Biology Reference
In-Depth Information
gene (Fischel-Ghodsian et al. 1997a). When compared with controls, the
results indicated that at least a proportion of people with presbycusis have
a significant load of mtDNA mutations in auditory tissue, and that there is
great individual variability in both quantity and cellular location of these
mutations. Similar data were obtained by Bai et al. (1997) when screening
cochlear tissue from temporal bones for the presence of large deletions,
although the ages of the presbycusis and control groups were not well
matched. The greatest advantage of studying acquired mutations in the ear
relates to the availability of temporal bone tissue banks, through which
functional audiological data are available. Thus, measurable functional
status, histology, immunohistochemistry of oxidative phosphorylation com-
plexes, and mtDNA analysis can be correlated.
There are, however, two problems with the mtDNA data from patients
with presbycusis. One problem relates to the fact that a sufficient number
of patients has not yet been examined to draw the firm conclusion that there
is indeed a clear difference between presbycusis patients and normal-
hearing controls of the same age. Part of the problem is that temporal bone
libraries have only the very rare patient with documented normal hearing
and advanced age. But even if the data will eventually unequivocally show
that presbycusis patients as a group have an increased number of mtDNA
mutations, the second problem is one of causality. Are these mutations the
cause or the result of the cochlear process leading to presbycusis? Two
models are possible. The first model assumes that some genetic and/or envi-
ronmental factors combine to cause acquired mtDNA mutations, which
then lead to hearing loss. This would imply a primary causative role for
mtDNA mutations. Alternatively, it is possible that the genes and environ-
ment cause presbycusis directly, and that the resulting cell death and
response mechanisms lead to increased oxygen radicals and an increased
rate of mtDNA mutations. In this case, the mtDNA mutations would only
be a sign of presbycusis, but not a cause. To differentiate between these two
models, it is necessary to use animal models in which the temporal rela-
tionship between mutations and hearing loss can be studied, as well as the
response to specific interventions.
4. Clinical Relevance of Mitochondrial DNA Mutations
Associated with Hearing Impairment
The major clinical relevance of mtDNA mutations to hearing loss remains
the prevention of aminoglycoside-induced hearing loss. In countries where
aminoglycosides are used commonly, aminoglycoside-induced ototoxicity is
a major cause of hearing loss. For example, in a study that reviewed all deaf-
mutes in a district of Shanghai, 21.9% had aminoglycoside-induced hearing
loss, representing 167 individuals in a population of nearly half a million
(Hu et al. 1991). The A1555G mutation accounted for at least 30% of these.
In the United States, the A1555G mutation accounts for about 15% of all
