Neurofibromatosis

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Neurofibromatosis

• By Shannon Weeks

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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

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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

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Genotype/Phenotypeect

• 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.

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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

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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

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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

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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

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3-D Visualization
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Ball and Stick
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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

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References

• http//www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db
  nucleotideval109826563
• http//www.ncbi.nlm.nih.gov/Structure/mmdb/mmdbsrv
  .cgi?form6dbtDoptsuid38151
• http//www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id
  162200