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  Down syndrome Registry/Repository Project – BioBank Altered Endocytosis in the Pathogenesis of Down Syndrome Leukemias The perceptual speech characteristics of individuals with Down syndrome Identification of susceptibility genes for Alzheimer’s Disease in Down Syndrome Down Syndrome Disintegrative Disorder: Possible Hashimoto’s Encephalopathy? Detecting Amblyopia in Children with Down Syndrome by Sweep Visual Evoked Potentials Down Syndrome Registry Program Down Syndrome Registry Program Continued Progress Report: Down Syndrome Registry Program Gene-Gene Interactions and Defects of the Atrial Septum A Follow-up Study of the Safety and Efficacy of Rivastigmine in Adolescents with Down Syndrome A pilot study screening for prevalence of iron deficiency in children with Down syndrome Down syndrome Registry/Repository Project – BioBank The Duke Down Syndrome Research Team proposes the development of a data registry and human tissue sample repository (blood and urine). For Down syndrome, clinical and epidemiological research is limited by very small numbers of cases and hard to find cases exhibiting a particular set of characteristics for investigation. A comprehensive collection of data and information in registries is an essential precondition to improve this situation (Pommerening et al, 2008). Within the United States, there are approximately 67 specialty centers providing for the unique medical needs of individuals with Down syndrome. Currently, only about one half of these centers participate in any kind of Down syndrome research. (Results of survey conducted as part of the Duke registry planning grant funded by Anna’s Angels)
Catherine P. Lavau, DVM, PhD; Title of Research Grant: Altered Endocytosis in the Pathogenesis of Down Syndrome Leukemias Lay Summary of Research: While leukemia is a very rare disease in childhood, its frequency is dramatically increased in children with Down Syndrome (DS). The cause of this predisposition is not well understood. Endocytosis is the cellular process by which substances outside a cell (nutrients, growth factors) become internalized. Our laboratory has been investigating how altered endocytosis contributes to the onset of a subset of leukemias that carry particular gene mutations. We believe that impairment of endocytosis favors unrestrained cell proliferation, which can then contribute to increased numbers of leukemia cells. It has recently been shown that endocytosis is abnormal in cells from individuals with DS; this phenomenon is thought to underlie some of the cognitive impairment symptoms that are common in DS patients. In this proposal, we are interested in determining whether impairment of endocytosis is one of the changes that can lead to leukemia development in general, and in DS patients in particular. Harrison N. Jones, PhD Title of Research Grant: The perceptual speech characteristics of individuals with Down syndrome Lay Summary of Projected Project: Down syndrome (DS) is the most common chromosomal condition associated with intellectual impairment and developmental disability in infants and children. The perceptual (or auditory) speech characteristics associated with many medical conditions are well described, though no such description is available for individuals with DS. This is problematic considering that perceptual assessment is considered to be the “gold standard” for the evaluation and treatment of speech disorders, as well as for advancing scientific efforts in this area. The proposed study will use established methods for the perceptual assessment of speech disorders in adults and apply it to individuals with DS. Thirty individuals ages 8 and above with DS will complete a variety of speech tasks which will be audio-recorded using high-quality equipment and sophisticated recording techniques. Digital sound files will be listened to by three speech-language pathologist expert listeners to determine the presence or absence of 38 speech characteristics and their severity. This study will allow for the first comprehensive perceptual description of the speech disorders of individuals with DS. Furthermore, this project will further the scientific understanding of speech disorders in DS and stimulate further research, leading to improvements in the evaluation and treatment of speech disorders and the optimization of functional communication. Adviye A. Tolun, MS, PhD Title of Research Grant: Oxidative Stress and Down syndrome: Development of urinary biomarkers Lay Summary of Research: Down syndrome (DS) is a complex disorder with many symptoms that are distressing to individuals and their families. There is evidence indicating that at least some of these adverse clinical symptoms are caused by overproduction of chemicals called reactive oxygen species (ROS) that cause oxidative damage to cells and compromise their normal function. Therapy aimed at reducing the effects of these oxidative species might improve the clinical status of individuals with DS and improve their quality of life. Preliminary efforts have already been made to assess the clinical impact of antioxidant therapy on DS, but the results have been inconclusive due to poor design. We believe that better antioxidant trials with focus, on using the best antioxidants, at the right dose, for optimal duration, on the right