Precision treatment for NF1 steps closer with mutation clues

A new genetic study suggests varying mutations in the NF1 gene may determine which particular disease symptoms arise in the cancer syndrome neurofibromatosis type 1. The finding opens the door to discovering ways to help doctors decide the best treatment for patients born with the disease.

The study investigates mutations that may raise the risk for optic gliomas, one of the most common brain tumors to arise in children with NF1.

The study, from the Washington University School of Medicine in St. Louis, MO, is published in the journal Human Molecular Genetics.
Children born with neurofibromatosis type 1 (NF1) usually develop brain and nerve tumors, in addition to other medical problems, including skin and bone defects, autism and epilepsy.
NF1 is among the world's most common genetic disorders, occurring in about 1 of every 3,000 births. Although it is caused by a mutation in the gene that bears its name, the symptoms that arise vary widely, making it difficult to determine the best course of treatment.
There are thousands of different mutations that can affect the function of the NF1 gene. By investigating the effect of a particular mutation in mice, the new study suggests specific mutations may give rise to specific clinical features.
The finding brings closer the day when doctors will be able to predict which specific NF1 symptoms are likely to arise in their patients by identifying particular mutations in their NF1 genes.
It suggests it may be possible to use mice genetically engineered with patient-specific NF1 gene mutations to predict which mutations are linked to which symptoms of the disease.
Senior author David H. Gutmann, a professor of neurology, says:
"These early-phase findings bring us one step closer to being able to individually tailor how we monitor and treat people with NF1."

Increased risk of developing optic gliomas

For their study, the team investigated mutations that may raise the risk of developing optic gliomas, one of the most common brain tumors to arise in children with NF1 and a known cause of vision loss in these patients.

Fast facts about NF

• Neurofibromatosis (NF) occurs worldwide in men and women of all races and ethnic groups
• Half of cases arise from spontaneous mutations in the NF gene
• Most people with NF type 1 have symptoms by the age of 10.

Learn more about NF

The researchers showed that one group of mice carrying one specific NF1 gene mutation from a human patient developed optic gliomas, while a second group of mice with another human NF1 gene mutation did not. The mice that developed the gliomas also developed vision problems.
On further investigation, the team found that the mutations appeared to affect the function of microglia - a type of immune cell in the central nervous system that is part of the first line of defense.
Further experiments revealed that the two mutations had different effects on the number and activity of microglia. The first group of mice had more microglia in their brains and they developed bigger tumors and more damage to the optic nerve. No such findings arose in the second group of mice.
The team is now investigating the underlying mechanism through which microglia may help the growth of optic glioma and lead to vision loss.
Prof. Gutmann says he and his colleagues are very excited by their findings. He notes that they can "now envision using a mini-clinic of mice with different NF1 gene mutations" that could offer a "valuable representation of the spectrum of clinical variability in this very heterogeneous disorder," and adds:source-medicalnewstoda