Mitochondrial disorders and audio-vestibular symptoms

By Marcello Cherchi, MD PhD

For patients

There are many mitochondrial diseases. These are due to genetic mutations. Some mitochondrial diseases cause hearing loss, a few cause disequilibrium. If your doctor is considering a mitochondrial disorder, then they may check several tests of hearing and balance, and perhaps brain imaging. Available treatments are not very good.

For clinicians

Overview

Mitochondria carry out oxidative phosphorylation to convert glucose and oxygen into adenosine triphosphate, a molecule that stores energy used for cellular processes. Since all cells require energy to function properly, mitochondrial disorders can manifest as dysfunction in multiple tissues, thus these are typically multi-system diseases. Many mitochondrial mutations have been associated with hearing loss; the relationship between mitochondrial disorders and vestibular function has been less well-studied. Patients with mitochondrial disorders complaining of disequilibrium may exhibit a variety of ocular motor and vestibular abnormalities, but none that is sensitive or specific for these diagnoses. If workup of these patients reveals no evidence for another (beyond an already diagnosed mitochondrial disorder), than it is medically reasonable to refer to audiology (for hearing loss) and vestibular rehabilitation therapy (for disequilibrium). Prognosis is poor.

Introduction

In healthy individuals, the characteristics of mitochondria vary between tissues and cells, and even within the same cell. Mitochondria in cochlear and vestibular hair cells exhibit particular distributions and characteristics (Lesus et al. 2019; Lysakowski et al. 2022). Many mitochondrial mutations have been associated with hearing loss (Lesus et al. 2019); the relationship between mitochondrial disorders and vestibular function has been less well-studied.

Here we present a brief overview of mitochondrial function and dysfunction, some epidemiologic features of these disorders, and we comment on two mitochondrial mutations in which some study of vestibular function has been undertaken.

Epidemiology

Davis and colleagues (Davis et al. 2018), citing Elliott and colleagues (Elliott et al. 2008), state that the prevalence of mitochondrial mutations overall in the general population has been estimated as 0.4% (1 in 250) to 0.5% (1 in 200).

Regarding specific mutations in which vestibular dysfunction has been reported:

  • Davis and colleagues (Davis et al. 2018), citing Manwaring and colleagues (Manwaring et al. 2007) state that the prevalence of the m.3243(A>G) mutation (to be explained below) is 1 in 500 in the Australian population.
  • Davis and colleagues (Davis et al. 2018), citing Vandebona and colleagues (Vandebona et al. 2009) state that the prevalence of the m.1555(A>G) mutation (to be explained below) is 1 in 500 in a population of individuals of European descent.

Genetics

Mitochondria are maternally inherited, and although most of the genetic code for mitochondria resides in the mitochondria themselves (mitochondrial DNA), the genes encoding some mitochondrial proteins reside in nuclear DNA, consequently some diseases resulting from mitochondrial dysfunction may not exhibit a pattern of maternal inheritance. Over 300 mutations in mitochondrial DNA, and over 250 mutations in nuclear DNA, have been identified as causes of mitochondrial dysfunction (Davis et al. 2018). Recognizing and diagnosing mitochondrial disorders is further complicated by factors such as heteroplasmy (the variable proportion of mutant DNA between cells) due to mitotic segregation (which can result in unequal distribution of normal versus mutant mitochondrial DNA between daughter cells) (Hougaard et al. 2019).

The fact that the mode of inheritance is mixed, the fact that these disorders often affect multiple organ systems, the fact that serum analyses (lactate, pyruvate, creatine kinase, alanine) and cerebrospinal fluid analyses (lactate) have low sensitivity and specificity, and the fact that muscle biopsy is invasive and also insufficiently sensitive and specific, means that these older diagnostic approaches have rapidly given way to advances in genetic testing, particularly next-generation sequencing-based platforms, in the diagnosis of mitochondrial disorders (Davis et al. 2018).

Pathophysiological mechanism of disease

Mitochondria carry out oxidative phosphorylation to convert glucose and oxygen into adenosine triphosphate (ATP), a molecule that stores energy used for cellular processes. Since all cells require energy to function properly, mitochondrial disorders can manifest as dysfunction in multiple tissues, thus these are typically multi-system diseases.

