Abstract
Niemann-Pick disease, type C1 (NPC1) is a rare lysosomal lipidosis that is most often the result of biallelic mutations in NPC1, and is characterized by a fatal neurological degeneration. The pathophysiology is complex, and the natural history of the disease is poorly understood. Recent findings from patients with NPC1 and hearing loss suggest that multiple steps along the auditory pathway are affected. The current study was undertaken to determine the auditory phenotype in the Npc1 nih mutant mouse model, to extend analyses to histologic evaluation of the inner ear, and to compare our findings to those reported from human patients. Auditory testing revealed a progressive high-frequency hearing loss in Npc1 -/- mice that is present as early as postnatal day 20 (P20), well before the onset of overt neurological symptoms, with evidence of abnormalities involving the cochlea, auditory nerve, and brainstem auditory centers. Distortion product otoacoustic emission amplitude and auditory brainstem response latency data provided evidence for a disruption in maturational development of the auditory system in Npc1 -/- mice. Anatomical study demonstrated accumulation of lysosomes in neurons, hair cells, and supporting cells of the inner ear in P30 Npc1 -/- mice, as well as increased numbers of inclusion bodies, myelin figures, and swollen nerve endings in older (P50-P70) mutant animals. These findings add unique perspective to the pathophysiology of NPC disease and suggest that hearing loss is an early and sensitive marker of disease progression.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 529-541 |
| Number of pages | 13 |
| Journal | JARO - Journal of the Association for Research in Otolaryngology |
| Volume | 15 |
| Issue number | 4 |
| DOIs | |
| State | Published - 2014 |
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Keywords
- auditory brainstem response (ABR)
- auditory maturation
- hearing
- NPC
ASJC Scopus subject areas
- Otorhinolaryngology
- Sensory Systems
- Medicine(all)
Cite this
Hearing loss is an early consequence of Npc1 gene deletion in the mouse model of Niemann-Pick disease, type C. / King, Kelly A.; Gordon-Salant, Sandra; Pawlowski, Karen S.; Taylor, Anna M.; Griffith, Andrew J.; Houser, Ari; Kurima, Kiyoto; Wassif, Christopher A.; Wright, Charles G.; Porter, Forbes D.; Repa, Joyce J.; Brewer, Carmen C.
In: JARO - Journal of the Association for Research in Otolaryngology, Vol. 15, No. 4, 2014, p. 529-541.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Hearing loss is an early consequence of Npc1 gene deletion in the mouse model of Niemann-Pick disease, type C
AU - King, Kelly A.
AU - Gordon-Salant, Sandra
AU - Pawlowski, Karen S.
AU - Taylor, Anna M.
AU - Griffith, Andrew J.
AU - Houser, Ari
AU - Kurima, Kiyoto
AU - Wassif, Christopher A.
AU - Wright, Charles G.
AU - Porter, Forbes D.
AU - Repa, Joyce J.
AU - Brewer, Carmen C.
PY - 2014
Y1 - 2014
N2 - Niemann-Pick disease, type C1 (NPC1) is a rare lysosomal lipidosis that is most often the result of biallelic mutations in NPC1, and is characterized by a fatal neurological degeneration. The pathophysiology is complex, and the natural history of the disease is poorly understood. Recent findings from patients with NPC1 and hearing loss suggest that multiple steps along the auditory pathway are affected. The current study was undertaken to determine the auditory phenotype in the Npc1 nih mutant mouse model, to extend analyses to histologic evaluation of the inner ear, and to compare our findings to those reported from human patients. Auditory testing revealed a progressive high-frequency hearing loss in Npc1 -/- mice that is present as early as postnatal day 20 (P20), well before the onset of overt neurological symptoms, with evidence of abnormalities involving the cochlea, auditory nerve, and brainstem auditory centers. Distortion product otoacoustic emission amplitude and auditory brainstem response latency data provided evidence for a disruption in maturational development of the auditory system in Npc1 -/- mice. Anatomical study demonstrated accumulation of lysosomes in neurons, hair cells, and supporting cells of the inner ear in P30 Npc1 -/- mice, as well as increased numbers of inclusion bodies, myelin figures, and swollen nerve endings in older (P50-P70) mutant animals. These findings add unique perspective to the pathophysiology of NPC disease and suggest that hearing loss is an early and sensitive marker of disease progression.
AB - Niemann-Pick disease, type C1 (NPC1) is a rare lysosomal lipidosis that is most often the result of biallelic mutations in NPC1, and is characterized by a fatal neurological degeneration. The pathophysiology is complex, and the natural history of the disease is poorly understood. Recent findings from patients with NPC1 and hearing loss suggest that multiple steps along the auditory pathway are affected. The current study was undertaken to determine the auditory phenotype in the Npc1 nih mutant mouse model, to extend analyses to histologic evaluation of the inner ear, and to compare our findings to those reported from human patients. Auditory testing revealed a progressive high-frequency hearing loss in Npc1 -/- mice that is present as early as postnatal day 20 (P20), well before the onset of overt neurological symptoms, with evidence of abnormalities involving the cochlea, auditory nerve, and brainstem auditory centers. Distortion product otoacoustic emission amplitude and auditory brainstem response latency data provided evidence for a disruption in maturational development of the auditory system in Npc1 -/- mice. Anatomical study demonstrated accumulation of lysosomes in neurons, hair cells, and supporting cells of the inner ear in P30 Npc1 -/- mice, as well as increased numbers of inclusion bodies, myelin figures, and swollen nerve endings in older (P50-P70) mutant animals. These findings add unique perspective to the pathophysiology of NPC disease and suggest that hearing loss is an early and sensitive marker of disease progression.
KW - auditory brainstem response (ABR)
KW - auditory maturation
KW - hearing
KW - NPC
UR - http://www.scopus.com/inward/record.url?scp=84904726070&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84904726070&partnerID=8YFLogxK
U2 - 10.1007/s10162-014-0459-7
DO - 10.1007/s10162-014-0459-7
M3 - Article
C2 - 24839095
AN - SCOPUS:84904726070
VL - 15
SP - 529
EP - 541
JO - JARO - Journal of the Association for Research in Otolaryngology
JF - JARO - Journal of the Association for Research in Otolaryngology
SN - 1525-3961
IS - 4
ER -