Biosci Rep (2007) 27:113–123 DOI 10.1007/s10540-007-9040-5 ORIGINAL PAPER
Mitochondrial Syndromic Sensorineural Hearing Loss F. Forli Æ S. Passetti Æ M. Mancuso Æ V. Seccia Æ G. Siciliano Æ C. Nesti Æ S. Berrettini
Published online: 8 May 2007 Ó The Biochemical Society 2007
Abstract Mitochondrial diseases (MD) are a clinically heterogeneous group of disorders that arise as a result of dysfunction of the mitochondrial respiratory chain. Sensorineural hearing loss (SNHL) is often associated to mitochondrial dysfunctions both in syndromic, nonsyndromic forms. SNHL has been described in association to different mitochondrial multisystemic syndromes, often characterized by an important neuromuscular involvement. Because of the clinical relevance of the associated neurological symptoms, the occurrence of SNHL is often underestimated and undiagnosed. In this study we evaluated the incidence of SNHL in a group of 17 patients with MD. We detected some degree of hearing impairment in 8/17 patients (47%), thus confirming the frequency of hearing impairment in MD. Furthermore, we want to highlight the role of the audiologist and otolaryngologist in the diagnosis and characterization of a MD, which should be suspected in all the cases in which the hearing loss is associated to signs and symptoms characteristic of mitochondrial dysfunction, especially if the family history is positive for hearing loss or MD in the maternal line.
Keywords Cochlea Mitochondrial hearing loss Sensorineural hearing loss Syndromic hearing loss
Introduction Mitochondrial diseases (MD) are a clinically heterogeneous group of disorders that arise as a result of dysfunction of the mitochondrial respiratory chain. Sensorineural F. Forli S. Passetti V. Seccia S. Berrettini (&) Division of ENT, Department of Neuroscience, University of Pisa, Via Savi 10, Pisa 56126, Italy e-mail:
[email protected] M. Mancuso G. Siciliano C. Nesti Neurological Clinic, Department of Neuroscience, University of Pisa, Pisa, Italy
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hearing loss (SNHL) is often associated to MD both in syndromic and nonsyndromic form. Due to the dual genetic control of mitochondria, both by mitochondrial DNA (mtDNA) and nuclear DNA, these diseases can either be caused by primary alterations of the mtDNA, or by mutations in nuclear genes affecting mitochondrial function. The phenotypic expression of a mitochondrial molecular defect can be influenced by multiple factors, such as the proportion of the mutation in different cells and tissues (the degree of heteroplasmy), and the nuclear genetic background of a given patient. Additionally, mtDNA haplotype and environmental factors are also known to play a crucial role. Consequently, the disorders inherited through the mtDNA can associate with an extremely variable clinical phenotype (DiMauro and Schon 2003). For these reasons the clinical manifestations of MD are known to be extremely variable and even the same molecular defect can associate with diverse phenotypes (DiMauro and Schon 2003). Furthermore, as mitochondria are ubiquitous, every tissue can be involved by mitochondrial dysfunctions. Nevertheless each tissue is differently sensible to mitochondrial dysfunctions. In MD, highly energetic tissues, such as muscles and neurons are predominantly affected because of their high energy consumption and absence of duplication (DiMauro and Schon 2003). Several inner ear structures have comparable metabolic activity and reproduction rates. The stria vascularis shows a high level of metabolic activity, abundant Na+ and K+-ATPase pumps that use ATP to maintain endolymphatic homeostasis of the ions (Chinnery et al. 2000; Korres et al. 2002), moreover stria vascularis cells have a low reproduction rate (Chinnery et al. 2000). Outer hair cells, responsible for amplification of the local sound stimuli are highly metabolically active and do not duplicate (Chinnery et al. 2000; Korres et al. 2002). Inner hair cells and their afferent nerves also require large amounts of energy and do not duplicate. Thus the hair cells and the stria vascularis would be compromised by