Elsevier

Hearing Research

Volume 281, Issues 1–2, November 2011, Pages 11-17
Hearing Research

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

https://doi.org/10.1016/j.heares.2011.05.009Get rights and content

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.

Highlights

► Enlargement of the vestibular aqueduct (EVA) is associated with hearing loss. ► Natural history of EVA-associated deafness is amenable to therapeutic interventions. ► Mutations of the SLC26A4 gene are a common cause of EVA. ► Slc26a4-deficient mice have endolymphatic enlargement and acidification. ► Slc26a4-deficient mice are deaf with loss of the endocochlear potential.

Section snippets

Clinical phenotypes associated with EVA

Enlargement of the vestibular aqueduct (EVA) is a common malformation identified in ears of children undergoing high-resolution imaging for sensorineural hearing loss (Fig. 1A). An enlarged vestibular aqueduct is also sometimes referred to as a dilated or large vestibular aqueduct (DVA or LVA). Valvassori and Clemis established the modern radiologic definition of EVA as a midpoint diameter of >1.5 mm or a grossly malformed overall morphology (Valvassori and Clemis, 1978). These criteria have

Genetics of EVA

EVA with hearing loss typically presents as a sole clinical abnormality, in which case it is termed nonsyndromic. EVA has been reported in association with congenital cytomegalovirus (CMV) infection (Bauman et al., 1994), which can cause a similar hearing loss phenotype (Dahle et al., 2000). However, congenital CMV infection is not a significant or common cause of EVA (Pryor et al., 2005a). EVA may also be associated with abnormalities of other organ systems as part of a genetic syndrome.

Pathophysiological mechanisms of hearing loss in EVA

Our most significant mechanistic insights into the pathogenesis of hearing loss associated with EVA are based upon the Slc26a4 knockout (Slc26a4−/−) mouse that segregates a targeted deletion of exon 8 of Slc26a4 (Everett et al., 2001). Other mouse models include the Foxi1 knockout mouse (Hulander et al., 2003) and the loop mouse line segregating a chemically induced mutation of Slc26a4 (Dror et al., 2010).

The pathogenesis of EVA begins during the embryonic development of the inner ear. The

Conclusions

Enlargement of the vestibular aqueduct (EVA) is a comparatively common but enigmatic sensorineural hearing loss disorder in children. Studies in mouse models demonstrate that enlargement and acidification of the scala media are early events in the pathogenesis of hearing loss. Future work to elucidate the mechanism of hearing loss should focus on fluid transport in cochlear development and alterations of cellular and molecular function and signaling in the lateral wall of the cochlea. The

Acknowledgments

The authors are supported by NIH intramural research fund Z01-DC-000060 (A.J.G.) and Kansas State University (P.W.). We thank our colleagues for critical review of this manuscript. Fig. 1, Fig. 2 were provided by the National Institute on Deafness and Other Communication Disorders.

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