CSF metabolomic analysis in two patients, one patient with Hereditary Sensory and Autonomic Neuropathy and intractable epilepsy, and one patient with congenital lactic acidosis and a severe movement disorder
The cerebrospinal fluid (CSF) is the "urine of the brain" that captures the waste compounds arising from metabolic processes in the brain. We can use basic biochemical analysis to measure certain compounds that can be useful in diagnosing a condition and also to choose the right treatment. We follow two young patients in the Metabolic Clinic, both with a diagnosed condition that seemed to be very stable over the last couple of years. Unfortunately, one of the patients developed suddenly a form of intractable epilepsy and his quality of life deteriorated dramatically. The other young patient developed recurrent episodes of severe movement disorder, needing repeated Intensive Care admissions and transfer from his home town to BC Children's Hospital. This is very disruptive for his family's life as his recovery usually takes a couple of weeks. Both these children had spinal fluid (CSF) analysis at times of their acute admissions to ICU and we looked at the chemicals and substances with conventional analyses, which are available to us, and found no abnormalities. Metabolomics is a new tool of investigations that can find hundreds of chemicals and substances in the CSF that could potentially shed light to new understanding of why certain seizures are not treatable to anti-seizure medication or why some patients have severe movement disorders, and could help us developing strategies to improve the patient's treatment. We have CSF samples stored from these collections that we could use for further testing in a research lab. We believe that if we have a better understanding of the underlying problem, we can use specific medications that would target those defects.
This study led to another larger funding application looking at CSF metabolomics in other patients with epilepsy and neurometabolic idsorders, with the aim to characterize better the biochemical changes in the brain leading to improved and personalized treatment modalities of these patients.
First steps towards newborn screening for GAMT deficiency
Creatine is a vital energy source in the brain which is deficient in guanidinoacetate methyltransferase (GAMT) deficiency. This condition cause intellectual disability, abnormal movements and seizures in children. High dose oral creatine and ornithine supplementation and protein restriction is the treatment for seizures and abnormal movements, but is not effective to prevent intellectual disability that occurred before diagnosis. Guanidinoacetate, which is chemical accumulates in individuals with GAMT deficiency, will be measured in 3000 anonymized newborn bloodspot-cards from the British Columbia Newborn Screening Program. This study will help us to set up newborn screening to prevent intellectual disability in babies.
Guanidinoacetate methyltransferase deficiency: first steps to newborn screening for a treatable neurometabolic disease. Mercimek-Mahmutoglu S, Sinclair G, van Dooren SJ, Kanhai W, Ashcraft P, Michel OJ, Nelson J, Betsalel OT, Sweetman L, Jakobs C, Salomons GS. Mol Genet Metab. 2012 Nov;107(3):433-7.
Non-invasive Imaging in Patients with Arrhythmogenic Right Ventricular Cardiomyopathy
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare familial heart condition known to cause sudden death in healthy young adults. It is passed through families from an affected parent, with each child having a 50:50 risk of inheriting the condition. It is estimated to affect 1:5,000 individuals. Early diagnosis of ARVC can provide early intervention with follow-up treatment and lifestyle modification that may prevent sudden death. ARVC however is notoriously difficult to diagnose. The investigators will compare the echocardiograms of young individuals with ARVC to young healthy individuals in the hopes of developing a reliable method to detect early changes in the heart that will diagnose early stages of ARVC so that effective healthcare can be implemented.
Pilot Study of Essential Omega-3 Fatty Acids in Lipodystrophies
In the rare disease called "lipodystrophy," fat cells under the skin die off and fat cells inside the body grow too big. Healthy fat cells make hormones that protect the body against diabetes and heart disease. When fat cells shrink through diet and exercise, people get healthier. But when healthy fat cells die off, the hormone balance is broken and patients get early heart disease and diabetes. We will study hormones and circulating fats in people with lipodystrophies, before and after prescribing a diet supplement of fish oil. We hope the fish oil will help the body normalize its hormones.