patient group, will prove to be effective. Efforts to improve oxidative status must be coupled with measurable changes in compounds that reflect reduced oxidation of cells in the body. These compounds are referred to as biomarkers of oxidative stress. Although these biomarkers are difficult to measure, our laboratory has used state of the art technology to develop methods for this purpose. Our aim is to measure several of these biomarkers in the urine of individuals with DS and compare them with normal individuals. If, as expected, any or all of these biomarkers prove to be present at consistently higher concentration in individuals with DS, then we will have a valuable method to assess the effectiveness of therapies in future clinical studies. Thomas M Murphy MD Title of Research Grant: The Role of NAD(P)H Oxidase and Transforming Growth Factor-Beta (TGF-) in Airway Hyperresponsiveness and Remodeling in Down Syndrome Lay Summary of Research: Chronic bronchial problems associated with twitchy bronchial tubes is a major cause of hospitalization and ill health in children with Down syndrome (DS). Since it differs from ordinary asthma, we and colleagues in Utah are committed to determining how atypical inflammation leads to chronic lung and bronchial disease ion in DS. A novel and important inflammatory factor, transforming growth factor beta (TGF-?), has been found to play important roles in a number of chronic bronchial problems and has been found in large quantities in their airways. TGF-? appears to increase the difficulty of breathing by increasing the numbers of smooth muscle cells and their thickness in bronchial tubes. At the same time medicines given to animals to correct this problem can actually make the level of difficulty breathing worse, because of a relaxing effect of the TGF-? on the bronchial muscles. Only by determining both how the insides of the bronchial tubes are narrowed by muscle tissue growth and how TGF-? contributes to relaxation can effective therapies for this important potential cause of inflammation and breathing problems in DS.
John Klingensmith, PhD Applicant’s Primary Department: Cell Biology Title of Proposed Project: Identifying transcriptional changes in the defective tissue underlying the major congenital heart defect of Down syndrome Summary of Projected Project: Forty percent of individuals with Down syndrome (DS) suffer from congenital heart defects, the most common of which is failure of the heart to properly divide into four chambers (atrioventricular septal defect, or AVSD). Recent studies of AVSD in trisomy 21 fetuses, which develop DS, demonstrate a failure to form the dorsal mesenchymal protrusion (DMP), an essential element of the atrial septum. The Ts16 mouse model of DS also exhibits AVSD at high penetrance, again due to a failure to form the DMP. The embryological and molecular basis of this defect has not been addressed. We have identified a new mouse model of AVSD in which disruption of Hedgehog signaling to the dorsal mesocardium results in absence of the DMP, and consequently leads to AVSD. We propose to use microarray screening to identify the transcriptional changes in the dorsal mesocardium, from which the DMP arises, in both models of AVSD. Analyzing disrupted transcription in each model alone will produce useful lists of misregulated genes potentially involved in the pathogenic mechanisms. Especially useful will be the identification of genes coordinately misregulated in both models, as they are likely to be fundamental to the normal development of the AV septal complex and mechanism of AVSD in DS. We will use quantitative PCR and in situ hybridization to confirm results, and analyze the known functions of the misregulated genes. These studies will shed new light on the molecular changes mediating the pathogenesis of AVSD and potentially of other manifestations of DS. Lay Summary of Projected Project: Forty percent of individuals with Down syndrome (DS) suffer from congenital heart defects, many of which require immediate surgical intervention at birth. The most common heart defect in DS is failure of the heart to properly divide into four chambers (atrioventricular septal defect, or AVSD). In DS patients with AVSD, a piece of tissue called the dorsal mesenchymal protrusion (DMP) fails to form. We have found that in mouse embryos, when the DMP fails to form, the walls between the four chambers do not form correctly and blood mixes between the left and right sides of the heart. As a result, blood leaving the heart to the rest of the body does not have enough oxygen. We have recently identified a mouse mutant that lacks the DMP and develops AVSD, similar to the case in DS patients. By comparing the genes misexpressed in this mutant and a well-characterized mouse model of DS with the same heart defect, we will begin to identify the genes important for formation of the DMP and correct compartmentalization of the developing heart – and that are likely to be among the downstream mediators of the genetic defect causing Down syndrome. Using microarray gene chips, we can simultaneously screen 40,000 genes to find those implicated in DMP formation and its failures in these mice. Identifying which genes are misregulated in the development of AVSD is a key step toward understanding why DS patients frequently present with this serious heart defect.
