LETTER TO JMG Non-syndromic recessive auditory neuropathy is the result of mutations in the otoferlin (OTOF) gene

It is estimated that about 1 in 500 children are born with a significant hearing loss. Non-syndromic recessive hearing loss (NSRHL) represents a major aetiologic factor in childhood hearing loss since it accounts for approximately 40% of all cases. Many of these genetic forms of hearing loss are indistinguishable with current clinical methods. Even so, more than 12 recessive genes have been identified primarily from large consanguineous pedigrees (see the Hereditary Hearing Loss Homepage http://www.uia.ac.be/dnalab/hhh for an overview). By definition, non-syndromic suggests a “simple” phenotype limited to hearing loss with no other associated symptoms. However, hearing is a complex process. Since a hearing defect might occur at any place along the auditory pathway, it would seem reasonable to expect to be able to differentiate types of NSRHL based on the location where the auditory process is disrupted. Indeed, new audiological testing strategies now give insight into the point where such defects have occurred. Pure tone audiometry has been the standard method used to measure hearing threshold but, since it subjectively tests the overall integrity of the auditory pathway, it gives only limited information about where that pathway is failing. The auditory brainstem response (ABR) is an objective measure of the overall auditory transduction process. The otoacoustic emissions (OAEs) test is another objective measure of the auditory pathway, which detects responses of the outer hair cells (OHCs) to environmental sound. A good review of auditory tests can be found in Hood. Some children have a hearing loss based on pure tone audiometry and ABR, but with normal OAEs. This type of hearing loss has been defined as auditory neuropathy (AN). Subjects with AN can have varying degrees of hearing loss with poor speech reception out of proportion to the degree of hearing loss. In contrast to those with non-AN hearing loss, most subjects with AN are not helped by hearing aids. The results of cochlear implantation (CI) have been mixed. Some cases of AN have been helped by CI, 10 whereas others have not had such good results. 12 The genetic study of AN is complicated by the fact that the term includes hearing losses with varied aetiologies. AN can be non-genetic, owing to factors such as neonatal hyperbilirubinaemia. AN is also observed in many syndromic peripheral neuropathies, like Friedreich’s ataxia and hereditary sensorimotor neuropathy (HSMN) formerly known as Charcot-Marie-Tooth disease. 14 15 Hearing loss in some forms of HSMN has been shown to be associated with specific genetic alterations, including 8q23 in HSMN-Lom and a mutation of Thr124Met in the myelin protein zero gene. The children with AN described here have an autosomal recessive disorder and are distinguished by their lack of any other detectable peripheral neuropathy. We have elected to call this non-syndromic recessive auditory neuropathy (NSRAN). Linkage studies and mutation analysis have identified the OTOF gene as being responsible for this type of hearing loss in our families. SUBJECTS AND METHODS The appropriate institutional review boards approved this study and informed consent was obtained from human subjects. We observed four families with two or more children who had sensorineural hearing loss and normal OHC function (fig 1). The degree of hearing loss was determined by standard pure tone audiometry. The scale used to classify the degree of hearing loss is as follows: 0-20 dB HL is normal, 21-40 dB HL is mild, 41-60 dB HL is moderate, 61-80 dB HL is severe, and above 80 dB HL is profound. The status of the auditory pathway was determined using tympanometry, middle ear muscle reflex (MEMR), and ABR. OHC function was measured using distortion product OAE (DPOAE), transient evoked OAE (TEOAE), and/or cochlear microphonics (CM). All subjects diagnosed with hearing loss were examined by an otolaryngologist, a neurologist, and geneticist and underwent testing to rule out syndromic disorders.