November 2013 Funded Microgrants

November 2013 Funded Microgrants

Detecting nuclear factor κB-mediated pathology in amyotrophic lateral sclerosis subtypes

Amyotrophic lateral sclerosis (ALS) is a progressive and invariably fatal neurological disease. The defining feature of ALS pathology is death of motor neurons leading to profound weakness and respiratory failure. There is currently no effective disease-modifying treatment other than Riluzole, which only has a modest effect on survival. According to the ALS Society of Canada, approximately 3,000 Canadians live with ALS (; many receive care at Sunnybrook Hospital. The majority of patients presenting with ALS have a sporadic type (sALS). Approximately 10% of patients however, have one of the familial forms of the disease (fALS). Mutations in several genes can cause fALS (e.g. C9orf72, SOD1, FUS), highlighting the daunting heterogeneity of ALS. It is conceivable that the various subgroups of patients respond differently to therapeutic interventions. Recent evidence suggests that the transcription factor nuclear factor κB (NFκB) may play a pivotal role in ALS pathology. Much effort has been made by the pharmaceutical industry to develop NFκB inhibitors and clinical trials are underway. Our goal is to further study the role of NFκB in sALS and fALS subgroups in order to identify individuals and families that may benefit from treatment with NFκB inhibitors.

Medical geneticists' discussion of the psychiatric manifestations of 22q11.2 deletion syndrome: a retrospective chart review

Early intervention for psychiatric disorders improves long term outcomes for the affected individual. In order to provide timely early intervention, families of people with genetic syndromes that put them at higher risk for these conditions - and their family doctors/pediatricians - need to know about this possibility. Though 22q11 Deletion syndrome (22q11DS) is associated with a high risk of psychiatric conditions, mental health services are underused by this population and parents report not being told about the risk for psychiatric disorders by their healthcare providers. However, in our previous (Rare Disease Foundation funded) work we showed that medical geneticists (who often diagnose the condition) self-report that they do usually discuss this issue (although often not at the initial diagnosis visit, but instead at follow-up visits). To resolve this discrepancy there is an urgent need to objectively determine whether the psychiatric aspects of the syndrome are addressed when a diagnosis is made. Thus, we will conduct a retrospective chart review of all patients seen at the BC Provincial Medical Genetics program (BCPMGP) for a diagnosis of 22q11DS between 2000 and 2012 to determine what information about the syndrome is communicated to referring physicians following appointments (we will look specifically to see whether information about the risk for psychiatric disorders is communicated), and whether a BCPMGP follow-up plan is described. In doing this, our goal is to generate information that will allow strategies to be implemented to increase access to mental health services within this population, which will improve outcomes for those affected.

Results - See publication below

Discussing the psychiatric manifestations of 22q11.2 deletion syndrome: an exploration of clinical practice among medical geneticists.

Morris E, Inglis A, Friedman J, Austin J. Genet Med. 2013 15(9):713-20. doi: 10.1038/gim.2013.31. PMID: 23579435

Norepinephrine replenishment therapy using L-DOPS in congenital insensitivity to pain with anhidrosis

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare hereditary disease that causes lack of pain perception, inability to sweat, and severe behavioral problems in children. Unfortunately, there is no treatment for the disease. We have recently found that children with CIPA have extremely low levels of a biological substance known as norepinephrine that plays an essential role in brain function. We propose a pilot study to learn whether a drug called L-DOPS, which is converted into norepinephrine by the body, can improve cognitive function in these children. If successful, this would have a major impact in the quality of life of these patients and their families.

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

Disease Gene Mapping and Identification in Consanguineous Families with Pyridoxine-responsive Neonatal Epilepsy

Some forms of epilepsy in children are resistant to common antiepileptic medicines but can be stopped by treatment with vitamin B6. They are designated as vitamin B6-reponsive epilepsies and are attributed to inborn errors of metabolism. Study of families afflicted with these forms of treatable neonatal epilepsy will help to identify their genetic causes and improve diagnosis and treatment.

