An international cadre of experts gathered in April in Boston to discuss the chemistry, biology, genetics, neuropathy, treatment, and potential for cure for HSAN1.They were joined by post-doctoral fellows, doctors, researchers, and 5 members of the Deater family. The welcome dinner provided time to fellowship and talk about funding issues and possibilities, as well as to remember Larry Deater and his dedication to this ongoing research.
Dominic Campopiano- Edenborough Scotland- discussed the basic chemistry of the biosynthesis of the enzyme serine palmitoyltransferase (SPT). The SPTLC1 gene provides instructions for making one part (subunit) of the SPT enzyme. The mutation of the gene interferes with the mechanism of the enzyme SPT. A question that remains is, “how is SPT regulated by the cell?”
Tere sa Dunn-Giroux- Bethesda Maryland- is focused on identifying and characterizing the enzymes responsible for sphingolipid synthesis, on determining how sphingolipid synthesis is regulated, and on clarifying the functions of these important lipids through a genetic and biochemical approach. The enzyme is more complex than previously thought.
Thorsten Hornemann- Zurich Switzerland- discussed the role of sphingolipids in the body. They play a major role in the neurological system- brain and nerves. We know that the blood levels of deoxysphingolipids is increased in HSAN1 because of the increased activity of the cells with alanine vs. serine. A similar increase is seen in persons with diabetes.
Garth Nicholson- Sydney Australia- talked about the difficulty of measuring the sensory progression in HSAN1 neuropathy because the nerve fibers at the point at which the affected person can feel are already depleted.
Naomi Chuying- presented her research on L-serine therapy in mouse models of diabetic neuropathy. She observed that deoxysphingolipid levels were elevated in Type II but not Type I Diabetes. L-serine supplementation improved gut transit time and pain response in mice.
Reza Seyedsedjadi- Massachusetts General Hospital- talked about questions that are asked to elicit responses that are used to measure symptoms. Some items are more sensitive than others and it is important in determining the natural history of the disease to have valid comparisons based on clear questions.
Hirosha Geeklyange- University of Massachusetts- discussed the role of sphingolipids in Alzheimer’s Disease. Ceramide, a sphingolipid, is found at 3 times the normal levels after death in patient with Alzheimer’s disease.
Vera Fridman- Denver Colorado- reviewed the results of the L-serine supplementation study. Half of the participants received L-serine and half received a placebo for a year. The second year all participants received L-serine. Standard nerve conduction tests were not sufficient to measure the study results. Patient reports were the most important and responsive results, along with positive reductions in the Chacrot-Marie-Tooth neuropathy scale.
Bob Brown and Havisha Karnam- University of Massachusetts- underscored that the mutant gene leads to neurotoxicity and targeting the gene may be the most reliable route to a cure of the disease by either suppressing or silencing the mutant gene. Working with Dr. Anastasia Khvorova, Havisha has determined that correcting the mutant gene in the neuron (dorsal root ganglia) may not be sufficient and treating the liver must be considered.
Anne Louise Oaklander- Massachusetts General Hospital- discussed her work on small fiber neuropathy and presented case studies of children. She is interested in studying children with neuropathy and suggests that microneuropathy, an electrophysiological technique used for recording nerve traffic directly from peripheral nerves may be helpful in imaging HSAN1.
Florian Eichler- Massachusetts General Hospital- talked about targeted gene correction to the dorsal root ganglia. In the L-serine study, the signal in motor and sensory nerves were modified by L-serine. He suggested engaging with industry to promote amino acid supplementation, but noted there is a critical limit of serine. Many questions remain. Is there a modifier gene? What is the actual cause, along the biologic pathway? The disease is present before any symptoms are manifest. A study in younger people, especially children, may be helpful.
The discussion and sharing of research ideas was invaluable, as participants asked questions of one another and discussed collaborations. The conference concluded with renewed dedication to seeking a long-term treatment and eventual cure for HSAN1.
This HSAN1 conference was fully funded by the Deater Foundation, Inc.