Brain, Vol. 123, No. 1, 82-92,
January 2000
© 2000 Oxford University Press
The spectrum of hearing loss due to mitochondrial DNA defects
1 Departments of Neurology, 2 Physiological Sciences and 3 Radiology, The University of Newcastle upon Tyne and 4 Department of Medical Physics, Freeman Hospital, Newcastle-upon-Tyne, UK
Correspondence to:
Dr P. F. Chinnery, Department of Neurology, The Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, UK E-mail: P.F.Chinnery{at}ncl.ac.uk
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Abstract |
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Heteroplasmic mitochondrial DNA (mtDNA) defects are an important cause of neurological disease. Although hearing impairment is common in patients with mtDNA defects, the spectrum and pathophysiology of the hearing loss is not well characterized. We therefore studied the relationship between cochlear and brainstem auditory function in 23 patients harbouring a range of different mtDNA mutations. Based upon the pure tone audiogram, patients fell into three distinct groups: (i) normal hearing, (ii) mild to moderate predominantly high frequency hearing loss, and (iii) severe or profound hearing loss at all frequencies. Within this study group only certain genetic defects were associated with hearing loss, and for individuals harbouring the A3243G point mutation, the severity of the hearing loss correlated with the percentage level of mutated mtDNA (mutation load) in skeletal muscle. The 10 patients who had a moderate hearing loss or less had normal brainstem auditory evoked responses and MRI, but it was not possible to interpret the brainstem auditory evoked responses in 13 patients with severe hearing loss. Otoacoustic emissions were absent in patients with a moderate or more severe hearing loss. These findings are consistent with a predominantly cochlear origin for the hearing deficit, which is determined by the precise genetic defect and the percentage mutation load.
mitochondrial encephalomyopathies; mtDNA mutation; mitochondrial hearing loss; genetic hearing loss
FSE = fast spin echo; MELAS = mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes; mtDNA = mitochondrial DNA; NARP = neurogenic weakness with ataxia and retinitis pigmentosa; PCR = polymerase chain reaction
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Introduction |
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TopAbstractIntroductionMaterial and methodsResultsDiscussionReferences |
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Mitochondrial DNA (mtDNA) defects are an important cause of neurological disease (Wallace, 1992a
; Chinnery and Turnbull, 1997; DiMauro and Bonilla, 1997). The clinical features of mtDNA disease are diverse, ranging from asymptomatic or mildly affected individuals with signs limited to extraocular and skeletal muscle, to severely affected individuals who develop central neurological complications at a young age (Chinnery and Turnbull, 1997). Pathological mtDNA mutations fall into two groups: rearrangement and point mutations. Over 100 different deletions of mtDNA have been associated with disease (Schon et al., 1997). Deletions usually cause chronic progressive external ophthalmoplegia and ptosis (Moraes et al., 1989), or the Kearns–Sayre syndrome (Zeviani et al., 1988). By contrast, point mutations cause a variety of different syndromes (Servidei, 1997). Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is caused by a relatively common point mutation in the leucine (UUR) transfer RNA (tRNA) gene at position 3243 of the mtDNA L-strand (Goto et al., 1990). Other point mutations are less common, such as the 8993 mutation which affects the ATPase 6 protein encoding gene, and is associated with neurogenic weakness with ataxia and retinitis pigmentosa (NARP) (Holt et al., 1990). Many mutations have only been described in a single family (Servidei, 1997).
Patients harbouring pathological mtDNA mutations usually have a mixture of mutated and wild-type (normal) mtDNA (heteroplasmy). In vitro studies have shown that a heteroplasmic mtDNA defect is only expressed when the percentage level exceeds a critical threshold level (Larsson and Clayton, 1995). The level of mutated mtDNA (mutation load) varies both between and within individuals with mtDNA disease (Lightowlers et al., 1997). This variability, coupled with tissue-specific differences in the threshold of expression, partly explains the diverse clinical phenotypes which are seen in patients harbouring the same mtDNA defect (Wallace, 1992a).