Weight-bearing MRI for evaluation of osteochondritis dissecans: a pilot study

Osteochondritis dissecans is a bone disease that most often occurs in teen boys. In this disease, a piece of cartilage and bone breaks off in the knee joint, where it can stay in its original place or move (flap, float, drift). If it stays in place, it can be repaired by surgery. If it is mobile, it may need to be removed; this leaves a void that is difficult to repair and often leads to joint problems and disability. Standard MRI, where the patient is lying down and the knee isn't taking weight, does not let us see if the piece of bone is mobile. An "upright" MRI, where the patient stands or squats, can instead be used to image the knee joint. These images should give us a better way to assess these patients and so improve their outcomes.

Identification of genes predisposing to Familial Arrhythmia syndromes

Normal contraction of the human heart depends on the proper movement of charged ions through special cardiac ion channels across the surface membrane of millions of cardiac cells. Disorders of the conductive ion flow lead to cardiac arrhythmias, which may predispose to sudden cardiac death (SCD) at a young age. Ventricular fibrillation is the most commonly identified arrhythmia in cardiac arrest patients. In the absence of identifiable structural heart disease or known 'electrical' abnormalities, it is referred to as idiopathic (cause unknown) ventricular fibrillation (IVF), which accounts for ~10% of sudden deaths. A family history of sudden cardiac death is present in 20% of IVF cases, suggesting that at least a subset of IVF is hereditary. The present lack of insight in the genetics of this disorder hinders the understanding of the pathophysiology of the disease and consequently hinders the developments of new therapies for the disorder. We care for a family with a rare overlap of arrhythmia syndromes. A 15-year old boy came to the clinic after he suffered from ventricular fibrillation (VF; uncoordinated contraction of the cardiac muscle of the ventricles in the heart) during sleep. Interestingly, the patient, like his father, also suffers from a common arrhythmia: atrial fibrillation (AFib). The father also suffers from AFib and ventricular tachycardia (VT), an arrhythmia related to and predisposing to VF. Other family members seem unaffected. Genetic testing in the patient revealed no causal mutation in the gene coding for the cardiac sodium channel (SCN5A), previously implicated in IVF. We have DNA samples from the patient and his parents, with research consents for use in this study. We propose to use a method to look at all genes in retained DNA from the 2 patients with arrhythmia's/ ECG abnormalities. 

Use of Negative Pressure Wound Therapy on Clean Closed Spinal Incisions

The prevalence of neuromuscular disorders ranges from < 1 in 2000 (rare) to 1 in 30,000. In addition, the incidence of scoliosis in patients with a neuromuscular disorder ranges from 25% to 90% of cases. Children with neuromuscular disorders such as cerebral palsy, Duchenne muscular dystrophy, and many more neuromuscular disorders have higher infection rates after scoliosis surgery to correct the curvature of their spine than healthy children who undergo scoliosis surgery. The purpose of our study is to compare the effect of Negative Pressure Wound Therapy (NPWT) on infection rates when compared to standard gauze dressing. Negative pressure wound therapy is the application of constant suction to the dressing which results in a vacuum over the wound. This has been scientifically shown to keep the wound dry, decrease wound tension, and promote faster healing at a cellular level, all of which helps in reducing infections. Participants with neuromuscular scoliosis will be randomized to the "NPWT" or "standard dressing" group. We will compare infection rates between the two groups.

The Isodicentric chromosome 15 (Idic (15)) Canadian National Registry

Isodicentric chromosome 15 (Idic(15)) is a rare chromosomal disorder in which affected people have additional genetic material derived from chromosome 15. An affected child typically has developmental delay/intellectual disability, seizures and autistic behavior. The seizures can be severe and difficult to treat and affected children and adults are at increased risk of sudden, unexpected and unexplained death. There are no specific guidelines for treatment and research is limited by small numbers of identified affected individuals and amount of accurate information available on them. Rare disease registries are vital for collecting accurate information and facilitating research which has significant impact on care. Given this, this study aims to develop an Idic(15) national registry to improve outcome of affected individuals by capturing information that will allow for earlier diagnoses and interventions, more effective research, and improved access for patients and clinicians to accurate and up-to-date information on this disorder.