Metabolic testing showed low leptin levels, high levels of serum amyloid A and the child also had hypoglycemia without hyperinsulinemia, indicating that insulin resistance was not occurring. Trio-based exome sequencing did not identify any variants within known familial lipodystrophy genes. Based on these results we concluded that a known genetic lipodystrophy was likely not the cause of this child’s abnormal fat distribution. Following these findings, a publication by Lindhurst et al. identified that some people with localized overgrowth of fibroadipose tissue had mutations within the gene PIK3CA which were present only in the affected tissue. This prompted us to preform deep resequencing of the child’s blood-derived DNA and tumour-derived DNA using a commercially available cancer panel which included the relevant critical regions within the PIK3CA gene. The sequencing found a mutation at a frequency of 18% within the tumour-derived DNA and not the blood-derived DNA, indicating this little girl had a somatic mosaic mutation within PIK3CA which was affecting her fat tissue. This gave us the correct diagnosis and ended the family’s diagnostic odyssey. It also showed us that omega-3 fatty acid supplementation would likely make no difference, but did suggest an alternative treatment called rapamycin. These results will be published in the American Journal of Medical Genetics in a manuscript entitled “Somatic Mosaicism for the p.His1047Arg mutation in PIK3CA in a Girl with Mesenteric Lipomatosis”. News release here
CHARGE association is a rare disorder diagnosed based on the non-random occurrence of congenital abnormalities involving the eye, heart, ear and genitals often in combination with delayed growth and development. CHARGE is caused by a mutation in Chromodomain Helicase DNA-binding protein 7 (CHD7). Mutations in CHD7 may cause downstream alterations in DNA methylation, a modification of DNA that can alter gene expression. Such DNA modifications can be used to understand the molecular pathways affected in this disease.
Currently writing a paper about CHARGE syndrome with data that was supported by the Rare Disease Foundation. When this article is completed and accepted I will send you a brief results section and the article itself.
CHARGE and Kabuki Syndromes: Gene-Specific DNA Methylation Signatures Identify Epigenetic Mechanisms Linking These Clinically Overlapping Conditions. Butcher DT, Cytrynbaum C, Turinsky AL, Siu MT, Inbar-Feigenberg M, Mendoza-Londono R, Chitayat D, Walker S, Machado J, Caluseriu O, Dupuis L, Grafodatskaya D, Reardon W, Gilbert-Dussardier B, Verloes A, Bilan F, Milunsky JM, Basran R, Papsin B, Stockley TL, Scherer SW, Choufani S, Brudno M, Weksberg R. Am J Hum Genet. 2017 May 4;100(5):773-788.
Inhibitors for Matrix Metalloproteinases: A Novel Therapeutic Approach for Marfan Syndrome
Marfan syndrome (MFS) is a genetic disease of the connective tissue (the matrix between cells, which provides material and support for skeleton, muscles, and blood vessels). MFS patients are always at risk of life-threatening problems, which usually involve damage to the valves in the heart or weakening of the large blood vessels leading from the heart (aorta). If the aorta weakens, it can balloon out (dilate) and break (rupture), leading to sudden death. So far, the best available treatment for Marfan syndrome has been the use of drugs that lower heart rate or blood pressure to keep patients from needing surgery or dying suddenly due to aortic rupture. During the last few years, our laboratory has been searching for a more effective therapy that would affect targets within blood vessel wall in an attempt to block or reverse aortic dilation. In this study, we will investigate whether a synthetic inhibitor of matrix metalloproteinases (enzymes that cut and digest important components of the connective tissues such as collagen and elastin in the aortic wall) can prevent blood vessels weakening and breakage. We will perform our study using a well-established mouse model of MFS. We hope to find a better and more effective treatment for Marfan patients that will not only slow arterial degradation, but also reverse it.
In recent years, our laboratory has been a pioneer in unveiling cellular defects in the aorta and small resistance arteries using a validated mouse model of Marfan. We were able to show that an increase in expression and activity of matrix metalloproteinase (MMP)-2 and -9, enzymes responsible for breaking down and digesting important components of the connective tissue surrounding the aorta, greatly contributed to the progression of aortic dilation and progression of aneurysm. In further studies, we sought to investigate the effectiveness of a specific and orally active inhibitor of MMPs. We were able to show that the inhibition of MMPs delayed the progression of aortic aneurysm in the MFS mouse model. Our data also showed that inhibition of MMPs activities resulted in normalization of elastic fiber organization within the aortic walls. By measuring the contractility of aortic segments using a wire myograph, we were able to show that MMP inhibitor could also normalize the contractile problems of the aorta. We hope that the results of this study provide insights on potential therapeutic value of MMP inhibition in Marfan patients with a view toward preventing the need for surgery and sudden death due to aortic rupture.
