non-mendelian mitochondrial inheritance as a cause of progressive genetic sensorineural hearing loss

INTERNATIDMl JOURNAL OF

Pediatric

International Journal of Pediatric Otorhinolaryngology

ELSEVIER 30 (1994) 91-104

Review article

Non-Mendelian mitochondrial inheritance as a cause of progressive genetic sensorineural

hearing loss

Michael Golda3b, Isabelle Rapin* b3c

“Department of Neurology, Universiiy of South Florida College of Medicine,

Tampa. FL, USA

‘Saul R. Korey Department of Neurology, Kennedy 807. ‘Department of Pediuiric.s

and Rose F. Kennedy Center for Research in Mental Retardation and Human Development,

Albert Einsiein College of Medicine. Bron.r. NY 10461. USA

(Received 24 November 1993; revision received 22 February 1994: accepted 27 February 1994)

Abstract

Awareness of non-Mendelian mitochondrial inheritance and of its role as an agent of gene-

tic sensorineural hearing loss (SNHL) is recent. Mitochondria are passed on exclusively from the ovum to all the offspring of both sexes, a novel pattern of inheritance. Owing to the critical role of mitochondria in cellular energy metabolism, deletions or point mutations of the mitochondrial DNA often cause progressive SNHL and a variety of disorders in other organ systems (mitochondrial cytopathies). The clinical expression of mitochondrial diseases varies and depends on the proportion of mutated mitochondria in various body tissues, as well as the nature of the mutation or deletion. In order to determine how often SNHL occurs in mitochondrial diseases and what is its presenting symptom, and also whether SNHL is a marker for particular phenotypes, we carried out a review of published case reports of patients with an established diagnosis of mitochondrial disease. The review indicates that SNHL occurs at all ages and in virtually all variants of mitochondrial diseases. It is not clear whether SNHL is a marker for a more severe and more rapid course of disease; the lower prevalence of SNHL in descriptions of live patients than of those who had died may be an artifact of case selection reported in the literature. Mitochondrial disease needs to be considered in progressive hearing loss and better longitudinal audiometric study of established cases will be required to answer these questions.

* Corresponding author.

0165-5876/94/$07.00 0 1994 Elsevier Science Ireland Ltd. All rights reserved

SSDI 0165-5876(94)01037-X

92 M. Gold, I. Rapin/lnt. J. Pediatr. Otorhinolaryngol. 30 (1994) 91-104

Keywords: Sensorineural hearing loss; Progressive hearing loss; Genetic hearing loss; Mito- chondrial cytopathy; Mitochondrial inheritance

1. Introduction

It is now well established that genetics is responsible for a large proportion of un- explained congenital and acquired hearing losses. There are many Mendelian genes for deafness, some of which are dominant, others recessive, and some X-linked [23,39,62]. The discovery of non-Mendelian mitochondrial inheritance in man is recent and has brought with it the realization that mitochondrial diseases are both more frequent and much more varied than previously thought. The fact that they are responsible for a significant number of cases of progressive SNHL in both child- ren and adults has attracted little attention thus far. In order to fill this gap, we carried out a review of published case studies of mitochondrial diseases in an attempt to determine the prevalence of hearing loss in mitochondrial diseases, how often it is their presenting symptom, whether it occurs preferentially in some syndromes, and whether it is a useful prognostic marker. Because mitochondrial diseases are still un- familiar to many professionals, we preface our review with a brief prlcis of mitochondrial biology and mitochondrially inherited diseases.

2. Mitochondrial biology

Mitochondria are intracellular organelles thought to have evolved from pro- karyotic organisms that developed a symbiotic relationship with eukaryotic cells. Mitochondria carry out ATP synthesis and oxidative phosphorylation and thus play the central role in cellular energy metabolism. They are the only cellular organelles to carry their own genetic material in the form of a circular double stranded mole- cule of DNA with 16 569 base pairs [13,26]. Each mitochondrion contains 2-10 copies of the mitochondrial genome and each cell contains hundreds or thousands of mitochondria that replicate independently of each other and of the host cell [13,26]. Mitochondrial DNA undergoes a higher rate of spontaneous mutation than nuclear DNA because ineffectual mitochondrial DNA repair often results in an ac- cumulation of mutations and in increased susceptibility to exogenous mutagenic fac- tors [69]. Consequently, late onset and sporadic disorders ascribable to mitochondrial dysfunction are fairly common. The severity or expression of mitochondrial diseases is variable and is a function of the proportion of mutated mitochondria in various tissues, the energy requirements of these tissues, and the severity of the functional impairment of the electron transport chain. The high energy requirements of brain, muscle, retina, and the inner ear are probably responsible for the vulnerability of these tissues to mitochondrial diseases.

