More than 24,000 children are born with hearing loss in the United States each year. Boys Town National Research Hospital is a national leader in the diagnosis and treatment of children with moderate to profound hearing loss.

Information on Hearing Loss - Genetics and Deafness - Mitochondrial Inheritance and Hearing Loss

by Nathan Fischel-Ghodsian, M.D.

Nearly all of our genes can be found in the nucleus of the cell on one of the 23 chromosome pairs. However there are other genes on the tiny chromosomes in the mitochondria of the cell. Recently, mutations in these mitochondrial chromsomes have been found to be associated with a variety of hearing defects. This article will give a short introduction to mitochondrial genetics, and outline the spectrum of clinical presentations of mitochondrially determined hearing impairments.

Normal Mitochondrial Genetics

There are hundreds of mitochondria in each cell and they serve a variety of metabolic functions, the most important being the synthesis of ATP by oxidative phosphorylation. Each mitochondrion contains 2-10 mitochondrial chromosomes, so that each cell contains thousands of mitochondrial chromosomes. In humans, each of these mitochondrial DNA molecules is 16,569 bp long, double stranded, forms a closed circle, and replicates and is transcribed within the mitochondrion. The mitochondrial DNA molecule encodes 13 mRNA genes, as well as two rRNAs and 22 organelle-specific tRNAs which are required for assembling a functional mitochondrial protein-synthesizing system. The 13 mRNAs are translated on mitochondrion-specific ribosomes, using a mitochondrion-specific genetic code, into 13 proteins. These proteins interact with approximately sixty nuclear encoded proteins to form the five enzyme complexes required for oxidative phosphorylation. These complexes are bound to the mitochondrial inner membrane, and are involved in electron transport and ATP synthesis (reviewed in Attardi and Schatz, 1988).

Mitochondrial DNA is transmitted exclusively through mothers, with sperm apparently contributing no mitochondrial DNA to the zygote. This leads to the expectation that a defect in a mitochondrial gene should lead to disease equally in both sexes, but can only be transmitted through the maternal line. These basic rules of mitochondrial genetics are complicated by at least four factors:

1. Some mitochondrial mutations might lead to disease only in the presence of a specific nuclear genotype or environmental agent (Jaber et al, 1992; Prezant et >al, 1993).
2. Some autosomal recessive and autosomal dominant inherited genetic disorders, as well as medications such as AZT, can lead to mitochondrial DNA pathology, such as acquired mutations/deletions or depletion (e.g. Zeviani 1992).
3. Although most healthy individuals appear to have only a single mitochondrial DNA genotype, i.e. are homoplasmic, in most mitochondrial disease states, the mitochondrial DNA population is mixed (a condition called heteroplasmy). However, homoplasmy of the mutant mitochondrial DNA is observed for some hearing disorders as described in the sections on non-syndromic and ototoxic hearing loss below.
4. The identical mitochondrial mutation can lead to entirely different phenotypes, examples of which are given in the section on syndromic hearing loss.

Mitochondrial DNA Mutations and Hearing Loss

Over the last few years hearing loss has been found to be associated with a multitude of different mitochondrial defects:

Syndromic Deafness

Initially mitochondrial DNA defects were described in a number of systemic neuromuscular diseases, such as Kearns-Sayre Syndrome, MERRF and MELAS. In each of these diseases the pathogenic mutation is heteroplasmic and varies from large deletion/insertions to point mutations. It is not surprising that a patient with generalized neuromuscular dysfunction will also present with hearing deficits, and thus these diseases were of no particular interest to clinicians or researchers in the hearing field.

This focus changed with the surprising description of several families with mitochondrial mutations, in whom sensorineural hearing loss and diabetes mellitus occur with significant penetrance but not always together (Ballinger et al, 1992; van den Ouweland et al, 1992; Reardon et al, 1992). Even more surprisingly, in most of these families the pathogenic heteroplasmic mutation is the same A->G transition mutation at nucleotide 3243 in the mitochondrial gene for tRNAleu(UUR) as in MELAS (van den Ouweland et al, 1992; Reardon et al, 1992). This association between diabetes mellitus, hearing loss, and mitochondrial mutations has been confirmed in population studies of diabetic patients (Oka et al, 1993; Kadowaki et al, 1994; Alcolado et al, 1994; Katagiri et al, 1994). Kadowaki et al, for example, found the heteroplasmic nucleotide 3243 mutation in 2-6% of diabetic patients in Japan, and in 3 out of 5 patients with diabetes and deafness. 27 of their 44 patients with diabetes and the nucleotide 3243 mutation also had hearing loss. In none of these cases were other neurological symptoms present. The hearing loss is sensorineural, and usually develops only after the onset of diabetes. We are not aware of a study that has looked for the frequency of the nucleotide 3243 mutation in a population of patients with adult onset sensorineural hearing loss.

