Niemann-Pick, type C disease (NPC) is a rare (1:120,000-150,000) autosomal recessive lysosomal lipidosis resulting in a progressive and fatal neurological deterioration. There is much about the pathogenesis and natural history of this complex, heterogeneous disorder that remains unknown. Limited literature suggests auditory dysfunction is part of the phenotype, but an aspect of the disease process that is poorly understood and, indeed, has likely been underreported. Experiment one includes auditory data from 55 patients with NPC seen at the National Institutes of Health between 8/14/2006 and 12/27/2010. These data confirm a prevalent high frequency hearing loss that progressively worsens in at least some individuals. Retrocochlear involvement is common, with abnormalities that suggest a profile of auditory neuropathy spectrum disorder in some patients. Analysis of late-onset cases suggests hearing loss is a premonitory symptom in this disease subcategory.

The investigation was expanded to include the mouse model for NPC (BALB/cNctr-Npc1m1N/J), in which symptomatology is clinically, biochemically, and morphologically comparable with affected humans. There have been no previous reports of auditory function in NPC mice, although brainstem histopathology has been localized to the auditory pathway. Experiment two includes auditory brainstem response (ABR) and otoacoustic emission (OAE) data revealing a high frequency hearing loss in mutant NPC mice as early as postnatal day (p) 20, which becomes progressively poorer across the experimental lifespan. With support for both a cochlear and retrocochlear site of lesion, OAE level and ABR latency data provide surprising evidence for a disruption in maturational development of the auditory system in diseased animals, which may add a unique perspective on the role of NPC pathogenesis. This comparative, translational study has, for the first time, addressed comprehensively the existence of, and implications for, auditory dysfunction in NPC. Similar auditory phenotypes between affected humans and mutant mice should aid future efforts in refining site of lesion. In combination, these data support the auditory system as a useful marker for disease status and provide valuable prognostic and quality of life information for patients and their families.