neurofibromatosis by shannon weeks. what is neurofibromatosis? neurofibromatosis type i (nf1) is...
Post on 19-Dec-2015
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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
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