November 2009

November 2009 Funded Microgrants

Management of Infantile Hemangiomas with Beta-Blocker Therapy

Hemangiomas are a common type of tumor that appear at and look like bright red birthmarks which generally fade as the child grows. However, a small subgroup of hemangiomas can cover a large portion of the face and interfere with breathing, eating and eyesight. There is no consensus on treating these rare hemangiomas amongst clinicians. Our project will investigate the impact of Propranolol, a recent drug that has shown some promise in reducing the side-effects of these hemangiomas.

Results -

Complex facial hemangiomas are tumours seen in infants that are often disfiguring or threaten their ability to breathe, see, hear or eat. For children who do not respond to surgery or medical therapy with corticosteroids, there are few or no options left.  As a recipient of a Rare Disease Foundation Microgrant, I was able to leverage my clinical observations and perform a study that led to a new treatment for children with this severe condition using medical therapy in the form of beta-blockers (blood pressure pills).  This contribution to the medical literature will offer a meaningful alternative to children who have exhausted the current standard of care. The support of the Rare Disease Foundation helped make this research possible and through sharing our research with our colleagues around the world, the net benefit is advancement in the care children receive.

Management of complicated facial hemangiomas with beta-blocker (propranolol) therapy.

Arneja JS, Pappas PN, Shwayder TA, Cullen ML, Becker CJ, Hamzavi FH, Roarty JD, Madgy DN, Baker JD. Plast Reconstr Surg. 2010 Sep;126(3):889-95.

Determining the role of IL-1ß in pyoderma gangrenosum

The immune system is tightly regulated to protect the body against threats. Defects can put the system into "overdrive", resulting in a hyper-inflammatory state (auto-inflammation). Despite growing understanding of inflammation, the underlying causes of many auto-inflammatory conditions remain unclear. Pyoderma gangrenosum (PG) is a poorly-understood non-infectious skin disease that affects an estimated 3-10 patients per million per year globally. PG is characterized by the formation of abscesses following mild injury. The deep ulcers that form are caused by an improper immune response rather than an infection. Our lab has begun to study one PG patient and found that his immune cells produce exceptionally high levels of certain the pro-inflammatory chemical signals known as interleukins (IL)-1ß and IL-17. I hypothesize that PG is caused by increased IL-1ß production due to upregulated production of IL-17 and/or defects in IL-1ß processing. I propose to examine the pathways involved in IL-1ß activation by comparing cellular processing equipment in the PG patient relative to controls.

Results - 

IL-1β production was examined in blood from 2 patients diagnosed with pyoderma gangrenosum. Patient A has suffered from multiple severe abscesses following trauma, which respond well to steroids. A commercially available IL-1β inhibitor (anakinra) has not been used to treat Patient A. Patient B has had 5 years of recurrent leg ulcers that respond partially to steroids but are unresponsive to anakinra.  Funding from the Rare Disease Foundation provided the ability to develop the test for a wide range of possible inflammasomopathies. Immune cells were isolated from whole blood and stimulated in a standard 2-step process for IL-1β activation. We found that Patient A blood cells produced profoundly more IL-1β compared to healthy controls and that a significant amount of IL-1β was produced in the absence of the second stimulus. In contrast, Patient B cells produced normal IL-1β. This may explain why Patient B is unresponsive to anakinra and suggests that the drug may be beneficial in reducing hyperinflammation in Patient A. We are very grateful to the Rare Disease Foundation for supporting this research to improve patient care. 

Understanding Long QT 6: The role of a KCNE2 truncation mutant in cardiac arrhythmias

Sudden death is a devastating event. A significant proportion of cases of sudden death in the young are due to abnormal heart rhythms, called arrhythmias. Abnormal proteins in the heart cells can lead to lethal arrhythmias. We aim to study a protein that causes a rare form of lethal arrhythmia by combining clinical testing of an affected family with basic science testing of the protein's function. We will improve the understanding of this type of lethal arrhythmia through these studies and better understand how to treat the young members of this family who carry the same mutation as their father.

Results -

We are hoping to understand this type of Long QT in order to be able to treat families with this rare form of Long QT. We have yet to understand this type of Long QT and are embarking on further studies using stem cells.