any deficiencies in intracellular ATP production due to mitochondrial dysfunction (Chinnery et al. 2000; Korres et al. 2002). It becomes clear that the cochlea is highly sensible to mitochondrial dysfunctions and this is the reason why SNHL is a symptom frequently present in MD, both in syndromic and isolated forms (Chinnery et al. 2000; Berrettini et al. 2001; Mancuso et al. 2004; Forli et al. 2006). Sensorineural hearing loss has been described in association to different mitochondrial multisystemic syndromes, often characterized by an important neuromuscular involvement (Chinnery et al. 2000; Fischel-Ghodsian 2003), nevertheless the occurrence of SNHL is often underestimated and undiagnosed because of the clinical relevance of the associated neurological symptoms. Next to large rearrangements involving several genes, all mitochondrial mutations leading to syndromic hearing impairment are point mutations in tRNA genes or single/multiple deletions of mtDNA. Moreover for most of the multisystemic mitochondrial syndromes the homoplasmic state would presumably be lethal, so the mtDNA mutations associated to mitochondrial syndromes are heteroplasmic, with variable degree (FischelGhodsian 2003). Acquired MD such as the Kearns-Sayre syndrome (KSS), defined by progressive external ophthalmoplegia, retinal pigmentary changes and cerebellar ataxia, the MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke like episodes), the MERRF syndrome (myoclonic epilepsy with regged red
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Table 1 Mitochondrial multisystemic syndromes in which is associated hearing impairment Syndrome
Mutations/deletions
Phenotype
MELAS
A3243G A3252G C3256T T3271C T3291C A11084G A8344G T8356C T7512C G12147A G611A mtDNA deletions
Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke like episodes and hearing loss
MERRF
KSS
Myoclonic epilepsy, ataxia, dementia, optic atrophy and hearing loss
Progressive external ophthalmoplegia, retinal pigmentary changes, cerebellar ataxia, myoclonic epilepsy, dementia and hearing loss Diabetes mellitus, diabetes insipidus, optic atrophy and hearing loss Diabetes mellitus and hearing loss
Wolfram syndrome Trasmissione autosomica recessiva, mtDNA deletions MIDD A3243G A8296G T14709C MtDNA deletions/duplications Others A7445G Hearing loss ± palmoplantar keratoderma 7472insC Hearing loss ± ataxia and myoclonus A1555G Hearing loss ± Parkinson, pigmentary disturbances and restrictive cardiomyopathy A5568G Hearing loss + hypopigmentation
MELAS: mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes. MERRF: Myoclonic Epilepsy with Ragged Red Fibres. KSS: Kearns-Sayre syndrome. mtDNA: mitochondrial DNA. MIDD: Maternally inherited diabetes and deafness
fibres) and the chronic external ophthalmoplegia (C-PEO), as well as maternally inherited diabetes are frequently associated to deafness (Table 1). Furthermore some of the mtDNA mutations, described in association to nonsyndromic deafness, have been found associated occasionally with other symptoms. The A7445G in the tRNAser gene mutation was initially described as a nonsyndromic deafness mutation, but was subsequently found to be also associated with the palmoplantar keratoderma in at least some of the cases (Fischel-Ghodsian et al. 1995; Reid et al. 1994; Sevior et al. 1998). Another mutation (7472insC) in the tRNAser gene has also been found in one family with ataxia and myoclonus (Tiranti et al. 1995). The most common nonsyndromic mutation, the A1555G mutation in the 12S rRNA gene has been described in one family with Parkinson (Fischel-Ghodsian 2003), in another with a constellation of spinal and pigmentary disturbances (Nye et al. 2000) and in one case of a woman with a restrictive cardiomyopathy (Santorelli et al. 1999). Similarly, the homoplasmic A5568G mutation in the tRNAtrp gene was proposed as pathogenic for a family with SNHL and hypopigmentation, but the evidence of pethogenicity is not clear (Fischel-Ghodsian 2003). The aim of this study as to evaluate the incidence of SNHL and to describe the audiological features in patients affected with mitochondrial syndromes.