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

Gene Discovery in a Gene-elusive Skin Fragility Syndrome

Hereditary blistering disorders of the skin are broadly classified as superficial or dystrophic; gene mutations of connective tissue proteins keratin and collagen respectively have been found in these conditions. However, in ¼ of families with the superficial disorder the cause remains elusive. Our skin specialists follow a family with an affected mother and three affected children who have negative clinical genetic testing for the known genes. We will use a method that assesses all genes (whole exome sequencing) to search for a mutation that is common to all individuals in this family, as a cause for their hereditary condition.

Effect of femoral epiphysis position and pin location on impingement in SCFE: a geometrical modelling 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 maybe related to obesity, and can lead to osteoarthritis, pain and sometimes 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. Creating computer models of hips with a range of deformities and simulating this surgery will allow surgeons to understand when using a screw will have a low risk of complications, leading to better treatment outcomes for these adolescents.

Challenging behaviors in Cardiofaciocutaneous syndrome: risk and protective factors

Cardiofaciocutaneous syndrome (CFC) is a rare genetic syndrome associated with heart disease, characteristic facial features, skin anomalies, and varying degrees of developmental delay. Children with CFC are at heightened risk for neurological complications including seizures, hydrocephalus, and intellectual disabilities.  At family advocacy group meetings, parents frequently report significant concerns regarding their child's challenging behaviors. However, there has been scant research to investigate emotional and behavioral difficulties in CFC and to understand what contributes to these difficulties. Our research will identify factors that place a child with CFC at higher risk for behavioral challenges (e.g., anxiety, self-injury) as well as those that contribute to better ability to self-regulate. The study will also investigate how child behavioral difficulties may impact the parenting experience. Results of this study will not only be submitted for scientific publication, but will also be used to create an informational brochure for caregivers outlining the study results, basic behavior management strategies, and potential treatment avenues and support resources for families.

Results - Results of this study indicated that children with CFC syndrome are at heightened risk for psychopathology, with attention problems, social difficulties, and unusual behaviors (e.g., obsessive thoughts, strange behaviors, repetitive acts) found to be especially prevalent. Behavioral challenges in children with CFC syndrome were significantly associated with a history of obstetric complications (e.g., premature birth, pre-eclampsia) and with problems modulating sensory information. With regard to the impact of child neurocognitive and behavioral issues on the caregiving experience, parent self-reported stress was significantly higher among parents of children who engaged in more problem behaviors, and lower among parents whose children could communicate effectively with others. Results of this study suggest avenues to help families cope with CFC-related stressors and enhance overall functioning. In particular, this study highlights the need for educational and treatment interventions aimed at addressing sensory needs, increasing functional communication, and identifying and managing challenging behaviors. 

Publication in American Journal of Medical Genetics resulting from the funding from the Rare Disease Foundation:

Characterization of ARVC using a Novel Cardiac Stress Test (Pharmacologic Stress-Induced Signal-Averaged Electrocardiogram)

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is a rare heart condition (1:2000 - 1:5000) that can lead to loss of consciousness, cardiac arrest, and sudden death in children and adults. It is a condition that is difficult to diagnose, and unfortunately, often presents with sudden death of the affected individual. Subsequently, family members are screened for ARVC, but the natural history and management options for the surviving individual and/or family members are unclear. Family members sharing the genetic mutation are thought to be at risk for sudden death, but their degree of risk and whether this necessitates aggressive interventions is still unknown.

To address this need, we started the Canadian ARVC Registry, a national database enrolling individuals diagnosed with ARVC and their affected family members at 12 centers across the country. Within this registry, we have a family of 4 whose young daughter had a cardiac arrest due to ARVC. Her brother and father have both been found to carry the same genetic mutation associated with ARVC, but they do not manifest any physical signs of the condition. We hope to develop a new "cardiac stress test" to help identify signs of ARVC earlier in the disease process and before other physical signs are present. This would allow us to better understand the link between genetics and the expression of ARVC, determine the risk associated with carrying a genetic mutation, and ultimately, guide the diagnosis and management of this complex and rare disease.

