May 2013

May 2013 Microgrants

Creating an information resource to support families of children "living without a diagnosis"

The purpose of this research project is to create an evidence-based virtual resource for families of children living without a diagnosis. This psychosocial information resource is being developed to assist families, ideally early on in the process of their diagnostic odyssey, by providing tools to promote empowerment, support and advocacy. While there is much overlap in the psychosocial and informational needs between parents of a child with a rare disease diagnosis and parents of a child without a specific diagnosis, parents of undiagnosed children have unique needs and experiences. We aim to collect feedback from families in our rare disease community who are living without a diagnosis to guide the development of our resource. Once developed, families and a variety of health professionals will participate in the piloting and evaluation of the resource. The final product will include a virtual printable booklet, specific to families in British Columbia in terms of local supports and contacts. A modifiable version of the booklet will also be created and freely available to health organizations, rare disease and family support groups within Canada and worldwide. The modifiable booklet would allow the group or organization to personalize the booklet according to the specific needs of their population. We hope that a future microgrant may support translation into French, Mandarin, and Spanish to further increase access to this valuable resource.

Treatment of brain iron accumulation in adult-onset Parkinsonism (due to PLA2G6 mutation) with the iron chelator Deferiprone

Neurodegeneration with brain iron accumulation (NBIA), encompasses a group of very rare neurodegenerative disorders, with an estimated prevalence of 1-3 per million. One member of this group includes mutations to a protein called phospholipase A2, Group VI (PLA2G6), a human protein responsible for membrane remodeling, and trans-membrane ion flux. When PLA2G6 is mutated there is accumulation of iron in the brain. Accumulation of iron in the brain has been associated with Parkinsonism and at present there are no therapies for iron removal in patients with PLA2G6 mutations. Deferiprone is a drug successfully used for 30 years to treat iron overload in Thalassemia and has recently been found to lower brain iron in patients with NBIA. At present there are no trials in Canada for Deferiprone treatment of NBIA. We want to determine if Deferiprone treatment can be used to lower brain iron, oxidative stress and symptoms of Parkinson's in patients with PLA2G6 mutations.

Is my treatment effective? A patient centered model to evaluate disease specific individualized outcomes and establish treatment benefit at individual level and effectiveness at population level

Evidence of drugs' effects is based on the average effect observed in the study population and may not apply directly to individual patients. Especially in pediatrics and rare diseases there is even more lack of evidence when physicians prescribe drugs, with considerable uncertainty regarding the treatment's effects. We propose to develop a personalized patient centered approach to confirm treatment safety and efficacy by combining what is important to the patient with traditional clinical outcomes. The aim of this project is to answer a patient's paramount question: "Given my personal characteristics, conditions and preferences, what is the best treatment for me and what can I do to improve the outcomes that are most important to me?"

Biophysical properties of the aorta and blood pressure monitoring in Turner Syndrome

Turner syndrome (TS) is a rare genetic disorder. TS is associated with an increased risk of aortic dissection, a potentially life-threatening tear in the large blood vessel leaving the heart. The reason for this increased risk is unknown. This study will use ultrasound pictures of the heart and blood pressure monitoring to assess whether aortic stiffness and blood pressure are increased in TS patients compared to healthy children. The results will help doctors identify TS patients who have the highest chance of aortic problems and who may benefit from specific monitoring or early medical and/or surgical treatment.

Results - 

We found that the aorta is stiffer in females with TS compared to those without TS. After performing some corrections for height, the size of the aorta was significantly larger in the TS group. Furthermore, twenty-four hour blood pressure monitoring found abnormal blood pressure in the majority of TS patients. Further studies are needed to determine the cause of aortic stiffening in this population, whether stiffening is a risk factor for aortic enlargement and dissection, and what role high blood pressure may play. This research has been presented at several conferences, both national and international.

Publications - 

Publication One

CONFEX

Science Direct

Identification of a Potentially Neurotoxic Viral Protein from Endogenous Retrovirus-K in the Central Nervous System of Patients with ALS

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease with no clear cause or cure. We have shown that there is active endogenous retrovirus-K (ERVK) in neurons of patients with ALS. Recently, my student has identified a novel conotoxin-like protein in the ERVK genome, with neurotoxic potential. We plan to assess the expression and function of this novel viral protein in cerebral spinal fluid, brain and spinal cord tissues from ALS patients and neuro-normal controls, to determine whether this toxic protein may play a role in causing neuronal damage in this disease. Our research will provide insight into ALS-specific viral biomarkers and avenues for novel therapies to treat ALS.

