April 2010 Funded Microgrants

April 2010 Funded Microgrants

Microarray homozygosity mapping to determine the causative mutation in a bone marrow failure patient

We are involved in the care of a 7 ½-year old girl with a previously undescribed form of progressive bone marrow failure and several birth abnormalities involving her skull, skin, kidneys and immune system. The bone marrow contains stem cells, which can develop into the red blood cells that carry oxygen, the white blood cells that fight infections and platelets that help with blood clotting. Because of her bone marrow disease, she is now dependent on blood transfusions and at significant risk for infections. She is also at significantly higher risk of developing leukemia and other cancers. At this time, we do not know what her underlying disease is. We are hopeful that we can treat her bone marrow failure with medications alone, but she will likely need a bone marrow transplant. If she needs a transplant, we need to find a source of donor cells that is best for her. Furthermore, in order to prepare her body for transplant, she will be given chemotherapy and possibly radiation therapy. This treatment, which eliminates her immune system so it can be replaced by the donated stem cells, is very severe and is associated with a high risk of illness and death. We need to choose the appropriate preparative regimen, depending on her underlying disease, to ensure the best outcome. Accurate diagnosis is required for optimal treatment and genetic counseling of patients with bone marrow failure syndromes. We are requesting funds to analyze her and her family's genetic material in order to find the potential cause so that we can choose a treatment that is best for her.

Results -  

This Rare Disease Foundation microgrant allowed us to access novel state-of-the art tools in order to diagnose a very rare primary immunodeficiency. There are less then 15 known cases in the world. We were able to give a frustrated patient and the family a diagnosis and more importantly it allowed us to shift our clinical care from not just treating symptoms of the disease but being able to offer a cure. This patient is the first in the world to undergo cord blood hematopoietic stem cell transplantation for this disease. We would not have been able to start this journey without the support of the Rare Disease Foundation and we are very grateful for the support. Thank you.

Ectopic Atrial Tachycardia A Multicentre Data Collection

Ectopic (or focal) atrial tachycardia (EAT) is a rare condition. EAT describes an abnormally fast heart rhythm that can lead to symptoms, heart muscle fatigue and even death in young children. There is no general agreement on the best management of this condition and limited information to inform doctors how to counsel families. Each center has only a few patients per year and so getting information from many centers will improve the information. We hope that the results will inform health professionals and families about the course of EAT in children and suggest which therapies may be most effective.

Results -

With the help of this microgrant, we enrolled 249 patients with Focal atrial tachycardia at 10 pediatric centers and obtained an average of 2.1 years of follow up data for each patient. We found that that certain drugs (beta blockers) were more effective than others and that spontaneous resolution is common in young children, emphasizing the role of delaying surgery in this group.  Among the different procedures used, we found one to be more effective (electroanatomic mapping) with fewer follow up procedures required. This is the largest and most comprehensive study performed to date on Focal atrial tachycardia.

Current management of focal atrial tachycardia in children: a multicenter experience.

Kang KT, Etheridge SP, Kantoch MJ, Tisma-Dupanovic S, Bradley DJ, Balaji S, Hamilton RM, Singh AK, Cannon BC, Schaffer MS, Potts JE, Sanatani SCirc Arrhythm Electrophysiol. 2014 7(4):664-670. doi: 10.1161/CIRCEP.113.001423. PMID: 25015944

Confirming pathogenic copy number variants and determining causative genes for a potential novel Intellectual Disability syndrome identified in two children

Array Genome Hybridization (AGH) is a recently developed technology that can identify genetic changes in ~10% of patients with intellectual disability (ID) of unknown cause after standard testing. These changes, termed copy number variants (CNV), involve the loss or gain of genetic material. A careful study of the genetic material involved in the CNV is required to establish whether the change is responsible for the ID, and if so, how.

We used AGH to identify previously undescribed losses of genetic material in the same region of chromosome 9 in two children who have similar clinical features. We confirmed the AGH findings by a second independent method. The fact that both patients share the same genetic change and the same clinical presentation is a strong indicator that they suffer from the same previously unidentified ID syndrome. In addition, the affected region involves several important genes that could cause disease when lost. We re-tested both patients using an advanced AGH platform that looks at the genome in an ultra high resolution. Results from this test show that the CNV in each patient is composed of several fragments of lost genetic material interspersed with intact genetic material. This pattern is typical of a newly discovered cause of CNV formation. Importantly this assay has helped us refine the list of genes involved and narrow down which are candidates to cause the syndrome.

