Evaluation of new therapeutic drugs for the rare inflammatory disease Aicardi-Goutieres Syndrome
Aicardi-Goutieres Syndrome (AGS) is a very rare and severe inflammatory disorder mostly affects infants and young children. The majority of AGS patients experience significant intellectual and physical problems with significantly shortened lifespan. However there is currently no effective treatment for this debilitating disorder. We propose to test two potential therapeutic drugs targeting a newly discovered enzyme for treatment of AGS patients, which might improve quality of life and extend lifespan for AGS affected individuals.
A Prospective, Randomized, Double-Blind Assessment of Deep Brain Stimulation for Vocal Dysfunction in Spasmodic Dysphonia
Spasmodic Dysphonia (SD) is a rare disease with a prevalence of 1 in 100,000. Patients with SD lose their ability to speak because of uncontrolled dystonic contractions of their throats. Current treatments such as botox and voice therapy only provide temporary relief and thus, we are exploring new strategies to provide long-term improvement. Deep Brain Stimulation (DBS) is a neurosurgical procedure that involves the implantation of electrodes to deliver electrical stimuli to specific brain regions. It is the standard treatment for essential tremor (ET) and can eliminate tremor with a resultant improvement in quality of life. Very rarely, ET occurs concurrently in a patient with SD. Our team has anecdotal evidence that the DBS therapy used for ET also had an unexpected benefit in the vocal symptoms of SD. This pilot study has been designed to test the hypothesis that DBS can improve the vocal dysfunction of SD.
Improving Diagnosis of Farber Disease
Farber disease is a devastating childhood disease. In its most severe form, the disease is lethal by age 2. Given its quick progression, it is pertinent to diagnose Farber disease as soon as possible to allow for an early intervention. However, due to the rarity of Farber disease, it is often not thought of and likely misdiagnosed as juvenile idiopathic arthritis or other diseases. We propose to develop a simple screening method for Farber disease that only involves blood collection and uses a commercially available test. Physicians will then be able to identify Farber patients more quickly and allow them to intervene to mitigate symptoms.
NANS deficiency as novel hyposialylation defect – developing a treatment for complex epileptic encephalopathy
Epileptic encephalopathy, resistant to anti-seizure medications, is a severe clinical condition as it always has a negative impact on psychomotor development, and often is accompanied by multi-organ involvement. The underlying causes are a thousand fold, with the majority extremely rare genetic conditions including inborn errors of metabolism (IEMs), which are unique in that a subset is amenable to causal treatment, which can control seizures and optimize development and other systems. Our Omics2TreatID research group applies high-throughput technologies to discover and characterize novel IEMs in epilepsy and developmental delay. Recently we discovered NANS deficiency in a 3-year old boy with severe neonatal seizures, bone abnormalities, platelet dysfunction and developmental arrest. Biochemical studies have unveiled a treatment target, and before applying it to this patient and the 8 other patients identified in Europe, we wish to test out different treatment approaches (and their safety and effectiveness) on a model organism, in this case a zebrafish, which recapitulates the human symptoms.
Targeted Therapy for Motoneuron Pathology in Pompe Disease
Pompe disease is associated with progressive accumulation of lysosomal glycogen and leads to respiratory insufficiency in the patient population. Recent evidence suggests the motor neuron and neuromuscular synapse may be affected and contribute to respiratory problems. This proposal will help identify novel targets for therapeutic intervention to attenuate neuromuscular failure in Pompe patients. Existing (acetylcholinesterase inhibitors) and novel drugs (virus-mediated gene delivery) will be tested in this study and will have direct application to the clinical population.
