Neurofibromatosis

By Shannon Weeks

What is Neurofibromatosis?• Neurofibromatosis type I (NF1) is caused by mutation in

the neurofibromin gene

• AKA von Recklinghausen disease , Watson disease

• An autosomal dominant neurogenetic disorder

• Characterized by the presence of multiple benign neurofibromas

• Affects the bone, the nervous system, soft tissue, and the skin

• Clinical symptoms increase over time

• Neurologic problems and malignancy may develop

Neurofibromatosis-1

• NF-1 occurs in approximately 1 of 2500-3300 live births

• This disease can involve various body systems over time

• Signs can range from benign cutaneous manifestations to extreme disfigurement

• The mortality rate is higher than that of the healthy

population because of the increased potential for malignant transformation of diseased tissues and the development of neurofibrosarcoma

• Patients with NF-1 have about a 3-15% additional risk of malignant disease in their lifetime

• All racial groups are affected equally

• Women and men are affected equally

Genotype/Phenotype…ect• Increased concentrations of nerve growth stimulating activity

have been linked with the development of neurofibromatosis

• NF-1 is a disorder with variable phenotypic expression

• Some patients may mainly have cutaneous expression, and others may have life-threatening or sever disfigurement

• The variation of this disease is even shown within families

• The spontaneous mutation rate is 100 times greater than for many genes, and it is thought to contribute to approximately 30-50% of neurofibromatosis cases.

• A genotype- phenotype analysis suggests that there is no clear relationship between specific NF1 mutations and clinical features of Neurofibromatosis type 1.

Diagnostic criteria for NF-1• (The diagnostic criteria are met

if 2 or more of the features listed are present.)

– Six or more café au lait macules larger than 5 mm in greatest diameter in prepubertal individuals and those larger than 15 mm in greatest diameter in postpubertal individuals

– Two or more neurofibromas of any type or 1 plexiform neurofibroma

– Freckling in the axillary or inguinal regions

– Optic glioma– Two or more Lisch nodules (iris

hamartomas)– A distinctive osseous lesion,

such as sphenoid dysplasia or thinning of the long bone cortex, with or without pseudoarthrosis

– A first-degree relative with NF-1 according to the above criteria

More Clinical Features of NF-1

• Scoliosis• Pseudarthrosis of the tibia• Pheochromocytoma• Meningioma• Glioma• Acoustic neuroma• Optic neuroma• Mental retardation• Hypertension• Hypoglycemia • Fibromas in Iris• Glaucoma - rare

Neurofibromas• Most common benign tumor of NF-1

• These tumors are made yp ofof Schwann cells, fibroblasts, mast cells, and vascular components

• They can form at any place along a nerve

• Three subtypes of neurofibroma exist: cutaneous, subcutaneous, and plexiform

• Cutaneous lesions and subcutaneous lesions are circumscribed. These nodules may be brown, pink, or skin colored. They may be soft or firm to the touch

• Plexiform neurofibromas are noncircumscribed, thick, and irregular, and they can cause disfigurement by entwining important supportive structures

• Cellular loss of wild type NF1 allele is associated with neurofibromas

Protein Function/Biochemistry• Neurofibromin is a cytoplasmic protein that is expressed in neurons, Schwann

cells, oligodendrocytes, astrocytes and leukocytes

• It is encoded by the gene NF1

• It is located on chromosome 17, at the band q11.2

• It has several biochemical functions, including association to microtubules and participation in several signaling pathways

• Alterations in the protein are responsible for a phacomatosis named neurofibromatosis type 1

• Neurofibromin has a guanosine triphosphatase (GTPase) region that binds to Ras and positively modulates conversion of guanosine triphosphate (GTP) to guanosine diphosphate (GDP)

• The protein is necessary for the negative regulation of Ras protein signal; telling us that neurofibromin acts as a tumor suppressor

• Needed for the negative regulation through the cell cycle

3-D Visualization

Ball and Stick

Analysis of mutations

• Many different mutations in the neurofibromatosis gene have been described.

• In 95% of NF1 individuals, a mutation is found in the NF1 gene

• 5% of the patients, the germline mutation consists of a microdeletion that includes the NF1 gene and several other genes

• 45 mutations within the NF1 gene are associated with neurofibromatosis type 1

• Mutations are found in exon 2

• Mutations in this exon involves an insertion of cytosine into codon 5662 and resulted in an early stop codon.

• Another mutation in exon 2 is from the insertion of the amino acid thymidine at nucleotide 5678, which also creates an early stop codon.

• Mutations in NF1 can also lead to juvenile myelomonocytic leukemia

References

• http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=nucleotide&val=109826563

• http://www.ncbi.nlm.nih.gov/Structure/mmdb/mmdbsrv.cgi?form=6&db=t&Dopt=s&uid=38151

• http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=162200