Chapter 254

Abstract

1. There is a high prevalence of hearing loss at any age. The conductive forms of deafness are defined as being due to external and/or middle ear defects, and the sensorineural forms as being due to an abnormal response to sound from the inner ear to the cortex. The various forms of deafness are classified into two categories, syndromic and nonsyndromic (also termed isolated). In the introduction, we provide background information on the structure of the ear, its functioning, its development, and the auditory pathway. Finally, we discuss the causes of hearing loss. About 80 percent of the prelingual cases are of genetic origin in developed countries.

2. Syndromic forms of deafness are almost exclusively hereditary in developed countries; several hundreds of syndromes including hearing loss have been described. Table 254-1 summarizes the data concerning the 100 or so syndromic forms of deafness for which the causative gene has been isolated. They are distributed into three classes: (a) the forms with external and middle ear anomalies, with or without a sensorineural component to the deafness; (b) the forms with middle ear anomalies, with or without sensorineural deafness; and (c) the sensorineural forms. It is noteworthy that several genes underlying a syndromic deafness also underlie one, or sometimes two, genetic forms of isolated deafness.

3. The core of the review concerns the nonsyndromic forms of deafness. These are genetically highly heterogeneous and appear to be almost exclusively monogenic diseases. A hundred or so genes are supposed to underlie this deficit. Fifty-three loci have presently been reported. The 17 deafness forms for which the genes have been identified are presented. Each form is introduced by a brief history of how the gene was discovered, followed by the description of its clinical features and the established or putative role of the encoded protein, as well as the current hypotheses concerning the associated pathophysiological processes. Deaf mouse mutants involving the orthologous genes are discussed at the same time. In addition, four genes that have been implicated in deafness in the mouse, but not yet in humans, are discussed.

4. From the molecular data presently available, three main epidemiologic results emerge: (a) Mutations in the gene encoding a gap junction protein, connexin 26, account for about half of the cases of prelingual isolated deafness in Caucasian populations; (b) Defects of the gene responsible for Pendred syndrome (hearing loss and thyroid dysfunction), encoding a iodide-chloride transporter, may also account for an underestimated proportion of isolated deafness (DFNB4), which is characterized by the presence of particular inner ear anomalies; and (c) Mutations in the mitochondrial gene encoding the 12S ribosomal RNA underlie aminoglycoside-induced hearing loss, and may also account for a high proportion of the cases of genetic deafness in the absence of any exposure to these antibiotics.

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