Biology Reference
In-Depth Information
aminoglycoside-induced deafness cases (Fischel-Ghodsian et al. 1997b).
The difference in frequency may reflect the fact that aminoglycosides are
generally used in the United States only for severe in-hospital infection.
These patients receive significantly higher levels for more prolonged
periods, and are more likely to have other medical conditions that cause or
exacerbate the hearing loss. The frequency of the DT961Cn predisposing
mutation is unknown, but it appears to be significantly lower.
Whatever the precise frequency, prevention of a major cause of
aminoglycoside-induced ototoxicity is now possible. Physicians need to
inquire about a family history of aminoglycoside-induced hearing loss prior
to the administration of systemic aminoglycosides, as well as prior to the
local administration of aminoglycosides into the cochlea as a treatment
for Meniere's disease. In addition, every individual with aminoglycoside-
induced hearing loss should probably be screened at least for the presence
of the G1555A and DT961Cn mutations because presence of a mutation
will allow counseling to all maternally related relatives to avoid aminogly-
cosides. Similarly, the study by Estivill et al. (1998) indicates that it might
be reasonable to screen every individual with nonsyndromic hearing loss
for the mutation, unless maternal inheritance can clearly be excluded.
Because the test is easily done, and prevention of hearing loss in maternal
relatives can easily be accomplished, this may be cost-effective medical
practice. The tragic and avoidable hearing loss of at least forty patients in
the report by Estivill et al. (1998) is a case in point.
With the exception of not administering aminoglycosides to patients with
mtDNA mutations in the
12S
rRNA gene, there are no proven preventive
or therapeutic interventions for mitochondrially related hearing impair-
ments. The diagnosis of such defects is, however, useful for genetic coun-
seling (Arnos and Oelrich, Chapter 9) and is indicated in all families with
an inheritance pattern of hearing loss that is consistent with maternal trans-
mission, and possibly in all patients who have both diabetes mellitus and
adult-onset hearing loss.
5. Pathophysiology of Mitochondrial DNA
Deafness Mutations
For aminoglycoside ototoxicity due to the A1555G mutation, it is interest-
ing to notice that this mutation lies exactly in the region of the gene for
which the resistance mutations in yeast and
Tetrahymena
have been
described, and in which aminoglycoside binding has been documented in
bacteria (Li et al. 1982; Spangler and Blackburn 1985; Gravel et al. 1987).
In addition, the mutation makes the mitochondrial RNA gene in this region
more similar to the bacterial ribosomal RNA gene (Prezant et al. 1993).
Because aminoglycosides are concentrated within cochlear cells, and
remain there for prolonged periods (Henley and Schacht 1988), it has been