Results - We discovered that this new viral protein is highly expressed in the neurons of cortical brain tissue from patients with ALS. We also found that this novel viral protein can be induced by inflammatory cytokines.When expressed, it is found in two locations in ERVK+ cells: the cell membrane and the nucleus. In the cell's nucleus this viral protein can bind to DNA. These findings have important biological ramifications for understanding how this virus damages human neurons in the brain. Our group is advocating for the use of antivirals and immunomodulatory drugs as potential therapeutics for ALS, considering the accumulating evidence that the virus ERVK has a clear pathogenic role in this disease. Future clinical trials that target ERVK activity are warranted.

Is the cause of pulmonary lymphangiectasis in the Ras pathway?

Congenital pulmonary lymphangiectasia is a developmental abnormality of the lymphatic vessels, which fail to adequately drain excess fluid from the lungs. Fluid accumulation then constrains lung growth, and, if severe and persistent, can impair a baby's ability to breathe. This is a very rare problem, and the cause for it is unknown. The fact that it has been reported to affect multiple children in the same family is strong evidence for a genetic cause. It has also been reported as a rare complication of Noonan syndrome. The genetic basis of Noonan syndrome is known; it is caused by alteration of a developmental signaling pathway called the Ras pathway. We are caring for a family with two children affected by pulmonary lymphangiectasia who have agreed to participate in a genetic study to look for gene mutations within the Ras pathway.

Hyperalertness-Restlessness and Adverse Drug Reaction. A new clinical syndrome at the interface between ADHD and Restless legs syndrome

We are currently following three children with developmental delay and ADHD-like behavior during daytime and restless legs during nighttime. Additionally these children have uniformly shown a severe adverse reaction to Ritalin, a stimulatory ADHD medication, whereas inhibitory medications such as Gabapentin resulted in significant improvement of all symptoms. At least one of their parents also has restless legs and chronic pain-like discomfort, which is alleviated by marijuana. We think that these families have a distinct, yet unknown gene defect. As a first step we want to collect more of these cases/families and exactly characterize their symptoms. Although rare, we hope to collect up to 10 families via a national Canadian collaboration. We apply for funding to support the collection of families and their data. This will set stage for genetic testing with appropriate technologies. If we were able to determine the underlying gene defect in these families, personalized treatment could be provided to effectively alleviate suffering.

Exome-sequencing for identification of rare genetic variants and novel genes contributing to Brugada Syndrome

Brugada syndrome (BrS) (also known as Sudden Unexplained Death Syndrome) is characterized by sudden cardiac death (SCD) at a young age, in combination with typical abnormalities on the electrocardiogram (ECG).  It has an estimated prevalence of 5-50 cases per 10,000 individuals and is believed to cause 4 to 12% of all SCDs.  BrS displays an autosomal dominant inheritance, but the genetic origin of BrS is still largely unraveled. Mutations in the cardiac voltage-gated sodium channel encoded gene SCN5A are found in only ~30% of BrS patients.  Mutations in 5 other genes have recently been identified in patients with BrS, but their prevalence remains low (less than 5% of cases, in total), suggesting involvement of other genes in the remaining 70% mutation-negative patients. Overall, clinical management of BrS suffers from poor molecular diagnostic tools. As a consequence, risk stratification for strategies aimed at preventing SCD is poor and often leads to inappropriate cardiac defibrillator implantation, currently the only available treatment. Predicting and preventing SCD remains a major challenge for which new strategies are needed, and understanding its mechanisms represents an enormous challenge for clinical and basic cardiovascular science. In this context, we care for a family with this life-threatening syndrome: a 45 years old man (proband) came to our clinic after his brother and uncle had died suddenly at a young age. The proband's ECG showed typical BrS abnormalities. Both his teenage daughter and son have abnormal ECGs. BrS gene testing did not uncover any mutations in the BrS associated genes. We have DNA samples from the parents and the 2 children, with research consents for use in this study. We propose to use a method to look at all genes in retained DNA and to compare identified variants between all 4 individuals: putative causal variants should be present in all 3 affected individuals and absent in the mother.

Results - This project did not proceed.

