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J Neurol (2005) 252 : 1101–1107 DOI 10.1007/s00415-005-0827-7
Cornelia Kornblum Rainer Broicher Eberhard Walther Stephan Herberhold Thomas Klockgether Claus Herberhold Rolf Schröder
Received: 5 May 2004 Received in revised form: 11 January 2005 Accepted: 27 January 2005 Published online: 15 April 2005
C. Kornblum, MD () · T. Klockgether · R. Schröder Dept. of Neurology, University of Bonn Sigmund-Freud-Strasse 25 53105 Bonn, Germany Tel.: +49-228/287-5712 Fax: +49-228/287-5024 E-Mail:
[email protected] R. Broicher · E. Walther · S. Herberhold · C. Herberhold Dept. of Otorhinolaryngology, University of Bonn Bonn, Germany
ORIGINAL COMMUNICATION
Sensorineural hearing loss in patients with chronic progressive external ophthalmoplegia or Kearns-Sayre syndrome
■ Abstract In the present study we assessed the prevalence and nature of hearing loss in patients with chronic progressive external ophthalmoplegia (CPEO) or Kearns-Sayre syndrome (KSS) due to single large-scale mitochondrial DNA (mtDNA) deletion or mtDNA tRNA Leu (UUR) A3243G point mutation (A3243G PM). 14 patients with mtDNA deletion and three patients with A3243G PM underwent audiological evaluation comprising pure-tone and speech audiometry as well as transient evoked otoacoustic emissions (OAE). Audiological evaluation revealed hearing impairment in 10/17 patients. Hearing loss was mild to moderate predominantly affecting high frequencies in five patients with sub-
Introduction
■ Key words mitochondrial disorders · hearing loss · mtDNA deletion · CPEO · cochlear dysfunction
DNA tRNA point mutations with the clinical syndrome of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), whereas comparably little is known about patients harbouring mtDNA deletions associated with the clinical syndromes of chronic progressive external ophthalmoplegia (CPEO) or Kearns-Sayre syndrome (KSS). The aim of our study was to assess the prevalence and nature of hearing loss in a clinically homogeneous series of patients with CPEO or KSS due to single large-scale mtDNA deletions and mtDNA tRNA Leu (UUR) A3243G point mutations (A3243G PM), respectively. JON 1827
Mitochondrial cytopathies are a heterogeneous group of multisystemic disorders that have in common defective oxidative phosphorylation resulting in energy depletion of the cells. As a consequence, tissues with high energy requirements such as the central nervous system, retina, muscle, kidney, liver and inner ear are often affected [2, 21]. Though hearing impairment is a clinically relevant and treatable symptom [14], there are few studies investigating hearing deficits in clinically and genetically defined mitochondrial cytopathies [1, 4, 5, 15, 26]. Most studies focussed on patients with mitochondrial (mt)
jective hearing problems (three patients with mtDNA deletions, two patients with A3243G PM). Subclinical hearing deficits restricted to high frequencies were seen in further five asymptomatic patients (four patients with mtDNA deletions, one patients with A3243G PM). Audiological findings suggested a cochlear origin of hearing loss in all subjects. Our results demonstrate that CPEO or KSS patients due to mtDNA deletion or A3243G PM are at high risk of developing sensorineural hearing deficits.
