Rare Neuromuscular Disease Identified In American And British Family; Genetic Mutation Responsible For Impaired Muscle Function

neuromuscular junction
A disruption in the synaptic transmission between a motor neuron and a muscle cell results in a neuromuscular disorder. Photo courtesy of Shutterstock

A rare inherited neuromuscular disorder was recently identified by researchers in an American family. The condition that is passed on through generations occurs due to a genetic mutation and disrupts communication between nerves and muscles. This results in impaired muscle control. The discovery was published today in the American Journal of Human Genetics.

The same condition was also identified in a family from Great Britain. "This discovery gives us new insight into the mechanisms of diseases that are caused by a breakdown in neuromuscular signal transmission," said David Herrmann, a professor in the Department of Neurology at the University of Rochester School of Medicine and Dentistry and co-lead author of the study, in a press release. "It is our hope that these findings will help identify new targets for therapies that can eventually be used to treat these diseases."

The neuromuscular system consists of axons that arise from the motor neurons of the spinal cord and terminate on muscle fibers at the neuromuscular junction. The neuromuscular junction connects the nervous system to the muscular system through signals. A disruption in the synaptic transmission between a motor neuron and a muscle cell results in a neuromuscular disorder.

These disorders are either acquired due to mutation or maybe the result of an autoimmune disorder. For example, in Lambert-Eaton myasthenic syndrome that is triggered by cancer, the immune system targets healthy nerves, rendering them incapable of transmitting pulses between nerves and muscles. Other disorders such as muscular dystrophy are inherited. Whatever the cause, neuromuscular disorders result in weakness and fatigue of the limbs.

In case of the two families, doctors couldn’t exactly pinpoint the condition they suffered from, since their symptoms were different from other neuromuscular disorders. Their condition was finally diagnosed as a completely new disorder that is genetic and resembles Lambert-Eaton disorder. Researchers conducted a whole exome sequencing of the family members in order to study the section of the DNA that codes for proteins. They discovered that members from both the families had a mutation in the gene that codes for the protein synaptotagmin 2 (SYT2).

SYT2 is a synaptotagmin, an integral membrane protein that acts as a calcium sensor. It is located at the pre-synaptic terminal, the end of the nerve cell that sits at the neuromuscular junction and helps the cells sense fluctuations in calcium levels. Calcium is important for the electrical function of cells and, in the case of the neuromuscular junction, helps dictate the release of acetylcholine, a chemical responsible for passing communication between the nerve and muscle cells.

Mutation is thought to hamper the ability of the nerve cells to detect changes in the calcium level, thus disrupting release of acetylcholine. As a result, communication gets disrupted and muscle control gets impaired.

Scientists are now trying to understand more about this rare disorder that has affected the two families by creating a mutation in the SYT2 protein in fruit fly models. This, they believe, may help in developing interventions for the condition.

Source: Herrmann D, Zuchner S, Littleton T, Horvath R. American Journal of Human Genetics. 2014.

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