Bilateral hearing loss is a well-recognized feature of mtDNA disease either in isolation (Prezant et al., 1993; Reid et al., 1994; Oshima et al., 1999) or as part of a mitochondrial encephalomyopathy (DiMauro and Bonilla, 1997), and there have been a number of detailed clinical and physiological studies of hearing loss looking at its severity and aetiology, particularly in oligo- or asymptomatic individuals (Elverland and Torbergsen, 1991; Braverman et al., 1996; Oshima et al., 1996; Yamasoba et al., 1996; Sue et al., 1998). A priori, hearing impairment in mitochondrial disease might arise from end-organ dysfunction due to deficient energy release within the stria vascularis or hair cells, which are metabolically active structures. However, patients with central neurological manifestations might also have a central component to their hearing loss. In this study we therefore investigated the auditory function of 23 patients with a representative range of mtDNA defects. Ten of the patients harboured the same mtDNA point mutation, which allowed us to relate the degree of hearing loss to mutation load. In addition to pure tone and speech audiometry, subjects were systematically investigated with otoacoustic emissions, a sensitive indicator of cochlear dysfunction, as well as with correlates of central auditory processing: auditory brainstem evoked potentials and high-resolution structural imaging.
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Material and methods |
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Patient selection
We identified 23 patients with mtDNA disease from our mitochondrial genetic database. The patients were selected on the basis of their genetic defect alone, irrespective of any known pre-existing hearing loss (Table 1
). We included seven patients with sporadic mtDNA deletions, one patient with sporadic multiple deletions, 10 patients harbouring the A3243G MELAS point mutation, one patient with the T8993G NARP point mutation and four patients with unique tRNA gene point mutations, one of whom harboured three species of mtDNA (triplasmy) (Bidooki et al., 1997; Chinnery et al., 1997; Weber et al., 1997; Taylor et al., 1998). One patient (patient 5) presented initially with intractable trigeminal neuralgia. In addition to a fixed external ophthalmoparesis and ptosis, she had periventricular high signal on T2-weighted MRI and unmatched oligoclonal bands in her CSF which led to an additional diagnosis of multiple sclerosis (Taylor et al., 1998).
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Ethical approval for the study was obtained from the Newcastle upon Tyne Joint University/Health Authority ethical committee. Informed consent was obtained from all subjects.
The investigation of mitochondrial DNA disease
Fresh muscle was analysed histochemically and respiratory chain complex assays were carried out as described previously (Johnson and Barron, 1996; Taylor and Turnbull, 1997). Total genomic DNA was extracted from blood and skeletal muscle and Southern blotting was carried out on skeletal muscle DNA (Moraes et al., 1989). Mutation analysis for the T8993G NARP, A12030G, T10010C, A5656G and A606G mutations was carried out as described previously (Holt et al., 1990; Bidooki et al., 1997; Chinnery et al., 1997; Weber, 1997; Taylor et al., 1998) and the percentage level of the A3243G mutation was quantified by last hot-cycle polymerase chain reaction (PCR) (Moraes et al., 1993).
Hearing assessment
A detailed hearing history was taken from each patient and they were asked to complete an auditory questionnaire which included details of unilateral and bilateral hearing problems, the presence of tinnitus or vertigo and questions designed to identify a problem with auditory recruitment. (The Questionnaire is available on request.) The progression of the hearing loss was ascertained through retrospective questioning, the case notes and prospective follow-up using the questionnaire described above.
Pure tone audiometry using air and bone conduction was performed according to British Society of Audiology procedures (British Society of Audiology, 1981, 1985, 1986), in a sound-treated booth (IAC Acoustics, Middlesex, UK) using a clinical audiometer (GSI-16, Graystad, Cradely Heath, UK). The degree of hearing loss was defined according to the mean hearing loss at frequencies of 250, 500, 1000, 2000 and 4000 Hz as follows: normal hearing = <20 dB hearing loss; mild = 20–40 dB hearing loss; moderate = 41–70 dB hearing loss; severe loss = 71–95 dB hearing loss; and profound >95 dB hearing loss. The age-corrected mean hearing loss was defined as the measured mean loss at 500, 1000, 2000 and 4000 Hz minus the expected mean loss for a mixed gender, otologically unscreened population of that age, using data reported in the National Study of Hearing (Davis, 1995). Tympanometry was carried out when a significant air–bone gap was encountered. Speech audiometry was performed on all subjects using recorded AB isophonemic word lists presented monaurally via earphones in a sound-treated booth. Relative intensity was controlled by the audiometer, and one list of 10 words was presented at each test level and scored by phonemes correctly repeated. The maximum discrimination score and the best two average pure tone thresholds (of 500, 1000 and 2000 Hz) were compared to decide whether abnormal speech audiograms were indicative of sensory or neural hearing loss, and the half peak level elevation of the speech curve was inspected for agreement with the pure tone threshold (Priede and Coles, 1976). Abnormally low maximum discrimination score or unexpectedly large half peak level elevation were regarded as evidence of possible neurological abnormality.