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Subjects and methods Diagnosis of mitochondrial disease was made by means of clinical, laboratory, histological, histochemical, biochemical and genetic investigations following generally accepted criteria and methods [9]. Molecular genetic analysis of skeletal muscle tissue for detection of mtDNA mutations was performed as previously described [13]. A consecutive series of 17 patients who were seen at our department between 00/07 and 02/10 were included in the study. All met the following criteria: (1) CPEO or KSS, (2) single large-scale mtDNA deletion or A3243G PM, (3) age ≤ 65 years. KSS was defined according to following criteria: (1) progressive external ophthalmoplegia, (2) age at onset ≤ 20 years, (3) pigmentary retinopathy, (4) cardiac conduction block and/or cerebellar ataxia. All CPEO patients presented with bilateral ptosis, incomplete progressive external ophthalmoplegia and further skeletal muscle/organ involvement (“CPEO plus”). Clinical neurological examination was performed prior to otorhinolaryngologic workup. The study was performed in accordance with the Declaration of Helsinki, and all patients gave their informed consent prior to their inclusion. ■ Pure tone audiometry Pure tone audiometry was performed by trained audiology assistants using a clinical computer audiometer type AT 300 (Auritec, Hamburg, Germany). Audiometry included air and bone conduction measurement using standard methods. Assessment of hearing loss (dB) was done according to bone-conducted signals or according to air-conducted signals, if bone-conducted signals were not available. Mean hearing loss was calculated over the frequencies of 0.5, 1, 2 and 4 kHz for both ears separately. Grading of hearing loss was done according to the binaural mean hearing loss (dB) at 0.5, 1, 2 and 4 kHz. Normal hearing was defined as 0–20 dB, mild hearing impairment as 21–40 dB, moderate as 41–70 dB and severe hearing impairment as > 70 dB mean binaural hearing loss [8]. In addition, mean high frequency (HF) hearing loss was calculated over the frequencies of 4, 6 and 8 kHz for both ears separately. Grading of HF hearing loss was done according to the binaural mean HF hearing loss (dB) at 4, 6 and 8 kHz. Mild HF hearing impairment was defined as 30–50 dB, moderate as 51–80 dB mean binaural hearing loss. Second, age- and sex-correction was done for the mean hearing loss and mean HF hearing loss for each ear separately. Age- and sexcorrected mean hearing loss was defined as the measured mean loss at 0.5, 1, 2 and 4 kHz minus the mean loss in an otologically unselected population of the same age and sex using data reported in the National Study of Hearing [3]. Age- and sex-corrected mean HF hearing loss was calculated over 4, 6 and 8 kHz according to the same criteria. The configuration of hearing impairment was further divided into HF hearing loss affecting only frequencies above 2000 Hz, predominantly high-frequency hearing loss affecting all frequencies with particular affection of frequencies above 2000 Hz and hearing loss similarly affecting all frequencies. ■ Speech audiometry Speech discrimination testing was performed in all patients using phonetically balanced word lists (“Freiburger Wortlisten”) comprising 20 monosyllabic words presented monaurally via earphones in a soundtreated booth (AT-300 audiometer). ■ Transient evoked otoacoustic emissions (TEOAE) Bilateral TEOAE were recorded and analyzed by use of ILO 92 software and hardware (Otodynamics, Hatfield, UK). The number of responses to be averaged was set at 260 using nonlinear click stimuli of
60–80 dB sound pressure level (SPL) and 0.2 ms duration. Otoacoustic emissions (OAE) were considered to be absent when there were no identifiable waves to nonlinear click stimulation under the same stimulation and recording conditions.
Results ■ Clinical and genetic findings Clinical and genetic data of the patients are given in Table 1. Eight were male and nine female, mean age was 47 ± 12 y (range 19–61). Four had KSS and 13 CPEO. Age at onset of neurological symptoms was 10.3 ± 6.7 y (range: 2–18) in KSS patients and 22.4 ± 15.2 y (range: 8–55) in CPEO patients. All subjects showed ragged-red fibers and cytochrome c-oxidase-negative fibers in open skeletal muscle biopsy. Molecular genetic analysis of mtDNA demonstrated heteroplasmic single large-scale mtDNA deletions in 14 patients (CPEO/KSS: 10/4) with a degree of heteroplasmy in skeletal muscle ranging from 5 % to 85 %. In three patients, CPEO was due to the A3243G PM of the mitochondrial genome.
■ Otological findings Five of 17 patients complained of hearing impairment, whereas 12 of 17 patients reported normal hearing and had never undergone an otological examination before. Audiological evaluation (Table 2) revealed hearing impairment in 10/17 patients (four female, six male). Five patients with abnormal audiological testing (four female, one male) did not complain on hearing deficits in the preceding clinical examination. These patients showed isolated HF hearing loss of mild to moderate extent.