The evolutionary process has left mammalian mitochondria with a progressively smaller genome due to the migration of some of the genomic elements required for mitochondrial function into the cell’s nuclear genome [43]. The mitochondrial genome contains only 37 genes that code for the 2% of mitochondrial polypeptides

M. Gold, 1. Rapin / Int. J. Pediatr. Otorhinolaryngol. 30 (1994) 91-104 93

that are not coded for by the nuclear genome and are not translocated into the mitochondria. Mitochondrial function is thus under both nuclear and mitochondrial genetic control. As a result, some mitochondrial disorders are inherited as classic Mendelian traits, whereas those resulting from mitochondrial DNA mutations or deletions are either maternally inherited and transmitted to both sexes or sporadic.

Cellular energy production depends on oxidative phosphorylation and the production of ATP molecules by the electron transport chain. Mitochondrial DNA codes for 13 of the enzymes required for cellular respiration and for messenger RNAs and transfer RNAs required for mitochondrial replication [13,15,64].

3. Mitochondrial diseases

The first report of a patient with a disease of mitochondrial function was published in 1962 [19,46]; the patient presented with a hypermetabolic state due to uncoupling of oxidative phosphorylation. Subsequent patients with recognized mitochondrial diseases had myopathies or encephalomyopathies and were identified by elevations of serum and CSF lactate and pyruvate levels and mitochondrial enzymatic deficits in combination with abnormal muscle biopsies showing ragged-red fibers (RRF) on histochemistry.

The abnormal staining of RRF is due to alterations in intramitochondrial protein synthesis. These fibers are characteristic of some, but not all, diseases due to mitochondrial DNA mutations and deletions and not of those due to nuclear DNA alterations [13]. The unique features of mitochondrial biology and inheritance were elucidated by study of the pedigrees of 30 families with members affected by these diseases. Transmission was exclusively maternal in 27 of the 30 families [ 11,181. The remaining cases, in which transmission was paternal, were attributable to mutations in the nuclear encoding of the defective mitochondrial enzymes. Molecular methods now make it possible to localize the specific point mutations or deletions responsible for these biochemical defects and to classify mitochondrial diseases rationally based on whether they are inherited as mitochondrial or Mendelian traits [13].

All clinical syndromes associated with mitochondrial DNA defects are associated with enzymatic deficits of the electron transport chain. Some disorders involve only one tissue, usually muscle, or the optic nerve in the case of Leber’s hereditary optic neuropathy which is due to a mitochondrial DNA point mutation (711, while others involve multiple systems. Kearns-Sayre Syndrome (KSS) is the prototypic condition associated with large scale mitochondrial DNA deletions or, occasionally, insertions [25,37,75]. In KSS the DNA rearrangements probably take place post-fertilization because the disorder is sporadic and is not transmitted to the offspring of affected women. It starts in childhood and is characterized by hearing loss, chronic progressive external ophthalmoplegia (CPEO) and pigmentary retinopathy, myopathy with ragged-red fibers and cardiomyopathy - often with heart block, short stature, parathyroid deficiency, and spongy changes in the cerebral white matter. Myoclonus epilepsy with ragged-red fibers (MERRF) [24,33,45,52,67], which is associated with ataxia and sponginess of the white matter, and mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) [12,29,31,55] are both due to one

94 M. Gold, I. Rapin /Int. J. Pediatr. Otorhinolaryngol. 30 (1994) 91-104

of several mitochondrial DNA point mutations. Both may be associated with progressive hearing loss and lactic acidosis. Patients with overlap syndromes [76] or with the sequential development of distinct clinically identifiable syndromes [ 11,281 in the face of a stable mitochondrial DNA deletion have been described. DeVivo [ 131 provides a lucid up-to-date review of known mitochondrial syndromes.