Study of salivary serotonin and cortisol as a non-invasive marker of central serotonin activity

The neurochemical serotonin plays important roles regulating our mood and cardiovascular system, among many other functions. We would like to find a non-invasive way to measure serotonin in the brain. To do this we will examine the relationship between salivary serotonin, blood serotonin, and spinal fluid serotonin in children. We will ask parents of children who undergo a lumbar puncture and spinal fluid serotonin measurement as part of their investigations in the neurology and metabolic clinics to consent for collection of a small amount of saliva with a plastic pipette from their children's mouth. A small amount of blood will be added to the standard collection for glucose measurement prior to LP. We will measure the levels of salivary serotonin and cortisol and compare to the results of the spinal fluid and blood serotonin that was requested by their neurologist or metabolic doctor. This way we will find out if there is good correlation between the brain serotonin level and the level in saliva, which then could be used as non-invasive measurement. It would be important to find out, because many rare disorders manifest autonomic dysfunction (recurrent vomiting, blood pressure or heart rate variations, temperature irregularities, rashes), or movement disorders, that could potentially be treated with 5-hydroxytryptophan (5HTP, precursor of serotonin), if we could show that they have low serotonin levels without performing a lumbar puncture.

Results - 

If results show that salivary serotonin is a good marker for brain serotonin content, then we will be able to use it as a noninvasive analysis for assessing serotonin in patients, with no need for spinal tap.

Mutations in ERF gene as the new genetic cause of craniosynostosis - enabling parents and clinicians to understand why a child is affected

Craniosynostosis is a rare but serious condition which means that a baby's skull bones fuse together too early. The brain continues to grow but the skull cannot grow with it and the pressure inside the brain rises. This can cause serious brain damage if untreated. The skull and facial bone shape is also unusual in this condition, causing lifelong medical and sometimes psychological issues. The treatment of this condition is surgical, involving a complex operation to open the skull and allow the brain to grow. There are significant risks to the child associated with the surgery, but left untreated the risks are also large. Parents understandably feel very anxious about their child's future and the child often goes through more than one major operation to prevent irreversible brain damage. Over the last 20 years, scientists have found that many children with craniosynostosis have a genetic cause for the condition. Discovering the cause allows the parents to understand why this happened, and allows the medical team to tailor treatment depending on the gene involved. However, we are not always able to find the genetic change and in those cases, we cannot give accurate advice to parents regarding the optimum follow up for the child, or indeed their risk of having another child with a similar condition. Recently, a team of researchers in Oxford have discovered a new gene called ERF that is a major cause of craniosynostosis, and it is now possible to test for this new gene in the UK. We would like to be able to offer this test to Canadian children at SickKids, since we already test other genes known to cause craniosynostosis. We are asking for this grant in order to set up this test at the molecular genetics lab at SickKids for research purposes. This project will help us determine if the test has clinical utility to support applications for continued testing at the Hospital for Sick Children. It will also help us explain to more parents why their child has craniosynostosis, predict the risk of having another affected child, offer testing during the future pregnancies, and in the long term will help with management once the natural history of this specific cause has been studied for a longer time.

Results - 

Study completed and published findings in the American Journal of Medical Genetics. We tested a total of 40 patients with craniosynostosis. These patients already had genetic testing available in Sickkids genetics lab which came back normal. Using our research funds, I sequenced ERF gene in these 40 study participants. We found that two of these patients had pathogenic mutations in ERF gene, which explains their craniosynostosis as well as other features like speech delays, intracranial anomalies etc. Both of these mutations that we found in ERF gene are novel i.e, haven't been published in literature previously. We are now pursuing confirmation of these research findings in a clinically accredited lab for both of these patients. Moreover. once we confirm it in our patients, we will offer genetic testing to their parents to delineate the recurrence risk in their future pregnancies (patients with ERF mutation have 50% risk of passing this on, in each one of the pregnancies). Read Article Here...

 Arrhythmogenic Right Ventricular Cardiomyopathy: Characterizing a North American Founder Population expressing a Plakophilin-2 (PKP2) Frameshift Mutation

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is a rare heart condition (1:2000-1:5000) that can lead to loss of consciousness, heart attack, and sudden death in children and adults. It is a condition that is difficult to diagnose, and unfortunately, often presents with sudden death of the affected individual. Subsequently, family members are screened for ARVC, but the natural history and management options for the surviving individual and/or family members are unclear. Family members sharing the genetic mutation are thought to be at risk for sudden death, but their degree of risk and whether this necessitates aggressive interventions is still unknown. To address this need, we started the Canadian ARVC Registry, a national database enrolling individuals diagnosed with ARVC and their affected family members at 12 centers across the country. Within this registry, we have identified a unique group of individuals sharing a common genetic mutation in both Ontario and British Columbia. By studying this subgroup, we aim to better understand the natural history of ARVC and ultimately, guide the diagnosis and management of this complex and rare disease.