Cognitive evaluation of a rare family with a mutation in the ER-beta gene

Intellectual disability (ID) affects 2.5% of children in North America. To optimize care for affected individuals, determining causes of ID is of fundamental importance. Identification of novel causes of ID reduces the burden for the affected child, their family and society. We recently discovered a novel cause of ID in a 3-generation family (a child and 2 adults) from B.C. They have an abnormality in the genetic instruction for estrogen function.  Estrogen is important in behaviour, cognition and memory. In order to fully understand this new disorder, we need to determine and characterize the physical, cognitive and genetic basis of this disease. For this proposal, we will evaluate the cognition of the affected individuals in order to determine the specific areas of weakness. By understanding this disease and how it affects this family, we can either provide already existing therapies or provide guidance for developing new ones. Therefore, this study will help: 1) improve care for this family; 2) increase our understanding of estrogen's role in human cognitive functioning; 3) enhance our knowledge of the genetic causes of ID.

Evidence Based Approach to Treatable Rare Diseases causing Intellectual Disability

Evidence based medicine (EBM) aims to apply the best available evidence gained from the scientific method to medical decision making, and is currently regarded as the gold standard in medical practice. EBM is not (yet) applied in the realm of rare diseases. Our project, focused on the identification of treatable conditions causing intellectual disability, is one of the first attempts to change this. We are currently performing a comprehensive, systematic review of the world literature to identify such conditions (inborn errors of metabolism) and analyze the effects of available treatments. Based on this evidence we will establish and publish guidelines to aid the clinician in identifying these IEM. As proper treatment may improve neurocognitive function or halt its decline, these rare diseases should not be missed in a diagnostic work-up. Our guidelines will directly improve the care of intellectually disabled individuals suffering a rare but treatable disease.

Results -

Intellectual disability is a debilitating condition affecting 2-3% of all children and adults around the world, defined by an IQ of less than 70, affecting every area of life: behavior, academic achievement, social interaction and more. The Rare Disease Foundation funded our research to identify a rare group of genetic conditions called metabolic diseases, which cause intellectual disability and for which therapy is available. In contrast to stark notions that genetic causes of ID cannot be prevented or treated, our research showed that there is life-changing therapy available for 75 such conditions, collectively termed 'treatable IDs'. Although each of them are rare, as a group they may constitute a considerable proportion of intellectual disability, and if correctly identified, this will allow initiation of appropriate treatment which dramatically improves health outcomes for affected children.

This motivated us to develop digital tools, high-tech diagnostic methods, and a state-of-the-art protocol to facilitate the timely identification of each of these 75 treatable conditions. Our evidence-based approach to rare diseases, made possible by a Rare Disease Foundation microgrant, formed the basis of a large research and care project: 'The Treatable Intellectual Disability Endeavor in B.C.' which was funded in 2011 by the BC Children's Hospital Foundation as the 1st Collaborative Area of Innovation with $2.25 million. TIDE-BC collaborates with the Rare Disease Foundation and its members to provide better care to all ID patients in British Columbia, through research and collaboration with all partners including patients and families. More information can be found on our website www.tidebc.org and can be summarized as follows:

We now know that the intellectual disability (ID) seen in some children may be due to treatable genetic conditions known as inborn errors of metabolism (IEM).  Many of these IEMs can be treated with diet or drugs and the affected child can grow up with improved intellectual abilities, benefitting the child, the family and society.  Presently, health care policy and institutional culture is still operating under the old premise that all ID is incurable and thus, many children being born with treatable ID are at risk of not being treated.

Our endeavour, TIDE-BC, is an amalgamation of like-minded clinicians and researchers, located at British Columbia Children's Hospital with the goal of finding and treating every child with treatable ID in BC and implementing a province-wide policy that supports this. With the CAI funding we will establish province-wide screening of all children suspected of having ID, to centralize and streamline the referral and diagnostic process, to use the latest technologies to improve diagnosis and treatment, and to educate all formal medical and advocacy groups in the new understanding of treatable ID.  Under the banner of CAI-sponsored TIDE-BC, we provide a critical mass of clinicians, researchers and patients in which to attract national and international collaborators in the field of treatable ID and provide a platform for leadership and reputation as "the place to go" for health care professionals, families and the general public, inside and outside of BC, who have an interest in treatable ID.

The metabolic evaluation of the child with an intellectual developmental disorder: diagnostic algorithm for identification of treatable causes and new digital resource.

van Karnebeek CD, Shevell M, Zschocke J, Moeschler JB, Stockler S. Mol Genet Metab. 2014 111(4):428-38. doi: 10.1016/j.ymgme.2014.01.011. PMID: 24518794

Parry-Romberg Disease: a CT study to evaluate bone morphology

Parry-Romberg syndrome is a rare disorder that affects the face and nervous system. Generally the first sign is facial changes in which the soft tissues of one side of the face begin to waste away and distort the face. The onset is typically in childhood or adolescence and over the course of about five years, one-half of the face becomes deformed.  We plan to use special x-rays to understand the changes that occur to the bones of the face and head.

