ABSTRACT
ATP8B1 deficiency is caused by autosomal recessive mutations in ATP8B1, which encodes the putative phospatidylserine flippase ATP8B1 (formerly called FIC1). ATP8B1 deficiency is primarily characterized by cholestasis, but extrahepatic symptoms are also found. Because patients sometimes report reduced hearing capability, we investigated the role of ATP8B1 in auditory function. Here we show that ATP8B1/Atp8b1 deficiency, both in patients and in Atp8b1(G308V/G308V) mutant mice, causes hearing loss, associated with progressive degeneration of cochlear hair cells. Atp8b1 is specifically localized in the stereocilia of these hair cells. This indicates that the mechanosensory function and integrity of the cochlear hair cells is critically dependent on ATP8B1 activity, possibly through maintaining lipid asymmetry in the cellular membranes of stereocilia.
Subject(s)
Adenosine Triphosphatases/physiology , Hearing/physiology , Adenosine Triphosphatases/genetics , Animals , Hearing Loss, Sensorineural/genetics , Hearing Loss, Sensorineural/physiopathology , Humans , Mice , Mice, Mutant Strains , Organ of Corti/pathology , Phospholipid Transfer ProteinsABSTRACT
CONCLUSIONS: Open-set speech perception in children with an inner ear malformation is equal to that of other congenitally deaf children after an average of 2 years follow-up. OBJECTIVE: To analyze audiological performance after cochlear implantation in a sample of children with radiographically detectable malformations of the inner ear compared to performance in prelingually deafened children at large. MATERIALS AND METHODS: Nine children with osseous inner ear malformations were compared to 22 congenitally deaf children, all of whom underwent cochlear implantation. All subjects were tested on their electrical evoked compound action potential. Speech perception tests were performed using the monosyllabic trochee polysyllabic test without visual support and the open-set monosyllabic wordlist. RESULTS: In all, 20% of the congenitally deaf children in our center study have inner ear abnormalities. Inner ear malformations were limited to incomplete partition of the cochlea; none of the subjects had common cavity malformations. Electrical compound action potentials were successfully recorded in both groups intraoperatively. Speech perception tests on open-set speech yielded an average of 48.8% (SD 21.2%) in the group of children with inner ear malformations vs 54.5% (SD 21.1%) in congenitally deaf children. In four of nine cases with an inner ear malformation we encountered a minor CSF leak.
Subject(s)
Cochlear Implantation , Deafness/congenital , Deafness/rehabilitation , Ear, Inner/abnormalities , Evoked Potentials, Auditory/physiology , Postoperative Complications/physiopathology , Child , Child, Preschool , Cochlear Nerve/physiopathology , Deafness/diagnostic imaging , Ear, Inner/diagnostic imaging , Electric Stimulation , Female , Follow-Up Studies , Humans , Infant , Male , Postoperative Complications/diagnostic imaging , Signal Processing, Computer-Assisted , Speech Perception/physiology , Telemetry , Tomography, X-Ray ComputedABSTRACT
Hearing deficit occurs in several lysosomal storage disorders but has so far not been recognized as a symptom of Pompe's disease (glycogen storage disease type II). We discovered quite unexpectedly 30-90 dB hearing loss in four infants with Pompe's disease, who participated in a study on the safety and efficacy of enzyme replacement therapy. Three other patients with juvenile Pompe's disease did not have this symptom. The ABR (auditory brainstem response) thresholds but not the interpeak latency times were increased. This pointed to middle or inner ear pathology rather than to involvement of the central auditory nervous system. The possible occurrence of cochlear pathology was supported by the absence of oto-acoustic emissions. We investigated this hypothesis in a knockout mouse model of Pompe's disease and found glycogen storage in the inner and outer hair cells of the cochlea, the supporting cells, the stria vascularis, and the spiral ganglion cells. We conclude that cochlear pathology is the most likely cause of hearing loss in infantile Pompe's disease and possibly a characteristic feature of this clinical subtype.
Subject(s)
Cochlea/pathology , Glycogen Storage Disease Type II/pathology , Hearing Loss/pathology , Acoustic Stimulation/methods , Adolescent , Adult , Animals , Child , Child, Preschool , Disease Models, Animal , Evoked Potentials, Auditory, Brain Stem/genetics , Glycogen Storage Disease Type II/genetics , Glycogen Storage Disease Type II/physiopathology , Hearing Loss/genetics , Hearing Loss/physiopathology , Humans , Mice , Mice, KnockoutABSTRACT
OBJECTIVE: To investigate the chance of detecting hearing loss with neonatal hearing screening in relation to exposure to tobramycin and vancomycin. STUDY DESIGN: Automated auditory brainstem response (A-ABR) hearing screening was performed in all neonates with at least one risk factor. Data on drug administration were abstracted from patient files. Exposure to these drugs was related to the result of hearing screening. In patients failing hearing screening, exposure to ototoxic medication was assessed in the light of other risk factors for hearing loss. RESULTS: Six hundred twenty-five patients were analyzed; 45 neonates failed hearing screening. Tobramycin, vancomycin, and furosemide were used in 508, 130, and 174 patients, respectively. Exposure to vancomycin, tobramycin, or furosemide or a combination, defined in terms of treatment duration, total dose, or serum concentrations of antibiotics, was not related to failure to pass A-ABR screening. Ototoxic medication was not the most probable risk factor in any of the patients with serum concentrations outside the therapeutic range. CONCLUSIONS: Routine therapeutic drug monitoring of vancomycin and tobramycin in neonates for ototoxicity reasons is not helpful in detecting patients at risk for clinically important hearing loss in the 2- to 4-kHz range. A longer period of audiometric follow-up is needed to determine any long-term effects.
