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
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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

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Figure 3

SGN survival in Ndp-KO mice.

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SGN survival in Ndp-KO mice. (A) Apical to basal spiral ganglia of WT an...
(A) Apical to basal spiral ganglia of WT and Ndp-KO mice at 1 month showing that Tubb3 is expressed in the SGNs and Kir4.1 is expressed in the surrounding satellite glial cells. (B) Number of Tubb3-positive SGNs per 10,000 μm2 in apical to basal spiral ganglia of WT and Ndp-KO mice at 1 month. (C) Average size (μm2) of SGNs in apical to basal spiral ganglia of WT and Ndp-KO mice at 1 month. (D) Apical to basal spiral ganglia of WT and Ndp-KO mice at 11–12 months showing that Nf200 is expressed in the spiral SGNs and Mbp is expressed in the surrounding satellite glial cells. (E) Number of Nf200-positive SGNs per 10,000 μm2 in apical to basal spiral ganglia of WT and Ndp-KO mice at 11–12 months. (F) Average size (μm2) of SGNs in apical to basal spiral ganglia of WT and Ndp-KO mice at 11–12 months. High-magnification images of SGNs are shown in Supplemental Figure 3. n = 3 WT, n = 3 Ndp-KO analyzed at each time point; bars indicate mean ± SD. Analyzed with 1-way ANOVA, Holm-Šidák correction for multiple comparisons; *P ≤ 0.05, **P ≤ 0.01; NS, P ≥ 0.05. Scale bars: 100 μm.