Patients with mtDNA deletion 50% of our patients with mtDNA deletion (7/14) showed clinical or audiological signs of hearing impairment. Age-corrected mild to moderate, predominantly high-frequency, downsloping hearing impairment was seen in 3/14 patients with mtDNA deletion. Two of these patients were classified as KSS and one as CPEO, all were male. In the CPEO patient, hearing loss of the left ear at 0.5, 1, 2 and 4 kHz could be related to age as well. All three patients were clinically symptomatic and depended on a hearing aid. The onset of subjective hearing impairment was 13 and 16 years later than the onset of first neurological symptoms in KSS patients. The CPEO patient noticed hearing impairment 47 years subsequent to first neurological symptoms. Clinical development of hearing impairment was slowly progressive without stepwise declines or spontaneous improvements in all patients.
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Table 1 Clinical and genetic data on our series of 17 CPEO or KSS patients Patient No.
Age (y)/ Sex
Diagnosis
Genetic Analysis
Grade of Heteroplasmy
Size of mtDNA deletion (kB)
Age at onset of of neurological symptoms (y)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
39/f 34/f 31/m 61/f 52/f 39/f 49/m 19/m 57/f 42/f 50/f 60/m 57/m 61/m 61/m 38/f 52/m
KSS CPEOplus KSS CPEOplus CPEOplus KSS CPEOplus KSS CPEOplus CPEOplus CPEOplus CPEOplus CPEOplus CPEOplus CPEOplus CPEOplus CPEOplus
mtDNA deletion mtDNA deletion mtDNA deletion A3243G PM mtDNA deletion mtDNA deletion mtDNA deletion mtDNA deletion mtDNA deletion mtDNA deletion mtDNA deletion A3243G PM A3243G PM mtDNA deletion mtDNA deletion mtDNA deletion mtDNA deletion
78% 16% 66% NA 60% 62% 32% NA 74% 26% 53% NA 26% 5% 46% 58% 85%
5 7.5 7 NA NA 3.5 2.7 NA 5 7.5 5 NA NA 5 6 7.5 5.6
9 10 12 40 25 18 44 2 16 14 12 10 19 55 8 10 28
Age at onset of clinical symptoms of hearing loss (y)
28
15
early childhood 46 55
kB kilo basepairs; y years; f female; m male; mtDNA mitochondrial DNA; NA not available
In additional 4/14 patients with mtDNA deletion (three female, one male), audiological examinations detected subclinical, age-corrected HF hearing loss of mild to moderate extent (Fig. 1A, patient 17).
Patients with A3243G PM Audiological evaluation of patients harbouring the A3243G PM revealed hearing deficits in all subjects. Moderate, predominantly high-frequency, age-corrected, bilateral, symmetrical hearing impairment was seen in one male patient requiring a hearing aid (Fig. 1B, patient 13). He first realised hearing impairment 27 years subsequent to the onset of neurological symptoms, and further development of hearing deficits was slowly progressive. One-sided deafness associated with contralateral mild to moderate, predominantly high-frequency hearing impairment was seen in a second male patient (patient 12). However, mild hearing loss at 0.5, 1, 2 and 4 kHz could be related to age as well in this patient, whereas moderate hearing loss at high frequencies was still present after age- and sex-correction. Unilateral deafness occurred with sudden onset in early childhood, a few years prior to first neurological symptoms. It is unknown, whether this abrupt hearing decline was associated with a preceding infectious disease not linked with the underlying mitochondrial disorder. Patient 4 with A3243G PM (female) was clinically asymptomatic, but presented with mild HF hearing loss
in audiological testing that could be related to age as well. In all patients with hearing impairment, audiometric bone and air conduction thresholds were similar, as seen in sensorineural hearing loss. None of our patients demonstrated signs of conductive impairment in puretone audiometry. Results of speech audiometry were in accordance with the degree of hearing loss in pure-tone audiometry without any signs of central nervous system pathology. OAE were absent in all patients with clinical symptoms of hearing loss and audiological signs of predominantly high-frequency hearing impairment, suggesting a cochlear origin of hearing deficits. In contrast, OAE were present in all but one clinically asymptomatic patients with normal results of pure-tone audiometry and in all patients with isolated HF hearing loss.