Biomarkers for Control of Androgen Excess in Congenital Adrenal Hyperplasia
Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive enzymatic defects in cortisol synthesis. The most common form of CAH is 21-hydroxylase deficiency (21OHD); in its most severe form, also called “classic”, 21OHD affects approximately 1 in 15,000 individuals worldwide. A hallmark of 21OHD is excessive adrenal androgen production. These androgens result from accumulation of precursors proximal to the defective enzymatic step and their subsequent diversion to testosterone and other potent androgens. Females with classic 21OHD are born with masculinized, ambiguous genitalia from androgen excess before birth, while adult women with nonclassic 21OHD might present with hirsutism, irregular menses, and subfertility1, features indistinguishable from those of polycystic ovary syndrome (PCOS). Accurate markers of adrenal androgenesis are lacking, however, they are critical in guiding appropriate treatment. We propose four 11-oxygenated 19-carbon steroids as adrenal-specific biomarker candidates, because their synthesis depends on 11-hydroxylase (CYP11B1), which is expressed only in the adrenal gland and not the gonads. Our preliminary data from patients with classic 21OHD illustrate that these patients have elevated 11-oxygenated 19-carbon steroids as compared to age- and sex-matched controls. In this study we will measure the same steroids in patients with PCOS, to demonstrate that they are specific to the adrenal gland, and not the gonad.
Evaluation of airway ciliary function in children with Autosomal Dominant Polycystic Kidney Disease: a case control study
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is an inherited condition in which fluid filled sacs, or cysts, form in the kidneys. The cysts increase in size and number over time, leading to kidney failure in adulthood. Research has shown that these cysts develop due to problems with the tiny hairs (‘cilia’) found on the surface of kidneys, which have an important role in normal kidney growth. Cilia are also found elsewhere in the body, including in the lungs and airways. Abnormalities of cilia in the airways stop mucus from being cleared normally, leading to chest infections and scarring of the lungs (‘bronchiectasis’). This may cause people to die at a younger age.
Validation studies of known and potential new genetic causes of Hereditary Sensory and Autonomic Neuropathies in 6 BC families
We are following six families at BC Children’s Hospital with eight affected children with symptoms of loss of pain sensation, self injurious behavior, lack of tear formation, tendency to overheating and heatstrokes, delays in development of various degrees and severe gastrointestinal dysfunction (repeated vomiting, constipation). The syndrome is called Hereditary Sensory and Autonomic Neuropathy (HSAN). These children are at risk of breaking their bones or injuring their eyes without noticing, because of the lack of feeling pain, developing severe heatstroke because of lack of sweating, repeated hospital admissions because of the repeated vomiting when they cannot tolerate any food, and are at risk for not growing properly because of lack of nutrition (some of these children have no ability to feel taste and hence will not have appetite to eat food). Some of them will have delayed motor and cognitive development and will need extra help in school. Recognizing the syndrome took many years in some of these children, although there was no genetic diagnosis or answer, some of the children benefited from the preventative treatment that we have advised (checking regularly for injuries, avoiding hot temperatures, or using artificial tears). Finding the final answer and genetic cause could further help in managing these children, by looking at the genetic defect and its consequences on the cellular function, and trying to improve that. Through a research collaboration, we have identified candidate genes in all but one family with Whole Genome Sequencing (looking at one’s whole genetic make-up). Some of these candidate genes have been previously described to cause HSAN, but not exactly the same change in the gene, and other candidate genes are new. We would like to prove that these genes are causing the HSAN in these children and finally give an answer to these families and hopefully expand the treatment options too. We have identified a laboratory to further collaborate with in the USA, and they are one of the leading North American researchers in this field.
Validation studies of compound heterozygous mutation in ATP2B3 gene presenting with developmental delay, speech delay, autistic features and epilepsy, improving on L-serine treatment
We are following a family with an affected son, with mild developmental delay, autism, epilepsy, who was found to have low levels of an amino acid, called serine in his blood and spinal fluid. Supplementation with the amino acid powder L-serine improved his attention and seizure control. He was found through the TIDEX Whole Exome Sequencing study to have a change in the gene called ATP2B3, which is encoding for a transporter in the membrane of the brain cells that helps calcium move out of the cells. Calcium in the brain cells has a vital function in processes such as neurotransmission, which are chemicals used by brain cells to communicate with each other. It is also important in releasing other chemicals, such as serine for example. Low levels of serine can cause seizures, as we can see in diseases where this amino acid is lacking because the brain cannot make enough of it. There has been one other family in the world described to have an ATB2B3 mutation in Italy, and we are collaborating with the Italian authors to find out if those children also have low levels of serine. If we can validate the finding in the child from BC that ATP2B3 gene mutation is causing his disease, it will not only help to end the family’s quest to find an answer (they went also to a couple of European centers for second opinions trying to come up with a diagnosis, but without any success), but will help other children with mutations in this gene to get a better treatment with L-serine.