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Materials and Methods In collaboration with the Neurological Clinic, at the ENT Unit of the University of Pisa, over the period 2001–2005, 17 patients, 14 females and 3 males, mean age 55.4 years (ranging from 27 to 75 years) affected with MD were submitted to an accurate audiological evaluation in order to investigate the presence and the incidence of an audiological involvement. In all the patients the diagnosis of MD was based on the combination of the clinical picture with histologic, histochemical biochemical and molecular analysis of a muscular fragment (DiMauro and Schon 2003). The sample was composed by 7 patients affected with mitochondrial myopathy, 6 cases affected by C-PEO, 1 patient affected by C-PEO and Parkinson’s disease, 1 patient with MERRF syndrome harbouring the G611A mutation and 2 patients affected by maternally inherited diabetes and deafness (MIDD) and myopathy harbouring the A3243G mutation. In some patients, it was not possible to detect any mtDNA mutation. The clinical features of the patients are summarised in Table 2. All the patients were submitted to a comprehensive audiological evaluation, including: – accurate clinical history to investigate the age at onset and the progression of deafness; – otoscopy and otomicroscopy; – pure tone audiometry, speech audiometry, tumpanometry and stapedial reflex study, brainstem evoked auditory potentials (BEAPs) and otoacoustic emissions. In order to exclude any other known cause of SNHL, a complete blood and immunological evaluation, according to a previously published protocol including molecular analysis for Connexin 26 and 30, has also been done (Berrettini et al. 1998).
Results The characteristics of the SNHL patients are summarised in Table 3. We found SNHL with a PTA (pure tone average between 500–1000–2000 Hz) worse than 30 dB in 8/17 patients (47%). In all the patients the hearing loss was sensorineural, bilateral in 6 patients and unilateral in 2. In the bilateral cases the hearing impairment was symmetrical in 4 patients and asymmetrical in the remaining 2. The degree of hearing loss was mild in 5 ears, moderate in 7 ears, severe in 1 ear and total in 1 ear. The hearing loss onset was during childhood in 4 patients, during adulthood 3 and in 1 patient the hearing impairment was subclinical, so it is not possible to estimate the age at onset; in 6/8 patients the hearing loss was progressive. Figure 1 reports the audiogram of patient number 16. With regard to the site of lesion, the hearing loss had a cochlear origin in all the cases but one, affected with mtDNA multiple deletions and mitochondrial myopathy associated to a hearing deficit showing the audiological and electrophysiological features of auditory neuropathy (Starr et al. 1996). This patient (n. 15, previously published Forli et al. 2006) presented a moderate left and a severe right progressive hearing loss, started during childhood, normal otoacoustic emissions, absent BEAPs at left and abnormal BEAPs at right, absent stapedial reflexes bilaterally and a
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Table 2 Clinical characteristics of all the patients of this study Patients
Diagnosis
Mitochondrial aetiology
Audiological involvement
Pt. 1, f. 72 yrs Pt. 2, f. 70 yrs Pt. 3, f. 61 yrs Pt. 4, f. 64 yrs Pt. 5, f. 54 yrs Pt. 6, f. 34 yrs Pt. 7, f. 38 yrs Pt. 8, f. 60 yrs Pt. 9, f. 69 yrs Pt. 10, f. 75 yrs Pt. 11, m. 27 yrs Pt. 12, f. 69 yrs Pt. 13, f. 53 yrs Pt. 14, f. 44 yrs Pt. 15, f. 54 yrs Pt. 16, m. 43 yrs Pt. 17, m. 53 yrs
Mitochondrial myopathy
None mtDNA mutation
No
CPEO
None mtDNA mutation
No
Mitochondrial myopathy, psychiatric symptoms CPEO
Yes
CPEO
Multiple mtDNA deletions Multiple mtDNA deletions None mtDNA mutation
Mitochondrial myopathy
None mtDNA mutation
No
CPEO
No
CPEO
Multiple mtDNA deletions Multiple mtDNA deletions Single mtDNA deletion
Mitochondrial myopathy
None mtDNA mutation
Yes
Mitochondrial myopathy
None mtDNA mutation
No
Mitochondrial myopathy
None mtDNA mutation
No
cPEO + Parkinson + hepatic cirrhosis
Multiple mtDNA deletions G611A mtDNA point mutation Multiple mtDNA deletions A3243G mtDNA point mutation A3243G mtDNA point mutation
No
CPEO
MERRF Mitochondrial myopathy Mitochondrial myopathy + diabetes mellitus Mitochondrial myopathy + diabetes mellitus
Yes Yes
No No
Yes Yes Yes Yes (subclinical)
cPEO: chronic external ophthalmoplegia. MERRF: Myoclonic Epilepsy associated with Ragged-Red Fibres. mtDNA: mitochondrial DNA
discrimination score at the speech audiometry of 0% at maximum intensity stimulation bilaterally.
