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Mitochondrial gene mutation is a significant predisposing factor in aminoglycoside ototoxicity
N Fischel-Ghodsian1, T R Prezant, W E Chaltraw
1Ahmanson Department of Pediatrics, Steven Spielberg Pediatric Research Center, Cedars-Sinai Research Institute, Los Angeles, CA 90048, USA. nfischel@mailgate.csmc.edu
Purpose:
Aminoglycoside-induced deafness caused by mutations in the mitochondrial 12S ribosomal RNA gene has been described in a number of Asian patients. The purpose of the current study is to analyze ethnically diverse patients in the United States with hearing loss after aminoglycoside exposure for presence or absence of these mitochondrial DNA mutations, and establish the frequency and clinical presentation associated with them.
Patients And Methods:
Clinical histories, medical records, and blood samples were obtained from 41 unrelated American individuals with hearing loss after aminoglycoside exposure. DNA was extracted from the blood of these individuals, amplified by the polymerase chain reaction, and analyzed for mitochondrial ribosomal RNA gene mutations by allele-specific oligonucleotide hybridization, restriction fragment length polymorphism analysis, and sequencing.
Results:
The nucleotide 1555 A-->G mutation was identified in 7 of 41 individuals (17%). None of the other known mutations was found. The ethnic origin of the individuals with predisposing mutations included Caucasians, Hispanics, and Asians. Four of the 7 patients with the 1555 A-->G mutation had a family history of aminoglycoside-induced ototoxicity. Particularly unexpected was the late onset of hearing loss in 3 of these patients, years after the aminoglycoside exposure. The 12S ribosomal RNA gene was sequenced in these patients, and a second sequence change that could be responsible for the milder phenotype was detected in 1 of the 3 patients.
Conclusion:
These findings imply that a significant proportion of patients with aminoglycoside-induced ototoxicity harbor mutations in the 12S rRNA gene, which can be detected by DNA screening. Also, the majority of these hearing losses could have been easily prevented by the simple taking of a clinical history. In these individuals, a genetic susceptibility to the ototoxic effects of aminoglycosides can be diagnosed, and deafness can be prevented in maternal relatives by avoidance of these antibiotics.