Longitudinal Study of Health-Related Quality of Life in Children with Duchenne Muscular Dystrophy
Quality of life (QOL) is a concept that is gaining more attention from researchers and clinicians caring for children with Duchenne Muscular Dystrophy (DMD). QOL is an individual’s perception of their own well-being. Many standardized questionnaires have been developed that measure QOL. Research into QOL is important for two reasons: 1) understanding factors that influence QOL could lead to improvement of QOL; and 2) QOL helps clinicians and researchers assess which treatments make the most impact on patient lives from their own point of view. Despite its importance, research on QOL in the DMD population is lacking. Particularly needed is a study of QOL that follows a group of DMD boys over time to assess whether their QOL changes with disease progression. Our study follows a group of boys with DMD over three years, and assesses their QOL from their own perspective, and their parents’ perspectives at three different time points. Our aims are to assess the trajectory of QOL over this time period and determine factors that influence QOL. Our project began in 2013 and data collections for the first two time points have already occurred. Data collection for the last time-point is due mid-2016. So far, we have found that levels of fatigue are related to Health Related QOL. Further data collection would help us clarify the relationship between fatigue and Health Related QOL and lead to better clinical management of fatigue.
Diagnostic uncertainty following newborn screening for inborn errors of metabolism: A national look at parents’ experiences
Expanded newborn screening (NBS) enables identification and treatment of an increasing number of rare disorders. However some infants receive uncertain diagnoses that may persist for months or years; families may experience burden in the form of labeling or over monitoring. The proposed national qualitative study will explore 40 families’ experiences with diagnostic uncertainty related to two inborn errors of metabolism (IEM). Understanding the lived experiences of parents who face diagnostic uncertainty in this context will assist in optimizing care plans for families who receive these results.
Variation in the nutritional management of phenylketonuria among Canadian metabolic dietitians
Treatment guidelines to help dietitians care for patients with phenylketonuria (PKU) have recently been published. We will use a survey to study Canadian dietitians’ awareness, opinions, and use of these guidelines, to better understand how helpful the guidelines are for those providing care. We will also study differences among Canadian dietitians in how they care for their patients with PKU. Understanding important differences in care will help us to identify those treatment decisions that are most in need of more research. Ultimately this will clarify which treatments are best.
Assessing the Variability and Clinical Utility of an Echo-Doppler Method to Measure Aortic Stiffness in Marfan Syndrome and Related Rare Diseases with Dilated Aortopathy
Marfan syndrome, Loeys-Dietz syndrome and familial thoracic aortic aneurysm and dissection are all rare genetic diseases associated with progressive enlargement of the aorta. This may produce a tear or rupture of the aorta and death. Fortunately, this is rare in children. We have developed a simple non-invasive imaging method using ultrasound to measure aortic wall stiffness and shown it to be abnormal in Marfan syndrome. However it is essential to know how reliable this method is if we want to use it to monitor disease progression and effectiveness of new treatments in Marfan syndrome and other related diseases. We plan to compare a number of different variations in our imaging and measurement protocol to determine what is the best method to use. We will also compare the reliability of this method in patients with enlarged aorta due to these rare diseases and healthy individuals with normal-sized aorta.
Establish a Canadian Porphyria Patient Registry: Phase 1 – Develop Interview Protocol
Porphyrias are a group of ultra-rare (from 1/10,000) genetic diseases, affecting both females and males of all ages that interfere with the body’s ability to properly assemble heme, an essential component of blood cells. The first steps in establishing a private, secure porphyria patient registry are: find people with porphyria; determine their unmet needs; and then put the resources in place to assist them and the physicians to which they are currently assigned. It is anticipated that this approach will also serve as a template for other ultra-rare disease groups who have little access to skills, resources and funds to support their own patient bases. The interview protocol (discussion guide) will be developed using accepted data collection methodologies for in person (75km radius from Ottawa and/or Montreal) or over the phone/Skype interviews. Since it will be the first formal contact, it will not only include basic health data, but also an in-depth patient needs assessment component.