Discussion Because of the unique significance of ATP as a fuel source for all cells, mitochondrial pathology is a heterogeneous group of disorders often with multi-system involvement. The clinical features of mtDNA diseases are diverse, ranging form asymptomatic or mildly affected individuals with signs limited to extra ocular and skeletal muscle, to severely affected individuals, who develop central neurological complications at young age. The diagnosis and classification of these disorders is difficult because well-defined clinical entities can be genetically heterogeneous; conversely, the same genetic cause may be associated with different clinical syndromes (DiMauro and Schon 2003; FischelGhodsian 2003).
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Table 3 Clinical characteristics of our patients with syndromic mitochondrial hearing loss Patients
Diagnosis
PTA
Site of lesion
Evolution SNHL
Pt. 3, f. 61 yrs
Mitochondrial encephalomyopathy (multiple mtDNA deletions)
R: 58.3 dB HL L: 45 dB HL R: anacusis L: normal hearing R: normal hearing L: 35 dB HL R: 32.6 dB HL L: 32.6 dB HL R: 61.6 dB HL L: 56.6 dB HL R: 76.6 dB HL L: 51.6 dB HL R: 45 dB HL L: 43.3 dB HL R: 31.6 dB HL L: 38.3 dB HL
R: cochlear origin
Progressive SNHL
Pt. 4, f. 64 yrs
CPEO
Pt. 5, f. 54 yrs
Mitochondrial myopathy
Pt. 10, f. 75 yrs
Mitochondrial myopathy
Pt. 14, f. 44 yrs
MERRF (G611A mutation)
Pt. 15, f. 54 yrs
Mitochondrial myopathy, (multiple mtDNA deletions)
Pt. 16, m. 43 yrs
Mitochondrial myopathy + diabetes mellitus (A3243G mutation)
Pt. 17, m. 53 yrs
Mitochondrial myopathy + diabetes mellitus (A3243G mutation)
L: cochlear origin R: cochlear origin
L: cochlear origin
R: cochlear origin
Not progressive SNHL Progressive SNHL Progressive SNHL
L: cochlear origin R: cochlear origin L: cochlear origin Bilateral auditory neuropathy
R: cochlear origin L: cochlear origin R: cochlear origin
Progressive SNHL Progressive SNHL
Progressive SNHL Subclinical SNHL
L: cochlear origin
PTA: pure tone audiometry. SNHL: sensorineural hearing loss
Sensorineural hearing loss is a common finding in patients with MD, although in most of the extensive relevant literature it is only incidentally mentioned. The reported auditory involvement in patients with MD is quite variable, ranging from 30 to 90%. Nevertheless in the studies in which the presence of hearing impairment is specifically investigated the reported incidence is generally higher, about 80–90%. Because SNHL
d B HL
BC=AC -10 0 10 20 30 40 50 60 70 80 90 100 110 120
-10 0 10 20 30 40 50 60
250
500
1000
2000
4000
8000
70 80 90 100 110 120 Hz
Fig. 1 The audiogram of patient number 16, affected by a bilateral sensorineural hearing loss associated to a mitochondrial myopathy and diabetes mellitus, harbouring the A3243G mtDNA mutation
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is often subclinical and is not the most relevant symptom, is not specifically investigated (Chinnery et al. 2000; Deschauer et al. 2001). Moreover, as a result of the extreme clinical and genetic heterogeneity of MD, it is difficult to study and establish the real incidence of hearing involvement in the various mitochondrial syndromes. To this regard, Deschauer et al. in 2001 in a clinical study on 16 patients carrying the A3243G mutation, demonstrated the presence of hearing impairment in 15/16 patients; in 4 out of the 15 hearing impaired patients the hearing loss was subclinical and discovered only at audiometric examination (Deschauer et al. 2001). Moreover, these authors found SNHL to be the most consistent symptom among their patients (Deschauer et al. 2001). Chinnery et al. in 2000 confirmed the high incidence of hearing loss among mitochondrial patients: they found hearing impairment in 8/10 A3243G patients enrolled in their study (Chinnery et al. 2000). Also Damian et al. previously reported similar results (Damian et al. 1995). In our study, SNHL was present in 47% of the patients; in one of our cases the hearing impairment was subclinical and diagnosed only after audiometric study. As previously mentioned, a typical aspect of MD is the phenotypic variability. In fact individuals with the same mutation may exhibit a wide range of clinical manifestations, from asymptomatic to profoundly affected or may even have completely different diseases. This clinical variability may be present also between