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

Bryant, Dale; Pauzuolyte, Valda; Ingham, Neil J; Patel, Aara; Pagarkar, Waheeda; Anderson, Lucy A; Smith, Katie E; ... Bitner-Glindzicz, Maria; + view all (2022) The timing of auditory sensory deficits in Norrie disease has implications for therapeutic intervention. JCI Insight , 7 (3) , Article e148586. 10.1172/jci.insight.148586. Green open access

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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.

Type: Article
Title: The timing of auditory sensory deficits in Norrie disease has implications for therapeutic intervention
Open access status: An open access version is available from UCL Discovery
DOI: 10.1172/jci.insight.148586
Publisher version: https://doi.org/10.1172/jci.insight.148586
Language: English
Additional information: © 2022, Bryant et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > The Ear Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10143740
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