Early repolarization and its familial inheritance in cardiac arrest survivors with preserved ejection fraction registry (CASPER)

An inherited arrhythmia is a rare heart rhythm disorder, which can cause very rapid irregular heartbeats and sudden death in otherwise healthy children and young adults. Inherited conditions can be passed from parent to child. One of these heart rhythm abnormalities is termed "early repolarization" and can be recorded on an electrocardiogram (ECG) in some people who have survived a cardiac arrest. It may also be found in their first-degree family members (children, siblings, mother or father). This heart rhythm abnormality may help identify why an individual had a cardiac arrest and may help to determine who else in their family may be at risk for a cardiac arrest or sudden death. Reviewing the ECGs of cardiac arrest survivors and their first degree families members will provide information that will improve treatment strategies for the survivor of the cardiac arrest and also identify other family members who could also be at risk of cardiac arrest.

Exploring the pathophysiology of Rab5 deficiency, the first human endosomal recycling defect

Novel gene sequencing technology allowed us to identify a so far undescribed gene defect in a six year-old girl with intractable epilepsy and severe developmental delay. This gene has an important function in recycling transport vehicles used for incorporation of molecules from outside the cell to compartments inside the cell (endosomal recycling). Such molecules include vitamins, minerals and lipids as well as receptors for neurotransmitters and hormones. This gene has also been shown to play a role in early brain development in animal models. We have identified a group of researchers with technologies and experimental expertise to help us verify that this gene defect is causal, i.e., has functional relevance. Results of these investigations are prerequisite to identify targets for treatments of this first human early endosomal recycling defects, which has relevance to this child as well as others suffering this devastating but not yet recognized condition.

Targeting the elimination of brain tumour initiating cells by disrupting the PI3K pathway

Brain tumours are the most common type of solid tumour in children. The principal issue affecting survival is that brain tumours often recur, and in many instances children with malignant brain tumours have less than a 50% chance of surviving one year after their initial diagnosis. There is research suggesting that one reason why brain tumours are so difficult to treat is that a unique stem cell type, the brain tumour initiating cell (BTIC), makes the tumours drug and/or radiation resistant. One challenge with past research is that non-human (animal model) brain tumours are not necessarily representative of human brain tumours. Our plan is to study, using human pediatric brain tumour preparations, new treatment approaches with the goal of improving patient cure rates. We plan to block a specific mechanism of growth of BTICs that we believe is responsible for the progression of those tumours. Once this mechanism is shut down, the cells will be deprived of necessary growth signals and they will die. We then plan to combine these inhibitors with classic agents used to treat brain tumours so that we are able to eliminate the cancer cells and improve cure rates.

Identification of genes predisposing to sudden cardiac death with gene-elusive conduction system disease

Sudden cardiac death (SCD) accounts for up to half a million of deaths yearly in the US. Although cardiac arrhythmia disorders leading to SCD are rare, its understanding is essential to unravel the mechanisms and pathogenesis of arrhythmias in the general population. Ventricular fibrillation is the most commonly identified arrhythmia in cardiac arrest patients. This arrhythmia is a severe derangement of the heartbeat that usually ends in death within minutes unless corrective measures are taken. In the absence of identifiable structural heart disease or known 'electrical' abnormalities, it is referred to as idiopathic (cause unknown) ventricular fibrillation (IVF), which accounts for ~10% of sudden deaths. A family history of sudden cardiac death is present in 20% of IVF cases, suggesting that at least a subset of IVF is hereditary. However, in only a few cases of IVF a genetic cause (mutation) has been found. The present lack of insight in the genetics of this disorder hinders the understanding of the pathophysiology of the disease and consequently hinders the developments of new therapies for the disorder. We care for a family who lost two children as teenagers to sudden cardiac death (SCD). One child, a 15-year old male, died suddenly while sitting in front of the computer in his room. A teenage sister had previously died while eating lunch at school. The father has evidence for abnormal conduction on a special kind of ECG called a signal-averaged ECG. Genetic testing in the family revealed no causal mutation in the genes encoding for the Brugada syndrome or arrhythmogenic right ventricular cardiomyopathy, the usual causes of an abnormal signal-averaged ECG. We have DNA samples and research consents for use in this study. The family is particularly motivated, as they are concerned about risk for their other children. We propose to use a method to look at all genes in retained DNA from the 2 parents and decedent.