individuals belonging to the same family. This is also true for mitochondrial hearing impairment and it was evident also in our group of patients. The exact reason of this variability is not clear yet and many factors have been involved, both environmental and genetic, such as mitochondrial haplotypes and the tight interaction existing between nuclear and mitochondrial genomes. Therefore, some mtDNA mutations lead to pathology only under certain conditions, such as a specific nuclear or mitochondrial haplotype or the concurrent presence of environmental agents. This phenotypic heterogeneity is in part attributable also to the heteroplasmic nature of most of the mtDNA mutations, with both normal and mutated mtDNAs being present in different proportions and tissue distributions. Chinnery et al. (2000) found a correlation between the level of heteroplasmy of the A3243G mutation at muscular level and the degree of hearing loss, while they could not find any correlation between mutation load in blood and the severity of hearing loss. Similarly, Oshima et al. (1999) did not demonstrate any correlation between the mutation rate in peripheral blood leukocytes and the degree of the audiological symptoms in three A3243G patients. These findings suggested the hypothesis that, being both the muscle and the cochlear cells post-mitothic, the level of mutated mtDNA in these tissues might be similar. Thus, one could expect that cochlear function could be related to the level of mtDNA in muscle (Chinnery et al. 2000). On the contrary, the lack of correlation between the level of mutated mtDNA in blood and the degree of hearing impairment, could reflect an age related decline in percentage of mutated mtDNA within the blood of patients with the A3243G mutation (Chinnery et al. 2000). The A3243G mutation is reported to be the most frequent mtDNA mutation and has an unpredictable phenotype-genotype correlation. This mutation was first described in MELAS patients, but subsequently it was correlated to a variety of clinical manifestations, such as C-PEO and MIDD. Hearing loss is frequent in patient with A3243G mutation, and it is often present at the onset of the pathology. Rarely, isolated SNHL has been described in patients carrying this mutation. Oshima et al. (1999) described three A3243G patients affected by nonsyndromic SNHL, with a wide clinical heterogeneity both for the degree of the hearing loss and for the age at onset and the
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presence of a clear maternal inheritance. We have recently described an Italian patient affected with profound nonsyndromic SNHL associated with very low levels of A3243G mutation in muscle (Mancuso et al. 2004). Two of the patients reported in the present study harbouring the A3243G mutation (n. 16 and 17) were affected by progressive SNHL associated to diabetes and mitochondrial myopathy causing proximal limbs weakness. The audiological features of mitochondrial syndromic deafness are quite variable. It is usually described as sensorineural, initially affecting the higher frequencies, predominantly bilateral, symmetrical and progressive (Chinnery et al. 2000; Sue et al. 1998; Guillausseau et al. 2001; Chae et al. 2004). However, cases with unilateral or asymmetrical hearing loss have been described (Sue et al. 1998; Zwirner and Wilichowski 2001). The age at onset is also variable, from infancy to adulthood (Chinnery et al. 2000; Sue et al. 1998; Guillausseau et al. 2001; Chae et al. 2004). In MELAS the hearing loss generally starts before the forties and in some cases during childhood, as reported by Zwirner and Wilichowski (2001). The hearing loss onset is generally gradual, even if in many MELAS cases a stepwise onset or progression has been reported. In the majority of MELAS patients an abrupt loss of hearing occurs especially in association with stroke-like episodes (Karkos et al. 2004; Sue et al. 1998) and also fluctuations of hearing have been reported (Sue et al. 1998), while in the MERRF syndrome the hearing loss is mostly slowly progressive (Tsutsumi et al. 2001). According to some authors, a worsening of the hearing threshold may be related to infective episodes, probably due to the increased metabolic demand associated to infections (Karkos et al. 2004). The degree of the hearing impairment is extremely variable, ranging from mild