What is Neurofibromatosis?

By Peter Dearden 23/03/2011

by Mary Gray, PhD Student, Clinical Genetics Research Group

I was reading this article a few days ago and felt inspired to write a few words about one of the most common genetic diseases that few people know about. Neurofibromatosis type one has a world wide incidence of 1/3000 people, meaning that around 1300 or so New Zealanders could be affected by this disease.

People with Neurofibromatosis type one (NF1) can have a very mild form of the disease and may not know they have it, or they can be very severely affected by the disease. Features of NF1 disease include pigment abnormalities where a person may have many ‘cafe-au-lait’ spots (coffee and cream coloured spots 2-5cm wide) and freckling especially around the arm-pits. Some people have scoliosis (curved spine), osteoporosis and pseudoarthosis (a non-healing fracture) of the shin bone, heart problems and mild learning problems. However the most striking feature of the disease (and where it gets its name from) are the often multiple non-cancerous tumours that form on nerve sheaths called neurofibromas. Neurofibromas may form anywhere a nerve exists; tumours can form internally causing pressure on vital organs, in the brain, in the eye causing blindness, in nerves that control muscle function causing weakness, or may form externally in the skin causing sometimes severe disfigurement. In up to 5% of NF1 cases these tumours may become malignant (cancerous) and people who have these malignant tumours have a poor prognosis for survival. Many patients also suffer from chronic depression, but it is not conclusive if this is due to the emotional burden that can come with dealing with some aspects of the disease (such as facial disfigurement) or if it is a biochemical susceptibility intrinsic to the disease.

Neurofibromatosis type one is caused by mutations in the NF1 gene. Around 50% of people with NF1 disease have new mutations, probably because the gene is very large making it quite a big target for mutations to occur in. The other 50% are familial cases – that is passed from parent to child. NF1 disease is an autosomal dominant disorder as you only need one defective copy of the NF1 gene to have the disease — and to have a 50% chance of passing it on to your children.

The NF1 gene is an important component of a cell signalling system known as the Ras/MAPK pathway. This Ras/MAPK pathway is composed of various proteins (made from genes) that tell cells to divide, to become specialised, to migrate and even to die. As you can imagine a pathway that has the power to tell a cell to do all or any of those things is very crucial for normal function and must be tightly controlled to prevent things like too much growth, cell survival when the cell should die or migration to incorrect locations.

The NF1 gene encodes a protein called neurofibromin and its role in the Ras/MAPK pathway is to help recycle the Ras protein so that there is always the correct amount of signalling and non-signalling Ras proteins in a cell. When a person has Neurofibromatosis type one, one of their copies of the NF1 gene doesn’t produce neurofibromin so they have half the amount they should, which is not enough to keep the level of Ras protein normal in a cell. This allows the Ras/MAPK pathway to signal too much so that cells may grow too much, live when they are meant to die and consequently form tumours. The NF1 gene is expressed in basically every cell in the body, but especially in nerve cells, hence why the nerves are the most affected by disease in NF1 patients. These nerve tumours can become cancerous when the other normal copy of the NF1 gene becomes defective so that there is very little control over the Ras/MAPK pathway.

This Ras/MAPK pathway is defective in several other genetic diseases that can be common as well. Noonan Syndrome is especially common and patients can have congenital heart defects, facial abnormalities such as widely spaced eyes, short stature and malformed chest. These disorders tell us a lot about how genes (and their proteins) work and let us know what genes are important for development of a human. When these processes go wrong, often there is not a lot that can be done to cure someone with a genetic disease. However understanding what is happening inside them at the molecular and genetic level can give us more ways to treat their disease, and ultimately improve their quality of life. If you would like to know a bit more about what it can be like living with NF1 check out Reggie Bibb’s website and click the ‘who am I?’ tab and read his blog.