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Norrie Disease: Historical Perspective

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Dr. Katherine Sims opens the Norrie Disease Association's first international conference with a warm welcome and historical overview of Norrie Disease. (NDA International Conference, 2009)

Dr. Katherine Sims opens the Norrie Disease Association's first international conference with a warm welcome and historical overview of Norrie Disease. (NDA International Conference, 2009)

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Norrie Disease: Historical Perspective

  1. 1. Welcome to Boston
  2. 2. Norrie Disease Association First International Conference Boston August 13 – 16, 2009
  3. 3. Norrie Disease Historical Perspective <ul><li>Katherine Sims MD </li></ul><ul><li>Massachusetts General Hospital </li></ul><ul><li>Center for Human Genetics </li></ul><ul><li>Harvard Medical School </li></ul><ul><li>August 2009 </li></ul>
  4. 4. Gordon Norrie M.D. <ul><li>Danish ophthalmologist (1855-1941) </li></ul><ul><li>Surgeon at the Danish Institute for the Blind </li></ul><ul><li>Norrie G. (1927) Causes of blindness in children. Acta Ophthalmol 5:357-386 </li></ul><ul><li>identified nine Danish boys with ‘atrophia oculi congenita’ </li></ul>
  5. 5. Mette Warburg M.D. <ul><li>Danish ophthalmologist (1926 - ) </li></ul><ul><li>Research interest in etiology of blindness in those with mental retardation </li></ul><ul><li>Anderson SRM and Warburg M (1961) </li></ul><ul><li>recognized X-linked nature of disease </li></ul><ul><li>proposed to name this congenital bilateral pseudotumour disorder Norrie disease </li></ul><ul><li>Warburg M (1966) </li></ul><ul><li>postulated blindness due to retinal dysplasia  retinal detachment and proliferation of retinal vessels ( </li></ul>
  6. 6. Clinical Characteristics <ul><li>Congenital blindness (pseudoglioma) </li></ul><ul><li>Cognitive difficulties – MR </li></ul><ul><li>Hearing loss </li></ul><ul><li>Contiguous gene syndrome </li></ul><ul><ul><ul><ul><ul><li>Gal et al 1985, 1986 </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Sims et al 1989 </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Collins et al 1992 </li></ul></ul></ul></ul></ul>1960’s - 1980’s
  7. 7. NDP gene identification <ul><li>Genetic mapping </li></ul><ul><li>Linkage to short-arm X-chromosome </li></ul><ul><ul><li>Bleeker-Wagemakers et al 1985; Gal et al 1985 </li></ul></ul><ul><li>Physical mapping </li></ul><ul><li>deletions, recombinations </li></ul><ul><ul><li>De la Chapelle et al 1985 </li></ul></ul><ul><ul><li>Donnai et al 1988 </li></ul></ul><ul><ul><li>Diergaarde et al 1989 </li></ul></ul><ul><ul><li>Sims et al 1989, 1992 </li></ul></ul>
  8. 8. NDP Exonic Structure
  9. 9. NDP Clinical Molecular Testing <ul><li>MGH DNA DIAGNOSTIC LAB (1994 - present) </li></ul><ul><ul><li>in 158 families (unpublished) </li></ul></ul><ul><ul><ul><li>pt mut (77 unique) </li></ul></ul></ul><ul><ul><ul><li>lg del (10) </li></ul></ul></ul><ul><ul><ul><li>intragenic del (25) </li></ul></ul></ul><ul><ul><li>18 pt mut/small del-ins in >1 family </li></ul></ul><ul><ul><li>22% deletions (intragenic > lg NDP + ) </li></ul></ul><ul><li>Other testing labs: Univ Zurich, Univ Iowa, Emory Univ </li></ul>
  10. 10. NDP Mutation spectrum <ul><ul><ul><ul><li>Schuback et al 1995 </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Berger et al 1992 </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Isashiki et al 1995 </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Berger & Ropers 2001 </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Up through present - number of single case reports </li></ul></ul></ul></ul>
  11. 11. Genotype-phenotype correlations? <ul><ul><li>Deletion mutations more severe </li></ul></ul><ul><ul><li>C-terminal missense possibly milder </li></ul></ul><ul><ul><li>(Chen et al 1993; Meindl et al 1995; Walker et al 1997) </li></ul></ul>
  12. 12. Expanding Clinical Spectrum <ul><li>Congenital blindness </li></ul><ul><li>(retinal detachment, pseudoglioma, vascular dysgenesis) </li></ul><ul><li>Progressive hearing loss </li></ul><ul><li>Mental retardation </li></ul><ul><li>Ocular phenotype overlap </li></ul><ul><ul><li>XL-FEVR, PHPV, Coats disease, ROP </li></ul></ul><ul><li>Audiology – Chris Halpin </li></ul><ul><li>Vascular – Heidi Rehm </li></ul><ul><li>Cognitive – </li></ul>
  13. 13. NDP gene product Norrin <ul><li>133 amino acids </li></ul><ul><li>Member cysteine-knot growth factor family (computer modelling) </li></ul><ul><li>Localization in retina (animal and human) </li></ul><ul><li>Presumed role in vascular development </li></ul><ul><ul><li>Retina, central nervous system, cochlear </li></ul></ul>
  14. 14. ND Biology/Pathobiology <ul><li>Knock-out mouse ( Ndph ) 1996 </li></ul><ul><li>vascular dysgenesis </li></ul><ul><li>Norrin Fzd-4/LRP5 ligand 2004 </li></ul><ul><li>role in development of retina and inner ear </li></ul><ul><li>Norrin induces Fzd4 and LRP5-dependent activation classic Wnt signaling pathway </li></ul><ul><li>role in vascular development, CNS function </li></ul>
  15. 15. Norrie Community <ul><li>Norrie listserve 1998 (Mike Kosior) </li></ul><ul><li>[email_address] </li></ul><ul><li>Norrie Disease Association 2006 </li></ul><ul><ul><li>to learn more about the clinical and medical symptoms of ND </li></ul></ul><ul><ul><li>to spur on and help fund Norrie research </li></ul></ul><ul><ul><li>to promote awarenss about Norrie disease </li></ul></ul><ul><ul><li>to provide support and information to those with Norrie and families </li></ul></ul><ul><li>NDA incorporated (2008) </li></ul><ul><li>www.norries.org </li></ul><ul><li>1st Norrie Disease Association (NDA) Conference Boston 2009 </li></ul>

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