Results - This project did not proceed.

Epilepsy Gene Panel in Children with Epilepsy

Many patients are diagnosed with epilepsy each year, the majority with onset before the age of 18. Uncontrolled seizures may cause irreversible impairment of intellectual development, particularly when they begin in infancy. Epilepsy places a substantial burden on children and families with a 2 to 4-fold higher mortality rate. In a subset of cases, affected patients will not respond to currently available antiepileptic medication. The economic impact is estimated at $2 billion/year. Many genetic causes of epilepsy have been identified including several where test results have ramifications for successful intervention. Individually these genetic disorders are rare, but collectively they constitute a significant portion of the epilepsy population: mutations in over 300 genes have been implicated in seizure disorders. Within Canada, access to genetic testing is limited to only a few genes and a diagnosis is often delayed due to current approaches to genetic testing. Only two genes are available for testing in BC. Current clinical practice requires testing one gene at a time, when the government agrees to reimbursement. Results may take several months, which delays the ability to implement effective treatments. Such delays in diagnosis and treatment can have disastrous consequences. We will develop a broad-based genomic approach to rapidly determine if a child has a known or novel mutation in a gene implicated in epilepsy. Results will impact the management and healthcare costs of seizures in children with treatment resistant epilepsy of unknown cause. Genetic findings will help ensure the correct treatment is used which should improve seizure control and reduce the time of hospitalization and emergency room visits as well as unnecessary invasive procedures. Reduced seizure activity will have a positive impact on patient's ability to function in day to day activities, quality of life for the child and his/her family, and reduction in productivity losses on the part of caregivers.

2q37 Deletion Syndrome

In this novel study we aim to study the genes integral to the rare 2q37 Deletion Syndrome (DS), including a nearby 2q37.3 genomic variant, as well as their respective, concordant clinical features relative to the (RNA) expression of 7 key candidate genes within this genomic region. Identification of a link between the small deletion at 2q37.3 and to the 2q37DS will be reviewed in terms of the genes involved, their expression and their respective influence on the 2q37DS phenotype, including intellectual disability (ID) and autism. It is noteworthy and an added benefit that study of a rare condition such as 2q37DS can offer insight into the clinical cause and course of more common, complex neurodevelopmental conditions such as ID and autism, which easily translate to functional genomic studies informing their pathogenesis.

Genome sequencing of an undefined autoinflammatory disease is a family affair

At present we are caring for a 6 yr old boy that has been sick with fevers, rashes, enlarged liver and spleen, and poor growth since 1 yr of age. We have treated him with anti-inflammatory agents, high-dose biologics, and steroids yet he remains unwell. Based on clinical considerations, it is clear that this boy has an autoinflammatory disease. Autoinflammatory diseases are characterized by seemingly unprovoked and recurrent episodes of inflammation. They are a collection of individual rare diseases with the more common forms having an incidence of 2 cases per 10 000 individuals. Causative single gene abnormalities have been identified in a small subset of patients, but the majority of autoinflammatory diseases, like that in our patient, are of as yet undefined origin, and in more than 80% of cases, do not carry any of the identified gene variants. Paradoxically, the only genetic testing available for autoinflammatory diseases is restricted to the known gene variants. In order to better understand their son's disease, our patient's parents have approached us proposing genome sequencing be done on their son and their immediate family including 2 healthy children. We are compelled to work with this family to identify genetic variants in this boy and use the knowledge gained to directly improve diagnosis and treatment for children with unclassified autoinflammatory diseases.

Identification of genes predisposing to Sudden Cardiac Death

Normal contraction of the human heart depends on the proper movement of charged ions through special cardiac ion channels across the surface membrane of millions of cardiac cells. Disorders of the conductive ion flow lead to cardiac arrhythmias, which may predispose to sudden cardiac death (SCD) at a young age. SCD accounts for up to half a million of deaths yearly in the US. Although many of these cardiac arrhythmia disorders leading to SCD are rare, its understanding is essential to unravel the mechanisms and pathogenesis of arrhythmias in the general population. Also the availability of genetic diagnostic tests adds an important diagnostic tool, providing new opportunities for patient management such as early (presymptomatic) identification and treatment of individuals at risk for developing fatal arrhythmias. We care for a family with multiple cases of SCD: two siblings both died at the age of 13 years. Their father showed mild ECG abnormalities associated with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), which is associated with progressive fibrofatty replacement of cardiac tissue. His youngest daughter is unaffected, as is the mother. Two brothers of the father also died suddenly at 2 years of age, suggesting that the father is an obligate carrier of the putative causal mutation. We have DNA samples from the father, deceased son and unaffected mother and daughter, with research consents for use in this study. We propose to use a method to look at all genes in retained DNA from the patient and his parents.