Cochlear function was assessed by the presence or absence of transient evoked otoacoustic emissions (Kemp, 1978; Martin et al., 1994) using click stimuli of 80 dB sound pressure level (Otodynamics ILO88, Hatfield, UK). The overall responses were classified as present if after 260 averages the whole wave reproducibility was 
50% and there was a response in at least three of five frequency bands of at least 3 dB above the noise level. Otoacoustic emissions were deemed to be absent when there were no discernible waves to click stimulation under the same stimulation and recording conditions. In addition, the power spectrum of the emission was compared with the audiogram. The presence of an emission in frequency regions where hearing levels exceed 30 dB was taken to suggest a possible non-cochlear hearing impairment.
Brainstem auditory evoked responses were carried out in a sound-proofed room, using TDT (Tucker Davis Technologies, Calif., USA) SigGen and BioSig software for stimulus delivery and response acquisition, implemented using TDT hardware. Alternate compression and rarefaction clicks were delivered at a sensation level of 65 dB up to a maximum of 100 dB sound pressure level, with contralateral aural masking, with white noise at a sensation level of 30 dB. Signals were recorded between the ipsilateral mastoid and vertex using the contralateral mastoid as the indifferent electrode. An average of 2000 responses was carried out on each side at click rates of 8 Hz and 15 Hz. Off-line filtering was carried out using a pass band of 100 Hz to 3 kHz. Latency of waves I–V and the amplitude ratio of waves V : I were measured by three independent observers and compared with established age-matched values (Abramovich, 1990).
Structural imaging
Twenty-two patients underwent cranial MRI at 1.0 T (Siemens, Impact Expert, Siemens, Erlangen, Germany). A 5 mm thick proton density, T2-weighted fast spin echo (FSE) and T1-weighted spin echo (SE) sequences were acquired axially through the cranium followed by sagittal T2-weighted FSE sequences.
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Historical features of hearing loss in relation to mitochondrial genotype
Of the 23 patients, 15 were female and eight were male, with an age range between 25 and 76 years (mean 45.6 years; Table 1
). Each patient harboured a mtDNA mutation causing mitochondrial disease (Schon et al., 1997). This included eight patients with rearrangements (seven single deletions and one multiple deletion), 10 patients with the A3243G point mutation, one patient with the T8993G point mutation and four patients harbouring novel mtDNA pathogenic point mutations which had been confirmed by single-fibre PCR analysis (Bidooki et al., 1997; Chinnery et al., 1997; Weber et al., 1997; Taylor et al., 1998).
Seventy-four per cent of the 23 patients had symptoms of hearing loss (Table 2). This ranged from mild difficulties in understanding speech in crowded rooms (patient 8) to complete hearing loss despite maximal amplification with a hearing aid (patient 22). The age of onset ranged from 4 years in a patient with Leigh syndrome (patient 23), to 70 years in a patient with chronic progressive external ophthalmoplegia (patient 9). One of the 10 patients harbouring the A3243G MELAS mutation had a severe hearing deficit before the age of 20 (patient 21, onset in early childhood). Of the nine A3243G patients who had a hearing loss at the time of the study, eight (89%) developed hearing loss before the age of 45.
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The development of hearing loss in patients harbouring the A3243G and T8993G mutations was different from that of the other patients (Tables 1 and 2
). Of the nine patients harbouring the A3243G mutation who had a hearing deficit, five (55%) reported a sudden onset of hearing loss or a stepwise decline in hearing loss. Of these five, four noted an abrupt decline in association with either stroke-like episodes or an encephalopathic illness. The patient with Leigh syndrome (patient 23) also developed hearing loss in association with episodes of encephalopathy. The remaining A3243G patients noted a slowly progressive loss over many years.
