Cochlear histopathology in human genetic hearing loss: State of the science and future prospects

Abstract

Sensorineural hearing loss (SNHL) is an extraordinarily common disability, affecting 466 million people across the globe. Half of these incidents are attributed to genetic mutations that disrupt the structure and function of the cochlea. The human cochlea's interior cannot be imaged or biopsied without damaging hearing; thus, everything known about the morphologic correlates of hereditary human deafness comes from histopathologic studies conducted in either cadaveric human temporal bone specimens or animal models of genetic deafness. The purpose of the present review is to a) summarize the findings from all published histopathologic studies conducted in human temporal bones with known SNHL-causing genetic mutations, and b) compare the reported phenotypes of human vs. mouse SNHL caused by the same genetic mutation. The fact that human temporal bone histopathologic analysis has been reported for only 22 of the nearly 200 identified deafness-causing genes suggests a great need for alternative and improved techniques for studying human hereditary deafness; in light of this, the present review concludes with a summary of promising future directions, specifically in the fields of high resolution cochlear imaging, intracochlear fluid biopsy, and gene therapy.

Keywords: Hearing loss; Histopathology; Temporal bone.

Figure 1:

Causes of congenital hearing loss in developed countries, as compiled in the Hereditary Hearing Loss home page (Van Camp et al.). Three genes implicated in autosomal dominant hearing loss (COCH, GSDME, and MYH9) and one gene implicated in recessive hearing loss (GJB2) have corresponding temporal bone histopathology. Eighteen genes implicated in syndromic hearing loss have corresponding temporal bone histopathology (COL4A5, EYA1, CDH23/PCDH15, PAX3, ERCC6, ERCC8, XPA, XPC, XPD, KCNQ1, TIMM8A, NDS, NF2, GJB2, CHD7, SLC26A4, and PHYH). Abbreviations: (*) = X-linked, mitochondrial, and other causes of hearing loss.

Figure 2:

The chromosomal location of genes with mutations causing SNHL. The genes are classified according to the type of genetic hearing loss that they are associated with and the color convention is the same as in Figure 1. Those with corresponding human temporal bone histopathology are identified with a purple star. Modified from Dror and Avraham 2010 (Dror et al., 2010). Note that several syndromes were diagnosed by clinical findings and while a particular gene is suggested as the cause, this has not always been confirmed by molecular testing.

Figure 3:

Visualization of human intracochlear anatomy using standard histopathology and dissection technique versus synchrotron radiation phase contrast imaging (SR-PCI) and subsequent virtual sectioning using computer software. a) Human cadaveric temporal bone specimen, drilled to expose the round (RW) and oval (OW) windows. b) Mid-modiolar section through a hematoxylin and eosin (H&E)-stained human cochlea. c) SR-PC image of a three-dimensionally intact, undecalcified, unstained temporal bone, showing the spiraling nature of the organ of Corti. d) Virtual cochlear whole mount sectioned at the level of the organ of Corti, revealing rows of cells.