Jonathan Pevsner is an Associate Professor in the Department of Neurology (Kennedy Krieger Institute) and the Department of Psychiatry (Johns Hopkins Medicine). He received his bachelor's degree from Haverford College, his Ph.D. from Johns Hopkins, and did his postdoctoral training at Stanford University. His laboratory studies the genetics of childhood brain disorders, and he began research on Sturge-Weber syndrome in 1999. He is the recipient of multiple teaching awards and wrote a textbook, Bioinformatics and Functional Genomics (2009).
A major goal of Sturge-Weber syndrome research has been to identify the underlying genetic mutation. Recent developments in technology allow us to determine the sequence of essentially all 3 billion base pairs in the human genome. We hypothesized that by sequencing the genome twice--from an affected part of the body (such as a port-wine stain) and from an unaffected part (such as blood)--we could compare the sequence within an individual to identify an altered gene. We obtained pairs of whole genome sequences from three individuals with Sturge-Weber syndrome and identified a single base pair change in the gene GNAQ on chromosome 9. This mutation occurred selectively in affected samples. We then confirmed this mutation by exhaustive sequencing of 90 samples from 50 individuals. This showed that nearly all affected skin samples, and many affected brain samples, harbor a mutation in GNAQ. This mutation is somatic (that is, it occurs early in development but is not inherited from the parents), and mosaic (it occurs in some but not all parts of the body; and within an affected region the amount of mutated sequence ranges from 1% to 18%). The full name of GNAQ is guanine nucleotide binding protein (G protein), q polypeptide. This gene encodes a protein, Gaq, that has been extensively studied for over 20 years. Gaq acts as a switch on the inside wall of many cells. When a variety of receptors on the cell surface receive a signal from outside the cell, Gaq has a key role in activating downstream pathways. The specific mutation that occurs in Sturge-Weber syndrome and port-wine stains persistently activates Gaq, inappropriately activating downstream pathways. Possible therapeutic approaches to Sturge-Weber syndrome include applying drugs to down-regulated Gaq activity.
Jack L. Arbiser, MD, PhD is a Professor in the Department of Dermatology and Winship Cancer Institute at Emory University. Dr. Arbiser joined the Dermatology Department at Emory after completing his PhD and medical school training, internship, and residency at Harvard Medical School, followed by a three-year Howard Hughes Fellowship in the laboratory of Dr. Judah Folkman. Dr. Arbiser’s research focuses on the regulation of angiogenesis and tumorigenesis by signal transduction pathways. His laboratory has chosen three model systems to study these relationships. The first area is the common vascular birthmarks of children and their malignant counterparts, angiosarcomas. The second application of these studies is benign neoplasms which develop in the autosomal dominant syndrome tuberous sclerosis (TS). The third application of these studies is in the pathogenesis of malignant melanoma. In addition, Dr. Arbiser has a long history of development of small molecules as antiangiogenic and antitumor therapies. The Arbiser laboratory has discovered the antiangiogenic and in vivo antitumor properties of honokiol, and has synthesized honokiol analogs along with Imipramine Blue, a novel NADPH oxidase inhibitor with systemic availability and antitumor efficacy. As a result of this research, Dr. Arbiser has authored or co-authored 170 peer-reviewed publications as well as many review articles and book chapters.
Three types of endothelial diseases are present in children. The most common is hemangioma of infancy, which arises rapidly, undergoes proliferation, followed by spontaneous involution. Severe cases of this can be treated with propranolol, a beta blocker that inhibits NADPH oxidase. The second most common type are nonregressing vascular malformations, which include Sturge-Weber disease. We have found activation of pS6 kinase in these lesions and have modeled them by overexpression of Akt. The rarest type are malignant vascular lesions, which we have modeled by overexpression of ras in endothelial cells. The current unmet need in vascular malformations are ways of causing them to undergo physiologic regression. Based upon our findings, clinical trials of rapamycin have been performed on vascular malformations and lymphangiomas, resulting in efficacy. In addition, we have found a biomarker that distinguishes hemangiomas of infancy from vascular malformations, namely Wilms tumor 1 (WT1). Further areas for exploration include induction of endoplasmic reticulum stress (ER stress) in vascular malformations, either by physical methods (laser, cryotherapy) or by novel drugs.