The next step is to use a quantitative genetic technology called qPCR to determine exactly the status of the genes that may have been lost. We are requesting funding to carry out this test. This last step will enable us to provide a specific diagnosis, determine causative genes and lend insight into the types and mechanisms of CNV occurrence. A meaningful diagnosis translates directly to better patient care; it offers the opportunity to address prognosis and future medical challenges, better define recurrence risk for the family, and has immediate implications for possible therapeutic interventions and better health outcomes. In addition learning more about CNVs and how they form has broader implications toward understanding the manifestation of ID.

Results -

We were able to use qPCR as intended to investigate the nature of the genetic changes in these patients. Our results were not conclusive however and indicated the nature of the genetic defect is more complex than we thought. The results from this test were important though as they gave us more information about the lesions and indicated what further direction we should take with our studies. We have now gone on to obtain further funding to carry out a very new technology that allows us to read the letters of the whole genome called 'next generation whole genome sequencing'. We are hopeful this ultimate test will allow us to make definitive conclusions about what is causing the ID in the children.

Prevalence of carpal tunnel syndrome in children and in adolescents in British Columbia

Carpal tunnel syndrome (CTS) is a medical condition in which the tunnel of bones and ligaments in the wrist has narrowed. This narrowed tunnel pinches a nerve, causing numbness, pain and disability in the hand. Most people who have CTS are over 30 years of age; however children can have CTS too. If there is no history of trauma the most common cause of CTS is mucopolysaccharidosis (MPS). MPS is a rare group of metabolic disease caused by the body's inability to produce specific enzymes, causing progressive damage throughout the body. There is a specific therapy for some of the subgroups of MPS including type I, II and VI. Review of nerve conduction studies in children and in adolescents will make an important contribution for the further studies to find out patients with this rare, partially treatable metabolic disease.

Results -

Carpal tunnel syndrome (CTS) is a medical condition caused by an entrapment of a nerve at the wrist. It is a common condition in adults and 1out of 20 people suffer from CTS. However, there are no studies in children and adolescents reporting how common is CTS in this age group. To find out an answer to this question, we investigated 2247 children and adolescents retrospectively, who had nerve conduction study at the British Columbia's Children's Hospital from 1992-2010.

Of all children and adolescents who had nerve conduction studies between 1992-2010 in BC, 6.5% had CTS. Half of the children and adolescents with CTS had history of trauma, which was the most common cause. The second most common cause of CTS was mucopolysaccharidosis (MPS), a group of rare metabolic genetic disorder. However, we did not find any specific cause of CTS in 25% of the children and adolescents. We think that these children and adolescents could be investigated further for MPS.

Our study was the first to look at the causes of CTS in children and adolescents systematically by looking at all nerve conduction study results. We presented our results in a national neurology conference as an oral presentation and in two international metabolic genetics conferences as a poster presentation. This information was very valuable especially for neurologists and electrophysiologists to recommend a referral to metabolic genetics clinics for further investigations of MPS after excluding trauma. We think that CTS may have a role as a screening indicator for diagnosis of MPS in children and adolescents, if there is no associated trauma. As enzyme replacement therapy is available for various types of MPS to improve patients' quality of life and disease related morbidity, identification of the patients with this rare disease by using CTS as a screening tool might be helpful.

Without the support of Rare Disease Foundation Microgrant Program, we would have not been able to perform the study and share valuable information with a wide range of physicians. We would like to thank you for your generosity by supporting our project.

Identification of the gene responsible for CAPOS syndrome

Cerebellar ataxia is a serious neurological condition in which affected children have problems with movement, balance, and speech. Cognitive delay is also common. Genetic forms usually get worse with time and frequently include other serious health problems. We have identified a second family with CAPOS syndrome, which is a genetic form of ataxia in which affected individuals also have progressive visual loss, and hearing loss following febrile illnesses. By performing genetic studies on this family and the first family reported in 1996, we aim to identify the genetic cause of this condition in order to improve genetic counseling and patient care for these families. Identifying the genetic cause of disease in these families will also enhance our understanding of the pathogenesis of ataxia which could lead to the development of better treatment options for patients with ataxia.