Ralf S Schmid Applicant’s Primary Department: Neurobiology Title of Proposed Project: Identification of susceptibility genes for Alzheimer’s Disease in Down Syndrome Scientific Summary of Proposed Project: Down Syndrome (DS) is the most common genetic cause of mental retardation, resulting from the overexpression of a number of genes due to a third copy of chromosome 21 (chr 21). Ongoing studies are providing increasingly refined lists of overexpressed genes and their contribution to disease symptoms that include neurodevelopmental defects, resulting in mental disability from the time of birth. However, it is unknown as to which of these genes may contribute to the striking clinical observation that a substantial proportion of DS patients develop Alzheimer’s disease (AD) in their 30s and 40s. AD is a fatal, progressive neurodegenerative disease that, in contrast, normally occurs only in the elderly of the general population. In this context, we propose to investigate the genetic and genomic factors that may trigger AD in comparatively young DS patients. We hypothesize that these genes may be those on chr 21 that are overexpressed due to the trisomy, and propose to evaluate directly the potential of these chr 21 genes to enhance the development of AD pathology in a novel AD neurodegeneration assay we have developed using biolistically transfected rat cortical/hippocampal brain slice explants. The outcome of this studies will increase our understanding of the biochemical pathways by which DS must pre-dispose for mid-life onset of AD, and will be critical for identifying drug target for specific use in reducing risk for and slowing the progression of AD in DS patients. Lay Summary of Proposed Project: Becoming elderly is often associated with various forms of dementia, but for people suffering from Down syndrome, the most common genetic disease causing mental retardation, dementia in the form of Alzheimer’s disease commonly begins in the 30s and 40s, several decades earlier than in the rest of the population. Alzheimer’s disease is a devastating neurodegenerative disorder that drastically decreases life expectancy likely due to the toxic effect of b-amyloid protein accumulation in the brain. The link between Down syndrome and such young onset of Alzheimer’s disease is poorly understood.
Priya Kishnani, MD and Gordon Worley, MD Applicant’s Primary Department: Pediatrics Title of Research: Down Syndrome Disintegrative Disorder: Possible Hashimoto’s Encephalopathy? Summary of Proposed Project: The prevalence of autoimmune disease is much higher in Down Syndrome (DS) than in the general population. We have encountered 10 patients in the Duke DS Comprehensive Clinic who developed cognitive regression, autistic characteristics, and insomnia beginning in their early teenage years. These patients all had thyroid autoimmunity without clinical thyroid disease. Cognitive and developmental regression associated with thyroid autoimmunity has not previously been described in children with DS. We are naming this condition DS Disintegrative Disorder (DSDD), because of its similarity to Disintegrative Disorder in three to five year old typical children. Hashimoto’s Encephalopathy (HE) is an autoimmune CNS disease associated with but not caused by thyroid autoimmunity, most commonly reported in adults, but also reported to occur in some children. Cerebral folate deficiency is caused by either autoimmunity to a tissue folate receptor or by abnormalities of folic acid metabolism. In children, cerebral folate deficiency can also lead to autism, regression, and insomnia. Chromosome 21 contains many genes for folate metabolism, folate transport, and for enzymes that require folate for activity (including N6ANTI). The purpose of the study is to characterize the clinical and laboratory findings in DSDD; evaluate thoroughly all patients with DSDD for known metabolic causes of regression; to test the hypotheses that antibodies to the tissue folate receptor and to alpha enolase are present in some subjects; and to evaluate subjects for evidence of abnormal folate metabolism. Lay Summary of Proposed Project: The prevalence of autoimmune disease is much higher in Down syndrome (DS) than in the general population. It appears that a subset of adolescent patients in the Duke Comprehensive DS Clinic have experienced significant regression. We would like to systematically evaluate these patients by review of medical records, laboratory evaluations, neuropsychological evaluations, and speech and language testing, and then compare the patients’ data to draw conclusions about their similarities. We are going to test these patients to see if they have a problem using folate correctly, and if they do, our next step in a future study is to treat the patients with folinic acid to see if their symptoms, such as learning, social withdrawal, perseverative thoughts, or trouble sleeping improve with treatment. Describing this subset of patients in the medical literature will help other clinicians caring for people with DS identify this dual diagnosis and monitor or treat these patients appropriately.