Measured hearing loss in relation to mitochondrial genotype
Based upon the pure tone audiogram the 23 patients fell into three distinct groups: (i) patients with audiograms which were normal for their age (n = 8), (ii) those with predominantly high frequency hearing loss (n = 5, e.g. Fig. 1B), (iii) those with a moderate, severe or profound hearing loss across all frequencies (n = 10, e.g. Fig. 1A).
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Four patients with chronic progressive external ophthalmoplegia due to a single deletion had normal hearing. One patient with chronic progressive external ophthalmoplegia due to a single deletion had a mild predominantly high frequency loss, as did the one patient with multiple deletions. One patient with Kearns–Sayre syndrome had a mild predominantly high frequency loss and two had a moderate hearing loss at all frequencies. Three patients with tRNA gene mutations (A12030G, G4928A and A606G) had normal hearing and one had a moderate hearing loss across all frequencies (T10010C/A5656G). One patient with Leigh syndrome (T8993G) had a severe hearing loss. Finally, the 10 patients harbouring the A3243G (MELAS) point mutation had a range of auditory function from normal (patient 1) to complete hearing loss (patient 22). Speech audiometry was consistent with cochlear impairment in all cases tested. In one case (patient 12) the scores were poorer than expected but this patient had very poor speech production which probably influenced the findings (Tables 1 and 2
). Only one patient showed a significant conductive impairment on pure tone audiometry. Patient 9 had air–bone gaps of not more than 30 dB at 1000 Hz and below in both ears, but showed normal (type A) tympanograms. This patient was subsequently found to have normal otoacoustic emissions.
Relationship between genotype and hearing loss for the A3243G MELAS mutation
In the 10 individuals harbouring the A3243G MELAS mutation there was a direct correlation between the percentage of mutated mtDNA in skeletal muscle and the binaural mean age-corrected hearing loss in dB at 4 kHz (r2 = 0.59, P < 0.05; Fig. 2). The correlation between mutation load in blood and the binaural mean age-corrected hearing loss at 4 kHz did not reach statistical significance (r2 = 0.40, P < 0.10). Similar trends were seen when we studied the relationship between the mutation load and the severity of the mean hearing loss across five frequencies (250–4000 Hz). We did not observe a relationship between the severity of the hearing loss and patient age, nor did we observe a significant relationship between the mutation load in muscle or blood and patient age.
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Measures of cochlear and central function
Otoacoustic emissions were present in the asymptomatic individuals with normal audiometry (Fig. 3A
), with two exceptions. They were absent in two of the three individuals with mild hearing loss and all of the tested individuals with a moderate, severe or profound hearing loss (Fig. 3B). Comparison of the power spectra with the audiograms did not reveal any cases with emissions present in frequency regions where the hearing level was 30 dB or worse. Brainstem auditory evoked responses could be elicited and reliably interpreted in the patients with mild or no hearing loss (Fig. 4A). The peak latencies, interpeak latencies and wave I : V amplitude ratios were normal in all 10 of these patients. It was not possible to discern brainstem auditory evoked response peaks in 13 patients with moderate, severe or profound hearing loss (Fig. 4B).
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Structural imaging
The patients with normal audiograms and brainstem auditory evoked responses had normal brainstem MRI. However, one of these individuals, patient 5, had periventricular high signal changes on MRI consistent with the clinical diagnosis of multiple sclerosis. Patient 1 had basal ganglia hyperintensities consistent with microcalcification. Two individuals with mild hearing loss had normal imaging. One of the 10 individuals with moderate, severe or profound hearing loss had normal imaging. One individual (patient 16 with Kearns–Sayre syndrome) had generalized atrophy with high signal intensity extending throughout the brainstem and midbrain to the globus pallidus bilaterally (Fig. 5A
), and one individual harbouring the A3243G mutation had evidence of extensive infarction and atrophy involving both temporal lobes (patient 22, Fig. 5B).
