April 2012 Funded Microgrants

April 2012 Funded Microgrants

How do FLNA mutations cause congenital emphysema and how can we treat it?

Congenital emphysema is a rare but devastating disorder affecting the lung's ability to exhale. In this disorder, the air sacs of the lung are like loose paper bags instead of springy balloons. Causes can be separated into two categories: the sporadically occurring congenital lobar emphysema and rare genetic disorders of weak connective tissue, such as cutis laxa, Marfan syndrome, or FLNA-related disease. FLNA is a gene that makes a structural support beam for the cell that also runs messages from the outside of the cell to the nucleus. These messages are somehow important for developing strong connective tissue, but no one knows in what way. Babies born with emphysema because of FLNA mutations face a disease that no one knows how to treat. We think the emphysema in this disease results from too few elastic fibers being made. If we prove this, then it may be treatable with medications that maximize production of elastic fibers, such as steroids.

What causes autosomal recessive heterotaxy?

Heterotaxy is a rare disorder featuring lack of normal left-right placement of the body's organs. It can cause a clean and complete swap of the left and right, such that the child is still perfectly healthy, or the confusion can lead to some organs on the correct and others on the incorrect side with some health risks. Worse, it can lead to confusion of left and right within an organ itself, such as the heart, with often unsurvivable effects. Heterotaxy can be classified as isolated versus syndromic (when other health and developmental issues exist too). It can also be classified as inherited or not inherited. Most of isolated heterotaxy seems not to be inherited, but there are a few families with an inherited form. For families passing the gene through healthy mothers on the X chromosome, the causative gene has been found, for example. We are caring for a family with many members affected by heterotaxy. We know from their family tree that the pattern of inheritance is one termed recessive. We will be able to find the causative gene by sequencing almost all the genes and looking for mutations that affect the parts of the cell needed for determining left versus right. This discovery will create a diagnostic test, which will help this family in reproductive planning.

Examining Unmet Health & Service Needs among Families of Children with Rare Diseases

The aim of this community-based research study is to examine unmet health and service needs among families of children with rare diseases who do not meet the criteria to access government funded (GF) programs and services. The study was developed in collaboration between The Western Society for Children, a non-profit society that supports these families in the community, and faculty at the UBC School of Nursing. This study will bring to light the unique needs of this subset of families and generate recommendations for social work and other healthcare professionals working with these families, in particular, in planning their transition from hospital-based care to the community in the absence of access to GF programs, such as Autism funding, the At Home Program, and Supported Child Development.

Carbonic Anhydrase deficiency: Validation studies of a new cause of a common metabolic phenotype causing intellectual disability

 We have used innovative sequencing techniques (whole exome sequencing) to investigate the DNA of two siblings with unexplained episodic lethargy, low blood sugar and high levels of blood lactic acid and ammonia. We identified a new gene defect in both siblings; the genetic encodes an enzyme called 'carbon anhydrase' which is vital for the metabolic control of glucose, lactate and ammonia levels in the body. These compounds when uncontrolled are damaging to the brain; the girl is already showing significant speech delay and the boy is awaiting further developmental assessment. The identification of this gene potentially allows us to prevent further injury to the brain through a medical diet, supplements, avoidance of drugs. We are applying for a micro-grant to fund further biological investigations of the gene mutations identified in both siblings to prove causality and further our understanding of this newly discovered metabolic disease. This process will also pave the way towards an effective treatment.

Post-translational consequences of missense mutations in the ATQ gene associated with pyridoxine dependent epilepsy

Pyridoxine dependent epilepsy (PDE) is a rare inherited disorder causing severe seizures starting in the neonatal period. Seizures are not controlled by current anti-epileptic medications but respond well to treatment with pyridoxine (vitamin B6).  In 2006, deficiency of a protein known as antiquitin (ATQ) and genetic errors in the associated gene were linked to PDE. With current diagnostic methods, the incidence of PDE is estimated at ~1/50,000 births in BC.  B6 therapy controls seizures but is not a complete solution. Many patients may still suffer long -term neurological problems. Our goal is to study the effects of genetic errors on the structure and function of the ATQ protein. This is a prerequisite towards a longer term goal of attempting to rescue partial ATQ function through the application of small chemical molecules that assist ATQ in achieving partial function, with the aim of improving outcomes of affected children.