Emily A. McCourt grew up in the suburbs of New York City. After a short career teaching seventh grade science, she attended medical school at the University of Buffalo (SUNY-Buffalo). Dr. McCourt completed her internship at Exempla St. Joseph’s Hospital in Denver followed by a residency in Ophthalmology at the University of Colorado. In 2012 she completed a fellowship in pediatric ophthalmology at Children's Hospital Colorado and joined the faculty of the University of Colorado as an Assistant Professor. She is currently the director of pediatric ophthalmology research.
Glaucoma and retinal detachment are the two most common eye disorders in patients with Sturge-Weber Syndrome. Both diseases require intense medical and surgical care. Additionally, retinal detachment and glaucoma can cause vision loss despite prompt and meticulous treatment. Current treatment modalities, an understanding of the mechanism of disease, as well as new treatments for eye disorders associated with Sturge-Weber will be discussed.
Csaba Juhasz, MD, PhD
Dr. Juhasz is an Associate Professor of Pediatrics and Neurology at Wayne State University in Detroit, and he works at the Translational Imaging Laboratory at the Children’s Hospital of Michigan. He is the principal Investigator of a prospective, longitudinal study (funded by the NIH since 2003), where, together with co-investigator Dr. Harry T. Chugani, he uses advanced neuroimaging techniques combined with neuro-cognitive assessments to evaluate brain functional abnormalities and reorganization in children with Sturge-Weber syndrome. Dr. Juhasz published more than 25 peer-reviewed papers and book chapters to present the results of these studies.
Neuroimaging plays a critical role in the diagnosis and management of patients affected by Sturge-Weber syndrome (SWS). Magnetic resonance imaging (MRI) is the gold standard to establish intracranial involvement in SWS and to evaluate the extent and severity of brain vessel and tissue abnormalities. New, advanced MRI techniques are emerging and allow us to evaluate structural and functional brain abnormalities even in the early disease stage with an increasing accuracy. Quantification of brain function using novel MRI and positron emission tomography (PET) techniques provides new insights in the pathophysiology of disease progression. Advanced imaging may also offer prognostic markers for neurocognitive outcome and can assist identification of patients who can benefit from epilepsy surgery to eliminate uncontrolled seizures and optimize brain development.
Dr. Morelli received his BA degree Summa Cum Laude with Honors in Biophysics from the University of Pennsylvania and his medical degree from Harvard University. Following completion of his Pediatric residency at the University of Colorado he returned to Harvard University Wellman labs for a fellowship in Photobiology. He then completed his Dermatology residency and an Immunodermatology fellowship at the University of Colorado. Following completion of his Immunodermatology fellowship, he joined the faculties of Dermatology and Pediatrics and he has been there since that time. He is also Section Head of Pediatric Dermatology at the Colorado Children’s Hospital.
The laser treatment of port wine stains began with non specific lasers in the 1970’s. These were largely unsuccessful because of the severe scarring associated with the treatments. The theory of selective photothermolysis elucidated in 1983 led to the development of the initial vascular specific pulsed dye lasers. These lasers were much safer and the results of treatment were much improved over previous lasers, but complete clearing of treated port wine stains remained uncommon. Several changes in the laser parameters were made to try to improve these results, but most were not helpful. One of the problems is that although the laser treatment destroys some of the excess blood vessels in the port wine stain, this sets up a wound healing response which leads to the growth of new blood vessels, so it is two steps forward and one step backwards. Inhibitors of new blood vessel growth used in conjunction with laser treatment may increase the efficacy of the treatments. Rapamycin is one such inhibitor. The use of rapamycin or yet to be developed inhibitors of blood vessel growth need further study. It is important for the members of the Sturge-Weber Foundation to participate in any study which has the potential to improve laser treatment outcomes.