification of Brugada syndrome and prevention of sudden death. Present understanding of this condition is that Asian populations are more at risk for Brugada syndrome and the cardiac events associated. British Columbia encompass' a substantial Asian population so that this project can potentially pave the way for a better understanding of Brugada syndrome.

Perspectives on genetic information in an Inborn Error of Metabolism: A retrospective study of parents of children with Zellweger Spectrum Disorder

Effective patient care for inborn errors of metabolism has been recommended to involve a multidisciplinary approach, which has been implemented by some multidisciplinary pediatric metabolic clinics to incorporate the skills of metabolic geneticists, pediatric dieticians, social workers, clinical pharmacists, nurses, and genetic counsellors. However, it remains to be shown how effectively such an approach is currently being implemented and how parents of children with such disorders perceive this care. The goal of this study is to gather information from parents surrounding their experience of the diagnosis and management of Zellweger spectrum disorder (ZSD). We aim to ascertain how genetic information was presented to them, as well as the impact had on the family's hope, understanding of the condition and prognosis, and family planning.

Results - the investigator was unable to complete this project for health reasons.

Determining the Cause of an Undiagnosed Lipid Storage Myopathy

We have seen a 32 year-old lady with recurrent, severely painful muscle spasms in her legs. She has been experiencing these spasms since her early teens. She is mostly wheelchair-bound and cannot work, and at least monthly the pain is so intense that she requires doses of morphine high enough that her breathing is suppressed and she needs ICU monitoring. We think that this is because she has a genetic condition that causes an abnormal build-up of fat in her muscles. Locating the genetic mutation that causes this fat build-up is an important step, because once we have this information, we can do something to modify this fat production and possibly stop the muscle spasms. In order to find the mutation in the gene causing these symptoms, our goal is to sequence all of the known genes in this lady's DNA.

Proving the genetic cause for a lethal neurodegenerative disorder

Several siblings presented with a progressive neurological disease in which there has been failure of brain growth, seizures, and early death. After ruling out known diseases, the family enrolled in a research study to find the cause. A mutation was found in a gene called VGLL4, which is important in maintaining stem cells. We hypothesize that their symptoms are caused by loss of neuronal stem cells in the brain. This microgrant will fund the necessary work to show that the mutation found in these children disables VGLL4. In the long term, this work will contribute to research in stem cell therapeutics. In the short term, our project will provide a diagnosis for other children affected with this devastating disease who remain undiagnosed after many investigations.

Exploring Synaptogamin-Like Peptide 2 deficiency as a novel cause of Sea Blue Histiocytosis

Enlarged spleens associated with abnormal cells, termed sea blue histiocytes, may be seen in association with an acquired disease of the blood system, or with a rare genetic disorder of metabolism. The Omics2TreatID gene discovery study used genomics technologies to identify the causal gene defect in our extensively investigated patient presenting with an enlarged spleen with prominent numbers of sea blue histiocytes, and other unexplained health problems. Damaging changes were identified in the gene encoding synaptogamin like 2 protein (SLP-2a). It is possible, that the presence of the SLP-2a mutations account for the finding of abundant sea blue histiocytes and splenomegaly in this patient. The goal of our project is to clarify whether SLP-2a mutations are having a deleterious effect on this patient's cell metabolism. If so, this patient's evolving disease would be monitored and treated differently. Further, this connection between SLP-2a and patient disease associated with enlarged dysfunctional liver and spleen would recognize a new disease syndrome, one that may be applicable to other similarly previously undiagnosed patients.

Defining revertant fibers in Duchenne muscular dystrophy

Duchenne muscular dystrophy is one of the most common genetic diseases of childhood, affecting 1:3500-1:5000 boys. It is a devastating disorder characterized by progressive loss of muscle function and early death. Currently there is no cure for DMD, and available modifying therapies only modestly alter the disease course. Therefore there is a great need for new strategies for therapy development. DMD is caused by mutations in an X-linked gene called dystrophin. Patients with DMD make basically no dystrophin protein. Interestingly, despite this, patients are known to have a small percentage of their muscle fibers that re-express dystrophin (called revertant fibers). The mechanism underlying how and why revertant fibers appear is not understood. However, their existence is potentially of great import. It is believed that only 20% of fibers need to express dystrophin for normal function to be restored. So, increasing the number of revertant fibers may represent a novel way of treating DMD. In this proposal, we will take advantage of the zebrafish model system to begin unraveling the nature of revertant fibers, with the ultimate goal of using this knowledge as a springboard for novel therapy development.

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