The Genetic Basis of Adams Oliver Syndrome
Adams Oliver syndrome is genetic disorder that causes malformations of the hands and feet (missing or very short fingers and toes) and a missing part of the scalp and / or skull. It frequently causes other health problems including heart defects, brain malformations, poor circulation in the skin, and poor circulation of blood through the lungs (pulmonary hypertension). This last feature, pulmonary hypertension, is usually lethal in early childhood when present. Despite the rapid identification of the genetic causes for many disorders, this disorder has proven elusive.
We explored whether or not the ARHGAP31 gene was a frequent cause of Adams Oliver syndrome. This gene was found previously to be altered in two affected families with dominant transmission. We sequenced the gene in 9 affected children and did not find any mutations, thus establishing that it is not a common cause. Adams Oliver syndrome is likely to be caused by a number of different genes. We are pursuing further candidate genes and additional diagnostic approaches in this group of patients.
Exome Sequencing in Charcot-Marie-Tooth Disease with Eye Abnormalities and Lipodystrophy
We would like to sequence all known genes in a young lady who has eye disease, nerve problems and muscle and fat loss. Currently 27 years old, she has lost 30 pounds over the past 5 years and now weighs 90 pounds. She is not anorexic and has not changed her diet or activity level. We think that she has a genetic problem with protein and fat storage, one that causes her to burn too many calories. We worry that she may die within the next 3-5 years if we don't find a way to treat her. Finding the gene is a necessary first step toward creating a rational treatment based on her genes that control nutrient processing.
We submitted DNA for this person and her parents for exome sequencing. We expected to find a rare mutation that was not present in either of her parents or a recessive mutation inherited from each of her parents. We expected this mutation to be present in a gene involved in protein and/or lipid metabolism or a mutation in the mitochondrial genome which could explain her muscle and fat wasting syndrome. The trio-based exome sequencing analysis has not yet identified any mutations which could explain this person’s CMT, so our plan is to re-analyze the exome sequencing results using more current analysis pipelines to see if we can find mutations which may have been missed during the first iteration. We are hopeful that the updated analysis pipeline will reveal the causative mutation.
Medical conditions associated with hypertrophic pyloric stenosis
Infantile hypertrophic pyloric stenosis develops between 2 and 7 weeks after birth, with symptoms such as severe vomiting and potentially life threatening complications. Surgical correction resolves the obstruction and provides excellent outcomes. However, longer-term medical problems among affected infants have not been adequately studied. Neurodevelopmental delays are suspected and a follow-up study is needed to identify adverse medical conditions and target preventive efforts
Rates of infantile hypertrophic pyloric stenosis (IHPS) and Sudden Infant Death Syndrome (SIDS) declined during the past decades. Similar temporal trends and other common features of IHPS and SIDS have led to hypotheses about common origins. For example, some suggested that back-to-sleep campaign (encouraging parents to put infants to sleep on their back), which resulted in SIDS decline over time, may have had similar effect on IHPS. We therefore carried out a population-based study to highlight similarities and differences between these two conditions. We used vital statistics and hospitalization data on all live births in Washington State, USA, between 1987 and 2009. Our study showed that although both IHPS and SIDS rates declined significantly between 1987 and 2008, the patterns and magnitude of the declines (40% and 74%, respectively) were different. IHPS and SIDS shared risk factors such as maternal smoking and single parent status but other factors showed different associations. For example, first born status was a risk factor for IHPS and a protective factor for SIDS while infant’s male sex had a much stronger association with IHPS than with SIDS. Interestingly, both IHPS and SIDS showed significantly shorter time between birth and diagnosis among infants born at older gestational ages. We concluded that even though some etiologic features may be similar between IHPS and SIDS, several risk factors have qualitatively or quantitatively different effects. In addition, recent temporal trends in the two diseases had different pattern. Infant’s supine sleeping position (on his/her back) does not seem to affect the risk of pyloric stenosis.
One step forward, two steps back: going back into family studies to make use of genomic data to improve care
Intellectual disability (ID) affects 1 in 100 individuals worldwide, frequently associated with brain malformations. We are caring for a family with two sisters with a rare undiagnosed form of ID with unique physical and brain features. We are using new technologies to understand the cause of their condition. Previously we analyzed the genetic information of the sister, but now understand that we need to look at the family as a whole to understand the children's problems. We therefore propose to use new genomic data of the parents combined with the children's to understand the cause of their condition, and through understanding their condition, to better help them thrive and help others with similar developmental problems.