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

Investigation of enzyme enhancement therapy for MPSIVA

The extremely rare Mucopolysaccharidosis (MPS) genetic diseases afflict less than 1 person in 200,000. MPS IVA (Morquio A disease) has deficient and/or compromised function of the lysosomal enzyme N-acetylgalactosamine-6 sulfatase (GALNS). At present there is no approved therapy for MPS IVA. We plan to investigate two strategies to enhance GALNS function: 1) small molecule chaperone therapy, which stabilises the patient's mutant GALNS protein and 2) enhancing the activity of GALNS by maintaining its disulfide bonding; this has been shown to increase human GALNS activity in vitro. Both of these strategies have the capacity to increase the level of enzyme activity either alone or in combination thus enabling treatment of the disease. Improved enzyme function in patients in the presence or absence of future enzyme replacement therapy would in turn improve mobility, muscle and respiratory functions in MPS IVA patients.

NF1 & me: What adolescents need to know and have to say about their health, privacy and social life

Neurofibromatosis type 1 (NF1) is an autosomal dominant disease that affects 1/3000 people. Its physical manifestations can deform the body and bring about cognitive problems. Those affected are not only victimized by the social stigma associated with the disease, they are also predisposed to anxiety and depression. Under these circumstances, adolescence is a particularly sensitive period when one is affected with NFI. Especially seeing as hormonal changes and periods of rapid growth may exacerbate physical deformities at an age when appearance, peer acceptance and social integration are of paramount importance. We must also consider that one is only beginning one's apprenticeship of love and sexuality at this point in life, and consequently, the fear of change in appearance, the risk of a pregnancy aggravating the illness, or the risk of giving birth to an affected child will complicate the situation even more. In this context, we sought to: 1) comprehend the concerns of late adolescents affected with NF1 as to the impact that the disease has on their lives, and thereby; 2) determine the relevance of intergenerational medical, parental and other types of dialogue. By way of an online questionnaire, we will interview 100 adolescents. Our goal is to generate knowledge allowing for a better understanding of the needs of late adolescents, such as: 1) medical, genetic and reproductive information, 2) clinical interventions and caregiving, 3) academic and psychological support, 4) intergenerational dialogue.

DECIDE-Genomics: a decision support tool for families

Our goal is to pilot test DECIDE-Genomics, a multi-media tool providing genetic e-counselling and decision support as an online option for parents choosing whether or not to have genome sequencing. There is currently a large gap between the power of WGS and our ability to provide adequate, accurate, affordable, accessible genetic counselling for this test. We have developed DECIDE-Genomics to fill this gap. Part 1 of DECIDE-Genomics (completed) integrates educational material with a decision aid to help parents make the choice of whether or not to have WGS. Part 2 (in development) helps them to choose whether or not to learn about incidental findings that could be discovered by WGS. This grant will allow us to complete and pilot test DECIDE-Genomics. We have UBC Research Ethics Board approval for usability and acceptability testing with families currently undergoing WGS. This research will provide invaluable data prior to a randomized controlled trial of the effectiveness of DECIDE-Genomics compared to conventional face-to-face genetic counselling.

Results - This grant enabled us to develop and test DECIDE, an online interactive educational and decision-support tool to help parents make choices about genome-wide sequencing for their children with undiagnosed rare diseases.  RDF funding allowed DECIDE to be successfully developed and pilot tested with input from health professionals, educators, decisional scientists, and parents. 

