Hearing loss is a common disorder affecting the communication abilities of more than 28 million Americans. A variety of etiologies for hearing loss have been identified including aging, noise exposure, ototoxic medications, and genetics. Over 90 different genetic loci have been linked to hereditary auditory impairment . The majority of these loci are associated with high frequency hearing loss or a deficit affecting all frequencies, with only four loci linked to low frequency hearing loss. It is not well understood why autosomal dominant mutations at these four loci cause low frequency hearing loss as opposed to reduced sensitivity in the higher frequencies.
Non-syndromic autosomal dominant low frequency sensorineural hearing loss (LFSNHL) has been mapped to the DFNA1, DFNA11, DFNA54, and DFNA6/14/38 loci. These four loci are described by the letters DFN, which stand for deafness, and the letter A to indicate autosomal dominant inheritance. The loci are labeled with a number indicating the order in which they were discovered. DFNA1, the first identified locus for LFSNHL, is associated with a mutation in the DIAPH1 gene (homologue of Drosophila diaphanous) and has been reported in only a single family . DFNA11 represents a second LFSNHL locus, where a heterozygous mutation in myosin VIIA (MYO7A) found in only a single family leads to non-syndromic LFSNHL . DFNA54 was mapped to LFSNHL in one family, but the gene has not yet been identified . The fourth and most common locus for LFSNHL is DFNA6/14/38, which results from heterozygous mutations in the Wolfram syndrome type 1 gene (WFS1) [5–7].
The hearing loss associated with autosomal dominant mutations in WFS1 is primarily bilateral and symmetric. The age of onset of hearing loss appears to occur before age 10 and initially affects 250, 500 and 1000 Hz . The mild hearing loss in the low frequencies seen in young children generally progresses to a moderate hearing loss in the low and mid frequencies by the second decade of life and then to a moderate to severe loss across the frequency range after age 40 . Homozygous mutations in WFS1 have been linked to the recessively inherited Wolfram syndrome, a syndrome whose features include diabetes insipidus, diabetes mellitus, optic atrophy and sensorineural hearing loss in the high frequencies .
WFS1 encodes for wolframin, an 890 amino acid protein of unknown function, which has been localized to the endoplasmic reticulum . Wolframin is predicted to have nine transmembrane spanning domains with a hydrophilic N- and C-terminus . Wolframin is expressed in the mouse inner ear throughout postnatal development (P1, 7, 14, 35) in a variety of cell types including outer and inner hair cells, support cells, spiral ganglion neurons and vestibular hair cells . No wolframin expression gradient is observed between the apical and basal ends of the cochlea.
Despite high levels of wolframin expression in the vestibular hair cells , individuals with heterozygous WFS1 mutations and LFSNHL generally do not complain of vestibular difficulty [7, 8, 13–17]. Ocular motor, caloric and vestibular ocular reflex testing have not revealed any consistent vestibular dysfunction in patients with Wolfram's syndrome or individuals with heterozygous WFS1 mutations and LFSNHL [15, 17–21]. Previous vestibular testing for individuals with heterozygous and homozygous WFS1 mutations has targeted the semicircular canals. To our knowledge, no clinical testing of otolith function such as the vestibular evoked myogenic potential (VEMP) has been completed in individuals with WFS1 mutations. In addition, the literature does not report electrocochleography (EcochG) findings for individuals with WFS1 mutations even though LFSNHL has also been associated with endolymphatic hydrops .
The goal of this study was to use genetic analysis to determine if a small American family's hereditary LFSNHL is linked to a mutation in the WFS1 gene and to use VEMP and EcochG testing to further characterize the family's audiovestibular phenotype.