Neurofibromatosis Type 1
- Although classified as an “orphan disease” by the FDA, NF1 is a relatively common genetic disorder (approximately 1 in 3000 live births), impacting an estimated 125,000 people in the U.S. and 2.5M people worldwide.
- NF1 is more prevalent than Duchenne Muscular Dystrophy, Cystic Fibrosis, Tay-Sachs and Huntington’s disease combined, and yet only one FDA-approved, disease-specific, treatment option exists (e.g. Koselugo).
- The NF1 gene has been studied and characterized since its discovery in 1990. NF1 is located on chromosome 17 (17q11.2) and is one of the largest of the 20,000 human genes, consisting of over 350,000 base pairs of genomic data with 61 (protein generating) exons.
- NF1 mutations and symptoms are highly varied. From the first 8,000 NF1 patient genomes that were sequenced (from unrelated patients), over 3,000 unique NF1 mutations were identified. Except in a small percentage of cases, the specific mutation a patient has (i.e. their genotype) does NOT correlate with any specific symptoms, or the severity of disease (i.e. phenotype). This includes the ~50% of people who inherit the same mutation as their parent, yet generally have unique NF1 symptoms and disease severity. Thus, in addition to the specific NF1 mutation a person has, there are many additional factors contributing to NF1 symptoms that researchers do not yet understand.
Symptoms and Complications
The impact of NF1 gene mutations is highly varied but generally involves symptoms of the nervous system, skin, skeleton, and cardiovascular system, including an increased risk of cancer and cardiovascular disease. The most common manifestations attributed to NF1 include:
- Slow-growing skin neurofibromas (i.e. bumps), from just a few to many thousands (present in 98+% of adults)
- Large and complex plexiform neurofibromas (‘benign’ tumors) that grow along nerves throughout the body, impacting organs, limbs, and bones, and often causing physical deformities and pain (30-50%)
- Bone dysplasia such as scoliosis (30-40%) and osteopenia
- Optic nerve gliomas which can result in vision loss/blindness as well as hormonal imbalances (10-20%)
- Cognitive, learning, executive functioning and social communication deficits (~60-75%)
- Café-au-lait hyperpigmentation macules (99%)
- Cancers (including MPNSTs and breast cancer) and cardiovascular disease occur about twice as often as the general population
In summary, NF1 is a progressive genetic disorder in which patients (and doctors) generally wait for symptoms to develop, and then react with symptomatic treatments such as tumor resections, spinal fusions, pain/ADD medications, school related interventions and (mostly ineffective) tumor therapies (i.e., MEK inhibitors).