Deater Foundation Helps Sponsor a Third International Symposium:
“Molecular Pathogenesis and Therapy of Hereditary Sensory and Autonomic Neuropathy Type 1”
By Tami Newcomer Murphy
The Deater Foundation, Inc. (DFI) recently had the privilege of helping to sponsor a third international HSAN1 symposium, which was held November 14-16, 2013 in Boston. These conferences are a valuable use of DFI’s resources as they bring together top scientists from around the world who are working on research to understand the causes, mechanisms, and potential treatments for HSAN1, the disease that has afflicted the Deater family for generations, and has been identified in others around the world.
Researchers presented their work on various aspects of HSAN1, including basic research at the cellular level, animal models, and human trials.
Some of the current research and updates included:
- Dr. Florian Eichler (Massachusetts General Hospital): Presented his findings in HSAN1 mice suggesting that diet may be a factor in how the disease progresses. Feeding the HSAN1 mice a diet high in fat seems to cause an earlier onset of the disease. Supplementation of the amino acid L-serine in mice has shown that amino acid selection plays a role in the disease, and perhaps lipids (fats) may as well. This may help explain why some people get the symptoms of the disease earlier, or it progresses more rapidly.
- Dr. Thorsten Hornemann (University of Zurich, Switzerland): Presented his research showing that when the disease causes other amino acids (alanine and glycine) besides serine to be used by the mutated enzyme, the byproduct that is formed cannot be broken down and gotten rid of by the body and becomes toxic to nerve cells. These byproducts can be found in the blood and in the nerves. These byproducts have also been found in the blood, but not the nerves, of mice with diabetes, and giving serine to diabetic mice was shown to improve their neuropathy significantly by the end of the study. This might be an indicator of what actually drives the neuropathy and whether or not focusing on just lowering the byproduct in the blood would be sufficient to treat the disease.
- Dr. Dominic Campopiano (School of Chemistry, Edinburgh, Scotland): Presented updates on the structural biology of SPT (the enzyme mutated in patients with HSAN1) and whether or not drug therapies targeting components of the SPT enzyme itself or the sphingolipid synthesis pathway as a whole might be viable options to consider for treatment development.
- Dr. Teresa Dunn (Uniformed Services University of the Health Sciences): Presented her research into the small subunits of the SPT enzyme and also provided more insight into how the SPT enzyme works as a whole. Her research indicated that many HSAN1 mutations elevate activity of the SPT enzyme, making it harder for the enzyme to be so selective, which in turn leads to alanine and glycine binding instead of just serine. Binding with these other two amino acids resulting in the toxic byproducts. She suggested that one avenue for potential therapy might include finding a method to lower the activity of SPT in HSAN1 patients, and therefore help maintain the enzyme’s selectivity for L-serine.
- Dr. Marc Freeman (University of Massachusetts): Presented his research on new insights into the death of nerve cell axons (the long slender projection of the nerve cell), specifically the identification of an axon death-signaling molecule and a novel fusion protein in both fly and mouse models that, when overexpressed, can actually block the degeneration of axons, if the cell body of the nerve is still intact. Future experiments to see how these findings could impact HSAN1 were discussed, including a potential treatment for HSAN1.
Other neuropathies relative to HSAN1 were discussed, including HSAN3 (Dr. Elisabetta Morini, MGH), Hereditary Spastic Paraplegia (Dr. John Fink, University of Michigan), and spinal muscular atrophy (Dr. Kenneth Fischbeck, NIH), as well as lessons learned from these diseases and how that information could potentially be applied to HSAN1. Dr. Anne Louise Oaklander (MGH) presented her research on painful neuropathies and the role of small nerve fibers in these diseases. She suggested that nerve injuries may be a common cause of bone fracture and that losing innervation to the bone may cause the bone to be more susceptible to fractures (as sometimes seen in patients with HSAN1). She also stated that women tend to have more sensory fibers in skin biopsies initially when compared to men (which might help explain the disease variance sometimes seen among HSAN1 patients of different gender), and also that skin biopsies taken in healthy individuals without HSAN1 show that a change occurs normally in small sensory fibers around age 22 (which could also point to a possible explanation as to why a more obvious symptom onset typically occurs around this time in patients with HSAN1). She explained that small nerve fibers may deteriorate due to lack of oxygen, especially in the toes and fingers, and therefore she suggested improving oxygenation to the extremities (hyperbaric chamber, exercise, smoking cessation, etc.) to help stop this loss of small nerve fibers. She concluded with the recommendation that patients with HSAN1 obtain bone scans frequently, especially of the heel area, in order to help monitor any changes that may be occurring.
Dr. Mary Reilly (University College London) presented lessons learned from previous clinical trials in peripheral neuropathies as well as information about the current HSAN1 patient population in London. She brought up discussion on potentially evaluating children who might be at risk for having HSAN1 in order to better understand what is going on in the early stages. She suggested that HSAN1 nerve degeneration is probably happening around ages 6-7, but there are no symptoms in the child yet. Most likely, by the time symptoms become apparent around age 12 or above, there is probably already about a 30% sensory loss of nerves at this point.
The meeting concluded with a discussion on HSAN1 patient populations in Boston and London, review of information obtained from the follow-up surveys done by Dr. Vera Fridman coupled with the original survey from the Deater Foundation in 2007, and the potential for an HSAN1 fly model (Dr. Vincent Timmerman, University of Antwerp). Many new ideas were generated, including improving clinical outcome measures, setting up an international registry of HSAN1 patients, completing a prospective natural history study, and possible pre-symptomatic study. Everyone present agreed to continue making advancements through collaboration and communication in order to further understand this disease. There was also a unanimous interest in holding more HSAN1 conferences in the future and also seeing if research pertaining to HSAN1 could be integrated into the broader-scale neuropathy symposiums held throughout the year, like the annual International Charcot-Marie-Tooth Consortium and/or Peripheral Neuropathy Meetings.
This 3rd symposium was a productive time of research presentation, idea discussion, and potential therapy proposals by these top researchers in order to further the goal of developing a treatment and cure for patients with HSAN1. We thank you all so much for your donations to DFI, and we want you to know that your generosity helped make this important meeting possible!