The timing of auditory sensory deficits in Norrie disease has implications for therapeutic intervention
Dale Bryant, Valda Pauzuolyte, Neil J. Ingham, Aara Patel, Waheeda Pagarkar, Lucy A. Anderson, Katie E. Smith, Dale A. Moulding, Yeh C. Leong, Daniyal J. Jafree, David A. Long, Amina Al-Yassin, Karen P. Steel, Daniel J. Jagger, Andrew Forge, Wolfgang Berger, Jane C. Sowden, Maria Bitner-Glindzicz
Dale Bryant, Valda Pauzuolyte, Neil J. Ingham, Aara Patel, Waheeda Pagarkar, Lucy A. Anderson, Katie E. Smith, Dale A. Moulding, Yeh C. Leong, Daniyal J. Jafree, David A. Long, Amina Al-Yassin, Karen P. Steel, Daniel J. Jagger, Andrew Forge, Wolfgang Berger, Jane C. Sowden, Maria Bitner-Glindzicz
View: Text | PDF
Research Article Development Otology

The timing of auditory sensory deficits in Norrie disease has implications for therapeutic intervention

Abstract

Norrie disease is caused by mutation of the NDP gene, presenting as congenital blindness followed by later onset of hearing loss. Protecting patients from hearing loss is critical for maintaining their quality of life. This study aimed to understand the onset of pathology in cochlear structure and function. By investigating patients and juvenile Ndp-mutant mice, we elucidated the sequence of onset of physiological changes (in auditory brainstem responses, distortion product otoacoustic emissions, endocochlear potential, blood-labyrinth barrier integrity) and determined the cellular, histological, and ultrastructural events leading to hearing loss. We found that cochlear vascular pathology occurs earlier than previously reported and precedes sensorineural hearing loss. The work defines a disease mechanism whereby early malformation of the cochlear microvasculature precedes loss of vessel integrity and decline of endocochlear potential, leading to hearing loss and hair cell death while sparing spiral ganglion cells. This provides essential information on events defining the optimal therapeutic window and indicates that early intervention is needed. In an era of advancing gene therapy and small-molecule technologies, this study establishes Ndp-mutant mice as a platform to test such interventions and has important implications for understanding the progression of hearing loss in Norrie disease.

Authors

Dale Bryant, Valda Pauzuolyte, Neil J. Ingham, Aara Patel, Waheeda Pagarkar, Lucy A. Anderson, Katie E. Smith, Dale A. Moulding, Yeh C. Leong, Daniyal J. Jafree, David A. Long, Amina Al-Yassin, Karen P. Steel, Daniel J. Jagger, Andrew Forge, Wolfgang Berger, Jane C. Sowden, Maria Bitner-Glindzicz

×

Figure 5

Electron microscopy of the cochlear lateral wall shows abnormalities of capillaries and marginal cells in Ndp-KO.

Options: View larger image (or click on image) Download as PowerPoint
Electron microscopy of the cochlear lateral wall shows abnormalities of ...
Stria vascularis of 1-month-old WT (A) and Ndp-KO (B–E) mice and 2-month-old WT (F) and Ndp-KO (G–J) mice. (A) Middle turn of the cochlea in WT at 1 month shows normal architecture. MC, marginal cell; IC, intermediate cell; BC, basal cell; CAP, enclosed capillary. (B–E) In Ndp-KO at 1 month, large spaces surround the capillaries in apical coils (arrows in B) and extend to basal coils (arrows in C) in some animals. The capillaries are surrounded by shrunken and disrupted cells (D) and large extracellular spaces (D and E) that fill with material that stains with heavy metals to a density similar to that of plasma inside the capillaries (E). Loosely distributed fibrils (arrows in E) are present within the spaces close to the capillary. Most marginal cells are largely unaffected (D); they retain intense staining of the cytoplasm, appearing “dark,” and the extensive infoldings of the basolateral membrane with the characteristic elongated scalloped morphology of their nuclei located close beneath the luminal plasma membrane. D and E are higher magnifications of B and C, respectively. (F) Stria vascularis of WT at 2 months. (G–J) In Ndp-KO at 2 months, the capillaries are surrounded by intact cells filling the spaces apparent at 1 month (G and H). The stria appears thinner than at 1 month (H and I), and many capillaries appear enlarged (H; asterisks). (I) Marginal cells occupy a lower area, have lost their basal infoldings (I and J) and electron-dense staining, appear more rounded, and show changes in nuclear morphology (J). n = 6 WT, n = 6 Ndp-KO at 1 and 2 months. Scale bars: 10 μm (A, D, and I), 1 μm (E), 2 μm (J).