Auditory phenotype of Niemann-Pick disease, type C1

Abstract

Objectives: The aim of this study was to comprehensively evaluate the auditory phenotype in Niemann-Pick disease, type C1 (NPC1), to understand better the natural history of this complex, heterogeneous disorder, and to define further the baseline auditory deficits associated with NPC1 so that use of potentially ototoxic interventions (e.g., 2-hydroxypropyl-ß-cyclodextrin) may be more appropriately monitored and understood.

Design: Fifty patients with NPC1 ranging in age from 4 months to 21 years (mean = 9.3 years) enrolled in a natural history/observational study at the National Institutes of Health. The auditory test battery included, when possible, immittance audiometry, pure-tone and speech audiometry, otoacoustic emission testing, and a neurotologic auditory brainstem response study. Longitudinal data were collected on a subset of patients.

Results: Over half of the cohort exhibited hearing loss involving the high frequencies ranging from a slight to moderate degree, and 74% of patients presented with clinically significant hearing loss involving the frequencies most important to speech understanding (0.5, 1, 2, 4 kHz). Despite the heterogeneity of the sample, results among patients were sufficiently consistent to implicate retrocochlear dysfunction in the majority (66%) of individuals, with (22%) or without (44%) accompanying cochlear involvement. Some patients (10%) presented with a profile for auditory neuropathy spectrum disorder. The combination of cross-sectional and longitudinal data indicates these patients are at risk for a progressive decline in auditory function.

Conclusions: This is the largest cohort of patients with NPC1 evaluated comprehensively for auditory dysfunction, and results implicate the pathological processes of NPC1 in the manifestation of hearing loss. Patients with NPC1 should be monitored audiologically throughout their lives, beginning at the time of diagnosis. Clinicians and researchers should be aware of this historically overlooked aspect of the phenotype.

Figures

Figure 1

Percent of ears with hearing loss (>15 dB HL) by frequency at baseline based on data from 31 patients.

Figure 2

Air-conduction hearing thresholds (ears) at baseline for both a four-frequency (top panel) and high-frequency (bottom panel) pure-tone average (PTA) by age at the time of test. Trend line plotted.

Figure 3

Air-conduction thresholds of the poorer-hearing ear plotted against total disease severity score (Yanjanin et al., 2009) at 4 kHz (top panel) and 8 kHz (bottom panel) for 25 and 22 patients, respectively, for whom these data were available.

Figure 4

Individual change in air-conduction thresholds from baseline to the final audiologic assessment, as a function of duration of follow-up (months) for a four-frequency (top panel) and high-frequency pure-tone average (PTA) (middle panel), and 8 kHz (bottom panel). Dashed line at 0 dB indicates no change in threshold; positive values depict a decline in threshold and negative values depict an improvement in threshold. Solid lines demarcate the range of test/retest variability standardly associated with pure-tone threshold assessment. Grayed symbols indicate overlapping data points.