This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.ABSTRACTAngelman syndrom (AS) is a nuerological disorder that causes global developmental delay, minimal or absent speech, seizures, uncoordinated gait (ataxia), sleep disturbances, and other medical and behavioral difficulties. AS is caused by deficiency of the maternally-transmitted gene that encodes E6-AP ubiquitin-protein ligase (gene symbol UBE3A) mapping to chromosome 15q11-q13.Although some aspects of AS are well known to the medical community, the natural history of AS has not been systematically described. Since AS is a rare disorder, few physicians follow more than a handful of patients at any given Center. A collaborative effort is needed to better understand the natural history of this rare condition. It is only with this knowledge that we will be able to formulate treatment interventions, devise therapies and propose future clinical trials. This study is part of an initiative under the auspices of the Rare Disease Clinical Research Netrowk and the NIH.This study is designed to conduct longitudinal multidisciplinary investigations on the natural history, morbidity and mortality of Angelman Syndrome (AS). We will collect detailed longitudinal data on a cohort of AS individuals to gain a better understanding of the disease progression, and follow the natural history of the clinical features of this patient cohort including assessment of quality of life and longevity.The participants to be recruited for the study will include 1) patients whohave a documented molecular diagnosis of AS and 2) patients with clear clinical diagnosis of Angelman Syndrome as determined by the Principal Investigator (PI) and the Co-investigators in this study but who don't have a known molecular defect.All participants will be seen every 12 months for 5 years during the first phase of accrual and follow-up, at Texas Children's Hospital (Baylor College of Medicine), and also at other centers that form part of this research endeavor including Children's Hospital of San Diego, Boston Children's Hospital, and the Greenwood Genetics Center. A second phase of 5 additional years of follow-up is also proposed. Clinical and relevant historical data will be collected during the clinical visit and examination and also by reviewing medical and laboratory records. Comparisons will be made within the clinically different groups of patients, as well as among the different molecular classes of AS individuals.HYPOTHESISConducting longitudinal multidisciplinary investigations in Angelman Syndrome (AS) drives the main hypothesis of this study . We propose to collect detailed longitudinal data on a cohort of AS individuals to gain a better understanding of the disease progression, and follow the natural history of the clinical features of this patient cohort icluding assessment of qualify of life and longevity. These systematic evaluations will allow us to gather valuable information that we can later apply to the follow-up and treatment modalities. We plan to look carefully at the different subtypes within this condition in order to formulate appropriate interventions.
SPECIFIC AIMS The following specific aims address several key questions on AS:1. Gain a better understanding of the natural history of this concition and its molecular sybtypes from the neonatal period to adulthood.2. Understand the frequent complications experienced by patients with AS during their lifetime and identify possible co-morbid associations that can be prevented or ameliorated with medical intervention.3. Establish a genotype-phenotype correlation over a broad spectrum of AS participatns (with regards to their molecular type).4. Determine the mortality and morbidity in AS.5. Determine if the molecular type of AS correlates with the co-morbid diagnosis of autism or other behavioral abnormalities.6. Determine if AS is associated with a particular medical, psychological or genetic abnormality in the family members.7. Determine the impact of Social and Economic level on the developmental outcome of patients with AS.
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