Tammy Yanovitch MD; Mentors/Collaborators: David Wallace MD MPH, Terri Young MD, Sharon Freedman MD, Sandra Holgado CO MD, Azita Sadgephor, Priya Kishnani MD, Blythe Crissman MS CGC, Gordon Worley MD Duke University Medical Center Applicant’s Primary Department: Ophthalmology Title of Research: Detecting Amblyopia in Children with Down Syndrome by Sweep Visual Evoked Potentials Summary of Research: Infants and children with Down syndrome have an increased risk of developing amblyopia, which is reduced vision in one or both eyes. Amblyopia occurs when the brain fails to receive adequate visual stimulation necessary for normal development during infancy and childhood. Most vision loss resulting from amblyopia, if diagnosed early, is easily treated by providing a clear image to the eye (e.g. correct refractive error with spectacles), and then forcing increased use of the weak eye by patching the visually stronger eye or blurring the visually stronger eye with eye drops. Because standard acuity tests depend on the cognitive ability of the patient and the experience of the examiner, some cases of amblyopia in infants and children with Down syndrome are undiagnosed, and therefore untreated. Sweep visual evoked potential (VEP) testing offers an additional method to assess visual performance without relying on patient response or observer accuracy. Sweep VEP testing measures electrical signals generated in the brain by specific visual stimulation. The purpose of this study is to determine the ability of sweep VEP to detect amblyopia in children with Down syndrome. We will also determine the relative contribution of reduced cognition and identifiable ocular structural changes to visual acuity in children with Down syndrome. We anticipate that these findings will provide a novel method of predictive testing for visual function. The use of sweep VEP as an additional means for detecting amblyopia in children with Down syndrome will aid in timely diagnosis and treatment of amblyopia, thus preventing vision loss and improving overall development. Title of Project: Down Syndrome Registry Program Summary Of Project: The Down Syndrome Registry Program is an 18 month planning grant to establish a Down syndrome disease registry at Duke University Medical Center. The plan is a project to establish a longitudinal, national, observational database that will track outcomes of clinical practice for individuals with Down syndrome. All physicians participating in the Registry are considered participants of the Down syndrome Registry Program. Data collected from these physicians will represent Down syndrome disease practice patterns under common clinical conditions. The data collected by this national collaborative Registry will provide information to better characterize the natural history, developmental progression and treatment outcomes associated with individuals with Down syndrome. Lay Summary Of Project: The Down syndrome registry is a database of medical information on patients with Down syndrome that can be analyzed and used by physicians treating patients with the same condition. The collective information from the registry is used to increase the understanding of the disease and to monitor patients over time, with the ultimate goal of improving the clinical outcomes of patients. The Registry Program is a project to establish a longitudinal, national, observational database that will track outcomes of clinical practice for individuals with Down syndrome. All physicians participating in the Registry are considered participants of the Down syndrome Registry Program. Data collected from these physicians will represent Down syndrome disease practice patterns under common clinical conditions. The data collected by this national collaborative Registry will provide information to better characterize the natural history, developmental progression and treatment outcomes associated with individuals with Down syndrome.