Mitochondrial diseases due to nuclear DNA defects, which are inherited as Mendelian traits, are associated with substrate transport and utilization deficits, including defects of fatty acid oxidation and pyruvate metabolism, but also with some deficits in the electron transport chain that overlap clinically with syndromes due to mitochondrial DNA defects.

4. Materials and Methods

We conducted a literature search on the topic of mitochondrial diseases for articles that included a case report and that were written in English and had appeared from 1984-1993. Cases reported prior to 1984 were generally excluded due to the lack of consistent clinical and biochemical evaluations and the unavailability of mitochondrial DNA analysis. Cases were accepted for this review when the diagnosis was confirmed on the basis of deletions/mutations in the mitochondrial DNA, or of a combination of morphological evidence on muscle biopsy (ragged-red fibers) and biochemical testing of the function of the respiratory chain. In addition, the case reports had to provide adequate information on the age of onset and the ages at which prominent clinical signs or symptoms became apparent. A total of 117 case reports were sufficiently complete to be incIuded in this review of hearing loss in mitochondrial disease.

We attempted to estimate the prevalence of SNHL in patients with mitochondrial disorders from a series of review articles describing large collections of patients or large pedigrees. Unfortunately, many reports did not mention hearing and data on age, sex and clinical severity were often inadequate.

We presumed that if SNHL were a marker for more severe disease, patients with SNHL would have an earlier age of onset of symptoms in other organ systems than patients with normal hearing. Due to the wide range of ages of reported patients, we started by carrying out a univariate analysis in order to determine that the use of parametric statistics was appropriate. After confirming the normal distribution of ages for the overall population, a series of two tailed r-tests was carried out to com- pare the groups with and without SNHL with regard to the age at presentation of the disease and at onset of the various clinical symptoms (external ophthalmoplegia, muscle weakness, myoclonus, retinal degeneration, stroke or stroke-like episodes, and cardiac arrhythmias).

We also supposed that if SNHL functioned as a marker for more severe disease, patients with SNHL would develop more of the clinical symptoms associated with mitochondrial encephalomyopathies than those without SNHL. We tested this hypothesis by determining the frequency of associated clinical symptoms in patients with and without SNHL. The data were analyzed with x2 tests with Yates correc- tion. Statistical analyses were carried out using SASSTAT version 6.03. A power

M. Gold, 1. Rapin /In!. J. Pediatr. Ororhmolar~~ngoi. 30 f 1994) 91-104 9s

Table I Prevalence of SNHL in literature reviews of mitochondrial encephalomyopathies

Author Total number

of patients

Number with

SNHL”

Percentage with

SNHL

Berenberg [4] 36 19 52.8

Egger 1171 13 4 30.x

Hasegawa [34] 6 3 50.0

Holt [37] II 1 9.1

Petty [56] 66 4 6.0

Sengers [63] 30 I 3.3

Total I62 32 19.x

%NHL. sensorineural hearing loss

analysis for a population of 117 subjects suggests that it should be large enough to detect a moderately sized effect (0.4 < h c 0.5) with a power of 0.8 with a 95% level of confidence.

Because mitochondrial diseases have been identified so recently, we also reviewed the sparse data on the pathology of the sensorineural mitochondrial hearing loss.

5. Results

5.1. Prevalence of SNHL

The set of review articles [4,17,34,37,57,64] (see Table 1) surveyed to obtain preli- minary evidence on the prevalence of SNHL in mitochondrial cytopathies included 162 patients, 32 of whom (19.8%) were stated to have a SNHL.

We retrieved a total of 117 case reports [ 1,3,6- 12,14,16,20,22,28,30,3 1,35,36,38,4 O-42,44,46-51,53-61, 65,66,68,70,72,73,76] with adequate data for analysis (see Table 2). Progressive loss of hearing was reported in the majority (69/l 17 or 59%).

Table 2

Description of case reports included in this review

Types of cases Number Percent

All Cases 117 100

Number with SNHL 69 59.0

Number without SNHL 48 41.0

Number with KSS 42 35.9

Number with MELAS 27 21.4

Number with MERRF 25 23. I Number with unspecified syndrome 29 24.8

Note: some patients met criteria for two or more clinical syndromes and were included in both categories.

