Understanding and Expanding the Phenotype in Norrie Disease
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Dr. Heidi Rehm discusses the effects of Norrie Disease on the eyes, ears, brain, and vascular system. (NDA International Conference, 2009)
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Understanding and Expanding the Phenotype in Norrie Disease
- 1. Heidi L. Rehm, PhD, FACMG Assistant Professor of Pathology, BWH and HMS Clinical Molecular Geneticist, Laboratory for Molecular Medicine, PCPGM Understanding and Expanding the Phenotype in Norrie Disease
- 2. Norrie Disease Pedigree from Costa Rica
- 3. Venous Insufficiency in the Costa Rican Norrie Disease Kindred
- 5. Retina Vasculature Loss of Fine Capillary Network in the Norrie Disease Retina Control Norrie Disease Central Peripheral
- 6. Retina Layers Outer Retina Inner Retina Norrie Disease Control 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+
- 12. Metabolic Recycling in the Cochlea K+ K+ Endolymph K+ K+ K+ K+ K+ K+
- 13. NDP Gene Expression in Inner Ear Zheng-Yi Chen
- 14. Hearing Loss in the Norrie Mouse Model
- 15. Norrie Mouse Inner Ear Pathology Control Knockout 3 month 15 month
- 16. Capillaries of the Cochlear Stria Vascularis
- 17. Vascular Changes in the Norrie Mouse Cochlea Norrie Disease Control 15 months
- 18. Vascular Changes in the Norrie Mouse Cochlea Norrie Disease Control 3 months
- 19. Changes in the Norrie Mouse Stria Vascularis 3 months
- 22. Norrie Disease Clinical Survey Study Number of Participants Age Range (years) 56 individuals with Norrie disease participated in our survey
- 23. 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.
- 24. 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.
- 25. 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% 23/51 Behavior Disturbance 28% 14/51 Cognitive Impairment 9% 5/56 Chronic Seizures 7% 4/56 Resolved Seizures 16% 9/56 Seizure Disorder Percentage N/Total
- 26. Participants Reporting Hearing Loss Age Range (years) Number of Participants 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.
Editor's Notes
- Slide 2: This pedigree shows a 6 generation family from Costa Rica with 15 males affected with blindness, progressive hearing loss and peripheral vascular disease. We eventually identified a mutation in the NDP gene which defined the first Norrie disease family with peripheral vascular disease.
- The peripheral vascular disease seen in the Costa Rican family was defined by varicose veins in the lower limbs and venous stasis ulcers.
- Another clue that Norrie disease may be due to a fundamental defect in vascular development is the fact that some patients with mutations in the NDP gene can present with vascular eye diseases such as FEVR (familial exudative vitreoretinopathy) or Coat’s disease. In FEVR, some patients are asymptomatic and the only evidence of disease is the lack of vascular development in the peripheral retina. In Coat’s disease, the blood vessels of the retina are dilated and tortuous.
- Looking at the retina of the Norrie mouse, we can see that much of the fine capillary network of retinal vessels is missing.
- If we separate the two layers of the retina into the inner retina and the outer retina we can see that the outer retinal vasculature is absent in the Norrie mouse.
- During normal retinal vascular development, blood vessels first populate the inner retina and then secondarily grow down into the outer retina. Therefore, this latter stage of retinal vascular development appears to be absent in the Norrie mouse retina.
- This slide shows the location of gene expression of the NDP gene in the inner ear (cochlea). The gene is expressed in the spiral ganglion, where the cochlear nerve is located as well as a rich supply of blood vessels. The NDP gene is also expressed in the stria vascularis, which houses most of the blood vessels that nourish the cochlea.
- The Norrie mouse model also develops a progressive hearing loss.
- The first evidence of disease in the cochlea of Norrie mice is abnormal blood vessels in the stria vascularis. Later, many areas of the cochlea degenerate including the stria vascularis, the hair cells and the spiral ganglion.
- Although the number of vessels does not appear to be affected until later stages of disease, early on, the abnormality of the vessels seems to be their diameter. Blood vessels of the Norrie cochlear are much larger in diameter.
- These images show the much larger diameter vessels in the Norrie mouse cochlea compared to control mice.
- 56 individuals with Norrie disease, aged 3 months to 87 years, participated in our survey of the clinical features of disease.
- 16% reported a seizure disorder, 28% reported cognitive impairment, and 45% reported various behavioral disturbances.