Title of Project: Down syndrome Registry Project Continued Summary Of Research: The Down syndrome Registry Program is a project to examine the feasibility of establishing a national, longitudinal, observational database that tracks the outcomes of routine clinical practice in individuals with Down syndrome. The outcome of the project will be a comprehensive plan with clearly defined goals that will outline three aspects of a DS registry program: medical, technical, and funding sources. As part of this project, we propose to survey the clinic coordinators of all Down syndrome clinics around the country for basic clinical information, basic technological information including internet access and use of electronic medical records, and interest in and concerns about participating in the registry program once established. We propose to use website survey methods to collect these data (supported by hard copy forms for programs unable or unwilling to utilize the web-based format) and to document the capability of centers to interact electronically. In addition, we propose to survey Down syndrome researchers around the country, using both web-based survey techniques and telephone interviews to solicit ideas on how a registry could facilitate both large population based research and to facilitate their own research interests in Down syndrome research. Facilities Available: This project will continue to operate within the Division of Medical Genetics at Duke University Medical Center. We will continue to utilize the technical expertise of the Duke Clinical Research Unit (including Mark Shapiro, project director of the CAPTN network and Dr. Alex Kemper, public health survey expert) to maintain the highest standards of data collection and use of technology. Progress Report: Down Syndrome (DS) Registry Program 1 Feb 2006- 31 Jan 2006 The Down syndrome Registry Program is a project to examine the feasibility of establishing a national, longitudinal, observational database that tracks the outcomes of routine clinical practice in individuals with Down syndrome. The outcome of the project will be a comprehensive plan with clearly defined goals that will outline three aspects of a DS registry program: medical, technical, and funding sources. In our research on the scope of the registry, it appears that the registry could serve both primary and secondary functions, including answering questions about Down syndrome in a large cohort of individuals, providing researchers with the ability to do larger scale studies of particular comorbidities associated with DS, and connecting families with research opportunities or support groups. The goals are to generate more research in the DS field, to further delineate the natural history of Down syndrome, and to aid in the development of empirically based Health Care Guidelines for Individuals with Down syndrome. Our team has identified several already existent databases, but have found no database with the structure, technical power or peer review that we can use as a prototype. However, these past projects have helped us identify what resources we need in order to build a successful registry. These databases we have identified are held by the Down Syndrome Research Foundation (DSRF), Cincinnati Children’s Hospital, Institute of Basic Research, Virginia Commonwealth University, University of Colorado, DS Surveillance Study-Ireland, and DS Registry of the UK, West Australia, and South Australia. This year, we piloted (with Drs. Cohen and Capone) and administered semi-structured interviews with leading researchers and clinicians at the National Down Syndrome Congress Convention in Atlanta, Georgia. We conducted these same interviews by telephone with individuals we were not able to meet in person. Each interviewee was asked to provide their opinions on the feasibility of a national DS registry, knowledge of current databases related to DS, knowledge of potential funding sources, top three topics needing large population based study, and recommendations for additional contacts. Our team formally presented the DS Registry Program at the Down Syndrome Medical Interest Group meeting in Vancouver Canada. This was followed by a round table discussion with input from attendees about the identification of the scope of the project, potential data collection fields, exploring the logistics of a multicenter registry, and identifying potential funding sources. We also facilitated a small break out session in the afternoon to obtain further national and international input. We have ongoing contact and consultation with representatives from the National Down Syndrome Society (NDSS), National Down Syndrome Congress (NDSC), Down Syndrome Research and Treatment Foundation (DSRTF), and the Down Syndrome Research Foundation (NSRF) in Canada, the International Mosaic Down Syndrome Society (IMDSA), and the newly created Down Syndrome Research Coalition. We have also asked for input from the NICHD. All of these entities are supportive of the development of a DS Registry Program, and have provided assistance in identifying resources for our program. We have determined that the primary site of data entry would be Down syndrome clinics across the United States. It would be ideal to have all sites begin the Program at the time the Registry is launched because we believe it will promote the idea that the Registry is a collaborative project and not one owned by one or two centers. This type of program has been successful in other rare disease groups, such as cystic fibrosis and spina bifida, and we are using their experience in order to further develop our program. We are also exploring the concept of an outreach component to include people who either do not live in a catchment area for a DS clinic or do not have the resources to attend a comprehensive clinic, as one of the main challenges is to collect clinical data and treatment outcomes on an unbiased sample of individuals. In order to determine the resources (technical, time, and qualified personnel) available at each site for data entry into the Registry, we plan to design and execute a national survey of all Down syndrome clinics in the United States. The NDSS has identified the clinics in practice and has garnered important demographic information about each of these clinics; they have generously shared this information with us. With our preliminary data and a sample survey from the Spina Bifida Association, our team began collaborating with the Duke Clinical Research Institute (DCRI) regarding our strategy in design and plans for data analysis of the Clinic Survey.
