Neurofibromatosis By Shannon Weeks What is Neurofibromatosis Neurofibromatosis

Neurofibromatosis By Shannon Weeks

What is Neurofibromatosis? • Neurofibromatosis type I (NF 1) 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 NF 1 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 NF 1 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 NF 1 • It is located on chromosome 17, at the band q 11. 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 NF 1 individuals, a mutation is found in the NF 1 gene • 5% of the patients, the germline mutation consists of a microdeletion that includes the NF 1 gene and several other genes • 45 mutations within the NF 1 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 NF 1 can also lead to juvenile myelomonocytic leukemia

References • http: //www. ncbi. nlm. nih. gov/entrez/vie wer. fcgi? db=nucleotide&val=109826563 • http: //www. ncbi. nlm. nih. gov/Structure/ mmdb/mmdbsrv. cgi? form=6&db=t&Do pt=s&uid=38151 • http: //www. ncbi. nlm. nih. gov/entrez/dis pomim. cgi? id=162200