Illuminating the Scleroderma Support Group Experience Through Qualitative Interviews
Scleroderma (systemic sclerosis, SSc) is an example of a rare disease where peer-led support groups play a central role in a rare disease community and for people with the disease. Currently, however, little is known about the factors that may encourage or discourage people with SSc from utilizing support groups, and how training and supportive resources can be designed to best fit the needs of facilitators of these groups. The proposed project involves conducting individual interviews with SSc support group facilitators, support group members, and those who have chosen not to attend support groups. We hope to understand how SSc peer-led support groups are formed and why people with SSc join and stay involved in them, as well as to identify the training and support needs of group facilitators. The findings of this study will inform a project, in which our research team will work with the Scleroderma Society of Canada and the Scleroderma Foundation in the US to develop a training program for support group leaders and, thus, improve access to support groups and the ability of support groups to meet members’ needs on a sustained basis.
Gene discovery in a gene elusive SCD/LQT family
Long QT syndrome (LQTS) is the prototypical cardiac genetic disease underlying a significant proportion of sudden cardiac death (SCD) in young individuals. It is a rare disease by definition, affecting ~1 in 2000 individuals. Yet SCD, because it affects young individuals, is a leading cause of life-years lost, exceeded only by all cancers. To date, mutations of 16 different genes have been identified to underlie LQTS, yet genetic causes remain elusive for a remaining 20% of affected families. We care for family who lost a child to SCD. Some of the remaining family members had borderline QT intervals, but recently the surviving sister demonstrates characteristic recordings of long QT syndrome, with QT prolongation to over 500 ms upon standing, and also at 3 minutes after exercise. Thus we now have 2 clearly affected siblings. Extensive clinical genetic testing for long QT syndrome (including copy number assessment) has been negative. The mode of inheritance in this family is uncertain. We will use whole exome sequencing to look for rare harmful gene changes, looking for either ‘single helping’ or ‘double helpings’ of these gene changes.
Intra-partum stillbirth: is it preventable?
Death of a baby during childbirth is a tremendous loss and a traumatic event for parents who anticipated a healthy newborn. This death is avoidable if we better identify women at risk and intervene early. This study will provide a unique opportunity to examine risk factors for stillbirth occurring during childbirth. Our goal is to predict and potentially prevent such death. With a successful statistical predictive model based on identified predictors, a web-based calculator will be created to assist clinicians with identifying women who are at high risk for stillbirth during labor. These women can undergo an early intervention to avoid prolonged delivery, fetal asphyxia and death.
Validation studies of potential new neurological disease causing gene KIF16B in a family with two affected children with epilepsy, autism and ataxia
We are following a family with two affected siblings, with seizures, ataxia, autistic features and developmental delay. The family was enrolled in the Care4Rare Canada-wide genome study. The boy is 16 years old, with moderate to severe intellectual disability, motor difficulties, autism and epilepsy. His epilepsy started when he was 4 weeks old, and they are difficult to control. He was even treated with ketogenic diet, which had to be stopped because he developed liver failure. He failed 12 different anti-seizure medications. His head MRI’s were consistently normal. He has a 13-year-old younger sister, who is similarly affected with moderate to severe intellectual disability, motor difficulties, unsteady when walking, anxiety and epilepsy. Her seizures are even more difficult to control, and she has multiple seizures in a day. Her head MRI was also normal. The genomic study results came back suggesting that a gene that transports important proteins to and from the brain cells is the candidate gene for these siblings’ problems. Validating this finding would mean not only that the family finally will have an answer after 16 years of search for a diagnosis, but could eventually lead to a novel treatment of their epilepsy. There is tremendous new research in developing new anti-seizure medications that have a well-defined description of the mechanism how they work, which can be applied to treating epilepsy individually, based on the genetic findings.