Non-syndromic Deafness

The first hint that non-syndromic deafness can be caused by mitochondrial mutations came from an Arab-Israeli pedigree, when the striking pattern of transmission only through mothers was first noted (Jaber et al, 1992). Formal segregation analysis of the inheritance pattern in this pedigree predicted a two locus disorder, in which the presence of both an homoplasmic mitochondrial mutation and an autosomal recessive mutation is required for phenotypic expression of the deafness phenotype (Jaber et al, 1992). Clinically, the deaf family members have predominately onset of severe to profound hearing loss during infancy, but a minority of family members had onset during childhood or even adulthood, with the loss sometimes occuring over a relatively short time period and then remaining stable. Audiologicaly, the hearing loss is sensorineural and of cochlear origin, and the vestibular system is unaffected. A homoplasmic mutation at nucleotide 1555 in the mitochondrial 12S rRNA gene was identified as the pathogenic mutation (Prezant et al, 1993), and the same mutation was also found to predispose to aminoglycoside induced hearing loss as described below.

A second family with a maternal inheritance pattern and non-syndromic deafness was described in Scotland, and confirmed and established in a third unrelated pedigree from New Zealand (Reid et al, 1994; Fischel-Ghodsian et al, in press). The mutation in these families was at nucleotide 7445, which is the last nucleotide of both the tRNASer(UCN) gene on one strand and the cytochrome oxidase I gene on the other strand. Since the sequence change in the cytochrome oxidase gene is a conservative change of the termination codon, it is most likely that the change of the 3' end of the tRNA molecule affects aminoacylation, and thus translational fidelity. The mutation is heteroplasmic in lymphoblastoid cells, with the abnormal molecules corresponding to over 95% of the population of mitochondrial chromosomes. The clinical phenotype is sensorineural hearing loss with onset usually during childhood or adolescence. Interestingly, the penetrance of this mutation in the Scottish pedigree is quite low, while in the New Zealand pedigree every individual over the age of 20 has hearing loss. Thus, in similarity to the Arab-Israeli pedigree, the mitochondrial mutation by itself does not appear to be sufficient to cause hearing loss, but requires an additional genetic or environmental factor, which seems to be rare in the Scottish pedigree and ubiquitous in the New Zealand pedigree.

Recently, additional pedigrees with a maternal inheritance pattern and the 1555 mutation were described (Matthijs et al, 1994; El-Shahawi et al, 1995). In some of them, deafness only occurs later in life, again demonstrating the remarkable heterogenity of phenotypic expression of the same genetic defect.

Ototoxic Deafness

Aminoglycoside ototoxicity is one of the most common causes of acquired deafness. Although vestibulo-cochlear damage is nearly universal when high drug levels are present for prolonged periods, at lower drug levels there appears to be a significant genetic component influencing susceptibility to aminoglycoside ototoxicity. Numerous families have been described in which several individuals became deaf after exposure to aminoglycosides (Konigsmark et al, 1976; Higashi, 1989; Hu et al, 1991), and dramatic species differences in susceptibility to these drugs also suggest a genetic component (Stebbins et al, 1981).

We analyzed three Chinese families in which several individuals developed deafness after the use of aminoglycosides (Prezant et al, 1993). The pattern of maternal inheritance in these pedigrees, the known effect of aminoglycosides on ribosomal translation ability, and the presence of resistance mutations in a range of prokaryotic and eukaryotic organisms, implicated the mitochondrial ribosomes, and in particular, the mitochondrially-encoded 12S rRNA gene, as the most likely locus of such predisposition to toxicity. In all three families, a mutation was identified in the 12S mitochondrial rRNA gene that affected a site known to be important both in the binding to aminoglycosides and in resistance to the antibiotic (Prezant et al, 1993). Also, a small proportion of "sporadic" patients, without a positive family history for aminoglycoside ototoxicity, exhibit this particular mutation (Fischel-Ghodsian et al, 1993). These findings were confirmed in 2 Japanese families and additional Chinese sporadic cases (Hutchin et al, 1993). Subsequently, an additional heteroplasmic nucleotide deletion/insertion mutation around nucleotide 961 in the 12S rRNA gene, and two potential homoplasmic mutations in the same gene, which also appear to predispose to aminoglycoside ototoxicity, were described (Bacino et al, 1995). Most interestingly, in one streptomycin induced deaf individual with a strong familial history of aminoglycoside induced hearing loss and the mitochondrial 1555 mutation, detailed vestibular examination revealed severe hearing loss with completely normal vestibular function.