Understanding a novel RYR2 mutation in a BC family

Type 1 catecholaminergic polymorphic ventricular tachycardia (CPVT1) is a rare genetic disease (~1 in 10,000). It has been called the 'perfect assassin' because apparently healthy young people can die suddenly. In most cases there is a mutation of a gene (RYR2), which codes a protein called the ryanodine receptor (RYR2). RYR2 releases Ca2+ into the cell causing the heart muscle to contract, while mutated RYR2 can cause inappropriately timed contractions leading to arrhythmia and death, although the mechanisms are not understood.  Dr. X is helping to treat a BC family harbouring a previously uncatalogued RYR2 mutation, and uncertainties surrounding this new mutation are complicating both diagnosis and treatment. We will therefore use biophysical techniques to characterize the functional properties of this novel mutation to help guide the clinicians and to assist this family.

Results - This project was not done.

Local temperature as a marker of disease activity and progression in patients with morphea

Morphea is a disease in which the skin progressively turns hard and becomes thin. Children are usually affected and, depending on where they have the disease, they can be very affected and have disabilities because of it. There is no cure and the treatment to control it is long and can have complications. Also, there is no good way to measure how active it is, if it is very severe or will be very aggressive. Temperature of the affected skin has been found to be a good way to see if a patient´s morphea is active. We want to conduct an experiment to see if temperature is a good way o evaluate the activity in morphea. What we plan to do is measure the temperature in the affected skin of 60 patients and then also evaluate the skin with several scores that can tell us how active it is: one is called a visual analogue scale and goes from 1 to 100, another is called a DIET scale and measures changes in color, hardness, redness and small blood vessels; and another is called the LoSCAT (short for Localized Scleroderma Cutaneous Activity Tool). We will try to establish a correlation between temperature and the activity of the morphea according to these scales.

Characterizing neuropsychological aspects of patients affected with Bardet-Biedl syndrome

Bardet-Biedl syndrome (BBS) is a rare multisystem debilitating disorder characterized by extra digits, retinal degeneration leading to blindness, genital and kidney malformation/function, cognitive impairment and obesity, among other less common features. The neuropsychological features affecting the patients have not been properly assessed, therefore poorly managed, which is debilitating to patients and families especially when combined with the blindness. Traditionally, patients with BBS were referred to as being "mentally retarded" but it has become clear that these patients are known to have a variable degree of cognitive impairment with a poor emotional control. Many become depressed, anxious and may show features of autism and/or obsessive compulsive tendencies. We propose a pilot study to determine whether a "neuropsychological trait" exists specifically for BBS by completing neuropsychological assessments on 15 cases of BBS for whom the genetic defect was identified. This novel information will not only be extremely valuable to patients and families but will provide very important outcome measures. These can then be used in the assessment of modifying influences (genetic or environmental) or of therapeutic interventions. The only way such assessments can be systematically obtained is by contracting a neuropsychologist.

Results - This project was not done.

Exome Capture and Parallel DNA Resequencing in a Pedigree with Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a late onset neurodegenerative disease characterized by the death of motor neurons in the central nervous system. To date, the basic pathogenic mechanism of most ALS cases remains unknown. Converging evidence suggests that a large number of rare genetic mutations underlie a substantial fraction of familial ALS cases. Such rare mutations can be identified by resequencing of patient`s DNA. Here, we propose to use modern and powerful DNA sequencing methods available to our group to resequence the entire coding genome (or exome) in a genetically unexplained family with two ALS individuals.

Characterization of mitochondrial Glycerol-3-phosphate acyltransferase enzyme mutation in a new disease

We are following a 5 year old boy with developmental delay, decreased tone, movement disorder, poor growth, and episodes of metabolic crises characterized by acidosis (increased acid in blood), elevated blood levels of lactate, ketones, and blood sugar fluctuations. He does not handle infections well, and every time he has an illness his neurological status deteriorates, and he needs a long time to recover. We have done numerous investigations, enzyme testing and genetic testing, including muscle biopsy, and ruled out all (or most) known diseases that can cause similar clinical and laboratory picture.

In February this year there was a publication about a new disorder that involves a previously unknown metabolic pathway linking the lipid metabolism with mitochondria. The patients described in the paper have similar presentation to our patient. We would like to perform two enzyme analyses with protein quantitative measurements on our patient's fibroblasts (skin biopsy already performed for other enzyme analysis) investigating this new metabolic pathway, with a laboratory method called Western blot. This experiment can be done in Dr. Marion-Coulter Mackie's lab and I am quite familiar performing the method, as I have done several Western blots in the past. If we find that an enzyme deficiency in this pathway is the cause of his disease, we can manipulate his diet (high fat, low carbohydrate) to help him get through his episodes of metabolic decompensation.