Abbreviations: SNHL. sensorineural hearing loss; KSS, Kearns-Sayre Syndrome: MERRF. myoclonus

epilepsy ragged-red fibers: MELAS, mitochondrial encephalopathy. lactic acidosis and stroke-like

episodes.

96 M. Gold, I. Rapin/Imt. f. Pediatr. Otorhinolaryngol. 30 (1994) 91-IO4

Unfortunately, only one report included an audiogram [67], and serial audiometric testing was not documented in any case. This points to the serious lack of data on the natural history of hearing loss in this family of disorders. There were no data on the course of the SNHL and its severity was described only qualitatively with terms such as mild, severe or deaf.

5.2. Onset of associated clinical signs The age at onset of the first symptom of mitochondrial disease was not signific-

antly different in patients with SNHL (17.5 years) and those without (20.3 years) (see Table 3). Sensorineural hearing loss was noted at a mean age of 25.2 years. There was no difference in the age at presentation of any associated symptom, with the ex- ception of retinal degeneration which occurred much earlier in patients with SNHL (18.85 years) than in those without (33.2 years) (Table 1). The diagnosis of mitochondrial disease was made at a mean age of about 30 years in both groups, 10 to 15 years after the appearance of the first symptom, but this is probably an artifact accounted for by improvements in the identification of mitochondrial diseases.

5.3. Prevalence of associated clinical signs Analysis of the prevalence of other signs and symptoms associated with SNHL is

reported in Table 4. Although death was more frequent in patients with SNHL than in those without, there was no significant difference between the 2 groups in the frequency of any of the classic clinical signs of mitochondrial disease such as external ophthalmoplegia, muscle weakness, myoclonus, retinal degeneration, stroke/stroke- like episodes, and cardiac complications.

We examined the prevalence of SNHL across clinical syndromes (Table 5). There was no difference in prevalence of SNHL (66-70%) among patients with a definable

Table 3 Mean age (years) at presentation and at onset of associated clinical features

Feature

First onset SNHL CPEO Weakness Myoclonus Retinopathy CVA-like episodes Cardiac symptoms Diagnosis Reported Death

SNHL No SNHL

II mean SD. n mean SD. 1

69 17.5 12.9 48 20.28 15.0 I .07 69 25.2 17.8 3s 20.4 IS.2 24 22.9 IS.1 0.62 51 23.5 IS.6 36 24.3 17.3 0.23 24 20.8 12.9 I2 18.3 12.4 -0.6 25 18.9 11.4 I5 33.2 IS.1 3.4* I8 25.8 13.6 8 18.3 II.5 -1.3 21 25.2 16.1 IO 29.2 17.6 0.6 69 31.1 16.7 48 30.9 16.4 -0.1 69 32.6 16.1 48 31.3 16.2 -0.4 20 28.4 14.6 5 26.7 13.6 -0.2

Abbreviations: SNHL, sensorineural hearing loss; n. number of cases with symptom or information reported; SD., standard deviation; 1, value of two-tailed f-test; CPEO, chronic progressive ophthalmoplegia; CVA, cardiovascular accident. *Significant at P < 0.05.

M. Gold, 1. Rapin /Inr. J. Pediatr. Olorhinolaryngol. 30 I19941 91-104 97

Table 4

x2 analysis of the frequency of clinical features

Feature

External ophthalmoplegia

Present

Not present Muscular weakness

Present

Not present Myoclonus

Present

Not present Retinal degeneration

Present

Not present Stroke/stroke-like episodes

Present

Not present Cardiac complications

Present

Not present Death

Yes

No

SNHL No SNHL

35 24

34 24

51 36

IH 12

24 12

45 36

25 15

44 33

18 x 51 40

21 10

48 38

20 5

49 43

xz statistic

0.0

0.0

0.85

0.13

0.96

0.x9

4.76*

Abbreviations: SNHL, sensorineural hearing loss

*Significant at P < 0.05 level.

clinical syndrome (KSS, MERRF or MELAS), whereas SNHL was much less prevalent (38%) among patients whose presentation could not be categorized.