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Discussion |
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We performed a detailed clinical, electrophysiological and imaging study of 23 patients harbouring a representative range of mtDNA mutations. We have shown that patients with pathogenic mtDNA mutations can have hearing which is normal for their age (35% within this study group) or a range of hearing defects from mild to complete hearing loss. We have also shown that, within this study group, certain mtDNA mutations are not associated with hearing loss, and for the A3243G MELAS mutation, the severity of the hearing loss correlates with the percentage of mutated mtDNA.
Normal audiograms, evoked potentials and cerebral imaging in patients with sporadic multiple or single deletions of mtDNA are consistent with the observation that the clinical effects of these mutations may be restricted to extraocular and skeletal muscle (Chinnery and Turnbull, 1997). Similarly, we have shown that patients with chronic progressive external ophthalmoplegia (patient 5) and a severe myopathy (patients 2 and 8) due to mtDNA tRNA mutations may also have pure muscle phenotype. In contrast, we have shown that individuals harbouring mutations which are known to cause central neurological disease (deletions and the A3243G and T8993G point mutations) are susceptible to hearing loss, and the vast majority of these patients noted symptoms before age 45 years. Our observations parallel the multi-system disease that may be a feature of certain mtDNA diseases.
Our data are in accordance with a cochlear basis for the hearing loss in patients with mtDNA disease. Otoacoustic emissions, a sensitive index of cochlear dysfunction, were universally absent in all of the subjects with a moderate or more severe hearing loss (Kemp, 1978; Martin et al., 1994). Furthermore, we did not identify a central pattern of brainstem auditory evoked response deficit in any of the patients with mild hearing loss, the only group with hearing deficits in whom the traces were consistently interpretable. No subject (with either normal hearing or with a hearing deficit) was identified with normal otoacoustic emissions, but with evidence of central auditory pathway disruption, on the basis of the brainstem auditory evoked responses.
What is the biophysical basis for the cochlear hearing losses that we observed? Normal hearing is dependent upon the stria vascularis, which maintains the ionic gradients necessary for sound signal transduction and the complex interaction between the inner and outer hair cells (Dallos and Evans, 1995). Both the stria vascularis and the hair cells are highly metabolically active (Thalmann et al., 1979, 1982; Hibino et al., 1997) and would be compromised by a deficiency of intracellular ATP due to mitochondrial dysfunction (Cortopassi and Hutchin, 1994), which might ultimately lead to cell death (Schon et al., 1997). In mammals, unlike amphibians and birds, both the stria vascularis and the hair cells are post-mitotic (Fernandez and Hinojosa, 1974) and it is likely that the level of mutated mtDNA in these cells is similar to the level in other post-mitotic tissues such as skeletal muscle (Lightowlers et al., 1997). A priori, one might expect, therefore, that cochlear function might be related to the level of mutated mtDNA in muscle. However, the relationship between the function of individual component cells and the function of the cochlea as a whole organ is highly complex. Our data are consistent with the hypothesis that higher levels of mutated mtDNA in muscle are associated with an increased number of cochlear cells which contain levels of mutated mtDNA above the critical threshold level (~94%; Chomyn et al., 1992) needed to cause respiratory chain dysfunction (Schon et al., 1997). Extreme variations in the tissue levels of mutated mtDNA may confound the relationship between muscle mutation load and the severity of the hearing loss (see patient 12 in Table 3; Fig. 2). In addition, both genetic and environmental influences may act synergistically and cause hearing loss in individuals with a lower mutation load. For example, it is well recognized that noise can interact to exacerbate a given hearing loss (Hyde and Rubel, 1995) and aminoglycoside antibiotics may precipitate deafness in persons with a particular mtDNA genotype (Prezant et al., 1993). These factors may influence the hearing loss due to other primary mtDNA mutations (Oshima et al., 1999) in a similar way to the complex genetic and environmental factors that modulate the expression of the mtDNA mutations that cause Leber's hereditary optic neuropathy (see Discussion in Howell, 1999). In agreement with other studies (van den Ouweland et al., 1992; Yamasoba et al., 1996) we did not observe a significant correlation between mutation load in blood and the severity of the hearing loss. This may reflect an age-related decline in percentage of mutated mtDNA within the blood of patients with the A3243G mutation ('t Hart et al., 1996).