Results - 

We identified the genetic cause of CAPOS syndrome. This provides the families involved with a rapid diagnostic test for their condition and opens the door to future therapy development.

A novel recurrent mutation in ATP1A3 causes CAPOS syndrome.

Demos MK, van Karnebeek CD, Ross CJ, Adam S, Shen Y, Zhan SH, Shyr C, Horvath G, Suri M, Fryer A, Jones SJ, Friedman JM; FORGE Canada Consortium. Orphanet J Rare Dis. 2014 9:15. doi: 10.1186/1750-1172-9-15. PMID: 24468074

Prevalence of myoclonic epilepsy in children in British Columbia: developing a diagnostic flow chart

Myoclonus is brief involuntary muscle twitching and may become frequent enough to be disabling. Progressive myoclonic epilepsy (PME) is the most severe form of myoclonic epilepsy (ME). With PME, the initial treatment effect of anti-seizure medications diminish and seizures become more frequent and neurological decline progresses. Patients have difficulty coordinating muscle movements and a decline in cognitive ability during the disease course. More than 40 genetic and metabolic conditions can cause PME and some of them can be treatable with various supplements and vitamins. Systematic chart review and development of diagnostic flow-chart will help diagnosing more patients for treatable metabolic conditions.

Results - 

We identified 100 children with ME. We found following underlying causes and genetic epilepsy syndromes in our children with ME: 1) genetic syndrome and chromosomal abnormality in 16%; 2) myoclonic-astatic epilepsy in 27%; 3) Dravet syndrome in 23%; 4) benign myoclonic epilepsy of infancy in 7%; 5) genetic metabolic disorders in 4%. However, we did not find any specific cause of ME in 23% of the children with ME.

After we completed our study, we generated a database for ME and developed a preliminary diagnostic flow-chart for investigations of ME. History, physical examination, electroclinical features, chromosomal microarray and SCN1A gene mutation analysis identified underlying cause in 77% of the children with ME. Although metabolic disorders are rare many have a specific treatment so baseline metabolic investigations should be included as first line tests. We think that in 23% of children with ME and no underlying cause, there could be an underlying genetic metabolic disorder and further testing in a prospective study would be important to organize.

Our study was the first to investigate children with ME retrospectively to find out underlying causes of ME. We presented our results in a national neurology grand round as an invited speaker and at an international metabolic genetics conference as a poster presentation. As we identify more and more new genetic disorders using new genetic technologies, we think that this ME database was very important to lay the groundwork for future prospective studies.

The Clinical Course of Patients with Long QT Syndrome: A Data Registry with DNA Screening and Banking

Long QT Syndrome (LQTS) is heart rhythm abnormality that runs in families. It causes the heart to beat very fast and can cause fainting and sudden death in young otherwise healthy individuals. First Nations individuals from Northern BC have one of the highest rates of LQTS in the world. Investigating an unique LQTS gene abnormality and possibly a second genetic cause can lead to improved understanding of these lethal heart disorders. In order for these individuals to participate in the LQTS Registry a research team of 2 will travel to their remote communities to invite willing individuals to participate by providing their blood samples, ECG readings and health history for inclusion in the registry. This will provide a better understanding of these disorders to improve diagnostic methods and healthcare for all individuals and families with LQTS.

Results -

Our Rare Disease Foundation microgrant funded a registry for patients with Long QT syndrome, an inherited arrhythmia causing sudden death, that includes DNA screening and banking. This Registry has been established is a long term data collection project that will have many benefits in the future. For now, we have been able to identify family members at risk by keeping this registry, potentially saving lives of those who do not know they are affected.

Sexual Sense of Self in Individuals with Complete Androgen Insensitivity

Complete androgen insensitivity syndrome (CAIS) is a rare condition in which a genetically male individual, with one X and one Y chromosome, does not respond to the effects of male hormones called androgens. Therefore, these individuals have the physical appearance of a woman and are typically raised and identify as females. At puberty individuals with CAIS develop breasts, but have little to no hair in the pubic and underarm areas and do not menstruate. The purpose of our study is to learn about how living with CAIS may affect sexual health, including the associated treatments and surgeries. Sexuality is an integral part of the personality of every human being and is a fundamental right of expression, and therefore affects a person's quality of life. The few studies looking at the sexual health of these individuals have indicated that the majority of them have sexual difficulties. We will be building on this research by interviewing these individuals, exploring different aspects of their experiences living with the condition in order to elucidate nuances that may impact sexual functioning. This research may lead to a better understanding of the sexual health needs of those with CAIS in order to provide care that more completely meets the needs of those with CAIS, thereby improving quality of life.