to profound, as well as variable is the hearing threshold shape (Karkos et al. 2004; Sue et al. 1998). Frequently the hearing threshold is downsloping, with higher impairment at high frequencies (Karkos et al. 2004), but also flat thresholds are reported (Karkos et al. 2004; Sue et al. 1998; Zwirner and Wilichowski 2001). A correlation between the hearing threshold and the severity of neuromuscular symptoms has not been documented. In this study, the audiological features in MD patients are also quite variable. The hearing loss was sensorineural in all the 8 hearing impaired patients, it was bilateral in 6/ 8 patients and unilateral in the remaining 2; among the bilateral cases the hearing loss was symmetrical in 4 cases and asymmetrical in 2. Also the entity of the hearing loss was variable, ranging from cases affected with a mild degree to cases with anacusis. The hearing loss onset was dated during childhood in 4/8 patients and in adulthood in 3/8 cases, while in 1 patient it is not possible to estimate the age at onset. The hearing loss was progressive in 6/8 patients and interestingly in 5/8 patients the hearing loss was the first clinical manifestation of the syndrome. With regard to the site of lesion, in most of the studies, a cochlear origin is reported (Chinnery et al. 2000; Sue et al. 1998), but in others a retrocochlear involvement is evident, as documented by abnormalities at BEAPs and preserved otoacoustic emissions (Zwirner and Wilichowski 2001; Tsutsumi et al. 2001; Elverland and Torbergsden 1991). Moreover, in some cases a central dysfunction has been reported (Chinnery et al. 2000; Korres et al. 2002). Sue et al. (1998), in a clinical study demonstrated a cochlear lesion in all the 18 MELAS patients with hearing loss reported in their study (Sue et al. 1998). Tsutsumi et al. in 2001 reported about two among three MERRF patients with hearing impairment, in whom a cochlear and retrocochlear involvement were associated. Tsutsumi et al. (2001) and Zwirner and Wilichowski
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(2001) demonstrated both a cochlear and retrocochlear involvement in deaf children with mitochondrial encephalomyopathy (Zwirner and Wilichowski 2001). They did not find any correlation between the degree of hearing loss and the site of lesion. Conversely, Elverland and Torbergsden (1991) found the cochlear lesions to be correlated to milder degree of hearing impairment in comparison to retrocochlear lesions. Some papers documented satisfactory results with hearing aids in this kind of patients and in the last few years good results have also been reported after cochlear implantation, supporting the cochlear involvement and the functioning of the auditory path in a good percentage of mitochondrial deafness (Mancuso et al. 2004; Karkos et al. 2004; Sue et al. 1998; Cullington 1999; Hill et al. 2001; Raut et al. 2002; Rosenthal et al. 1999; Counter et al. 2001). Seven out of the eight hearing impaired patients reported in this study presented a cochlear lesion, while one patient presented the clinical and audiological features of an auditory neuropathy (Starr et al. 1996). This is a rare association, the first one observed in Italy, between auditory neuropathy and mitochondrial myopathy in a patient with mtDNA multiple deletions. The patient presented bilateral SNHL started in infancy, preserved otoacoustic emissions bilaterally, difficulty in understanding speech, out of proportion with the hearing impairment and did not receive any benefit from hearing aids fitting; BAEPs were absent on the left side and abnormal on the right and the stapedial reflexes were absent bilaterally. To our knowledge, auditory neuropathy has been rarely associated with MD. Deltenre et al. (1997) reported a case of a newborn affected with a mitochondrial enzymatic defect of the COX who also developed auditory neuropathy. Further, a 1year old child with MD was reported to have developed auditory neuropathy with progressive deterioration of hearing and speech abilities (Corley and Crabbe 1999). Some Authors hypotised that in these cases the metabolic damage caused by mitochondrial dysfunction could lead a desyncrhonisation of the auditory nerve fibres firing and to a reduction of the number of the firing fibres, finally leading to a neural dysfunction (Deltenre et al. 1997; Corley and Crabbe 1999).