Results - This study led to a bigger grant application with Whole Genome Sequencing and finding another candidate gene in this patient, which has a specific treatment for the severe movement disorder crisis that he presents with, that being deep brain stimulation.

Defining the molecular etiologies of Russell Silver syndrome with unknown molecular results

Russell-Silver syndrome (RSS) is a genetic condition associated with poor growth during pregnancy and childhood, along with typical facial features, body asymmetry and in some cases developmental delay. The prevalence is likely underestimated at one in 100,000.  The molecular causes of RSS are known to be heterogeneous. Approximately 45-60% of RSS cases are explained by molecular defects on chromosomes 7 or 11. Improving the ability to molecularly confirm clinically suspected cases of RSS will impact the diagnostic odyssey for patients and their families and the ability to provide accurate recurrence risks. It may potentially also provide new therapeutic targets.

Results - This project was not done.

31P-MRS study in a family with MELAS mitochondrial mutation with different degrees of mutation load and clinical phenotype

We are following a family with three affected members with MELAS (a mitochondrial disease that affects muscle and brain, can cause hearing loss, diabetes, migraines and strokes). Mitochondrial disease affects multiple organs and the severity depends on how much affected (non-functioning) mitochondria do the individuals have in the affected organs, which we call "mutation load". The three members in our family have very different mutation load, and are affected in different ways and degrees. Treatment is not curative, but some vitamins, cofactors and antioxidants have been shown to be beneficial, although no systematic studies have been conducted. MRS (magnetic resonance spectroscopy) is routinely performed on brain MRI's but has not been routinely done in muscle. It measures chemicals that are released from the muscle during exercise, and has the potential to measure the muscle energy (ATP) production. We have already done a pilot project on one patient and had good results, collaborating with Dr. Alex MacKay at the UBC MRI facility. We would like to perform MRS studies in the three members of the same family with the same mitochondrial mutation but different mutation load, to assess if MRS is a sensitive tool to predict outcome and to monitor efficacy of treatment. If this is the case we would like to propose a study to monitor treatment of mitochondrial disease with a newer antioxidant called idebenone that had promising results in another type of mitochondrial disease affecting vision.

Results - This study led to development of a specific exercise program for the family with MELAS mutation, and development of an exercise booklet for children with mitochondrial disorders, found on the BCCH website here

Finding the genetic condition causing early onset epilepsia partialis continua with fatal course

Epilepsia partialis continua is a unique and rare type of prolonged seizure that affects a limited part of the body. Seizures occur for a minimum of one hour and recur at intervals of no more than ten seconds. The prognosis depends on the underlying genetic or non-genetic condition and can range from treatable to progressive fatal disease. We aim to identify the so far unknown underlying genetic cause in a family with two affected children presenting an early and fatal course of the disease. Understanding the cause will help to provide a diagnosis in further families, adapt disease management and evaluate potential treatment options.

Treatment of Congenital Central Hypoventilation Syndrome by Recovering Phox2b Function

Congenital central hypoventilation syndrome (CCHS) is a rare genetic condition (prevalence 1:200,000 live-births) in which the brain/brainstem "forgets" to control breathing. The lack of breathing occurs during sleep in most patients, but also during wakefulness in many. Lifelong ventilation and tracheostomy is needed in all patients. CCHS is associated with mutations in the Phox2b gene.  Our study is intended to research treatment modalities to restore normal breathing in these children using a model developed in our lab. We will test clinically available drugs on our cellular model of CCHS for their ability to restore Phox2b function and therefore normal breathing responses. Any successful treatment would be rapidly applicable and available to the targeted patient population, possibly leading to ventilator independence for these children.

Results - We created constructs representing all common mutations in the protein Phox2B known to cause Congenital Central Hypoventilation Syndrome (CCHS). Cells expressing these proteins showed that only the most severe disease causing mutations were dysfunctional in the cell. After exposure to the anesthetic agents isoflurane and morphine but not propofol, mutations that did not produce a disease phenotype at baseline, now showed a phenotype consistent with CCHS. This is consistent with the observed induction of the disease after exposure to anesthesia and is the first evidence of how anesthesia can cause CCHS. Our experiments also produced a system to test and discover therapeutics to prevent the damaging effects of anesthetic agents on Phox2B and induction of CCHS.