Mutation in mitochondrial DNA at nucleotide pair 3243

In 1990, Goto and colleagues (Goto et al. 1990) reported that a mitochondrial DNA point mutation at nucleotide pair 3243 (“m.3243”) from alanine to glycine (“A>G”) was responsible for the clinical syndrome of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (abbreviated MELAS). It was later recognized that about 80% of MELAS cases result from this m.3243(A>G) mutation; the remainder of cases result from mitochondrial DNA mutations at mitochondrial nucleotide pair 3271 (threonine to cysteine) and 3252 (alanine to glycine) (El-Hattab et al. 2015).

In some patients with m.3243(A>G) mutation manifests with a syndrome of maternally inherited diabetes and deafness (abbreviated MIDD), though even these patients can exhibit vestibular dysfunction (Cardenas-Robledo et al. 2016).

Inoue and colleagues (Inoue et al. 2019), citing multiple sources, note that 30% – 75% of MELAS patients with a m.3243(A>G) mutation exhibit sensorineural hearing loss.

The study by Holmes and colleagues (Holmes et al. 2019), though criticized by Finster (Finsterer 2019), discussed patients with genetically confirmed m.3243(A>G) mutation and reported that:

  • Out of 33 patients with vestibular complaints, thirty (91%) exhibited some vestibular abnormality.
  • Out of those 30 patients, twenty-three (77%) had some kind of “peripheral vestibulopathy.”

They further noted that:

  • Out of 33 patients with vestibular complaints, twenty-seven (82%) exhibited sensorineural hearing loss.
  • Of those 27 patients with sensorineural hearing loss, twenty (74%) had “coexistent peripheral vestibulopathy.”
  • Of those 20 patients with sensorineural hearing loss and “peripheral vestibulopathy,” the vestibulopathy was bilateral in eleven (55%).
  • Of those 20 patients with sensorineural hearing loss and “peripheral vestibulopathy,” the sensorineural hearing loss was bilateral in eighteen (90%).

Hougaard and colleagues (Hougaard et al. 2019) studied eight unrelated patients with genetically confirmed m.3243(A>G) mutation using audiometry, cervical vestibular evoked myogenic potentials (cVEMP) and video head impulse testing (vHIT). They reported that:

  • All patients exhibited bilateral sensorineural hearing loss.
  • All patients exhibited bilaterally absent ocular vestibular evoked myogenic potentials (oVEMPs).
  • Of 7 patients tested with cervical vestibular evoked myogenic potentials (cVEMP), four (57%) had bilaterally absent responses, and one (14%) had unilaterally absent responses.
  • On video head impulse testing (vHIT) they observed observing different patterns of semicircular canal dysfunction in patients with MELAS.

Iwasaki and colleagues (Iwasaki et al. 2011) studied thirteen unrelated Japanese patients with genetically confirmed m.3243(A>G) mutation (6 with MELAS, seven with MIDD) using audiometry, ice water calorics, air-conducted cervical vestibular evoked myogenic potentials (cVEMP) and galvanic cervical vestibular evoked myogenic potentials (cVEMP). They reported that:

  • Of all 13 patients tested with ice water calorics, seven (54%) had bilaterally reduced or absent responses, three (23%) showed unilaterally reduced responses, and the remaining three (23%) had normal caloric responses.
  • Of all 13 patients tested with air-conducted cervical vestibular evoked myogenic potentials (cVEMP), nine (69%) had bilaterally absent responses, three (23%) had unilaterally absent responses, and one (8%) had bilaterally normal responses.
  • Overall, 85% of m.3243(A>G) patients reported vestibular symptoms, and 90% of them had detectable vestibular dysfunction on calorics or cervical vestibular evoked myogenic potentials (cVEMP).

Inoue and colleagues (Inoue et al. 2019) studied six unrelated Japanese patients with genetically confirmed m.3243(A>G) mutation using audiometry, air caloric testing and cervical vestibular evoked myogenic potentials (cVEMP). They followed these patients over time, and noted that:

  • The bilateral sensorineural hearing loss, which can be asymmetrical, is progressive over time.
  • The loss of cervical vestibular evoked myogenic potentials (cVEMP) responses progresses (in some cases asymmetrically) over time.
  • Caloric responses progressively decline, in some cases asymmetrically, over time.

Kim and colleagues (Kim et al. 2016) studied three Korean patients with genetically confirmed m.3243(A>G) mutation. They reported that:

  • All three patients exhibited normal caloric responses.
  • Two (66%) patients exhibited low gain on video head impulse testing (vHIT) involving the lateral and posterior canals, but normal gain in the anterior canals.
  • Bedside video oculography revealed combinations of square wave jerks, impaired horizontal smooth pursuit, abnormal horizontal saccades (hypometric and/or slow) and horizontal gaze-evoked nystagmus.