It appears at this time that, at least in China, Japan, and Mongolia, nearly every case of familial aminoglycoside induced ototoxcity, as well as a small proportion of the sporadic cases, has the 1555 mutation. About a third of all aminoglycoside induced deafness cases in China appear to be due to the 1555 mutation (Hu et al, 1991). Preliminary data from our own laboratory indicates that about 15-20% of U.S. patients from various ethnic backgrounds and with a history compatible with aminoglycoside induced ototoxicity have the 1555 mutation.

Presbyacusis

The relationship between mitochondrial DNA defects and presbyacusis is entirely speculative at this time. However, the resulting loss of oxidative phosphorylation activity resulting from acquired mitochondrial DNA mutations seem to play an important role in the aging process (reviewed by Nagley et al, 1993). These mutations are thought to be associated with the insidious decline in physiologic and biochemical performance of an organ and to contribute significantly to the aging process and ultimately death. Because of the higher energy requirements of muscle and nervous tissue, and the fact that small numbers of dysfunctional muscle and nerve cells can interrupt the function of many neighbouring normal cells, mitochondrial DNA mutations of those particular tissues are thought to be particularly harmful. In humans, accumulation of mitochondrial DNA defects has been documented in the greatest detail in brain and heart. In general, investigators have concentrated on the detection of deletions, and in particular a 4977 nucleotide deletion, which is also called the 'common deletion'. This deletion has been found in high concentration in many sporadic mitochondrial disorders, and is thought to arise by illegitimate recombination involving the13-basepair repeats found at both deletion breakpoints. One particularly fascinating and perplexing finding in the human studies was the dramatic difference in the levels of acquired mitochondrial DNA deletions among different tissues in the same individual. For example, the 4977 nucleotide common deletion was found consistently at levels of hundreds to 2000 times more commonly in the caudate, putamen, and substantia nigra than in the cerebellum, with the cortex having intermediate levels of deletion acquisition (Soong et al, 1992; Corral-Debrinski et al, 1992). Investigations of the auditory system in aged animal models are beginning to find mitochondrial DNA deletions (Seidman et al, 1995; Ueda et al, 1995). However, no investigation in human aging has yet been done for the auditory system.

Clinical Relevance of Mitochondrially Induced Hearing Loss At This Time

The clinical relevance of the findings on the role of the mitochondrial genome in hearing loss is so far mainly limited to the prevention of aminoglycoside induced hearing loss. Physicians need to inquire about a family history of aminoglycoside induced hearing loss prior to the administration of systemic aminoglycosides as antimicrobials, as well as prior to the local administration of aminoglycosides into the cochlea as treatment for Meniere's disease. In addition, every individual with aminoglycoside induced hearing loss should be screened at least for the presence of the mitochondrial 1555 mutation, since presence of the mutation will allow counselling to all maternally related relatives to avoid aminoglycosides (Patients with a history suggestive of aminoglycoside induced ototoxicity can be referred to Dr. Rena Falk at 310-855-6451 or myself at 310-855-4423, and we will screen for the known predisposing mutations). No sufficient data is currently available to know whether vestibular testing can consistently separate between aminoglycoside induced ototoxicity due to mitochondrial predisposition and other causes.

Hearing maternal relatives of deaf individuals with non-syndromic hearing loss and the 1555 mutation are also at risk for aminoglycoside induced hearing loss. However, since the 1555 mutation will only extremely rarely be responsible for non-syndromic hearing loss, it is not warranted at this time to screen such patients for clinical reasons for the 1555 mutation.

With the exception of aminoglycosides and mitochondrial mutations in the 12S rRNA gene, there are no proven preventive or therapeutic interventions for mitochondrially related hearing impairments. The diagnosis of such defects is however useful for genetic counselling and is indicated in all families with an inheritance pattern of hearing loss consistent with maternal transmission, and possibly in all patients who have both diabetes mellitus and adult onset hearing loss (screening for the common mutation associated with diabetes mellitus and hearing loss can be performed in a number of genetic laboratories - Locally we use the molecular diagnostics laboratory at Children's Hospital of Los Angeles under the direction of Dr. Lee-Jun Wong - 213-669-5619).