Results - 

Women with complete androgen insensitivity syndrome (CAIS) were interviewed to identify factors important to successful adult sexual functioning.  Such women are sex reversed; they are conceived as XY, but are unable to recognize and use male hormone throughout their bodies.  Feelings of being different in terms of not having a uterus, not achieving periods, and being infertile were strongly expressed.  Having knowledge at important points in life and a supportive partner were identified as key issues.  This information can be used to help new parents support and educate their affected daughters. The results of this study were presented at an international meeting.

Developing a method to change skin cells into cartilage

About 3% of children have short stature. One cause of more severe short stature is the group of over 150 inherited rare disorders known as the chondrodystrophies. A major problem in studying this group of conditions is that we cannot study cartilage, the affected tissue, because it usually cannot be safely biopsied. This proposal aims to remedy this problem by using new knowledge about stem cells to reprogram skin-derived cells, a readily available tissue, into cartilage cells. A boy we care for has a unique disorder of severe short stature and jaw tumour, normal hormone testing and normal bones, suggesting a problem with cartilage. We propose to treat his skin cells in a culture dish with different methods to induce them to become cartilage cells. We will then use these cells to better understand the cause of his condition. More distantly, we can use the resulting cells to test ways to fix any problems we find and ultimately to test potential therapies. The immediate impact of this grant on this child will be minimal but these studies offer hope to his family and a step forward to find the cause of his disease. If successful this process will be an immensely useful tool for people studying and developing therapies for many of the chondrodystrophies.

Results -

Our approach failed completely. Around the same time, another group published a very costly and complicated method to accomplish this goal in mice, so we didn't feel as bad. The remaining microgrant funding was then switched to studying our patient's skin cells, in comparison to those of his father's and to his jaw tumour, by expression array and to performing whole exome sequencing on blood. The molecular cause of his condition remains elusive.

Inflammasome mutation: a cause of an undescribed neurodegeneration

We are caring for a family whose children are affected with a devastating disease causing their brain to degenerate following minor infections. Our work has identified candidate genetic causes of this disease and several of these pathways already have drugs developed for them that could be potential therapies. Additionally, identification of the cause of disease in this family will make it possible to offer genetic testing for family members, in particular the siblings who are living in dread that they too will develop this disease. Also, such a test will also provide at least one diagnostic test for the many children who have similar problems but are not diagnosable with current techniques. Ultimately, accurate diagnosis combined with understanding of the pathways involved will aid in the establishment of long-term prognosis and will open doors for directed therapeutic intervention and improved care.

Results -

The support of the Rare Disease Foundation was very important to this family. We were able to identify in the two affected girls mutations in the PRF1 gene, which was previously known to cause a severe blood disorder (familial hemophagicytic lymphohistiocytosis, FHL). This is the first time that children with mutations in this gene are found to have severe neurodegeneration without FHL, and presenting very unusual immune studies. This provided the family with answers, as well as the possibility of genetic couselling and genetic testing of carriers. While the answer came too late for these two young girls, who passed away, it brings hope to the family, and to other patients who may potentially have this previously unrecognized form of neurodegeneration. Importantly, FHL can be treated through medication and bone marrow transplant, which opens the door for potential treatment in patients diagnosed early with PRF1-associated neurodegeneration. We have shared this case with the broader medical and scientific community through a published article (link below). We expect that the publication of the case will help to identify, and potentially treat, undiagnosed patients with this phenotype. On behalf of the many people involved in these girls' care and research, many thanks to the Rare Disease Foundation.

Recurrent subacute post-viral onset of ataxia associated with a PRF1 mutation.

Dias C, McDonald A, Sincan M, Rupps R, Markello T, Salvarinova R, Santos RF, Menghrajani K, Ahaghotu C, Sutherland DP, Fortuno ES 3rd, Kollmann TR, Demos M, Friedman JM, Speert DP, Gahl WA, Boerkoel CF.  Eur J Hum Genet. 2013 21(11):1232-1239. doi: 10.1038/ejhg.2013.20. PMID: 23443029

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