Takahashi and colleagues (Takahashi et al. 2003) reported on one patient with genetically confirmed m.3243(A>G) mutation, stating that electronystagmography (ENG) showed bilaterally decreased caloric responses, poor optokinetic nystagmus, and “ataxic pursuit eye movement.”

The literature provides variable evidence of the anatomical areas affected by mitochondrial dysfunction in m.3243(A>G).

  • As far as cochlear structures are concerned, Takahashi and colleagues (Takahashi et al. 2003) performed a temporal bone study on two MELAS patients and reported:
    • “Both cases showed a similar, diffuse and severe loss of the stria vascularis in all turns.”
    • “There was a disproportionate loss of spiral ganglion cells compared with loss of hair cells of the organ of Corti in case 1. In case 2, many spiral ganglion cells showed degenerative change, although the number of spiral ganglion cells was preserved.”
    • “Although the organ of Corti showed some loss of hair cells in both cases, it was insufficient to explain the observed loss of spiral ganglion cells as a secondary event. Thus, spiral ganglion cell loss appears to be a primary event in MELAS, rather than secondary degeneration resulting from hair cell loss.”
  • As far as vestibular structures are concerned:
    • Hougaard and colleagues (Hougaard et al. 2019) observed different patterns of semicircular canal dysfunction on video head impulse testing (vHIT) in several MELAS patients, and on this basis concluded that that the site of dysfunction is in the end-organ rather than in the vestibular nerve.
    • Takahashi and colleagues (Takahashi et al. 2003) reported, “Reduction in the numbers of hair cells in the cristae and maculae.”

In other words, there is histopathological evidence that the site of auditory dysfunction is spiral ganglion (rather than the cochlea), and there is clinical and histopathological evidence suggesting that the site of vestibular dysfunction is the labyrinth (rather than Scarpa’s ganglion).

In summary, in patients with m.3243(A>G) mutation:

  • Video oculography may show combinations of square wave jerks, impaired horizontal smooth pursuit, abnormal horizontal saccades (hypometric and/or slow), horizontal gaze-evoked nystagmus, and poor optokinetic responses.
  • Most exhibit bilateral sensorineural hearing loss that can be asymmetrical, and progressively deteriorates over time.
  • Cervical vestibular evoked myogenic potentials (cVEMP) can be reduced or absent, unilaterally or bilaterally, and progressively deteriorate over time.
  • All exhibit bilaterally absent ocular vestibular evoked myogenic potentials (oVEMP).
  • Caloric responses can be unilaterally or bilaterally reduced, and progressively deteriorate over time.

Mutation in mitochondrial DNA at nucleotide pair 1555

A point mutation in mitochondrial DNA nucleotide pair 1555 from alanine to glycine (“m.1555(A>G)”) appears to increase susceptibility to aminoglycoside-related sensorineural hearing loss, though it has also been associated with hearing loss in the absence of any aminoglycoside exposure (Kawashima et al. 2009), and has further been reported to cause vestibular dysfunction.

Kawashima and colleagues (Kawashima et al. 2009) studied five unrelated Japanese patients with genetically confirmed m.1555(A>G) mutation using video oculography, monothermal caloric testing and cervical vestibular evoked myogenic potentials (cVEMP). They reported that:

  • One (20%) patient exhibited bilateral caloric weakness.
  • One (20%) patient exhibited unilateral caloric weakness.
  • All (100%) patients exhibited unilaterally or bilaterally reduced or absent cervical vestibular evoked myogenic potentials (cVEMP) responses.

Noguchi and colleagues (Noguchi et al. 2004) studied seven unrelated Japanese patients with genetically confirmed m.1555(A>G) mutation, of whom one was sporadically occurring, and six were familial. They examined these patients using audiometry, distortion product otoacoustic emissions (dpOAE), electrocochleography (ECoG) and electronystagmography (ENG). They reported that:

  • Distortion product otoacoustic emissions (dpOAE) were “reduced to noise levels, suggesting the A1555G mutation caused cochlear deafness.”
  • “The electronystagmographic findings indicated no apparent vestibular dysfunction.”

Usami and colleagues (Usami et al. 1997) studied five Japanese families with aminoglycoside-induced hearing loss. They found that 28 out of 32 subjects had a m.1555(A>G) mutation, and reported that the hearing loss was high (greater than low) frequency and progressive.