A description of the tool and pilot testing was presented at the 2015 American Society for Human Genetics meeting, and has recently been published: Friedman JM, Adam S, Birch PH, Coe R, Hicklin J, Bansback N. DECIDE: Development of an interactive tool to guide parents’ choices regarding genomic incidental findings results. Proceedings of the 65th Annual Meeting of the American Society of Human Genetics (Abstract/Program #2162). Baltimore, 2015 (poster). Birch PH, Adam S, Bansback N, Coe RR, Hicklin, J, Lehman A, Li KC, Friedman JM. DECIDE: a Decision Support Tool to Facilitate Parents’ Choices Regarding Genome-Wide Sequencing. J Genetic Counseling. (in press) DOI 10.1007/s10897-016-9971-8.  

DECIDE is currently being used in a large clinical research program to offer parents the option of genome-wide sequencing to diagnose the underlying cause of their children’s intractable epilepsy.  To date, it has been used by over 100 families and appears to be a valuable adjunct to genetic counselling, resulting in knowledge and understanding that is equivalent to that obtained by in-person genetic counselling. 

Interim results of this work were presented in poster form at the 2015 American Society for Human Genetics meeting: Adam S, Bansback N, Birch PH, Coe R, Connolly MB, Toyota E, Farrer MJ, Demos MK, Friedman JM. Can an online decision-aid help parents of children with treatment-resistant epilepsy make whole exome sequencing decisions?  Proceedings of the 65th Annual Meeting of the American Society of Human Genetics  (Abstract/program #2161), Baltimore, 2015 (poster). 

Complete results of the epilepsy project will be submitted for publication upon study completion. The availability of DECIDE also facilitated our successful application for CIHR funding for a randomized controlled trial using DECIDE instead of conventional genetic counselling for families considering genome-wide sequencing for a variety of rare, and presumed genetic, disorders.  This research is currently underway. Our demonstration version of DECIDE, without information for any specific research study, can be viewed here: 

We anticipate using DECIDE in clinical care as soon as the results from the current CIHR research project have been analyzed.

Testing the Feasibility of the Changing Faces Practitioner Training and Induction Program for Scleroderma Patients

People living with rare diseases do not typically have access to important components of care relevant to their condition. Scleroderma (SSc) is a rare disease with many unmet needs, such as resources to support coping with disfiguring appearance changes associated with the illness. Changing Faces, a UK-based not-for-profit organization, designed a program to train health professionals how to address the needs of people living with visible differences. The proposed project involves training the applicant to administer the Changing Faces program to people with visible differences from SSc, and subsequently, to test the interest in and effectiveness of the program.

Development of a system to obtain fetal electrocardiograms using a blind source separation method of signal processing

While we can now view ultrasound images of the fetal heart, obtaining a fetal electrocardiogram (ECG) is still difficult. A fetal ECG would help in diagnosing fetal heart dysfunction and abnormal heart rhythms (arrhythmias). The difficulty in obtaining an ECG is that the fetal heart generates signals that are much smaller than those from the mother. As a result, ECG machines screen the fetal ECG signal out as "noise". A possible solution is Blind source separation (BSS), which uses mathematical equations (algorithms) to separate the maternal and fetal signals. Using BSS, it may be possible to show a clean fetal ECG signal alongside ultrasound images of the fetal heart, helping to diagnose fetal heart dysfunction and arrhythmias. We have started to develop and test a BSS algorithm to extract fetal ECG. More work is needed to develop this algorithm, build a prototype and test it on fetal ECG signals.

Results - Unfortunately this project was never initiated due to a technical problem that could not be resolved by the investigator.

Patient- and family-oriented outcomes for inborn errors of metabolism research: the perspective of patient advocacy and support groups

Health researchers don't always focus on outcomes that are the most important priorities for patients and families when studying diseases and possible treatments. The importance of tailoring care and outcomes to meet individual patient needs is even more important for people with rare diseases like inborn errors of metabolism (IEM). Patient advocacy and support organizations are uniquely positioned to understand such patient- and family-oriented outcomes. We will consult with IEM-specific patient advocacy and support organizations to identify experiences, outcomes, and health care gaps that are most important to children with IEM and their families. The results will be used in our studies that evaluate treatments and health services for IEM, and will directly facilitate patient-centered approaches to care.