Results - this project did not proceed.

Genetics of Hairy Cell Leukemia in Rare Families

Hairy cell leukemia (HCL) is one of the rarest types of blood cancer, with an incidence of <1 in 100,000 per year. HCL is so named because seen under a microscope the cells have small projections that resemble hair. 16 families with HCL have been reported worldwide to date, suggesting that there may be a genetic component to HCL risk. We have identified a rare family in which a father and son have HCL. We have also formed an international consortium with colleagues who have identified a 4 other HCL families. Using new technology that allows us to simultaneously look at sequences of all genes, we will look for genetic differences shared by the father and son with HCL, and also shared by or similar to genetic features in the 4 HCL families identified by our colleagues. This research will help us understand why some members of these families developed HCL, identify genetic features that will be useful in predicting risk in other family members, and provide insights that may inform their treatment.

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

Creatine is a vital energy source in the brain. Creatine deficiency disorders (CDS) are genetic disorders causing creatine deficiency in the brain. CDS result in global developmental delay, intellectual disability, uncontrollable seizures and behavioral problems in children. The diagnosis needs a suspicion and ordering of specific urine metabolites and cranial magnetic resonance spectroscopy, which are not widely available in all hospitals. 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. We will investigate children with low levels of muscle enzyme, called creatine kinase (CK), which is available easily in all hospitals. If we find any child with low CK, we will measure urine metabolites specific to CDS. If we identify individuals with CDS, then we will use low CK test as disease marker to make physicians aware to use this testing in their patients to think about CDS.

A Unique Family with Castleman Disease: Insights into B-Cell Proliferation

Castleman Disease (CD) is characterized by overgrowth of cells of the immune system, causing enlarged lymph nodes that press on organs and tissues leading to breathing problems and abdominal pain. CD weakens the immune system, making it hard to fight infections, and can lead to death. Patients can experience anemia, fevers, weight loss, fatigue, night sweats and nerve damage leading to weakness and numbness. Individuals with CD have an increased risk of lymphoma, a cancer of the immune system. The prevalence of CD is less than 1/100,000; to date, there have been no published reports of CD running in families. We have identified a family in which 3 individuals over 3 generations have CD. Using new technology that allows us to simultaneously look at sequences of all genes, we will look for genetic features shared by all 3 affected individuals in this unique family. Identifying the genetic basis for CD in this family may provide insights into causes and treatments for other individuals with this debilitating condition.

Results - Project was suspended due to a lack of participants.

Enhancing erythropoiesis using L-leucine in Diamond Blackfan Anemia

Diamond Blackfan Anemia (DBA) is extremely rare and afflicts less than 7 people per million. DBA shows increased iron burden and organ failure and at present the only therapy is transfusion and/or glucocorticoid treatment, both of which have great side effects. L-leucine is an essential amino acid that has recently been shown to increase red blood cell production in models of DBA. It may be possible to use L-leucine to improve erythropoiesis, hypoxia and quality of life in DBA patients.

Application of Stable Isotopes to Determine Individual Protein Requirements in Children with Phenylketonuria (PKU)

Phenylketonuria (PKU) is an inherited inborn error of phenylalanine (PHE) metabolism affecting1:15,000 births. This disorder is caused by a decreased activity of an enzyme in the liver called phenylalanine hydroxylase (PAH) enzyme which is important to convert PHE (an amino acid) into tyrosine (an amino acid). Therefore, PHE accumulates in plasma leading to mental problems and developmental delay. Treatment is mainly nutritional management with decreased amount of PHE in the diet and supply of enough protein. But the exact amount of protein to be given is unknown. A new technique called indicator amino acid oxidation (IAAO) has been used to determine the protein requirements in healthy children (6-10y). The IAAO uses stable isotope (a very safe form of isotope, which is used in medical research) followed by collection of breath samples to determine protein synthesis. The response to the stable isotope in breath will indicate the protein need in each child with PKU. This study will help treat and manage children with enough protein to ensure proper growth and development.


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