Identification of genes predisposing to recurrent aneuploid miscarriages

Recurrent miscarriages represent a major concern for couples who wish to have children. More than half of all miscarriages are caused by an unequal distribution of chromosomes during egg division leading to an extra chromosome in the fertilized egg. A recognized risk factor is advanced maternal age, but in very rare young couples we see much more repeated miscarriages (e.g. 9 or more) due to extra chromosomes than we would ever expect. We aim to identify rare mutations in genes that may predispose these women to modified egg division. Understanding the cause will help the couples and their families to better estimate their future risks and to choose the appropriate option of reproductive therapies.

RNA-sequencing of patients from a Canadian Wilms' tumor family

Wilms' tumor is a common childhood kidney tumor, occurring in 1 in 10,000 children in North Americaand accounting for 8% of childhood cancers, but familial cases of Wilms' tumor are relatively rare. In this project, we will apply high-throughput sequencing technology to identify the gene contributing to the hereditary Wilms' tumor in patients from an extended Canadian family. This is the largest Wilms' tumor family in the world, many of its members live in Eastern Canada, and hundreds stand to benefit from the results of our research. Identifying the first familial Wilms' tumor gene (fWT1) will be instrumental to understanding the genetic lesions underlying fWT and will also increase our general understanding tumor development. In a long term, we aim to translate our findings into an effective therapy by targeting the mutated gene or its associated pathways.

Characterizing the clinical spectrum of Peters anomaly

Peters anomaly is a rare disease in which a baby is born with cloudy corneas. Cornea is the transparent window in front of the eye that allows clear images to enter. Without a clear image, vision cannot develop and the child will be blind. The disease happens when normal development is somehow defective and contents of the eye (cornea, iris and lens) remain stuck together rather than separate normally. Understanding the degree and severity of Peters anomaly is vital to managing the patient successfully. Unfortunately a clear classification is lacking as no one has enough patients to clearly study the disease and hence our understanding of management options and prognosis also remains poor. We aim to remedy this shortfall as we have the highest number of patients within a unit due to the presence of two specialists that are doubly qualified in cornea and paediatric ophthalmology.

Glucose Tolerance and Islet Function in Patients with Tangier Disease

Tangier disease is a rare genetic disease in which patients have extremely low levels of HDL ("good") cholesterol and suffer from heart disease and nerve problems. We recently showed in an animal model of Tangier disease that this condition also causes impaired control of blood sugar and predisposes to diabetes. It is unknown if humans with Tangier disease are also at risk for diabetes and whether they should be monitored or treated for this. Because this condition is so rare, it has been difficult to answer this question. We recently identified a large family in BC affected by Tangier disease and are proposing to measure glucose tolerance in these patients and unaffected family member controls. These results will both answer the important question of whether Tangier disease causes abnormal blood sugar control in humans and provide this family with important information about their health, thus allowing them to take appropriate steps, including both lifestyle changes and use of medications, to prevent or treat diabetes.

Improving Testing for Congenital Disorders of Glycosylation through Glycan profiling

Congenital Disorders of Glycosylation (CDG) are a group of inherited metabolic disorders resulting from defects in protein glycosylation. The manifestations typically include severe developmental delay, hypotonia and hypoglycemia. It is critical to provide an accurate diagnosis early in the course of the disease, because it will impact clinical management and treatment. Currently the only test available in clinical laboratories for the diagnosis of CDGs is based on the profiling of serum transferrin isoforms.  However, testing for CDG by serum transferrin isoforms is limited by false-positives (because of young age, or other diseases) or false-negatives. The goal of this proposal is the development and validation of a sensitive clinical test for the diagnosis of CDG based on profiling of all the glycans of serum glycoproteins. This assay will be simple, rapid and cost-effective, thus allowing us to test all patients suspected with CDG.

Is low serum creatine kinase a screening marker for creatine deficiency syndromes?

Creatine deficiency disorders (CDS) are genetic disorders causing creatine deficiency in the brain. Creatine is a vital energy source in the brain. CDS cause global developmental delay, intellectual disability, uncontrollable seizures and behavioral problems in children. The diagnosis needs a suspicion and ordering of specific tests and cranial magnetic resonance spectroscopy, which are not widely available in all centers. As long as these tests are not performed, we cannot diagnose children with CDS. However it is important to diagnose these disorders while there are specific treatments to prevent disease progression, stop seizures or treat abnormal movements (1). We will investigate children with global developmental delay or intellectual disability who have low levels of muscle enzyme, called CK, whether this will be helpful to identify children with CDS, to be able to treat.