Costs of Caring for Children with Rare Diseases

A great many of the costs of caring for children with rare diseases are not covered by the health care system but are borne by families and society. Examples of expenses paid by families include travel to medical appointments; special therapies; or quitting a job to better care for a child. Examples of societal costs may include travel subsidies or employer-paid time off for a parent caring for a child. Surprisingly, no Canadian study has ever performed a careful calculation of these financial costs. There are two main reasons this information would be useful: (1) to raise awareness of the monetary realities of caring for children with such conditions - information that will provide accurate data to governments and others regarding families' financial needs; (2) to measure the financial cost-benefit to families and society of introducing of new tests or therapies. For example, early language therapy applied at an appropriate developmental stage might be more effective and less expensive than twice as much therapy at another developmental stage. But without knowing the baseline costs, the long term financial impact to families and society of introducing such tests or therapy cannot be measured. We have developed and pilot tested an on-line cost diary for which we have obtained Research Ethics Board approval. Our tool is designed to enable families to capture these costs. We have designed mathematical methods of converting the data into a total dollar value that will allow us to provide data to individuals, or, more importantly, average data to organizations, such as the Rare Disease Foundation. The user interface of the cost diary can be seen here: Our tool was initially developed with families of children for whom intellectual disability is a component of their rare disease but we anticipate the tool will be easily adaptable for a variety of conditions.

Results - Video: The Cost of Caring

This RDF grant allowed us to refine and use an online cost diary, SCOPE, previously developed by us, to measure the economic impact to parents of raising a child with a rare disease that included an intellectual developmental disorder.  Such financial impact has never been calculated before in Canada.  We were able to calculate parents’ median annual expenses for a variety of circumstances.  The data collected also allowed us to demonstrate the inadequacy of governmental financial support for these families. 

One interesting observation was that the degree of the child’s disability was not a large factor in determining parents’ cost of caring. This is because the major financial impact on families comes from income loss, most commonly the mother’s, and income loss occurs in parents of children with a variety conditions.  A significant expense for a small number of families was found to be travel from remote areas, which is not adequately subsidized. 

These data may be used a baseline to measure the financial impact on families of the introduction of new technologies such as genome-wide sequencing, or of new treatments.  

The results of the RDF-funded study were presented orally and have been published in a peer reviewed journal: 

Birch PH, Genereaux D, van Karnebeek C.  The costs of caring: calculating the parental and societal costs of raising a child with intellectual disability. Proceedings of the Canadian Association of Genetic Counsellors Annual Meeting, Vancouver.  2014. (presentation) 

Genereaux D, van Karnebeek CDM, Birch PH. Costs of caring for children with an intellectual developmental disorder. Disability and Health Journal. 2015;8:646-51. doi: 10.1016/j.dhjo.2015.03.011 

In addition, SCOPE can be used to collect costing data for children or adults with any physical or intellectual disability.  It is therefore being used as the basis of a broader health economic study for children enrolled in CAUSES Clinic.  The goal of this current study is to obtain a complete health economic audit of families’ costs, as well as health system costs.  CAUSES Clinic is funded by BC Children’s Hospital Foundation (Mining for Miracles).

The Surgical Management of Pierre Robin Sequence-When and Which Type of Surgery?

Pierre Robin Sequence (PRS) is an uncommon condition with a frequency ranging from 1:3000 to 1:30000 births. Children are born with a small chin, a retroflexed tongue, and difficulty breathing, with or without a cleft palate. The most significant problem in the neonatal period is difficulty with breathing and feeding. Some children have quite severe breathing problems that require surgery. There are several surgical options for severe PRS, and the challenge for the attending surgeon is to determine which surgical technique to perform. A team-based approach is essential to the optimization of the care of these complex patients. The goal of this study is to retrospectively review the management of babies with Pierre Robin sequence admitted to BC Children's Hospital over the past 10 years and assess the incidence of PRS, how many babies were managed without surgery, indications for surgery, the type of surgical procedures performed and their outcomes related to breathing and feeding. 

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