Conclusions Hearing impairment is a frequent manifestation of MD and in some cases may be the first symptom, even if it is often underestimated and undiagnosed because of the clinical relevance of the associated symptoms. Moreover, the hearing impairment is frequently mild or subclinical, therefore, if not specifically investigated, it can be missed. Conversely, in the case of a syndromic hearing loss it could be difficult to suspect a MD, both because the clinical manifestations associated to deafness are quite variable and because the hearing loss may be the only manifestation in the early stages. For these reasons, the audiologist and the otolaryngologist play an important role in the diagnosis and characterization of a MD. A MD should be suspected in all the cases in whom the hearing loss is associated to signs and symptoms characteristic of mitochondrial dysfunction, especially if the family history is positive for hearing loss or MD in the maternal line. Finally, we want to highlight the importance of muscular biopsy in the diagnosis of syndromal mitochondrial hearing loss. The mitochondrial mutations responsible of sindromic deafness are generally heteroplasmic and may not be found in the mtDNA of peripheral lymphocytes.
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References Berrettini S, Ravecca F, Forli F, Sellari-Franceschini S, Piragine F (1998) Approccio diagnostico e terapeutico alle ipoacusie neurosensoriali progressive. Acta Otorhinolaryngol Ital 4(Suppl 59):87–94 Berrettini S, Forli F, Siciliano G, Mancuso M (2001) Sudden bilateral hearing loss and sporadic mitochondrial DNA deletion. J Laryngol Otol 115:128–131 Chae JH, Hwang H, Lim BC, Cheong HI, Hwang YS, Kim KJ (2004) Clinical features of A3243G mitochondrial tRNA mutation. Brain Dev 26:459–462 Chinnery PF, Elliott C, Green GR, Rees A, Coulthard A, Turnbull DM, Griffiths TD (2000) The spectrum of hearing loss due to mitochondrial DNA defects. Brain 123:82–92 Corley VM, Crabbe LS (1999) Auditory neuropathy and a mitochondrial disorder in a child: case study. J Am Acad Audiol 10:484–488 Counter PR, Hilton MP, Webster D, Wardell T, Taylor RW, Besley G, Turnbull DM, Robinson PJ (2001) Cochlear implantation of a patient with a previously undescribed mitochondrial DNA defect. J Laryngol Otol 115:730–732 Cullington HE (1999) Cochlear implantation of a deaf blind patient with mitochondrial cytopathy. J Laryngol Otol 113:353–354 Damian MS, Seibel P, Reichmann H, Schachenmayr W, Laube H, Bachmann G, Wassill KH, Dorndorf W (1995) Clinical spectrum of the MELAS mutation in a large pedigree. Acta Neurol Scand 92:409– 415 Deltenre P, Mansbach AL, Bozet C, Clercx A, Hecox KE (1997) Auditory neuropathy: a report on three cases with early onsets and major neonatal illnesses. Electroencephalogr Clin Neurophysiol 104:17– 22 Deschauer M, Muller T, Wieser T, Schulte-Mattler W, Kornhuber M, Zierz S (2001) Hearing impairment is common in various phenotypes of the mitochondrial DNA A3243G mutation. Arch Neurol 58:1885–1888 DiMauro S, Schon EA (2003) Mitochondrial respiratory-chain diseases. N Engl J Med 348:2656–2668 Elverland HH, Torbergsden T (1991) Audiologic findings in a family with mitochondrial disorder. Am J Otol 12:459–465 Fischel-Ghodsian N (2003) Mitochondrial hearing impairment. Audiol Med 1:55–66 Fischel-Ghodsian N, Prezant TR, Fournier P, Steward IA, Maw M (1995) Mitochondrial mutation associated with non-syndromic deafness. Am J Otol 16:403–408 Forli F, Mancuso M, Santoro A, Dotti MT, Siciliano G, Berrettini S (2006) Auditory