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It is interesting that the natural history of the hearing loss may differ between patients with mtDNA defects. For example, the three patients with Kearns–Sayre syndrome and large deletions of mtDNA reported a slowly progressive hearing loss. This is consistent with a progressive loss of function due to degeneration of the stria vascularis which has been documented with Kearns–Sayre syndrome (Lindsay and Hinojosa, 1976
), and the neurodegenerative neuropathology with spongiform change which is also characteristic of Kearns–Sayre syndrome (Sparaco et al., 1993). In contrast, 80% of the A3243G (MELAS) patients, one patient with the T8993G point mutation and one patient with the T10010C/A5656G mutations, described an abrupt, stepwise loss of hearing which usually occurred in association with encephalopathic or stroke-like episodes. Sue and colleagues reported a similar finding in their cohort of A3243G (MELAS) patients (Sue et al., 1998), which suggests that acute metabolic compromise of the stria vascularis may cause irreversible functional loss of cochlear hair cells.
One of the principal motivations for this study was to seek deficits in central auditory processing in mitochondrial disease. In the case of individuals with normal hearing, the brainstem auditory evoked responses and imaging data exclude a central pathway defect. In this case the evoked responses are easy to interpret, and the structural imaging did not demonstrate the sort of small brainstem lesions that we have shown in other neurological disorders which produce subtle psychoacoustic deficits (Griffiths et al., 1997, 1998). In the case of individuals with hearing loss, the brainstem auditory evoked responses and imaging data do not support the presence of a central pathway deficit, although we cannot conclude that there is no central contribution to the hearing loss. The absence of central peaks in the brainstem auditory evoked responses for subjects with moderate hearing loss is of interest because one would expect to detect an evoked response in individuals with this level of hearing impairment due to a pure cochlear lesion. Many of these individuals had structural lesions that are likely to affect the ascending auditory pathway or the auditory cortex, which may explain our findings. Apart from the deficits in basic auditory processing principally considered here, such lesions can produce deficits in complex sound processing, including apperceptive auditory agnosias (Griffiths et al., 1999). However, such complex-sound processing disorders are often symptomatic. Structured interview of our patients suggested no perceptual disorders, other than ones in keeping with peripheral hearing disorders.
Otoacoustic emissions and speech audiometry are helpful in establishing whether an individual with a mtDNA defect has a primarily cochlear defect, but evoked response audiometry is of limited use in patients who have moderate or more severe hearing loss. Although patients with mtDNA disease and hearing loss may respond well to a cochlear implant (Sue et al., 1998), central neurological involvement may limit the improvement and detailed brain imaging is mandatory. For the first time we have shown a correlation between the percentage level of mutant mtDNA in muscle and the severity of the auditory phenotype. This relationship is, however, likely to be complex. Tissue-specific differences in the level of mutated mtDNA and the bioenergetic threshold may contribute to the variability (Wallace, 1992b) and nuclear genetic factors may be important (Chinnery and Turnbull, 1998). It would therefore be unwise to use the data presented here for predictive purposes for individual patients.
It is of particular interest that hearing impairment is so prominent in many oligosymptomatic individuals with mtDNA disease. In one study, 7.4% of the patients with sensorineural hearing loss harboured the A3243G mutation (Majamaa et al., 1998), making mitochondrial disease one of the more common genetic causes of hearing loss. Individuals who harbour high levels of the A3243G mutation are at high risk of developing severe hearing deficit, and these individuals should avoid ototoxic agents, such as aminoglycoside antibiotics, which may further compromise cochlear function (Estivill et al., 1998). Recently there has been great interest in the role of the mitochondrion in the aetiology of presbyacusis (Fischel-Ghodsian et al., 1997; Seidman et al., 1997; Tao et al., 1987; Fischel-Ghodsian, 1998) and hair cell survival after toxin and noise-induced auditory damage (Hyde and Rubel, 1995). A deeper understanding of the mechanisms of hearing loss in patients with established mtDNA disease may thus have important implications for many patients with sporadic and genetic hearing deficits.
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Acknowledgments |
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We would like to thank Dr M. A. Johnson for her expertise with the histochemistry. P.F.C. and T.D.G. are supported by the Wellcome Trust.
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Received May 25, 1999. Revised July 13, 1999. Accepted July 16, 1999.
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