Auditory phenotype of Niemann-Pick disease, type C1.
OBJECTIVE
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.


METHODS
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.
1Department of Health and Human Services, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD; 2Department of Hearing and Speech Sciences, University of Maryland College Park, College Park, MD; 3Department of Health and Human Services, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD; 4Department of Human Development and Quantitative Methodology, University of Maryland College Park, College Park, MD.
Kelly A
KA
King
Sandra
S
Gordon-Salant
Nicole
N
Yanjanin
Christopher
C
Zalewski
Ari
A
Houser
Forbes D
FD
Porter
Carmen C
CC
Brewer
D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives / Q000627:therapeutic use; D000293:Adolescent; D001301:Audiometry, Pure-Tone; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003408:Cresols; D018450:Disease Progression; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D016057:Evoked Potentials, Auditory, Brain Stem / Q000502:physiology*; D005260:Female; D005557:Formaldehyde; D034381:Hearing Loss / Q000209:etiology / Q000503:physiopathology*; D006801:Humans; D007223:Infant; D016014:Linear Models; D008137:Longitudinal Studies; D008297:Male; D052556:Niemann-Pick Disease, Type C / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D017084:Otoacoustic Emissions, Spontaneous / Q000502:physiology*; D012118:Resorcinols; D013067:Speech Perception / Q000502:physiology*; D055815:Young Adult
D003408:Cresols; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D012118:Resorcinols; D017485:1-Deoxynojirimycin; D005557:Formaldehyde; C050719:phenoaldehyde; C059896:miglustat