Results -

This study was not performed. We were unable to determine the precise reason for this.

A New Autosomal Recessive Limb Girdle Muscular Dystrophy?

Limb girdle muscular dystrophy (LGMD) is a progressive disease affecting shoulder and hip muscles. There are many types of limb girdle muscular dystrophy with different genetic causes. Many of the inherited causes remain unknown. We care for a family of two sisters affected with LGMD. This suggests a pattern of inheritance where both parents contribute genetic information to cause the condition. Standard diagnostic techniques have not identified the type of LGMD.  Because the family has common ancestral roots, we can use new techniques to look for genetic regions in which the affected sisters have two identical copies and each of the parents carry only one of these copies along with a different one. The goal is to identify the region that is likely to contain the genetic instruction (gene) responsible for this disorder. This study could show that the family has a previously defined LGMD but with new features not described before; this outcome would provide immediate insight to provide therapies to slow progression.  Alternatively, the information from this study may provide the preliminary data for further studies to identify an unreported inherited cause of LGMD in this family.  Regardless, the goal is offer treatment to improve the quality of life for these sisters and other similarly affected individuals.

Results - 

This study enrolled two sisters affected with an undiagnosed form of limb girdle muscular dystrophy as well as the parents and unaffected brother.  There are over 50 genes known to cause this group of disorders. The sisters, one in her early 20s and the other in her late teens, had undergone a battery of histological and targeted genetic testing without arriving at a diagnosis. We used exome sequencing to identify a homozygous nucleotide deletion in CAPN3 (c.550delA frameshift: p.T184RfsX36).  This specific mutation has been previously reported in individuals with LGMD2A, also known as calpainopathy and is particularly common in others from the same ethnic population.  Previous studies in this family on muscle biopsy had been falsely negative for calpainopathy, illustrating the value of exome sequencing.  Providing a diagnosis for the family allowed appropriate genetic counselling, and gave the family information about disease prognosis and management.

The elder sister expressed the value of having a specific diagnosis, "By participating in this research we all found the answers we needed and now we know exactly what we are fighting against...I do not have to worry anymore about what may be wrong because I have one of the most important questions answered. That to me is priceless."  Having a diagnosis has also inspired her to get involved in advocacy for research. "I definitely want to do something."

In addition, the research made possible by the Rare Disease Foundation microgrant also contributed important data to a publication:

An analysis of exome sequencing for diagnostic testing of the genes associated with muscle disease and spastic paraplegia.

Dias C, Sincan M, Cherukuri PF, Rupps R, Huang Y, Briemberg H, Selby K, Mullikin JC, Markello TC, Adams DR, Gahl WA, Boerkoel CF. Hum Mutat. 2012 33(4):614-626. doi: 10.1002/humu.22032. PMID: 22311686

The role of NSDHL in the cognition of carrier females

Approximately 20% of Canadian children and youth have ID or psychiatric disease. Although much progress has been made in the understanding of these diseases, little is known about their genetic causes. We have identified a family with a rare disorder where affected males have mild to severe ID and females have behavioral problems. We have fully described the physical and mental characteristics of the affected males and identified the genetic cause of this disorder. The next phase of this study involves defining the intellect of the carrier females. A total of 5 females (1 girl and 4 women) will undergo psychological evaluation. The purpose of this grant is to cover the psychologists' costs for the administration of the various tests. Once this final phase of the study is done, we will better understand this disorder and thus be able to identify appropriate supports and interventions for this family.

Defining a medical treatment for progressive & life-threatening blood vessel closure

We aim to improve the care for a boy with life threatening progressive narrowing of blood vessels in his body. The poor blood supply to his brain, kidneys and intestine have caused multiple strokes with brain damage, severe high blood pressure, headaches and severe abdominal pain as well as malnutrition from the pain of eating. Our investigations have shown that he has a defect of the tissue that provides structure and integrity to blood vessel walls. Others have identified medications that favorably alter the course of similar blood vessel diseases. The objective of this study is to determine if such therapy would be warranted for this boy. If it is, it might slow or halt the narrowing of his blood vessels and thereby improve the quality and possibly the span of his life. Since the current therapies inhibit production of the protein TGF-β1, we will measure if this is increased in his blood and cultured and cells, and if it is, determine if the drugs inhibit its production in his cells. This would provide the basis for treating this boy with these drugs.