We determined the cause to be a known but ultra-rare condition called desmosterolosis. We reviewed the literature and proposed guidelines for when to consider this diagnosis among children with ID. No therapy is apparent based on these results but the family is very happy to finally have an end to their long diagnostic odyssey.
Desmosterolosis: an illustration of diagnostic ambiguity of cholesterol synthesis disorders. Dias C, Rupps R, Millar B, Choi K, Marra M, Demos M, Kratz LE, Boerkoel CF. Orphanet J Rare Dis. 2014; 9:94.
High Throughput Sequencing for Mitochondrial Disorders
Mitochondrial disorders result when cells in various tissues of the body fail to produce enough energy; this can provoke a wide range of symptoms that make diagnosis, and subsequent treatment, difficult. The current process of ruling in or ruling out the diagnosis of mitochondrial disease is long, invasive, and expensive. We propose an alternate diagnostic strategy that would include more in depth analysis of DNA from a simple urine sample. This strategy reflects the rapid improvement in our ability to sequence many genes at once, as well as recent evidence showing the similar tendency of urine, as seen in muscle, to harbor mitochondrial mutations. Individuals with rare diseases deserve a rapid, painless diagnostic process.
I proposed to sequence the mitochondrial genome from uroepithelial cells with next gen sequencing. Upon learning that Dr. J. Schoffner (Medical Neurogenetics, Inc, Atlanta) was working on the same technique, I applied for a re-purposing of the funds. This request was granted by the Rare Disease Foundation, and the second study was completed. A small number (7) of candidate genes were identified from next generation sequencing from a proband and were confirmed with Sanger sequencing. It could not be determined which one was causative.
Medical Geneticists' discussion of psychiatric risks during diagnosis of 22q deletion syndrome
22q deletion syndrome (22qDS) affects 1/4000 newborns. People with this condition can have various medical problems, and approximately 30% develop psychiatric illness such as bipolar disorder or schizophrenia. A recent study explored parents' experience of receiving a diagnosis of 22qDS for their child. Families identified an unmet need for information from their healthcare providers about the psychiatric features of 22qDS, and indicated that risk for psychiatric illness was a major source of anxiety for them, compared to the other features of the disease. No studies have ever asked Medical Geneticists (doctors who are often involved in telling families about a diagnosis of 22qDS) about how they approach telling families about the various features of 22qDS. The purpose of our study is to find out if and when Medical Geneticists discuss different features of 22qDS with families when making a diagnosis, and to explore in particular their approach towards providing information about the psychiatric risks associated with the condition. We will send Medical Geneticists a questionnaire, which will include questions about how they approach discussing different features - including psychiatric features - of 22qDS with families, and a scale that has been validated to measure stigmatizing attitudes towards people with mental illness in health care professionals. We think that Medical Geneticists will discuss psychiatric illness with families less frequently than they discuss other features of the condition and that those Medical Geneticists with higher levels of stigma towards mental illness will discuss psychiatric illness less often than those with lower levels of stigma towards mental illness. If our study shows that this is the case, we will be able to develop ways to reduce Medical Geneticists' negative attitudes towards people with mental illness, which may help them to discuss the psychiatric features of 22qDS with families.
Platelet proteomic analysis in two siblings with familial hemiplegic migraines and a neurodegenerative disease
We identified two sisters with severe hemiplegic migraines who developed after the age of 15 years: lower limb spasticity, generalized muscle weakness, ataxia, dysarthria, bladder instability, depression, and a sleep disorder. Magnetic resonance imaging (MRI) of the brain showed atrophy of the medulla and spinal cord. Cerebrospinal fluid (CSF) neurotransmitter results showed markedly reduced levels of the serotonin end-metabolite, 5-hydroxyindoleacetic (5HIAA). Platelet serotonin levels were also significantly low. Platelet serotonin uptake was diminished revealing a serotonin transporter dysfunction. Brain magnetic resonance spectroscopy (MRS) showed low levels of creatine, similar to what we see in creatine transporter disorders. The patients responded partly to treatment with 5-HTP (5-hydroxytryptophan), a serotonin precursor, by showing improved strength, and mood. Their hemiplegic migraines persisted and one of the sisters was in a prolonged coma after such an episode, suggesting a neuronal membrane calcium channel dysfunction, which has been described in other families with hemiplegic migraines. Overall these results are suggestive of dysfunction of several proteins in the cellular membrane, like the transporters and channels, which can be caused by a defective targeting mechanism of these proteins to the membrane.
