HSN1 (Hereditary Sensory Neuropathy 1)

HSN1 (Hereditary Sensory Neuropathy 1)
Submitted by: Ellen Burns, Medical Liaison

The year 2006 was a relatively quiet period in HSN-1 research. An article in Clinical Neurology and Neurosurgery published in 2006 describes the autopsy findings of a 93-year-old woman who developed symptoms of HSN-1 after age 64. An article in Brain examines the cases of a number of people with various neuropathies, focusing on HSN- 1 and highlighting how differently the symptoms are expressed in different individuals. Throughout 2006 and into 2007, work continued at the Day Lab on the mice that were developed to mimic the results of the genetic mutation that causes HSN-1.

In October 2005 Alexander McCampbell, then at the Day Lab for Neuromuscular Research, was the primary author of an article in Human Molecular Genetics: “Mutant SPTLC1 Dominantly Inhibits Serine Palmitoyltransferase Activity in vivo and Confers an Age-Dependent Neuropathy.” This article describes the research Alex completed in developing the mouse model for HSN-1. Genes in mice were altered, resulting in mice that over produce the enzyme (SPT) associated with HSN-1. One line of mice over produce the enzyme using the normal gene, and another line of mice over produce the enzyme with the gene that has the HSN-1 mutation.

Genes make (encode) proteins, and proteins make enzymes. In HSN-1 there is a mutation in the SPTLC1 gene. The SPTLC1 gene encodes a protein that is a sub-unit of the enzyme serine palmitoyltransferase (SPT). SPT acts as a catalyst in the process of the development and regulation of sphingolipids. This process creates sphingosine, which leads to ceramides. Ceramides are important in intracellular signaling—sending messages within cells (although how that happens is not clear).

The research concluded that mice with the mutant gene develop age dependent weight loss and mild sensory and motor impairments. Aged mice lose large nerve cells at the spinal cord. The mice were examined at all levels, including how elements move within the cells. The mice did not develop ulcers on the extremities, and the overall neurological involvement was not as severe in the mice as it is in the advanced stage of people with HSN-1. However, the mice present a new model of peripheral neuropathy and confirm the link between the mutation of SPT and the nerve disorder.

Alex McCampbell has left the Day Lab; and Dr. Florian Eichler, a neurologist, has joined the team there. Much of his time this last year has been spent working on a project involving Lorenzo’s oil disease, another degenerative spine and nerve disease. Dr. Eichler has also worked with the HSN-1 mice as they have aged and has noted significant changes. He plans to publish those results.

The Day Lab has a couple more years of a grant received from the National Institutes of Health (NIH), in conjunction with other researchers, to study HSN-1. A medical student has been hired as a full time technician. The team awarded the NIH grant meets yearly to discuss progress. This team includes Dr. Teresa Dunn at the Department of Biochemistry and Molecular Biology, who is an expert in processes at the cellular level.

It is believed that the primary pathology of HSN-1 is a decrease in enzyme activity. This could lead to potential treatment trials involving increasing enzyme activity. A conference of those involved in HSN-1 research could provide a fresh look at the studies so far and suggest ways to treat the disease.