Developing lead drugs that can recover peroxisome function in patient cell lines with Peroxisome Biogenesis Disorder

The Peroxisome Biogenesis Disorders (PBD) are a group of rare disorders with an incidence of 1/50,000. They are progressive neurological disorders, featuring deafness, blindness and degeneration of brain white matter, or leukodystrophy. If targeted therapies could be identified, this neurological progression could be halted and greatly improve the outcome for these children. We have been working on drug therapies that target a common mutation, PEX1-Gly843Asp. In our initial assay using patient skin cells, we identified a flavonoid compound, diosmetin, that efficiently recovers peroxisome functions. Flavonoids are normal constituents of the human diet and have been studied in clinical trials for various disorders, thus making this an attractive group of compounds to pursue. However, we need to define a 'lead' compound in order to get further funding. This means defining the attachments to the flavonoid backbone that are responsible for its peroxisome recovery. We have enlisted the help of a medicinal chemist to synthesize the derivatives we need to determine this. The current funds are needed for this synthesis.

Results - We found diosmetin to be the most robust molecule to improve peroxisome functions, proposed a chaperone-like mechanism of action and found enhancement of the effect by betaine.  Our studies form the rational basis for advancing this already approved molecule into human clinical trials. 

MacLean GE, Argyriou C, Di Pietro E, Sun X, Birjandian S, Saberian P, Hacia JG, Braverman NE.  Zellweger spectrum disorder patient-derived fibroblasts with the PEX1-Gly843Asp allele recover peroxisome functions in response to flavonoids.  J Cell Biochem 120(3):3243-3258, 2019.

First steps to the improvement of long-term outcome of GAMT deficiency by using an international database

Guanidinoacetate methyltransferase (GAMT) is a critical enzyme involved in production of creatine, which is a vital energy source in the brain (1,2). GAMT deficiency causes global developmental delay, intellectual disability, abnormal movements and uncontrollable seizures in children (1,2). Patients with this disorder are treated with creatine and ornithine supplementation and protein restricted diet. This therapy is effective to treat seizures and abnormal movements and to stop brain damage (3,4,5,6). GAMT deficiency is a rare disease and there is no well-established treatment protocol. We will generate a database from the GAMT patients followed in the various numbers of countries. We will develop a universal treatment protocol for patients with GAMT deficiency and share this protocol with all centers.

Results - I would like to thank the Rare Disease Foundation for their generous support of our project, funded in April 2012. We finalized our study and published our results recently (Khaikin et al, European Journal of Pediatric Neurology, 2018). We reported treatment outcomes for 22 patients with GAMT deficiency as an international treatment registry study. We published a treatment algorithm for the physicians who diagnosed and have been treating patients with GAMT deficiency to help them with decision making. Because of our publication the lead author and PI of the study has been invited to give a talk at the cerebral creatine deficiency syndrome conference in July 2018 in Austin, TX, USA. I am going to meet families and other experts on creatine deficiency disorders during the meeting. Your support made all these possible. Thank you very much for the ongoing funding support.

Treatment outcome of twenty-two patients with guanidinoacetate methyltransferase deficiency: An international retrospective cohort study.  Khaikin et al.  Eur J Paediatr Neurol. 2018 22(3):369-379.

Are Parkinson disease genes involved in children with intellectual disability?

Developmental delay and intellectual disability (ID) are frequent and have devastating consequences for families. Using Chromosome microarray analysis (CMA) in patients with ID and malformations, we found 15 deletions and 1 duplication within PARK2. The significance of these changes are not known: mutations in the PARK2 gene can cause early-onset Parkinson disease but are not a known cause of ID; these gains and losses are not reported as normal variants. In this project, we will define the clinical features of these patients, confirm these gains and losses with a different technique called MLPA, search for another possible mutation in the same patients within the same gene and test other Parkinson disease-causing genes in a set of other patients with similar clinical features. As an outcome, we expect to know whether these copy number variants play a significant role in intellectual disability and, if so, to provide a clear diagnosis and offer prevention of these conditions to affected families.

Results - This project was not done.

