By Ellen Burns
Report on HSAN1 Symposium
It was Wednesday, April 23, 2008, and unusually warm for Boston, with spring trees and flowers bursting into bloom. A group of scientists gathered at the Royal Sonesta Hotel for dinner the night before the first HSAN1 Symposium. Many knew one another’s work. Some had met at other conferences. Still others had communicated by e-mail. This night they met to match the person with the work. This is much the same goal as the Deater Foundation has in meeting doctors and scientists and attending conferences. We want the specialists who are working with cells and test tubes and sophisticated analysis instruments to remember the people behind the disease.
Eric Newcomer and Cindy, Larry Deater and Rory, and Ellen Deater Burns were also at the dinner, which buzzed with excitement about sphingolipids and cellular biology. Donna Crowe, with the Day Laboratory at Massachusetts General Hospital (MGH) arranged a wonderful meal for the gathering, and she and Diane McKenna-Yasek, the Neuromuscular Research Coordinator, joined us and the many researchers there. Dr. Robert H. Brown, Jr. served as host, as he and Dr. Florian Eichler had invited the participants there. People were so interested in sharing ideas, the hotel staff had to move the tables out from under us to get the group to leave the room! Many people moved to the lounge area where the discussions continued.
The next morning the group re-convened, with additional members including Tami Newcomer Murphy, at the MGH research facilities at the Charlestown Navy Yard. Dr. Brown welcomed the group. Then Teresa Dunn, PhD, who has been working in cooperation with the Day Laboratory on a NIH grant for HSAN1, presented her recent work with yeast and sphingolipid metabolism.
Hereditary Sensory Neuropathy Type 1 (HSN1), sometimes called Hereditary Sensory Autonomic Neuropathy Type 1, is known to be caused in some, but not all cases, by a defect in a gene on chromosome 9. The gene is identified as SPTLC1. Genes make proteins and proteins make enzymes. SPTLC1 encodes one subunit of the enzyme serine palmitoyltransferase (SPT). In yeast, there are 3 sub-units of this enzyme. In mammals, there are thought to be only 2: LCB1 and LCB2.
Teresa Dunn, who works at the Uniformed Services University of Health Sciences, Bethesda, Maryland, has been studying the interaction of the serine sub-units. Her research shows that the structure of the enzyme is very complicated. The dynamics between the two subunits are affected by the mutation. This affects their stability and the ability of the sub-units to regulate the production of glycosyl ceramide, a fatty substance in the body.
Dominic Cappopiano, PhD Chemist from the University of Edinburgh, Scotland demonstrated the crystalline structure of the enzyme serine palmitoyltransferase. Chemists have been working to discern this structure for 20 years. He postulates that because of a loss of flexibility, there is a deficit in serine binding that leads to the enzyme’s malfunction.
Christopher Haynes, a graduate student in the School of Biology at the Georgia Institute of Technology, Atlanta, presented impressive mass spectrometry imaging of the structure of sphingolipids.
Garth Nicholson, PhD, the University of Sidney, Australia, whose team was first to discover the location of the genetic mutation, raised many questions still to be answered. He does not believe there is truly an autonomic dimension to the disease, but does believe there is a motor component. He proposed that an alteration in the enzyme activity may damage the nerve axons. This brings to question: where are lipids (like glycosyl ceramide) synthesized? It is believed that the enzyme is in the cell body; then what is the mechanism of the enzyme to go from the cell body to the axon?
Thorsten Hornemann, PhD, at the Institute for Clinical Chemistry, University Hospital, Zurich, Switzerland, presented what seemed to be the most radical proposition. He demonstrated the presence of a third sub-unit in the enzyme serine palmitoyltransferase. He suggests that there is a toxic side product that builds up in cells and causes the disease. He proposes that the presence of a third sub-unit may present a method of treatment for the disease.
Alex McCampbell, PhD, with Merck Research Laboratories, West Point, Pennsylvania, but formerly with the Day Lab, presented on his experience with developing the mouse model of HSAN1. He underscored the question of whether the disease is caused by a toxic property or a rate-limiting step in the synthesis of ceramide. Research currently supports both hypotheses.
Florian Eichler, PhD, Department of Neurology, Massachusetts General Hospital, updated the group on the newest findings from the mouse model of HSN1. The observations seem to demonstrate that decreased SPT activity causes the disease although there are differences in the ways the disease is expressed in humans and mice.
Ann Moser, BA, Research Associate in Neurology at the Kennedy Krieger Institute in Baltimore, was able to use new state of the art equipment to conduct a lipid analysis of the mouse model of HSAN1.
Robert Brown, Jr., MD, PhD, Director of the Day Laboratory for Neuromuscular Research, Massachusetts General Hospital, discussed potential strategies of intervention in HSAN1, taking into consideration both the loss of function model and the gain of function (toxic properties) model. Other questions were raised, including what is the basis for cellular specificity: why are sensory nerves the target for the alteration in the enzyme?
Kurt Fishbeck, PhD, Chief of the Neurogenetics Branch of the National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, led the discussion to close the conference. He especially engaged the participants who are currently working in industry. These included Alex McCampbell, Gilmore O’Neil, MD, PhD (formerly with the Day Lab), and Bob Anderson. A lively discussion followed, much of which focused on the need for further study to confirm the mechanism of action of the altered enzyme.
The participants representing the Deater family proposed another study to provide blood samples to the scientists representing the various views. Dr. Brown proposed to initiate the study and it is hoped that many- if not all- affected members of the family will volunteer to participate.
The scientists at the symposium all expressed enthusiasm and dedication for the work they are doing. They shared research information with candor. They were hopeful of being “on the brink” of new discoveries in HSAN1. And they all expressed great appreciation to the Deater Foundation for the opportunity to share their views in this forum. Eric, Tami, Larry, Rory, and I were encouraged by the process and the people who are leading the way to a treatment- and potential cure.