5.4. Size of effect and power of Ihe study The 117 subjects in this study provided a sample large enough to detect a

moderately sized effect when analysing the proportion of patients presenting with the various clinical features of mitochondrial disease. An analysis of the size of the effect of proportions for the associated clinical syndromes that did not show a difference between patients with and those without SNHL was performed. The power analysis revealed uniformly low size effects (h statistic) ranging from 0.02-0.381.

Table 5

x’ analysis of the frequency of SNHL within clinical groups

Clinical syndrome SNHL present SNHL absent

KSS 28 14

MERRF 17 8

MELAS 19 8

Unspecified 11 18

x2 = 8.564. d.f. = 3, P = 0.036; abbreviations: see Table 2

98 M. Gold, I. Rapin /IN. J. Pediatr. Otorhinolaryngol. 30 (1994) 91-104

Using a small size effect (h = 0.10) as a conservative estimate, a study with a power of 0.8, and a confidence level of 95% would require over 1200 subjects in order to detect a effect of such small size.

5.5. Pathology of mitochondrial SNHL Of the 20 patients with mitochondrial disease with hearing loss who died by the

time their case was reported, only 5 cases, those of Bordarier [7], Oldfors [54] and McKelvie [49] provide data on pathological changes in the auditory pathways but unfortunately they do not provide data on the cochlea. Bordarier [7] described the autopsy findings in 2 cases of KSS with SNHL. The first had demyelination of the brain-stem sparing the medial longitudinal fasciculus and the central tegmental tracts, along with severe spongiosis with loss of myelin in the cerebral white matter and brain stem, including the substantia nigra and the nuclei of cranial nerves III, VI and VIII. The second case also had severe spongiosis of the white matter of the cerebral hemispheres and brain stem, including cranial nerve VIII. In both cases, the neurons of the cranial nerve nuclei appeared normal. Oldfors [54], describing a case of KSS with SNHL, showed by electron microscopy that sponginess of the white matter was due to extracellular edema with splitting of myelin along the minor dense line. There was severe neuronal loss with gliosis in the basal ganglia, iron deposition in the globus pallidus, and a reduction in the number of cells in the inferior olivary nucleus. McKelvie 1491 describing the findings in 2 patients with MERRF, noted vacuolar changes and pallor of the myelin in the cerebrum. Brain-stem structures showed the same vacuolation in multiple cranial nerve nuclei including the vestibular nuclei. Lindsay and Hinojosa [44] provide the only data on the inner ear in a case of KSS with SNHL. They described advanced cochlear degeneration with collapse of Reisner’s membrane and degeneration of the organ of Corti, tectorial membrane, and stria vascularis. There was a 60-70”/0 reduction in the number of neurons along the entire length of the spiral ganglion.

6. Discussion

Our review of 117 adequately documented cases of mitochondrial cytopathy described over the past decade indicates that progressive SNHL may be present in almost two thirds of the cases, a figure twice as high as previously estimated. This figure may be an inadequate estimate of the true prevalence of SNHL because these disorders have only been recognized for the past 20-30 years and because of a bias towards reporting only the more severe cases. The entire spectrum of these diseases is not yet fully known and there is no information on how many cases of apparently isolated progressive SNHL will eventually declare themselves as due to mitochondrial cytopathies.

What this review points out is the dearth of information on the character, severity, and course of mitochondrial SNHL. Information about the pathology of this disorder, both in the cochlea and the central auditory pathway, is almost nonexistent. The fact that patients with SNHL may develop retinal degeneration earlier than those without is compatible with a selective vulnerability of certain tissues to defective

M. Gold, 1. Rapin /Int. J. Pediatr. Ororhinolaryngoi. 30 (1994) 91-104 99

energy metabolism, since energy metabolism is high both in the cochlea, whose ion pumps are continuously active, and in the retina due to rapid turnover of visual pig- ment proteins.