Discovery of the gene causing hydranencephaly, multinucleated neurons, and renal agenesis

A Manitoba family followed by the genetics department in Winnipeg had two children that died shortly after birth due to multiple severe anomalies. Both children had no kidneys and their brains were largely replaced by fluid. Research into this combination of problems led to the identification of 6 other cases that have been reported in the medical literature over the last 50 years. There is strong evidence that this is due to a very rare genetic problem and the family is at significant risk of having another child with the same issues. Currently the cause of this disorder is completely unknown. In order to provide this family with a diagnosis and prenatal testing for subsequent pregnancies, we propose a plan to identify the causative gene. Finding this gene may also provide insights into the early development of the brain that can be used in other areas of science and medicine.

Results - As it turned out the PI received another source of funding for the validation of this project with direct payout to the University. The PI was grateful for the award and happy to acknowledge Rare Disease Foundation in their upcoming publication but the project was not funded by Rare Disease Foundation.

Non-operative management of suspected eosinophilic granuloma of skull

Eosinophilic granuloma (EG) is a rare form of non-cancerous growth most commonly located on the skull. While surgical removal is considered the mainstay of EG treatment, recent medical literature suggests that EG can resolve without surgery. The purpose of this study is to observe a group of patients with untreated solitary skull EG over twelve months to determine how often such EG will resolve without any treatment.

Exome sequencing to identify the gene underlying Alveolar Capillary Dysplasia, a rare cause of pulmonary hypertension lethal to infants

We care for a family who lost an infant to Alveolar Capillary Dysplasia (ACD, diagnosis definitively confirmed by our pathologist), a rare cause of lung hypertension resulting in death in infancy. Only 50 cases have been reported in the literature. Of 29 cases with identified family histories, the presence of affected siblings suggests a genetic cause. We have research-consented DNA samples from a triad of an affected deceased infant with pathologically confirmed ACD and his 2 parents, as well as lung tissue sections for research investigation, and a DNA sample of 2 surviving unaffected children. We will use a method to look at all genes in retained DNA from this infant victim, and compare it to the surviving parents and children.

Results - This work was stopped because the family had withdrawn consent. This was entirely a personal choice on their part. I continue to follow their surviving child for another condition. As always, I thank the Foundation for their tremendous support. We discovered novel genes for several families now, partially thanks to the great support from the Foundation, and will make sure we credit the Foundation for their support.

Exome sequencing to identify a new gene underlying Arrhythmogenic Right Ventricular Cardiomyopathy

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is a rare disorder of adolescents and young adults, causing fibrofatty replacement of heart muscle tissue in the free wall of the right pumping chamber of the heart. ARVC is hereditary, but genes have only been identified for half of affected families. We seek to investigate a family where one parent and 2 of 4 children are affected, are negative for known genes underlying ARVC, and have consented to be studied. We will use a technique that looks at all genes that make proteins in the body. We will use information that we already have pathways that might cause ARVC to narrow down our search for a causative gene. We have already looked at genes expressed in the oldest affected child, and now wish to look at 2 remaining affected and 3 unaffected family members. Gene identification will allow us to understand and further genetically identify ARVC and develop novel therapies.

Effects of Creatine Supplementation on Muscle Pathophysiology in Children with Dermatomyositis

Juvenile Dermatomyositis (DM) is a rare disease that affects the muscle and skin in children. The consequence of DM is extreme muscle weakness and fatigue. Despite improvements in drug therapies, patients with DM experience loss of function reducing their quality of life. Adding Creatine, which increases muscle, may enable patients to increase and enhance their muscle and decrease weakness and fatigue. This initial study will provide valuable evidence regarding the effects of adding Creatine on muscle in DM; if successful, we will use Creatine to improve the lives of children affected by DM.

Results - This project was not done.

Exome sequencing to identify the gene underlying Congenital Junctional Ectopic Tachycardia

Congenital Junctional Ectopic Tachycardia (CJET) is a rare and unique form of rapid heart beat that occurs in newborns, causes heart failure and risk to life in infancy and requires catheter ablation, with a high risk of needing a pacemaker for life. We and one other group have identified that CJET is hereditary, occurring in a familial pattern in 20% of the 99 individuals that we described in a multicentred study.

We seek to investigate a family (2 unaffected parents and 2 affected children) who have consented to study, using a technique that looks at all genes that make proteins in the body. We will use information that we already have about the genes that are expressed in the immature cardiac junction to narrow down our search for a causative gene. We have already looked at genes expressed in one of the affected children, and found a change in a heart rhythm gene that shows 5-fold higher expression in the tissue of interest (cardiac junction). This funding will allow us to look at genes expressed in the other affected child, and compare both children to the unaffected parents. Gene identification will allow us to understand CJET and develop novel therapies.