Improving the Diagnosis of Congenital Adrenal Hyperplasia
Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive enzymatic defects in cortisol synthesis. The most common form of CAH is 21-hydroxylase deficiency (21OHD); in its most severe form, also called “classic”, 21OHD affects approximately 1 in 15,000 individuals worldwide. Current diagnosis relies on measurement of 17α-hydroxyprogesterone (17OHP), the main substrate of the defective enzyme. However, 17OHP testing has multiple pitfalls, including several causes of false positive (leading to additional testing and distress of the families involved) or negative results (which might cause delay in diagnosis). The pathophysiology of 21OHD promotes the elevation of other steroids upstream the enzymatic blockage, such as 21-deoxycortisol (21dF) (previously studied but not yet implemented clinically), 16α-hydroxyprogesterone (16OHP) and 11b-hydroxyprogesterone (11OHP). The latter two were found to be significantly higher in patients with classic 21OHD versus controls in our recent pilot study. A panel of steroid biomarkers with improved sensitivity and specificity for 21OHD would be of substantial clinical value. To test the specificity of the proposed biomarkers for 21OHD, we will compare them with a group of patients with Cushing’s disease, who, like patients with 21OHD have elevated levels of ACTH, but have no enzymatic deficiency.
Development of an assay to better diagnose and treat auto-inflammatory patients
Auto-inflammatory syndromes are rare diseases characterized by recurrent inflammation. They are caused by genetic mutations leading to uncontrolled secretion of factors called cytokines. Symptoms are often due to cytokine IL-1β overexpression, but other cytokines can also be over-secreted. Due to absence of diagnostic tests, these diseases are difficult to identify. Treatment is usually started with anti-IL1, but it can be changed to other therapies in case the patient does not respond. We propose to develop a diagnostic tool based on the secretion of cytokines by the patient’s blood cells. With this test, the appropriate anti-cytokine treatment will be tailored to each patient.
Searching for a microcephaly gene amongst an endogamous Irish Population
The causes of developmental delay are numerous and achieving a diagnosis can be difficult. For many patients with rare diseases, routine investigations do not provide a diagnosis, resulting in significant frustration. In some cases, doctors can tell from the family structure that the recurrence risk is high but are not able to pinpoint the gene. We have identified four Irish Traveller families (11 patients) in Ireland and the UK with the same rare form of microcephaly (small brain) and developmental delay. Despite extensive investigations we have not been able to locate the gene but we have narrowed the search to a region on chromosome 11. We propose to use new techniques to find this gene. Finding the gene would allow us develop a simple blood-based test which would help Doctors make earlier diagnoses in the future. We think there are more families worldwide with microcephaly due to alterations in the same gene. Hence, our findings could lead to diagnoses for many families worldwide.
How do health and disability policies affect employment of people living with Charcot-Marie-Tooth disease (CMT) in the United States?
According to the U.S. Bureau of Labor Statistics, in 2013, only 17.6% of persons with disabilities were employed. Charcot-Marie-Tooth disease (CMT), a subtype of muscular dystrophy, affects motor and sensory nerves, and causes weakness of lower arm and leg muscles, resulting in foot deformities and muscle atrophy in the hands later in the disease. Living conditions of people with CMT disease are under-researched and thus are underrepresented in the existing literature. For people living with CMT disease, they cannot benefit from an effective treatment or orphan drug, and need to cope with their progressively deteriorating health, which results in varied degree of disability, throughout their life. Thus, what are the existing social policies in the U.S. that are applicable to people with chronic and deteriorating diseases like CMT? Can the current healthcare system address their medical needs, so that they can concentrate on their jobs? Do they think the existing care and disability policies affect their opportunities of being employed? My research is expected to find new evidence to prove the correlation between care policy and employment of people with significant medical needs. The results may be of value to policy makers and contribute to improving quality of life and social inclusion of people with rare diseases. The funds will be used to cover the field work to interview patients.