Discussion In our study we systematically evaluated the prevalence, extent and pattern of hearing impairment in 17 patients with CPEO or KSS due to single large-scale mtDNA deletion or A3243G PM. Hearing deficits were found in 50 % of our patients with single mtDNA deletion and in all of our patients with A3243G PM. These findings are in accordance with previous studies demonstrating a lower prevalence of
3/0
5/0
35/25
8/0
1/0
21/6
8/0
36/31
8/0
10/0
8/0
21/0
36/13
13/0
50/29
8/0
15/0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
50/15
10/0
73/28
23/0
62/22
51/6
33/8
35/15
25/0
75/65
18/0
52/34
5/0
35/0
50/35
14/0
7/0
Mean loss (4, 6, 8 kHz)/ age-corrected
55
10
80
25
68
55
55
45
40
80
20
55
5
55
55
20
20
Maximum loss
19/0
9/0
25/0
11/0
48/25
deaf
16/1
12/0
8/0
34/29
10/0
9/0
2/0
4/0
43/33
8/0
2/0
Mean loss (0.5, 1, 2, 4 kHz)/ age-corrected
Left ear, dB
65/30
18/0
51/6
23/0
66/26
deaf
45/20
37/17
25/0
75/65
22/0
35/17
9/0
30/0
64/49
22/7
6/0
Mean loss (4, 6, 8 kHz)/ age-corrected
20
20
60
25
70
deaf
60
50
30
80
25
50
10
40
65
30
10
Maximum loss
17
8.5
37.5
12
42
21 (right ear)
12
11
8
35
9
15
1.5
6
39
6.5
2.5
Mean binaural loss (0.5, 1, 2, 4 kHz), dB
57.5
14
62
23
64
51 (right ear)
39
36
25
75
20
43.5
7
32.5
57
18
6.5
Mean binaural HF loss (4, 6, 8 kHz), dB
Binaural audiological data
normal hearing
normal hearing
mild
normal hearing
moderate
mild (right ear)
normal hearing
normal hearing
normal hearing
mild
normal hearing
normal hearing
normal hearing
normal hearing
mild
normal hearing
normal hearing
Grading of hearing loss (0.5, 1, 2, 4 kHz)*
kB kilo basepairs dB dezibel OAE otoacoustic emissions HF high-frequency hearing loss only affecting frequencies above 2000 Hz pred. HF predominantly high-frequency hearing loss, i. e. hearing loss at all frequencies particularly affecting frequencies above 2000 Hz * according to mean binaural hearing loss at 0.5, 1, 2, 4 kHz: < 20 dB = normal, 21–40 dB = mild, 41–70 dB = moderate, > 70 dB = severe mean hearing loss ** according to mean binaural HF hearing loss at 4, 6, 8 kHz: < 30 dB = normal, 31–50 dB = mild, 51–80 dB = moderate mean HF hearing loss NA not available
Mean loss (0.5, 1, 2, 4 kHz)/ age-corrected
Patient No.
Right ear, dB
Table 2 Audiological data on our series of 17 CPEO or KSS patients
moderate
normal hearing
moderate
normal hearing
moderate
moderate (right ear)
mild
mild
normal hearing
moderate
normal hearing
mild
normal hearing
mild
moderate
normal hearing
normal hearing
Grading of HF hearing loss (4, 6, 8 kHz)**
HF
normal
pred. HF
normal
pred. HF
pred. HF (right ear)
HF
HF
normal
pred. HF
normal
HF
normal
HF
pred. HF
normal
normal
Configuration of pure tone audiometry
present
present
absent
present
absent
absent
present
present
absent
absent
present
present
present
present
absent
present
present
OAE
no
no
yes
no
yes
no
no
no
no
yes
no
no
no
no
yes
no
no
Hearing aid
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Fig. 1 A: Pure-tone audiogramm in patient 17 with mtDNA deletion showing a downsloping, bilateral, symmetrical high-frequency sensorineural hearing loss of moderate extent. Frequencies up to 2 kHz are not affected. B: Pure-tone audiogramm in patient 13 with A3243G PM showing a downsloping, bilateral and symmetrical sensorineural hearing loss of moderate extent. Symbols: > = bone-conducted signals right ear, o = air-conducted signals right ear, < = bone-conducted signals left ear, x = air-conducted signals left ear
A
B
hearing deficits in patients with mtDNA deletions (11–64 %) [1, 4] when compared to patients with A3243G PM (74–94 %) [1, 4, 5, 14, 15, 17, 19, 22]. It is noteworthy that in our series of patients clinically irrelevant, isolated HF hearing deficits were most common in women. In contrast, predominantly highfrequency, clinically relevant hearing impairment was restricted to men. These gender differences are in keeping with a previously published population-based study showing that men harbouring A3243G PM are in general
