Heidi L. Rehm, PhD, FACMGHeidi L. Rehm, PhD, FACMGAssistant Professor of Pathology, BWH and HMS

Clinical Molecular Geneticist, Laboratory for Molecular Medicine, PCPGM

Understanding and Expanding the Phenotype in Norrie Disease

Norrie Disease Pedigree from Costa Rica

Venous Insufficiency in the Costa Rican Norrie Disease Kindred

Other Eye Disorders due to Norrie Disease Gene Mutations

Familial exudative vitreoretinopathy (XL)

peripheral retinal avascularity → exudation and retinal detachment

Coats’ disease

retinal telangiectasia (dilated and tortuous vessels) → exudation and retinal detachment

Loss of Fine Capillary Network in the Norrie Disease Retina

Control

NorrieDisease

Central Peripheral

Outer Retina

Inner Retina

Nor

rie D

isea

seC

ontr

ol

Missing Outer Vasculature in the Norrie Disease Retina

Inner Outer

10

Hair Cell Stimulation

Sound wave

11

Hair Cell Transduction

K+

K+

K+K+ K+

K+

K+

K+

K+ K+

K+K+K+

K+

K+

K+K+

K+

K+K+

K+

K+

K+

K+

K+

K+K+

K+

K+

K+

Metabolic Recycling in the Cochlea

K+

K+

Endolymph

NDP Gene Expression in Inner Ear

Zheng-Yi Chen

Hearing Loss in the Norrie Mouse Model

Norrie Mouse Inner Ear Pathology

Control Knockout

3 m

onth

15 m

onth

Capillaries of the Cochlear Stria Vascularis

Vascular Changes in the Norrie Mouse Cochlea

Norrie DiseaseControl15 months

Vascular Changes in the Norrie Mouse Cochlea

Norrie DiseaseControl3 months

Changes in the Norrie Mouse Stria Vascularis

3 months

Summary

One of the primary defects in Norrie disease may be dysfunction of the cells that interact with blood vessels.

Norrin may also have a broader role in vascular biology.

Norrie Disease Clinical Survey Study

0

2

4

6

8

10

12

0-3 4-10 11-20 21-30 31-40 41-50 51-60 60+

Num

ber

of P

art

icip

ant

s

Age Range (years)

56 individuals with Norrie disease participated in our survey

Participants Reporting Peripheral Vascular Disease

Peripheral vascular disease (PVD), including varicose veins, leg ulcers, and/or erectile dysfunction, was reported in 21/56 (38%) of all participants or 21/36 (58%) of those 16 or older.

Erectile Dysfunction in Norrie Disease

Of the 24 men queried 14/24 (58%) reported erectile dysfunction. Three men had decreased penile blood flow documented by angiography and Doppler ultrasound. Two had successful penile implants.

Neurological Phenotype in Norrie Disease

2%1/51 Mood Disorders

25%13/51 Labile Affect

6%3/51 Anxiety

8%4/51 Attention Difficulties

27%14/51 Autism/Autistic-like

45%23/51Behavior Disturbance

28%14/51Cognitive Impairment

9%5/56 Chronic Seizures

7%4/56 Resolved Seizures

16%9/56Seizure Disorder

PercentageN/Total

Participants Reporting Hearing Loss

0

1

2

3

4

5

6

7

8

0-3 4-10 11-20 21-30 31-40 41-50 51-60 60+

Registered

HL

Age Range (years)

Nu

mb

er o

f Par

ticip

ants

The average age of hearing loss was 12 yrs. With one exception, all individuals 25 and older had developed hearing loss and the earliest age of onset was 5 yrs.

Acknowledgments

Kathie SimsSharon Smith

David Corey Duan-Sun ZhangZheng-Yi Chen

Max Planck Institut Wolfgang Berger

MEEIChris BrownBarbara BurgessJoe AdamsChris Halpin

Cynthia Morton