Acknowledgements

This work was supported by NIH/NIDCD grants DC01402 and DC02273.

Bibliography

Alcolado, J. C., Majid, A., Brockington, M., Sweeney, M.G., Morgan, R., Rees, Harding, A.E & Barnett, A.H. (1994). Mitochondrial gene defects in patients with NIDDM. Diabetologia 37, 372-376.

Attardi, G. & Schatz, G. (1988). Biogenesis of mitochondria. Annu Rev Cell Biol 4, 289-333.

Bacino, C., Prezant, T.R., Bu, X., Fournier, P. & Fischel-Ghodsian, N. (1995). Susceptibility mutations in the mitochondrial small ribosomal RNA gene in aminoglycoside induced deafness. Pharmacogenetics 5, 165-172.

Ballinger, S.W., Shoffner, J.M., Hedaya, E.V., Trounce, I., Polak, M.A., Koontz, D.A. & Wallace, D.C. (1992). Maternally transmitted diabetes and deafness associated with a 10.4 kb mitochondrial deletion. Nature Genetics 1, 11-15.

Corral-Debrinski, M., Horton, T., Lott, M.T., Shoffner, J.M., Beal, M.F. & Wallace, D.C. (1992). Mitochondrial DNA deletions in human brain: Regional variabilityand increase with advanced age. Nature Genet 2, 324-329.

El-Schahawi, M., Santorelli, F.M., Shanske, S., Demunain, L. & Dimauro, S. (1995). A family with mitochondrially inherited deafness and the mtDNA mutation at np 1555 in the 12S rRNA gene. Neurology 45 Suppl. 4, 1006P (abstract).

Fischel-Ghodsian, N., Prezant, T.R, Bu, X., & Öztas, S. (1993). Mitochondrial ribosomal RNA gene mutation associated with aminoglycoside ototoxicity. Am J Otolaryngol 14,399-403.

Fischel-Ghodsian, N., Prezant, T.R., Fournier, P., Stewart, I.A., & Maw, M. (1995). Mitochondrial tRNA mutation associated with non-syndromic deafness. Am J Otolaryngol Vol 16(6) (in press)

Goto, Y., Nonaka, I. & Horai, S. (1990). A mutation in the tRNALeu(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 348,651-653.

Higashi, K. (1989). Unique inheritance of streptomycin-induced deafness. Clin Genet 35,433-436.

Howell , N. (1994). Mitochondrial gene mutations and human diseases: a prolegomenon. Am J Hum Genet 55,219-224.

Hu , D-N., Qui, W-Q. , Wu, B-T., Fang, L-Z., Gu, Y-P., Zhang, Q-H., Yan, J-H. , Ding, Y-Q. & Wong, H. (1991). Genetic aspects of antibiotic induced deafness: mitochondrial inheritance. J Med Genet 28,79-83.

Hutchin, T., Haworth, I., Higasgi. K., Fischel-Ghodsian, N., Stoneking, M., Saha, N., Arnos, K. & Cortopassi G. (1993) A molecular basis for human hypersensitivity to aminoglycoside antibiotics. Nucleic Acids Res 21,4174-4179.

Jaber, L., Shohat, M., Bu, X., Fischel-Ghodsian, N., Yang, H.Y., Wang, S.J. & Rotter, J.I. (1992). Sensorineural deafness inherited as a tissue specific mitochondrial disorder. J Med Genet 29,86-90.

Kadowaki, T., Kadowaki, H., Mori, Y., Tobe, K., Sakuta, R., Suzuki, Y., Tanabe, Y., Sakura, H., Awata, T., Goto, Y-I., Hayakawa, T., Matsuota, K., Kawamori, R., Kamada, T., Horai, S., Nonaka, I., Hagura, R., Akanuma, Y. & Yazaki, Y. (1994) A subtype of diabetes mellitus associated with a mutation of mitochondrial DNA. New Engl J Med 330,962-968.

Katagiri, H., Asano, T., Ishihara, H., Inukai, K., Anai, M., Yamanouchi, T., Tsukuda, K., Kikuchi, M., Kitaoka, H., Ohsawa, N., Yazaki, Y. & Oka, Y. (1994). Mitochondrial diabetes mellitus: prevalence and clinical characterization of diabetes due to mitochondrial tRNALeu(UUR) gene mutation in Japanese patients. Diabetologia 37,504-510.