This study led to a better understanding of the mechanism of disease in this family, leading to improved treatment, a manuscript was submitted with results of treatment with 5-hydroxytryptophan showing improvement in strength and ambulation.
Hemiplegic migraine, seizures, progressive spastic paraparesis, mood disorder, and coma in siblings with low systemic serotonin. Horvath GA, Selby K, Poskitt K, Hyland K, Waters PJ, Coulter-Mackie M, Stockler-Ipsiroglu SG. Cephalalgia. 2011; 31(15):1580-1586.
Beta-endorphin as a Biomarker for Nociceptive/Inflammatory Pain in a Pediatric Population: A Proof-of-Principle Study
Children with rare diseases often have pain, yet many of them have language delays and cannot tell us. This project will study Beta-endorphin, the body's natural pain reliever. If we could detect Beta-endorphin, it would tell us something about the kind of pain the child is having, and help us treat it. We call substances like Beta-endorphin "biomarkers". Finding a biomarker, or signal, for pain would dramatically improve pain management and quality of life for non-verbal infants, children and youth with rare diseases. The results may even help us with others who cannot speak such as infants, people with dementia, and even pets.
The results were very exciting; we showed that beta-endorphin, the body’s internal opioid, is produced by white blood cells when there is an injury or inflammation. We have known for some time that white cells produced it, but it was always the cells right at the injured tissue. Now we have shown that it is produced by the white cells that are circulating in the blood. This means it can be detected with a blood sample. This is a step towards our goal of identifying pain in children who cannot speak, many of whom have rare diseases. The poster presentation of this work won an award for Best Student Poster from the Child & Family Research Institute. We are writing a manuscript to submit this work for publication.
Exome sequencing to determine causative mutation of a unique disorder present in two related children.
Gene identification is the first step for improved genetic counseling, prevention, and possibly treatment of rare diseases. In two related children affected by an unknown disorder (developmental delay, microcephaly, ichthyosis (skin scaling) and hearing loss), we plan to identify the genetic defect using new sequencing techniques. We will look for deleterious mutations in the chromosomal regions inherited from their common ancestor and shared by both affected children. We expect that this procedure will provide us with an explanation for this disorder will allow for better management of these patients and their family.
Using M-mode 2-D Echocardiography to Help Guide Patient Care in Neurofibromatosis 1 Vasculopathy
Neurofibromatosis 1 (NF1) is a rare genetic disorder recognized by multiple non-cancerous tumors, bone abnormalities, learning difficulties, and vascular disease. Vascular disease may present as high blood pressure, stroke, arterial rupture, or aneurysm (in which the vessel balloons out). Vascular disease can occur in the heart, brain, or in other peripheral vessels (the vessels outside of the heart). Vascular disease is a significant cause of premature death in patients with NF1, but in many cases it is not recognized until it is too late. This may be because the patient does not have symptoms of disease or because symptoms of disease are thought to be "normal" symptoms related to other manifestations the patient's NF1. Together with Dr. David Ingram at theUniversityofIndianaour lab has obtained funding to examine vascular function, vascular disease risk, and markers of vascular disease in the blood of young adult patients with NF1. This study will provide the basis for developing markers of disease in patients who do not have overt symptoms, rational preventative strategies and treatment interventions for vascular disease in people with NF1.
Preliminary data from this study indicates that some of these patients show evidence of vascular disease in their peripheral vessels even when they do not have other symptoms of vascular disease. A recent study in 21 children and adults with NF1 also showed that, in general, patients with NF1 have signs of cardiac dysfunction on an echocardiogram. An echocardiogram is a test that examines cardiac function and gives information on the function of the major vessels in the heart. We believe that an echocardiogram with an additional measurement on the large blood vessel leading from the heart (aorta) will add to the ongoing study on vascular disease in NF1 in our lab and help better guide patient care and follow-up.
Application of homozygosity mapping by SNP microarray in a consanguineous family to guide mutation screening in a heterogeneous autosomal recessive disorder
Gene identification is the first step for improved genetic counseling, prevention, and possibly treatment of rare diseases. In a child affected by Joubert Syndrome (JS), a rare disorder characterized by developmental delay, polydactyly, hepatic and renal failure, we plan to identify the genetic defect using a new approach. We will prioritize the JS-related genes for mutational analysis by their location in chromosomal regions shown to be inherited from a common ancestor. We expect that this strategy will help us identify the causative gene and allow for better management of this family.