Treatment of insomnia and sleep disturbances with LED-blue light therapy in individuals with Cornelia de Lange Syndrome a cross over interventional study

Everyone who has ever disembarked from a flight that has crossed time zones can attest to the uncomfortable challenge of dealing with jet lag. Thankfully, for most of us, the uncomfortable consequences of crossing time zones don't last long and within a few days, our internal clock, also known as our circadian rhythm, usually adjusts. For most people that is a very small price to pay to travel and experience new cultures. Unfortunately there are individuals that suffer continuously with an internal clock that just can't tell time. This can lead to increased daytime sleepiness and an increase in negative health consequences and ultimately in the quality of one's life.

We are now beginning to understand the basic biology behind why some people with rare genetic conditions and their families are struggling to cope with sleep disturbances. A recent study found that individuals with a rare condition, called Cornelia de Lange Syndrome (CdLS), also known as Brachmann-de Lange syndrome, suffer from sleep disturbances independent of intellectual disability, which we believe may be related to problems with their internal clocks.

The goal of this study is to directly treat the sleep disturbance reported in individuals with CdLS, while simultaneously improving our basic understanding of this syndrome and to produce preliminary data for a large study. To meet this goal, we are proposing the use of a noninvasive existing light treatment device that uses blue light-emitting diodes (LEDs) to treat sleep disturbances and measure the levels of hormones involved in sleep and appetite, in an attempt to directly impact the lives of individuals with CdLS.

Results - This project was not done.

Interventional study of N-acetylcysteine in patients with Fanconi Anemia

Every day we are exposed to damaging agents from the environment; for example, sun rays, smoking and infections. These exposures can create high levels of damaging particles in our body called oxidants. High levels of oxidants in our body can damage many types of molecules including the genetic material that is called DNA. If the DNA is damaged, the cells can die or turn to cancer cells.

To fight these potentially harmful exposures and production of oxidants, the cells in our body have very effective tools to prevent or quickly repair such damage. Yet not all people can deal with a high load of oxidants. Children and adults with a rare genetic disease, called Fanconi anemia cannot effectively repair the DNA damage caused by oxidants and by other damaging agents. Unfortunately, these patients also have a tendency to accumulate oxidants.

Scientists believe that the medical problems in patients with Fanconi anemia are caused at least in part by high levels of oxidants. The medical problems in Fanconi anemia include impaired ability to form blood cells in the bone marrow and frequently need treatment with bone marrow transplantation. Also, it is estimated that the risk of cancer is up to 80% by the age of 50 years. Due to these medical problems, the life expectance of patients with Fanconi anemia is substantially reduced (average of about 30 years).

Foods such as fresh fruits, vegetables and some spices that contain compounds called antioxidants, are also thought to help the body deal with damage caused by oxidants. Interestingly, antioxidants have been found to decrease the incidence of cancer in mice models of FA.

This research has created significant opportunities to try to intervene to promote a less "stressful" internal environment within the cells and organs of people with FA. Being able to intervene and directly impact, treat and prevent the cellular damage that occurs in FA would be a considerable leap forward. We are therefore proposing to study whether a pharmaceutical grade of the antioxidant, N-acetylcysteine (NAC), would be able to reduce the damage seen in people with FA.

Results - This project was not done.

Dysregulation of fatty acid oxidation by defective SMN1 gene: Implications for therapy

Spinal muscular atrophy (SMA) is the most common autosomal recessive genetic cause of infant mortality with an estimated incidence of 1:6000. We and others have shown abnormalities of fat metabolism in the blood, urine and muscle of affected children which correlate with the severity of the SMA. We plan to study which parts of the fat metabolism pathway are most affected. This may lead to new therapies.

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) a Multicentre Data Collection

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a rare and often fatal inherited cardiac condition that usually presents in childhood and causes abnormal heart rhythms. Many of those affected have a mutation in one of two genes responsible for regulating cardiac muscle contraction. However, some affected families do not have any of these known mutations, suggesting that another unknown mutation may exist. Treatment options are also very limited for those diagnosed with CPVT. We aim to define the course of CPVT in children and to determine candidate genes, optimal screening and treatment approaches. Because CPVT is very rare and most centers have few patients, we intend to include cases from multiple pediatric centers acrossNorth America.

