Transcript Neurofibromatosis

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/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