Hearing loss associated with enlargement of the vestibular aqueduct: mechanistic insights from clinical phenotypes, genotypes, and mouse models

Abstract

Enlargement of the vestibular aqueduct (EVA) is one of the most common inner ear malformations associated with sensorineural hearing loss in children. The delayed onset and progressive nature of this phenotype offer a window of opportunity to prevent or retard progression of hearing loss. EVA is not the direct cause of hearing loss in these patients, but rather is a radiologic marker for some underlying pathogenetic defect. Mutations of the SLC26A4 gene are a common cause of EVA. Studies of an Slc26a4 knockout mouse demonstrate that acidification and enlargement of the scala media are early events in the pathogenesis of deafness. The enlargement is driven by fluid secretion in the vestibular labyrinth and a failure of fluid absorption in the embryonic endolymphatic sac. Elucidating the mechanism of hearing loss may offer clues to potential therapeutic strategies.

Fig 1

Radiologic imaging of an enlarged vestibular aqueduct. A) Axial computed tomography (CT) scan of an enlarged vestibular aqueduct (arrow). B) Axial MR (magnetic resonance) image of the soft tissue correlate of an enlarged vestibular aqueduct: an enlarged endolymphatic duct and sac (arrow). Reproduced from http://www.nidcd.nih.gov/health/hearing/eva-intro.htm.

Fig 2

Schematic illustration of an enlarged vestibular aqueduct and endolymphatic sac and duct. Reproduced from http://www.nidcd.nih.gov/health/hearing/vestAque.htm.

Fig 3

Cochlear enlargement. Reproduced from Kim et al. (Kim et al., 2010). A) Diagram based on a cochlea obtained from an E18.5 Slc26a4^+/− mouse. B) Diagram based on the enlarged cochlea obtained from an E18.5 Slc26a4^−/− mouse. C) Measurements of cross-sectional areas of scala media from the basal turn of the cochlea in Slc26a4^+/− and Slc26a4^−/− mice. Note that the growth of the lumen is parallel between Slc26a4^+/− and Slc26a4^−/− mice and that a ∼10-fold enlargement is maintained throughout development. Abbreviations: C, otic capsule; S, stria vascularis; H, sensory hair cells; M, modiolus; N, cochlear nerve. Spaces occupied by mesenchymal cell (green) are compressed in Slc26a4^−/− mice, and fibrocytes in the modiolus (M) and between the otic capsule (C) and stria vascularis (S) are displaced.

Fig 4

Hypothetical mechanism for fluctuating hearing loss. A) Diagram based on a cochlea obtained from a P7 Slc26a4^+/− mouse. B) Diagram of the stria vascularis illustrating a negative feedback mechanism that leads to fluctuating loss of KCNJ10, the K⁺ channel that generates the endocochlear potential. Fluctuating loss of the endocochlear potential can be expected to the lead to fluctuating loss of hearing.