Title of Project: Gene-Gene Interactions and Defects of the Atrial Septum Summary Of Project: Down’s syndrome (DS) is associated with congenital heart disease including defects of the atrial septum, although little is understood about the role of trisomy 21 in the developing heart. A long held view of the developmental defects seen in DS patients is that trisomy 21 leads to a deleterious increase in genes located in the Down’s syndrome critical region (DSCR). However, recent investigations into the etiology of DS-AML have implicated gene-gene interaction between trisomy 21 and GATA-1, a member of the GATA family of transcription factors. In addition, another GATA family member, GATA-4, has been implicated in the autosomal dominant transmission of ostium secundum atrial septal defects. This proposal will investigate whether the congenital heart disease seen in DS is mediated by an interaction between GATA-4 and componenents of the NFAT/calcineurin signaling pathway found in the Down’s syndrome critical region that are known binding partners of GATA-4. This work may explain the defects of atrial septum found in association with trisomy 21, as well as the role of altered calcineurin signaling in the formation of sporadically congenital heart disease. Lay Summary Of Project: Patients with Down’s syndrome often suffer from congenital heart defects but little is understood about the mechanism by which trisomy 21 leads to dysregulation of the developing heart. In addition, the heart defects seen in DS patients are also seen in patients without DS, namely defects in the wall that separates the top two chambers of the heart called the atrial septum. Recent work into the mechanisms of the Down’s syndrome related leukemia have revealed an unexpected association between trisomy 21 and a gene called GATA-1. In addition, another gene related to GATA-1, GATA-4, has been found in families who suffer from defects of the atrial septum independent of DS. Therefore we will investigate if a similar relationship between GATA-4 and trisomy 21 is present in DS patients with congenital heart disease. We will collect blood from patients with defects of the atrial septum and analyze it for mutations in genes which have been implicated in the formation of the developing heart. Once the mutations have been identified we can work to better understand the mechanism of congenital heart disease seen in DS as well that seen in patients without DS. This understanding will help us to identify patients with heart problems earlier, and may enable us to design treatments to prevent congenital heart disease in the future.
Title of Project: A Follow-up Study of the Safety and Efficacy of Rivastigmine in Adolescents with Down Syndrome Summary Of Project: Down syndrome (DS) is the most common chromosome condition associated with mental retardation. Individuals with DS have neuropathological and neurochemical brain changes similar to individuals with Alzheimer disease. Brain cholinergic deficits, due to reduced level of acetylcholine, may contribute to the cognitive deficits of individuals with DS. Our research team was the first to demonstrate that cholinergic therapy, i.e. the use of cholinesterase inhibitors (ChEIs) may be an effective treatment of selected cognitive deficits in individuals with DS. In a series of trials, we found that cholinergic therapy (donepezil and rivastigmine) was effective in improving language performance in adults and children with DS. Recently, in a 20 week trial (16 weeks of treatment), we found that rivastigmine was effective in improving, attention, memory, and language in adolescents with DS. Based on their experience in the clinical trial, parents of 5 of 11 subjects arranged with their local physician to have their child/ward continue rivastigmine therapy after the trial. We propose to re-evaluate all 11 adolescent subjects from the 20 week rivastigmine trial to determine the long term safety and efficacy of rivastigmine treatment. Long term safety will be determined by a review of side effect profiles of subjects on treatment and subjects not on medication. Long term efficacy will be determined by a) a within subject comparison of current performance on selected language and cognitive measures with their performance on these measures during the treatment study and b) a between subject comparison of long term performance trends of subjects on and off treatment. Lay Summary Of Project: Our research group has been investigating the safety and potential usefulness of two medications (donepezil and rivastigmine) on cognitive and language functioning in individuals with Down syndrome (DS). Donepezil and rivastigmine are two of four FDA approved drugs for the treatment of the