Konigsmark, B.W. & Gorlin, R.J. (1976). Genetic and metabolic deafness. Page 364-365. W.B. Saunders Co.

Matthijs, G., Claes, S., Longo-Mbenza, B., & Cassiman, J.J. (1994). Teenage-onset non-syndromic deafness associated with a mutation and a polymorphism in the mitochondrial 12S ribosomal RNA gene in a large Zairese pedigree. Am J Hum Genet 55,1346 (abstract).

Nagley, P., Zhang, C., Martinus, R.D., Vaillant, F. & Linnane, A.W. (1993). Mitochondrial DNA mutation and human aging: Molecular biology, bioenergetics, and redox therapy. In: DiMauro S and Wallace DC (eds). Mitochondrial DNA in human pathology. Raven Press, New York.

Oka, Y., Katagiri, H., Yazaki, Y., Murase, T. & Kobayashi, T. (1993). Mitochondrial gene mutation in islet-cell-antibody-positive patients who were initially non-insulin-dependent diabetics. Lancet 342,527-528.

Prezant, T.R., Agapian, J.V., Bohlman, M.C., Bu, X., Oztas, S., Qiu, W.Q., Arnos, K.S., Cortopassi, G.A., Jaber, L, Rotter, J.I., Shohat, M. & Fischel-Ghodsian, N. (1993). Mitochondrial ribosomal RNA mutation associated with both antibiotic-induced and non-syndromic deafness. Nature Genetics 4,289-294.

Reardon, W., Ross, R.J.M., Sweeney, M.G., Luxon, L.M., Pembrey, M.E., Harding, A.E. & Trembath, R.C. (1992). Diabetes mellitus associated with a pathogenic point mutation in mitochondrial DNA. Lancet 340,1376-1379.

Reid, F.M., Vernham, G.A. & Jacobs, H.T. (1994). A novel mitochondrial point mutation in a maternal pedigree with sensorineural deafness. Hum Mut 3,243-247.

Seidman, M.D., Khan, M.J., Bai, U., & Castora, F.J. (1995). Mitochondrial DNA deletions and hearing loss. Molecular Biology of Hearing and Deafness. Bethesda, MD, (abstract).

Soong, N.W., Hinton, D.R., Cortopassi, G. & Arnheim, N. (1992). Mosaicism for a specific somatic mitochondrial DNA mutation in adult human brain. Nature Genet 2,318-323.

Stebbins, W.C., Mcginn, C.S., Feitosa, A.G., et. al. (1981). Animal models in the study of ototoxic hearing loss, in Lerner SA, Matz GL, Hawkins JE jr (eds):Aminoglycoside Ototoxicity, pp. 5-25. Boston, Little, Brown and Company.

Ueda, N., Oshima, T., Ikeda, T. & Takasaka, T. (1995). Mitochondrial deletion and presbyacusis. Molecular Biology of Hearing and Deafness. Bethesda, MD (abstract).

Van Den Ouweland, J.M.W., Lemkes, H.H.P.J., Ruitenbeek, W., Sandkuiji, L.A., De Vijlder, M.F., Struyvenberg, P.A.A., Van De Kamp, J.J.P. & Maassen, J.A. (1992). Mutation in mitochondrial tRNALeu(UUR) gene in a large pedigree with maternally transmitted Type II diabetes mellitus and deafness. Nature Genet 1;368-371.

Zeviani, M. (1992). Nucleus-driven mutations of human mitochondrial DNA. J Inher Metab Dis 15,456-471.

Date Originally Created: Fall of 1987

The information presented here first appeared in publications of the Boys Town National Research Register for Hereditary Hearing Loss, the National Institute on Deafness and Other Communication Disorders (NIDCD), Hereditary Hearing Impairment Resource Registry (HHIRR), or the Boys Town Research Registry for Hereditary Hearing Loss.

The Boys Town Research Registry for Hereditary Hearing Loss

The Boys Town Research Registry for Hereditary Hearing Loss (Registry) is designed to foster a partnership between families, clinicians and researchers in the area of hereditary hearing loss/deafness through three primary functions. First, the Registry disseminates information to professionals and families about clinical and research issues related to hereditary deafness/hearing loss. Second, the Registry collects information from individuals interested in supporting and participating in research projects. This information is used to support the third function of the Registry - matching families with collaborating research projects.

For more information, contact us at:

Research Registry for Hereditary Hearing Loss
555 N. 30th Street Omaha, NE 68131
800 320-1171 (V/TDD)
402 498-6331 (FAX)