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Norrie Disease AssociationFirst International Conference

BostonAugust 13 – 16, 2009

Norrie DiseaseHistorical Perspective

Katherine Sims MDMassachusetts General Hospital

Center for Human GeneticsHarvard 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 5:357-386identified 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 mappingLinkage to short-arm X-chromosome – Bleeker-Wagemakers et al 1985; Gal et

al 1985

• Physical mappingdeletions, 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– in 158 families (unpublished)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) 1996vascular dysgenesis

• Norrin Fzd-4/LRP5 ligand 2004role in development of retina and inner ear

• Norrin induces Fzd4 and LRP5-dependent activation classic Wnt signaling pathwayrole in vascular development, CNS function

Norrie Community

• Norrie listserve 1998 (Mike Kosior)norries@yahoogroups.com

• 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