neuropathy in a patient with mitochondrial myopathy and multiple mtDNA deletions. J Laryngol Otol 120:888–891 Guillausseau PJ, Massin P, Dubois-LaForgue D, Timsit J, Virally M, Gin H, Bertin E, Blickle JF, Bouhanick B, Cahen J, Caillat-Zucman S, Charpentier G, Chedin P, Derrien C, Ducluzeau PH, Grimaldi A, Guerci B, Kaloustian E, Murat A, Olivier F, Paques M, Paquis-Flucklinger V, Porokhov B, Samuel-Lajeunesse J, Vialettes B (2001) Maternally inherited diabetes and deafness: a multicenter study. Ann Intern Med 134:721–728 Hill D, Wintersgill S, Stott L, Cadge B, Graham J (2001) Cochlear implantation in a profoundly deaf patient with MELAS syndrome. J Neurol Neurosurg Psychiatr 71:281 Karkos PD, Waldron M, Johnson IJ (2004) The MELAS syndrome. Review of the literature: the role of the otologist. Clin Otolaryngol 29:1–4 Korres S, Balatsouras D, Manta P, Economou C, Yiotakis I, Adamopoulos G (2002) Cochlear dysfunction in patients with mitochondrial myopathy. ORL J Otorhinolaryngol Relat Spec 64:315– 320 Mancuso M, Filosto M, Forli F, Rocchi A, Berrettini S, Siciliano G, Murri L (2004) A non-syndromic hearing loss caused by very low levels of the mtDNA A3243G mutation. Acta Neurol Scand 110:72– 74 Nye JS, Hayes EA, Amendola M, Vaughn D, Charrow J, McLone DG, Speer MC, Nance WE, Pandya A (2000) Myelocystocele-cloacal exstrophy in a pedigree with a mitochondrial 12S rRNA mutation, amynoglicoside induced deafness, pigmentary disturbances and spinal anomalies. Teratology 61:165– 171 Oshima T, Ueda N, Ikeda K, Abe K, Takasaka T (1999) Hearing loss with a mitochondrial gene mutation is highly prevalent in Japan. Laryngoscope 109:334–338 Raut V, Sinnathuray AR, Toner JG (2002) Cochlear implantation in maternal inherited diabetes and deafness syndrome. J Laryngol Otol 116:373–375 Reid FM, Vernham GA, Jacobs HT (1994) A novel mitochondrial point mutation in a maternal pedigree with sensorineural deafness. Hum Mutat 3:243–247
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Biosci Rep (2007) 27:113–123
123
Rosenthal EL, Kileny PR, Boerst A, Telian SA (1999) Successful cochlear implantation in a patient with MELAS syndrome. Am J Otol 20:187–190 Santorelli FM, Tanji K, Manta P, Casali C, Krishna S, Hays AP, Mancini DM, DiMauro S, Hirano M (1999) Maternally inherited cardiomyopathy: an atypical presentation of the mtDNA 12S rRNA gene A1555G mutation. Am J Hum Genet 64:295–300 Sevior KB, Hatamochi A, Stewart IA, Bykhovskaya Y, Allen-Powell DR, Fischel-Ghodsian N, Maw MA (1998) Mitochondrial A7445G mutation in two pedigrees with palmoplantar keratoderma and deafness. Am J Med Genet 13:179–185 Starr A, Picton TW, Sininger Y, Hood LJ, Berlin CI (1996) Auditory neuropathy. Brain 119:741–753 Sue CM, Lipsett LJ, Crimmins DS, Tsang CS, Boyages SC, Presgrave CM, Gibson WP, Byrne E, Morris JG (1998) Cochlear origin of hearing loss in MELAS syndrome. Ann Neurol 43:350–359 Tiranti V, Chariot P, Carella F, Toscano A, Soliveri P, Girlanda P, Carrara F, Fratta GM, Reid FM, Mariotti C (1995) Maternally inherited hearing loss, ataxia and myoclonus associated with a novel point mutation in mitochondrial tRNAser (UCN) gene. Hum Mol Genet 4:1421–1427 Tsutsumi T, Nishida H, Noguchi Y, Komatsuzaki A, Kitamura K (2001) Audiological findings in patients with myoclonic epilepsy associated with ragged-red fibres. J Laryngol Otol 115:777–781 Zwirner P, Wilichowski E (2001) Progressive sensorineural hearing loss in children with mitochondrial encephalomyopathies. Laryngoscope 111:515–521
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