Diagnosis of Hormonal Defects in Mesenteric Lipodystrophy

Fat tissue pumps out many hormones into the blood. Women and children generally have more fat under the skin, which tends to make beneficial hormones that protect against diabetes and heart disease. One reason that men and older women get diabetes and heart disease is that they tend to put on belly fat, which is inside the body and wrapped around the organs. This belly fat puts out hormones that promote diabetes and heart disease, and the more of this belly fat you have, the worse off you are in terms of risk. We wish to help a young girl who has a genetic disorder that forces her to gain belly fat. We want to test all of the proteins in her blood to find out which hormones her extra belly fat is making, so that we can design treatments for her based on antidiabetic drugs that are already available.

Results -

This microgrant allowed us to find a young girl's diagnosis, ending years of tests and referrals to explain her puzzling symptoms: an overgrowth of fatty tissue on specific parts of her body including her belly and one leg. Fibroadipose hyperplasia is caused by a change in a gene called PIK3CA. Fewer than 1 in 1 million people are estimated to have the disease. For the young girl with fibroadipose hyperplasia, this diagnosis means the family no longer has to worry that their daughter will need surgery to remove the excess belly fat. Previously, her doctors were worried that her belly fat might turn into a more aggressive tumour, but now they know that this is very unlikely because that tends not to happen in patients with PIK3CA gene changes. This microgrant illustrates how studying rare genetic diseases can inform our understanding of common diseases. Improving our understanding of fibroadipose hyperplasia may help to explain why some fat deposits grow more than others, even in patients without this rare genetic mutation.

Somatic mosaicism for the p.His1047Arg mutation in PIK3CA in a girl with mesenteric lipomatosis.

Cohen AS, Townsend KN, Xiang QS, Attariwala R, Borchers C, Senger C, Picker W, Levi J, Yewchuk L, Tan J, Eydoux P, Lum A, Yong SL, McKinnon ML, Lear SA, Everett R, Jones SJ, Yip S, Gibson WT. Am J Med Genet A. 2014 164(9):2360-4. doi: 10.1002/ajmg.a.36622. PMID: 24903541

A Standardized Approach to Idiopathic Pain / Irritability in Children with Rare Neurological Conditions

The purpose of this project is to find a more consistent way to treat unexplained pain and irritability in infants, children and youth with rare diseases, especially those affecting the nervous system. Children with rare diseases often experience pain due to unknown causes. Strategies to treat this pain (both behavioural and pharmaceutical) often vary between physicians; this may result in inconsistent or inefficient care. We are interested in developing and testing a step-by-step guide to pain management to streamline the care provided to these children.

Results -

Our project identified that, because there is a lack of evidence, even a group of expert clinicians working the same health care centre choose different combinations of medications when treating pain /irritability in children with rare neurological conditions. In the second phase of the study we set up a small pilot program to treat these children with guidelines for the medications. We found that even before starting medications, simply looking for possible pain sources in a standard way will address most of the problems. The study was published in Pain Research & Management in 2013.  Since our study was a pilot project, we plan to test it in a larger group.

Physician variability in treating pain and irritability of unknown origin in children with severe neurological impairment.

Siden HB, Carleton BC, Oberlander TF. Pain Res Manag. 2013 18(5):243-8. PMID: 23885348

Evaluation of choline and acetylcholine pathways in a child with progressive cholinergic failure

We follow a patient with long standing muscle weakness, moderate developmental delay, memory problems, severe constipation, dry eyes, dry mouth, low blood sugars and repeated infections, who had several investigations to find the cause of his symptoms. His symptoms are consistent with failure of the autonomic nervous system that uses as neurotransmitter acetylcholine. Acetylcholine is synthesized from choline and acetyl-CoA by the enzyme choline acetylcholine synthetase. Choline is taken up into cells by the choline transporter. Acetylcholine then is degraded by acetylcholinesterase in the synapse into choline and acetate. This pathway can have defects at different levels, either enzymes or transporters. In order to find the defect we can measure the individual substances by a method that is not available on clinical basis but it is offered at the Child & Family Research Institute in Vancouver, at Dr. Sheila Innis' Lab. If we find the defect in this pathway, we can work out treatment strategies to increase acetylcholine levels in this child, and hopefully halt the progression and even reverse some of his symptoms.

Results -

Very good result; patient was shown to have low levels of acetylcholine. He was put on choline replacement therapy, pyridostigmine and a central cholinesterase inhibitor and his symptoms stabilized.


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