The dependence of the hair cells and stria vascularis on the availability of high energy compounds and oxidative phosphorylation has been investigated by exposing animal cochleas to anoxia, ischemia, and metabolic decouplers. Exposure to carbon monoxide, a model for hypoxia, led to reversible losses in compound action poten- tials, starting in the high frequency range, and to compensatory increases in blood flow [21]. Total cochlear ischemia rapidly resulted in pathological changes in the structure of the cochlea [5]. There was detectable swelling of nerve endings of inner hair cells within 15 min of the onset of ischemia that eventually led to their rupture. Outer hair cells became swollen within 30 min and showed alterations of intracellular organelles, including the mitochondria. The effect of the ototoxic drug, kanamycin, on cochlear ultrastructure was to induce mitochondrial lesions in the stria vascularis [32]. The dependence of the cochlea on high energy metabolism can be inferred from intense histochemical staining of the tegmentum vasculosum (analog structure of the stria vascularis) for Na+-K+-ATPase histochemistry in chicken cochleas which showed intense staining of the tegmentum vasculosum, especially the basal portion (high-frequency) portion of the tegmentum [63]. A central and high energy role of the stria vascularis is to maintain the ionic composition of the endo- lymph by active transport [2]. Cultured hair cells may also be more dependent on oxidative phosphorylation since they must maintain the -70 mV transmembrane potential critical to sound transduction [27].

This review of published data does not support the hypothesis that SNHL is a marker for earlier presentation of mitochondrial encephalopathies or for more severe phenotypic expression. The seemingly higher mortality of patients with SNHL may be a sampling artifact. The similar proportion of patients with KSS, MERRF and MELAS who eventually developed SNHL suggests a common metabolic defect affecting both the cochlea and neural tissue. All 3 syndromes are associated with mitochondrial DNA defects interfering with oxidative phosphorylation and not with abnormal products of the nuclear genome.

One of the difficulties in attempting to define the natural history of SNHL in mitochondrial diseases from published reports is the often prolonged interval between clinical evaluations of the patients. These gaps create a bias towards delayed reporting of the onset of signs and symptoms. In fact, these gaps may have obscured any markers for earlier onset or more severe disease. The present data suggest that SNHL is not of value for predicting the eventual appearance of other clinical manifestations or the progression of the disease.

A power analysis of the data suggests that the lack of difference between patients with SNHL and those without in terms of associated clinical syndromes is not an artifact of a small sample size but is rather due to very small differences in the proportion of patients that are affected. Given the sparse data on the natural history of SNHL in patients with mitochondrial diseases any questions regarding clinical associations will require very large sample sizes. Conversely, better clinical and audiologic data will lead to better characterization of these two patient populations


and should provide the answers to the questions we have raised with a more realistic number of patients.

The concept of mitochondrial inheritance is new. Physicians dealing with patients, both pediatric and adult, with an acquired SNHL need to consider the possibility of a mitochondrial disorder because of the potential involvement of other organ systems and of the unusual pattern of inheritance. They should not only inquire specifically about progressive hearing loss in the family but also about other symptoms suggestive of a mitochondrial disorder among maternal relatives. If the history is suspicious, they should examine living relatives, especially maternal ones, for clinical markers of mitochondrial disease. The determination of maternal inheritance is crucial for genetic counselling in affected patients and their offspring.

Blood tests of mitochondrial function and molecular approaches to diagnosis using blood, skin tibroblasts, and muscle samples provide an opportunity for early and specific diagnosis [74]. Some of these disorders may respond to future therapies directed at replacing the defective enzyme or components thereof. The development of enzymatic replacement therapies depends on identifying the exact deficiency and establishing a correlation between the defective enzyme and particular functional deficits.

Note added in proof

Two more mitochondrial syndromes with hearing loss have been identified, one autosomal recessive with gastrointestinal pseudo-obstruction and encephalomyopathy (Hirano et al., 1994) the other maternally transmitted with insulin-dependent diabetes mellitus (Kadowaki et al., 1994).

Hirano, M., Silvestri, G., Blake, D.M., et al. (1994) Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): Clinical, biochemical, and genetic features of an autosomal recessive mitochondrial disorder. Neurology 44, 721-727.

Kadowaki, T., Kadowaki, H., Mori, Y. et al. (1994) A subtype of diabetes mellitus associated with a mutation of mitochondrial DNA. N. Engl. J. Med. 330, 962-968.

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non-mendelian mitochondrial inheritance as a cause of progressive genetic sensorineural hearing loss

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