Genetic discovery sheds light on infection-triggered neuropathy

Neuropathy, a disorder in which damage to nerves can impair sensation and movement, has many causes, including infection. Now, researchers from the UK have identified distinct genetic changes in a newly-discovered neuropathy and believe that their work will provide insights into the causal mechanism and why some previously healthy people develop neuropathies after infection whereas others do not.

Dr. Rob Harkness, a postdoctoral research Fellow at the University of Manchester, Manchester, UK, will tell the annual conference of the European Society of Human Genetics today (Monday) how the researchers were alerted to the case of a child in intensive care who had been fit and well until seven months old. Following a mild fever and rash she became very floppy and weak, needed help with her breathing and died before reaching her first birthday. A similar pattern had affected two of her elder brothers.

"At that point we undertook a genetic discovery study. We identified a change in a gene that we thought was likely to be the cause but it wasn't until around ten years later that we identified a second affected family with changes in the same gene with a similar clinical history – rapid neuropathy following a mild infection. Now we know of 12 affected families with changes in this gene," says Dr. Harkness.

The physical effects caused by changes in this gene are similar to those seen in patients with the neuropathy called Guillain-Barré syndrome, which can also be triggered by infections including Epstein-Barr virus and the bacterium campylobacter. The condition can start in people who are completely healthy and cause them to develop weakness of the legs that can spread to the whole body, including affecting their breathing.

We hope that our discovery will provide insights into the mechanisms that cause the problem. The experiments we have undertaken on cells from patients show similar features to those seen in motor neurone disease (MND), and we may be able to use knowledge gained in research on MND to help patients affected by this newly-defined condition, and vice versa. Unfortunately, there are currently no effective prevention strategies for such neuropathies, but our greater understanding of the causes of these conditions will be the first step towards developing treatments."

Dr. Rob Harkness, postdoctoral research Fellow, University of Manchester, Manchester, UK

The new results allow a rapid, accurate diagnosis rather than numerous lengthy and expensive investigations. They will already permit preconception testing of individuals at risk of having an affected child so that this can inform their future reproductive choices. Since the researchers began to publicise their work, more families across the world have been identified, leading them to believe that the rare condition is more common than they originally believed. They are continuing their work by making nerves from skin cells donated by affected people, allowing them to understand why this disorder affects the nervous system specifically, and to test potential treatments. "We are also mirroring these studies using fruit flies," says Dr. Harkness.

"Our hypothesis that there would be a change to a single gene responsible for this particular neuropathy was correct. However, we could not predict which gene it would be and what its role was. Now we know that the gene we identified is vital in controlling how proteins and nucleic acids move between the cell nucleus and the cytoplasm, the gelatinous liquid filling the inside of the cell. This movement is very sensitively controlled and extremely susceptible to stress, temperature and infection in patients with this condition, and when it affects the nerves, they cannot be repaired."

Chair of the conference Professor Alexandre Reymond said: "This is a textbook example of gene-environment interaction. All of us carry on our respective genomes small alterations (genetic variants) that put us at risk of environmental changes, in this case specific infections."