Norrie Disease: Historical Perspective

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Norrie Disease Association First International Conference Boston August 13 – 16, 2009

Norrie Disease Historical Perspective
Katherine Sims MD
Massachusetts General Hospital
Center for Human Genetics
Harvard Medical School
August 2009

Gordon Norrie M.D.
Danish ophthalmologist (1855-1941)
Surgeon at the Danish Institute for the Blind
Norrie G. (1927) Causes of blindness in children. Acta Ophthalmol 5:357-386
identified nine Danish boys with ‘atrophia oculi congenita’

Mette Warburg M.D.
Danish ophthalmologist (1926 - )
Research interest in etiology of blindness in those with mental retardation
Anderson SRM and Warburg M (1961)
recognized X-linked nature of disease
proposed to name this congenital bilateral pseudotumour disorder Norrie disease
Warburg M (1966)
postulated blindness due to retinal dysplasia  retinal detachment and proliferation of retinal vessels (

Clinical Characteristics
Congenital blindness (pseudoglioma)
Cognitive difficulties – MR
Hearing loss
Contiguous gene syndrome
Gal et al 1985, 1986
Sims et al 1989
Collins et al 1992
1960’s - 1980’s

NDP gene identification
Genetic mapping
Linkage to short-arm X-chromosome
Bleeker-Wagemakers et al 1985; Gal et al 1985
Physical mapping
deletions, recombinations
De la Chapelle et al 1985
Donnai et al 1988
Diergaarde et al 1989
Sims et al 1989, 1992

NDP Exonic Structure

NDP Clinical Molecular Testing
MGH DNA DIAGNOSTIC LAB (1994 - present)
in 158 families (unpublished)
pt mut (77 unique)
lg del (10)
intragenic del (25)
18 pt mut/small del-ins in >1 family
22% deletions (intragenic > lg NDP + )
Other testing labs: Univ Zurich, Univ Iowa, Emory Univ

NDP Mutation spectrum
Schuback et al 1995
Berger et al 1992
Isashiki et al 1995
Berger & Ropers 2001
Up through present - number of single case reports

Genotype-phenotype correlations?
Deletion mutations more severe
C-terminal missense possibly milder
(Chen et al 1993; Meindl et al 1995; Walker et al 1997)

Expanding Clinical Spectrum
Congenital blindness
(retinal detachment, pseudoglioma, vascular dysgenesis)
Progressive hearing loss
Mental retardation
Ocular phenotype overlap
XL-FEVR, PHPV, Coats disease, ROP
Audiology – Chris Halpin
Vascular – Heidi Rehm
Cognitive –

NDP gene product Norrin
133 amino acids
Member cysteine-knot growth factor family (computer modelling)
Localization in retina (animal and human)
Presumed role in vascular development
Retina, central nervous system, cochlear

ND Biology/Pathobiology
Knock-out mouse ( Ndph ) 1996
vascular dysgenesis
Norrin Fzd-4/LRP5 ligand 2004
role in development of retina and inner ear
Norrin induces Fzd4 and LRP5-dependent activation classic Wnt signaling pathway
role in vascular development, CNS function

Norrie Community
Norrie listserve 1998 (Mike Kosior)
[email_address]
Norrie Disease Association 2006
to learn more about the clinical and medical symptoms of ND
to spur on and help fund Norrie research
to promote awarenss about Norrie disease
to provide support and information to those with Norrie and families
NDA incorporated (2008)
www.norries.org
1st Norrie Disease Association (NDA) Conference Boston 2009

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Norrie Disease: Historical Perspective

by Norrie Disease Association on Sep 09, 2009

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Norrie Disease: Historical Perspective — Webinar Transcript