In summary, in patients with m.1555(A>G) mutation:

  • They are more susceptible to aminoglycoside-related sensorineural hearing loss.
  • All exhibit unilaterally or bilaterally reduced or absent cervical vestibular evoked myogenic potentials (cVEMP) responses.
  • Some (though not all) reports find that these patients exhibit unilateral or bilateral caloric weakness.

Clinical presentation

The auditory and vestibular manifestations of m.3243(A>G) and m.1555(A>G) are usually insidious in onset and gradually progressive, although the “stroke-like episodes” of MELAS can present acutely.

Other mitochondrial disorders have been less well-studied, and may present differently, such as m.961(T>G) (point mutation in mitochondrial DNA nucleotide pair 961 from threonine to glycine) (Turchetta et al. 2012), which has been associated with congenital otologic malformations.

Physical examination

Mitochondrial disorders tend to be multi-system diseases, so physical examination findings vary accordingly.

Ocular motor examination

The video-oculography findings of patients with mitochondrial disorders (discussed above) are neither sensitive nor specific for these disorders.

Imaging

Patients with mitochondrial disorders can exhibit a variety of abnormalities on brain MRI, including areas of demyelination, and cerebellar atrophy.

Differential diagnosis

Symptomatic mitochondrial disease is uncommon, and few of these patients ever get referred to an otoneurology clinic. On the rare occasions when a patient with a known mitochondrial disease is referred to an otoneurology clinic for complaints of hearing loss and/or disequilibrium, the implicit clinical query is usually whether there is some disease (other than the already diagnosed mitochondrial disorder) that might be contributory and treatable. In such cases, beyond physical examination and bedside video oculography, it is medically reasonable to consider checking:

  • Audiometry
  • Otoacoustic emissions (OAE)
  • Cervical vestibular evoked myogenic potentials (cVEMP)
  • Ocular vestibular evoked myogenic potentials (oVEMP)
  • Video head impulse testing (vHIT)
  • Videonystagmography (VNG)
  • Rotatory chair testing (RCT)

In patients with a combination of auditory and vestibular dysfunction in whom a diagnosis of mitochondrial disease is being entertained, then differential can also include:

Treatment and prognosis

Treatment for mitochondrial disorders is mainly supportive (Davis et al. 2018), and prognosis is poor. Trials of L-arginine in patients with MELAS have been disappointing. Patients with mitochondrial disorders who have a deficiency of coenzyme Q10 may benefit from supplementation.

Regarding hearing loss, referral to audiology to be evaluated for amplification is always reasonable. There have been some attempts at cochlear implantation for management of hearing loss in mitochondrial disorders (Sinnathuray et al. 2003).

Regarding disequilibrium, referral to a vestibular physical therapist is medically reasonable.

References

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Davis RL, Liang C, Sue CM (2018) Mitochondrial diseases. Handb Clin Neurol 147: 125-141. doi: 10.1016/B978-0-444-63233-3.00010-5

El-Hattab AW, Adesina AM, Jones J, Scaglia F (2015) MELAS syndrome: Clinical manifestations, pathogenesis, and treatment options. Mol Genet Metab 116: 4-12. doi: 10.1016/j.ymgme.2015.06.004

Elliott HR, Samuels DC, Eden JA, Relton CL, Chinnery PF (2008) Pathogenic mitochondrial DNA mutations are common in the general population. Am J Hum Genet 83: 254-60. doi: 10.1016/j.ajhg.2008.07.004

Finsterer J (2019) Assessment of Audiological and Vestibular Involvement in Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes Requires in-Depth Background Information. J Int Adv Otol 15: 474-475. doi: 10.5152/iao.2019.7559

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Inoue A, Iwasaki S, Fujimoto C, Kinoshita M, Yamasoba T (2019) Progression of Peripheral Vestibular Dysfunctions in Patients With a Mitochondrial A3243G Mutation. Otol Neurotol 40: 359-364. doi: 10.1097/mao.0000000000002091

Iwasaki S, Egami N, Fujimoto C, Chihara Y, Ushio M, Kashio A, Yamasoba T (2011) The mitochondrial A3243G mutation involves the peripheral vestibule as well as the cochlea. Laryngoscope 121: 1821-4. doi: 10.1002/lary.21879

Kawashima Y, Noguchi Y, Ito T, Kitamura K (2009) Vestibular evoked myogenic potentials in patients with the mitochondrial A1555G mutation. Laryngoscope 119: 1874-9. doi: 10.1002/lary.20584

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Page first published on September 22, 2024. Page last updated on September 22, 2024

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