more severely affected and show a more rapid progression of clinically relevant hearing deficits than women [19]. The initial and predominant affection of higher frequencies in our series of patients may be regarded as typical in mitochondrial cytopathies and has been reported before [4, 26]. Our finding of a slowly progressive course of hearing impairment in all but one of our patients (patient 12 with A3243G PM) is mainly in accordance with previously reported results demonstrating
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slowly progressive hearing loss in KSS patients with mtDNA deletions in contrast to abrupt, stepwise loss of hearing in patients harbouring A3243G PM often associated with MELAS [1, 15]. Sudden deterioration of hearing in MELAS with stepwise progression and transient partial recoveries may indicate acute metabolic dysfunction of the stria vascularis and cochlear hair cells, whereas slowly progressive symptoms in KSS or CPEO may be explained by progressive degeneration of inner ear structures as formerly described [7]. Audiological results were in line with sensorineural hearing loss in our series of patients. The absence of OAE in all patients with clinically relevant, predominantly high-frequency hearing impairment stresses a cochlear origin of hearing deficits. However, the presence of OAE in all patients with clinically irrelevant, isolated HF hearing loss is not fully understood, but may be explained by the mildness of deficits in this group of patients. Our audiological analysis is in line with previous studies suggesting a predominant cochlear basis for hearing impairment in mitochondrial diseases [1, 5, 11, 15, 16, 24, 25]. Cochlear dysfunction with particular high-frequency hearing loss may be explained by the high metabolic demand of the stria vascularis and hair cells, especially the outer hair cells of the basal coil that respond to high-frequency sound [6, 14, 16, 18].A recent study addressed the precise mechanism of cochlear damage in patients with A3243G PM and provided evidence for both inner hair cell and outer hair cell dysfunction [5]. Detailed psychophysical in vivo examinations demonstrated selective deficits over specific frequency ranges not consistent with a general effect of stria vascularis dysfunction. Reduced intracellular energy supply caused by a defect of oxidative phosphorylation may be accompanied by ionic imbalance and may result first in dysfunction
and finally in cell injury and cell death. Recently, histopathological examinations of temporal bones of MELAS patients harbouring the A3243G PM demonstrated severe degeneration of the stria vascularis and spiral ganglion cells which similarly had been described in KSS patients some years ago [7, 16]. Both hair cells and stria vascularis are post-mitotic tissues and accumulation of mutant mtDNA is likely, thus making cochlear structures further susceptible to mtDNA disease. Our results indicate that hearing deficits are more common in audiological examination than expected from the clinical aspect. However, therapeutical consequences are low at the moment since treatment efforts will be restricted to patients with clinically relevant and disabling deficits. Extensive audiological evaluation is essential in patients with mitochondrial disorders and subjective hearing impairment since sensorineural hearing loss may be seriously impeding and is a treatable symptom by now. Cochlear implantation may be successful and represents the only cure for sensorineural hearing deficits to date [14]. This technique is of special favour in mitochondrial disorders since amplification of frequencies may not be efficient enough due to the inner hair cell dysfunction resulting in transduction deficits [5]. Extended experience exists in patients with nonsyndromic hearing impairment harbouring the A1555G mtDNA mutation that predisposes to aminoglycoside-induced sensorineural hearing loss [20]. However, first MELAS and CPEO/KSS patients with syndromic hearing impairment have been successfully rehabilitated by cochlear implantation [10, 12, 23]. At present, this therapeutical strategy can be offered to patients with profound mitochondrial sensorineural hearing loss, when severe pathological changes in the higher auditory pathways have been excluded [14].
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