A rare genomic duplication in 2p14 underlies autosomal dominant hearing loss DFNA58.

Here we define a ~200 Kb genomic duplication in 2p14 as the genetic signature that segregates with postlingual progressive sensorineural autosomal dominant hearing loss (HL) in 20 affected individuals from the DFNA58 family, first reported in 2009. The duplication includes two entire genes, PLEK and CNRIP1, and the first exon of PPP3R1 (protein coding), in addition to four uncharacterized long non-coding (lnc) RNA genes and part of a novel protein-coding gene. Quantitative analysis of mRNA expression in blood samples revealed selective overexpression of CNRIP1 and of two lncRNA genes (LOC107985892 and LOC102724389) in all affected members tested, but not in unaffected ones. Qualitative analysis of mRNA expression identified also fusion transcripts involving parts of PPP3R1, CNRIP1 and an intergenic region between PLEK and CNRIP1, in the blood of all carriers of the duplication, but were heterogeneous in nature. By in situ hybridization and immunofluorescence, we showed that Cnrip1, Plek and Ppp3r1 genes are all expressed in the adult mouse cochlea including the spiral ganglion neurons, suggesting changes in expression levels of these genes in the hearing organ could underlie the DFNA58 form of deafness. Our study highlights the value of studying rare genomic events leading to HL, such as copy number variations. Further studies will be required to determine which of these genes, either coding proteins or non-coding RNAs, is or are responsible for DFNA58 HL.

Cochlear neuropathy in human presbycusis: Confocal analysis of hidden hearing loss in post-mortem tissue.

Recent animal work has suggested that cochlear synapses are more vulnerable than hair cells in both noise-induced and age-related hearing loss. This synaptopathy is invisible in conventional histopathological analysis, because cochlear nerve cell bodies in the spiral ganglion survive for years, and synaptic analysis requires special immunostaining or serial-section electron microscopy. Here, we show that the same quadruple-immunostaining protocols that allow synaptic counts, hair cell counts, neuronal counts and differentiation of afferent and efferent fibers in mouse can be applied to human temporal bones, when harvested within 9 h post-mortem and prepared as dissected whole mounts of the sensory epithelium and osseous spiral lamina. Quantitative analysis of five "normal" ears, aged 54-89 yrs, without any history of otologic disease, suggests that cochlear synaptopathy and the degeneration of cochlear nerve peripheral axons, despite a near-normal hair cell population, may be an important component of human presbycusis. Although primary cochlear nerve degeneration is not expected to affect audiometric thresholds, it may be key to problems with hearing in noise that are characteristic of declining hearing abilities in the aging ear.

Within-subject comparison of word recognition and spiral ganglion cell count in bilateral cochlear implant recipients.

OBJECTIVES: Although published reports have not demonstrated a positive correlation between the number of residual spiral ganglion cells (SGCs) and word recognition scores in patients with unilateral multichannel cochlear implants, this study was designed to retest this hypothesis in patients with bilateral multichannel cochlear implants. MATERIALS AND METHODS: From a pool of 133 temporal bones, all subjects with bilateral multichannel cochlear implants who were deafened bilaterally by the same etiology were studied. A total of 12 temporal bones from 6 subjects were identified and processed after death for histology. The SGCs were counted using standard techniques. The differences between left and right SGC counts as well as the differences in word recognition scores were calculated for each subject. Correlation analysis was performed between the differences of SGC counts and the differences of word recognition scores. RESULTS: Differences in SGC counts were highly correlated with the differences in word recognition scores (R = 0.934, p = 0.006). CONCLUSION: This study suggests higher residual SGCs predicted better performance after implantation in a given patient. The results also support attempts to identify factors which may promote survival of SGCs.

Histopathological morphometric study of cochleosaccular dysplasia in Dalmatian dogs.

OBJECTIVE: To analyze temporal bones of deaf Dalmatian dogs from 5 days after birth to adulthood to better understand the pathogenesis of cochleosaccular dysplasia. METHODS: This is an experimental animal histopathological temporal bone study that included two groups of temporal bones. Group I consisted of 41 temporal bones from deaf Dalmatian dogs and group II of 25 temporal bones from 15 "normal" aged-matched, hearing Black Labradors. Morphometric analysis included: stria vascularis and spiral ligament area measurements, and cell counts of spiral ganglion, Scarpa's ganglion, and hair cells of saccular macula. RESULTS: The following findings were significantly less in deaf Dalmatian group compared to hearing Labradors: (1) cellular area of the stria vascularis in all cochlear turns; (2) cellular area of spiral ligament in the inferior part of the basal turn; (3) cellular density of spiral ganglion cells within segments III and IV; (4) number of Scarpa's ganglion cells; and (5) density of saccular hair cells types I and II. A borderline negative correlation was found between average density of spiral ganglion cells of segments III and IV and age in group I. Young deaf animals showed some cochlear hair cells, however in adult dogs all hair cells were replaced by supporting cells. CONCLUSION: General pattern of cochleosaccular dysplasia is variable, even when only one etiology, the genetic one, is involved. The gradual degeneration of inner ear elements in the cochleosaccular degeneration might indicate that early intervention might be crucial to stop the progression of cochleosaccular dysplasia.

Cochleosaccular dysplasia: a morphometric and histopathologic study in a series of temporal bones.

OBJECTIVE: The objective of this study was to perform a morphometric analysis of a series of temporal bones with cochleosaccular dysplasia to clarify the extent of inner ear changes in this disease. STUDY DESIGN: This human temporal bone histopathologic study of a series of deaf-mute cases involves morphometric analysis, including stria vascularis and spiral ligament area measurements and spiral ganglion and hair cells counts. SUBJECTS: Thirteen temporal bones were selected from 35 with deaf mutism based on the histopathologic findings described by Scheibe. Twenty normal age-matched control subjects were used for comparisons. RESULTS: All temporal bones had the main histopathologic findings described by Scheibe, as well as severe affected stria vascularis. Seven temporal bones had cystic areas in the stria and three had concretions. Cross-sectional strial areas in temporal bones with cochleosaccular dysplasia were smaller than normal in all cochlear turns; however, no difference was found in spiral ligament cross-sectional areas. Reissner's membrane was hydropic in three temporal bones and the organ of Corti was absent in at least one cochlear turn in five. Concretions were present in the macula of seven temporal bones. Twelve temporal bones showed some level of spiral ganglion cell loss. No hair cells were observed in any temporal bone. A familial history of deafness was found in three cases. CONCLUSION: Pathologic findings were variable and limited to the saccule and scala media. The variation, perhaps, reflects the different etiologies involved in the origin of cochleosaccular dysplasia.