Treatment of Neurofibromastosis 1 Vasculopathy with AMD3100 a CXCR4 antagonist
Neurofibromatosis 1 (NF1) is a rare genetic disorder recognized by multiple non-cancerous tumors, bone abnormalities, learning difficulties, and vascular disease. Vascular disease is a significant cause of death in patients with NF1 and some evidence suggests standard treatments may not be as effective in patients with NF1 vascular disease. Vascular disease may present as high blood pressure, stroke, arterial rupture, or aneurysm (in which the vessel balloons out). The cause of vascular disease in NF1 is unknown but preliminary data in patients with NF1 indicates that inflammatory factors (agents that cause an inflammatory reaction) play a role in the disease. Several inflammatory factors are overproduced in patients with NF1 and are known to play a role in vascular disease in people who do not have NF1. We theorize that neutralizing abnormally produced inflammatory factors in NF1 patients may offer a promising therapy to treat vascular disease in NF1. We will study the effect of blocking these factors using a drug that blocks an inflammatory protein called stromal derived factor-1α (SDF-1α) from attaching to the outside of vascular cells and causing an inflammatory response. To perform this study we will use a well-established mouse model of NF1 vascular disease. This study may offer a promising treatment option that is more effective for patients with NF1 vascular disease.
Aetiology of carpal and tarsal tunnel syndrome in children and in adolescents in British Columbia
Carpal tunnel syndrome (CTS) and tarsal tunnel syndrome (TTS) are medical conditions caused by a pinched nerve at the wrist and at the ankle respectively. Both conditions cause pain, numbness and disability in the hand in CTS and in the feet in TTS. Mucopolysaccharidosis (MPS) and mucolipidosis (ML) are rare genetic conditions. Various sugar-protein complexes are stored in cells of the body because of these conditions. Individuals with these conditions can have developmental delay, coarse facial features, big liver and spleen, upper airway problems and joint stiffness. MPS and ML are the most common causes of CTS/TTS in the absence of trauma in children and in adolescents. We purpose to conduct a study to look for MPS and ML in this age group who has CTS and or TTS with no history of trauma.
Establishing high-throughput screening assays for chemical suppressors of nonsense and missense mutations - special grant award
One of the severe impediments to treatment of rare diseases is their rarity. As rare conditions, these diseases individually are not a commercially viable market that can support pharmaceutical development. This calls for a paradigm shift for the treatment of rare diseases. By focusing on the classes of mutations causing these rare inherited diseases, therapies can potentially be developed that are applicable to thousands of disorders. This application requests seed funding to develop methods to screen for treatments for the two most common classes of mutations causing rare diseases. The goal is to establish cell-based high-throughput assays that will enable us to screen large collections of chemicals to identify chemical suppressors of these mutations. We will use simple assays whereby introduction of a nonsense or missense mutation in a yeast biosynthetic gene causes a slow growth phenotype and chemical suppressors restore growth.
The funds will be used to 1) construct yeast strains carrying nonsense or missense mutations of the ADE2, HIS3, LEU2, LYS2, TRP1 and URA3 genes, which cause a slow growth phenotype in media poor in adenine, histidine, leucine, lysine, tryptophan and uracil, respectively; 2) establish slow growth conditions that are suitable for drug screening and determine the extent of growth restoration by positive controls, e.g. paromomycin to suppress nonsense mutations; 3) carry out pilot screens of 10,000 chemicals using three nonsense and three missense strains to validate the screening assays; 4) identify suppressors of nonsense mutations or missense mutations. 5) optimize compounds: acquire and test a limited number of close analogues of the active chemicals to identify more potent and active analogues.
So far, one follow on grant has been obtained by the team, building directly on the Rare Disease Foundation grant of $17,660. The follow on grant was received from the Canadian Cancer Research Society Innovation fund for 2 years (2013-2015) totaling $199,842. In addition, one individual received a two-year salary award for $90,000 that was enabled by the Rare Disease Foundation grant. A proof of concept grant application has been submitted to Genome BC. The initial award from Rare Disease Foundation has enabled the research team to start research on rare diseases and it has already had a big impact on their ability to raise additional funding to further support the work. Press release here.