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Neurofibromatosis Type 1 (NF1) Von Recklinghausen Disease

Neurofibromatosis Type 1 (NF1) Von Recklinghausen Disease. By: Dr. Mahmoud Almutadares , House officer at KAU, MBBS. Objectives. Epidemiology of NF1 Neurofibromin gene Clinical features of NF1 Molecular basis of NF1 Gene strategies to identify modifier genes. Epidemiology.

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Neurofibromatosis Type 1 (NF1) Von Recklinghausen Disease

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  1. NeurofibromatosisType 1 (NF1)Von Recklinghausen Disease By: Dr. MahmoudAlmutadares, House officer at KAU, MBBS

  2. Objectives • Epidemiology of NF1 • Neurofibromin gene • Clinical features of NF1 • Molecular basis of NF1 • Gene strategies to identify modifier genes

  3. Epidemiology • Birth incidence: 1:2500 • Prevalence of 1:4000 • Autosomal Dominant with variable expression

  4. Neurofibromin 1 • Located in 17q11.2 • Approximately 350kb and contains 61 exons • A tumor suppressor gene. • Encodes for Neurofibromin • Over 300 different mutations reported worldwide

  5. Clinical Features • Short statured • Café-au-lait(CAL) spots • Freckling • Lisch Nodules • Neurofibromas • Optic gliomas

  6. Café-au-lait Freckles

  7. Dermal Neurofibromas Plexiform Neurofibroma

  8. Lisch Nodules Optic Glioma

  9. Distinctive osseous lesion such as sphenoid dysplasia or cortical thinning of long bones

  10. Expressivity • Expressivity is the variations in a phenotype among individuals carrying a particular genotype, it is analogous to the severity of a condition in clinical medicine. • Variable expressivity occurs when a phenotype is expressed to a different degree among individuals with the same genotype.

  11. Molecular basis of NF1

  12. 5-10% >90% Intragenic Mutations Large 17q11 deletions No clear-cut allele-phenotype correlations More sever phenotype 3-bp frame deletion (c.2970-2972 del ATT) on exon 17 Absence of Dermal neurofibromas

  13. 1132 Individuals from 313 families No apparentinfluenceof the NF1 gene

  14. Cohort Family Studies

  15. 75% of families have an interfamilial difference in clinical features NF1

  16. mpnst NF1+/- p53

  17. NF1+/- p53 +/- NF1+/- p53+/- p53 p53 p53 p53 NF1 NF1 NF1 NF1

  18. NF1 expression level Nstr1 11q12-13 5p13-15 Nstr2 8q22-24 ch11

  19. Gene strategies to identify modifier genes Approach scanning the whole genome Approach focusing on candidate genes Number of variants are generally small. However, detailed understanding of the candidate gene product.

  20. Candidate gene approach • Generate hypothesis and identifying candidate genes: • Understanding the biochemical function of NF1 • Identifying variants (SNPs) near these genes • Genotyping these variants in a populations

  21. Miss MatchRepair Gene NF1-/- NF1+/- NF1+/- NF1+/- MLH1 MSH6 PMS2 MSH2 Plexiform Neurofibroma > Dermal Neurofibroma

  22. SKP NF1+/- NF1+/+ NF1+/+ NF1+/+ Males and Non-Pregnant Females Pregnant Females

  23. NF1-/- NF1+/- NF1+/- 5% expressed estrogen receptors 75% expressed progesterone receptors • NF1 patients typically develop dermal neurofibromas around puberty • Increased potential for malignant transformation of plexiform neurofibromas with pregnancy

  24. Whole genomic gene approach Pasmant et al • CDKN2A-CDNK2B-ARF • ANRIL Tag SNPs • In 1105 subjects (306 families): • Allele T of SNP rs2151280 was strongly associated with plexiform neurofibromas

  25. Refrences • Nelson Textbook of pediatric, 19th edition • Oxford Handbook of Clinical Medicine, 8th edition • Pasmant E, Vidaud M, Vidaud D, Wolkenstein P. Neurofibromatosis type 1: from genotype to phenotype. J Med Genet 2012;49:483-489 • Heim RA, Silverman LM, Farber RA, Kam-Morgan LNW, Luce MC. Screening for truncated NF1 proteins. Nature Genet. 8: 218-219, 1994.  • Trovo-Marqui AB, Tajara EH. Neurofibromin: a general outlook. Clin. Genet. 70: 1-13, 2006. 

  26. Thank you

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