A multidisciplinary, inter-institutional group of investigators with long-standing interest in brain vascular malformations proposes to establish a RDCRC. The diseases of study are common Hispanic mutation familial Cavernous Malformations (CCM), Sturge-Weber Syndrome (SWS) and Brain Arteriovenous Malformation (BAVM) in Hereditary Hemorrhagic Telangectasia (HHT). The three projects will focus on (a) establishment of scalable, relational databases to facilitate observational studies and clinical trials, working with the RDCRN DMCC;and (b) development of markers for disease progression with near-term potential for aiding prognostication and clinical trial development.
The aims for CCM include identification of genetic markers for disease progression in cross-sectional and longitudinal study designs using a Genome-Wide Association approach.
The aims for SWS are to use urinary excretion of angiogenic mediators as markers for disease progression. Further, we will establish somatic mutations as an underlying disease mechanism with an eye towards adapting such knowledge into a biomarker strategy.
The aims for HHT include quantitative estimation of intracranial hemorrhage (ICH) risk in cross-sectional and longitudinal study designs, using both angioarchitectural features and genetic variation in inflammatory genes. Pilot projects will evaluate novel treatment strategies for the diseases, including the use of aspirin in SWS and tetracycline-class agents in hemorrhagic vascular malformations. We will utilize CTSAs or GCRCs at UCSF, Duke, New Mexico, Kennedy Krieger and Univ. Toronto, with a detailed program for training new investigators in clinical research on rare diseases. Three international Patient Support Organizations (PSOs)?Angioma Alliance, Sturge Weber Foundation, HHT Foundation International?will actively participate. With the DMCC, we will develop a website as a portal for web-based data entry and include a wide range of information for patients, families and professionals. We will utilize a network of established Centers of Excellence in SWS and HHT to identify patients. This RDCRC will provide a much-needed and valuable resource for the clinical neurovascular community for the study of these three disorders.
Brain vascular malformations are resource-intensive to manage effectively, and have high probability of serious neurological morbidity. Specific medical therapies for these diseases are lacking. The identification of markers for progression would improve patient surveillance and optimize management, and treatment trials will require risk stratification for selection and surrogate outcomes for trial development..
|Walcott, Brian P; Choudhri, Omar; Lawton, Michael T (2016) Brainstem cavernous malformations: Natural history versus surgical management. J Clin Neurosci 32:164-5|
|Choquet, HÃ©lÃ¨ne; Trapani, Eliana; Goitre, Luca et al. (2016) Cytochrome P450 and matrix metalloproteinase genetic modifiers of disease severity in Cerebral Cavernous Malformation type 1. Free Radic Biol Med 92:100-9|
|Kavanaugh, Brian; Sreenivasan, Aditya; Bachur, Catherine et al. (2016) [Formula: see text]Intellectual and adaptive functioning in Sturge-Weber Syndrome. Child Neuropsychol 22:635-48|
|Merkel, Peter A; Manion, Michele; Gopal-Srivastava, Rashmi et al. (2016) The partnership of patient advocacy groups and clinical investigators in the rare diseases clinical research network. Orphanet J Rare Dis 11:66|
|Walcott, Brian P; Winkler, Ethan A; Rouleau, Guy A et al. (2016) Molecular, Cellular, and Genetic Determinants of Sporadic Brain Arteriovenous Malformations. Neurosurgery 63 Suppl 1:37-42|
|Kaplan, Emma H; Kossoff, Eric H; Bachur, Catherine D et al. (2016) Anticonvulsant Efficacy in Sturge-Weber Syndrome. Pediatr Neurol 58:31-6|
|Krings, T; Kim, H; Power, S et al. (2015) Neurovascular manifestations in hereditary hemorrhagic telangiectasia: imaging features and genotype-phenotype correlations. AJNR Am J Neuroradiol 36:863-70|
|Golden, Michael; Saeidi, Saba; Liem, Benny et al. (2015) Sensitivity of patients with familial cerebral cavernous malformations to therapeutic radiation. J Med Imaging Radiat Oncol 59:134-6|
|Choquet, H; Pawlikowska, L; Lawton, M T et al. (2015) Genetics of cerebral cavernous malformations: current status and future prospects. J Neurosurg Sci 59:211-20|
|Comi, Anne M (2015) Sturge-Weber syndrome. Handb Clin Neurol 132:157-68|
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