Histidyl-tRNA synthetase deficiency in an Ontario Amish population

Histidyl-tRNA synthetase (HARS) deficiency was recently described as a new autosomal recessively inherited genetic disease with only two known affected children. Within a highly consanguineous Old Order Amish extended family, we have identified at least nine children who have had a unique presentation with a febrile illness, usually in the first 2 years, accompanied by acute encephalopathy and seizures.  During the acute illness, the children appear to lose vision and are extremely difficult to console, as they appear to be quite frightened.  Those who are old enough have described visual hallucinations.  Vision usually returns after these acute episodes, but there tends to be gradual visual loss, accompanied by the development of a retinal dystrophy. Hearing impairment is detected, either during the acute illness, or within weeks of the initial onset of illness. Walking is achieved late, usually around the age of 2, and affected children exhibit an unsteady gait, but no deterioration.  In one family, 3 children developed sudden fever, and seizures, followed soon thereafter by unexpected death before one year of age. Preliminary data indicate that several of these children have HARS deficiency. We propose to diagnose more children, identify the incidence of the disease in the Old Order Amish Community. This information will be used to provide genetic health care to families in the community. Laboratory research will be done to further understand the biochemistry of HARS deficiency. It is anticipated that these results will enable further research funding into HARS deficiency.

The safety of modern anesthesia for children with Long QT Syndrome

Long QT syndrome (LQTS) is a rare condition that causes the heart to beat irregularly, which is called arrhythmia. Commonly, arrhythmias occur when a patient with LQTS experiences an increase in arousal, such as intense emotion, fright or exertion. The process of undergoing a surgical procedure exposes children to anxiety, stress, and a myriad of medications. These circumstances may increase the risk of arrhythmia in children with LQTS, increasing the likelihood of serious adverse events during surgery. Unfortunately, because LQTS is an uncommon disorder (1 in 2500), there is a lack of comprehensive information for anesthesiologists to appropriately manage children with LQTS during the surgical period.

Our research study will retrospectively collect data, from multiple children's hospitals acrossNorth America, concerning the conduct of anesthesia in children with LQTS and will directly impact patient care by providing evidence for the optimal anesthetic management for this patient population.

Parents' experiences of receiving their child's genetic diagnosis: A qualitative study to inform clinical genetics practice

Many children with developmental challenges are referred to the genetics clinic to explore whether the cause of their symptoms can be explained by genetic differences. We seek to understand the experience of the medical genetics visit at which a genetic diagnosis for a child's developmental and/or intellectual challenges is made from the perspective of parents. To do this, we will telephone parents who (a) attended an appointment at the Provincial Medical Genetics Program to receive a genetic diagnosis for their child, and (b) signed a consent form at the time of the appointment to allow researchers to contact them about research studies. With those parents who consent to participate, we will schedule a time to conduct a telephone interview to explore their perceptions and experiences of the diagnosis session. Through developing a better appreciation for how parents feel their experience during the diagnosis session could be improved, the findings from our study could have direct implications for patient care at the genetics clinic. This will be the first study (of which we are aware) to provide insight into how parents perceive and remember their experience at the genetics clinic.

Genomic Analysis of the DNA Repairome in a Hypermutator

With funding from a previous Rare Disease Foundation microgrant, we sequenced all known genes from a young lady with a rare disease that caused damage to her eyes when she was a baby, and has caused the nerves in her legs and arms to die off. She is also losing a lot of weight, and now has trouble swallowing food. When we compared her DNA to her parents' DNA, we found that she had 1000 times as many "brand-new" mutations in her genome as we would expect. We think the underlying problem is an inability to fix DNA when it becomes damaged, so that these mutations accumulate and put her at risk for nerve damage and cancer. Now we want to try to identify which DNA repair gene is causing her problem.

Cellular toxicity of anaesthetics in children with mitochondrial disease

Children with mitochondrial disease frequently need to be put to sleep for diagnostic and surgical procedures. The most common drug used for that purpose is ketamine. Recently, leading healthcare authorities have raised concern about ketamine's potential to cause permanent brain damage in children, based on studies demonstrating increased risk for learning disabilities in exposed children. In our lab, we have found an alarming effect of ketamine on the mitochondria in human cells, including damage to the genetic substance (DNA), and persistent impairment of cellular functions required for healthy life. To explore whether this effect is occurring in patients, we will recruit three children with mitochondrial diseases and six healthy children without mitochondrial disease, who are put to sleep to undergo procedures as part of their routine care. We will draw blood samples (2 ml) before the administration of ketamine and an hour after, quantifying the effect ketamine has on the shape and function of each child's mitochondria, and compare this effect between the 2 groups of children.

Results - This project was not done.

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