symptoms of Alzheimer disease (AD). Research has shown that individuals with DS have similar brain changes (chemical and brain pathology) to individuals with AD. Specifically, there is a deficiency in brain chemicals (substances that facilitate nerve transmission) in the cholinergic system. The brain chemical that is deficient is a substance called acetylcholine. The medications donepezil and rivastigmine increase the levels of acetylcholine in the brain. In a preliminary study, we were the first to report that donepezil was safe and effective in improving cognitive performance in adults with DS. In a subsequent study, we were the first to report that donepezil was effective in improving language performance in children with DS. Recently, we found that rivastigmine was effective in improving attention, memory, and language in adolescents with DS. Based on their experience in the clinical trial, the parents of 5 of 11 adolescent subjects arranged with their local physician for a continuation of rivastigmine treatment after our study was completed. We propose to re-evaluate all 11 subjects from the 20 week rivastigmine trial to help determine the long term safety and usefulness of long term medication treatment. This information is important because there are currently no reports of the safety and usefulness of rivastigmine beyond 16 weeks of treatment in individuals with DS. The data from these studies will guide us in the design of future trials.
Priya S. Kishnani, MD Title of Project: A pilot study screening for prevalence of iron deficiency in children with Down syndrome Summary Of Project: Down Syndrome (DS) is the most common genetic cause of mild to moderate mental retardation. With improved medical care, the average lifespan of individuals with DS is currently >50 years. Current health supervision guidelines recommend the same well child care as outlined for the general pediatric population as well as preventative health care specific for people with DS. At the current time testing for iron deficiency /iron deficiency anemia (ID/IDA) in DS is based on a complete blood count (CBC) at 12 months of age, similar to that for the general pediatric population. A diagnosis of ID or IDA could be missed if a CBC is done as these patients have an underlying macrocytosis. The macrocytosis of RBC's of children and adolescents with DS may thus obscure the diagnosis of ID/IDA. Given the important role of iron in brain development, identification of ID/IDA in the DS population is of paramount importance. The proposed study is a pilot single center, prospective study which involves a one time laboratory evaluation of 100 patients ages > 12 months followed in the Duke Down Syndrome clinic for ID or IDA. These lab indices will be used to determine prevalence of ID/IDA in DS. A CBC, reticulocyte count, serum iron, total iron binding capacity and serum ferritin, will be done on all patients. Causes for IDA such as poor nutrition, comorbidities and a stool sample for occult blood loss will be done. Patients identified with ID/IDA will be matched to controls with DS (age, gender and ethnic backgrounds). Causes for ID/IDA will be evaluated and future studies and recommendations will be planned based on results. Lay Summary Of Project: The Duke Down syndrome (DS) clinic was established in 1995 and has seen over 500 patients with DS. A main purpose of the clinic is to improve the care of children with DS by providing good medical care and advancing our understanding of DS via research. Iron deficiency (ID) and iron deficiency anemia (IDA) are conditions where a person has inadequate amounts of iron to meet body demands. IDA is a decrease in the amount/size of red cells in the blood caused by having too little iron. At the current time, testing for ID/IDA in DS is based on labs looking at the size of the red blood cells. However, people with DS can have enlarged red blood cells, therefore, lab results may mask a diagnosis of ID/IDA. Iron is important in brain development; therefore, people with DS and ID or IDA must be identified and treated with oral supplements of iron. The proposed study will take place at Duke and involves a one time laboratory evaluation of 100 patients with DS 12 months or older to look for ID or IDA. We will look at several blood parameters, including red blood cell measures, low serum ferritin, low serum iron levels, high iron binding capacity in blood, and blood in stool. Lab results will be used to determine how common ID/IDA is in our DS clinic. The patients that are diagnosed will be matched to their peers with DS and without ID/IDA to make comparisons and try to determine what factors cause these conditions, which lay the groundwork for future studies. |