Inherited susceptibility to aminoglycoside ototoxicity: Genetic heterogeneity and clinical implications

Purpose: Aminoglycoside-induced ototoxicity appears to have a genetic susce ptibility in some individuals, and the A1555G mutation in the mitochondrial 12S ribosomal RNA gene has been shown to be responsible for this susceptib ility in all familiar cases. An Italian family with 5 family members who be came deaf after aminoglycoside exposure presented to us, and molecular anal ysis excluded the A1555G mutation. The purpose of this study is to identify the molecular basis for the aminoglycoside susceptibility in this family. Patients and Methods: Two sisters and three of their children developed sev ere to profound high-frequency hearing loss after aminoglycoside exposure. DNA was extracted from the blood of these individuals and their unaffected relatives, and analyzed for mitochondrial DNA mutations. The region around nucleotide 961 was also cloned and individual clones were sequenced. Results: Sequencing of the 12S ribosomal RNA gene revealed a thymidine dele tion at position 961, with a complex pattern of sequence around this mutati on. Sequencing of individual clones around the 961 mutation demonstrated a varying number of inserted cytosines in different mitochondrial molecules. Conclusion: This family establishes the nucleotide 961 thymidine deletion a ssociated with a varying number of inserted cytosines in the mitochondrial 12S ribosomal RNA gene as the second pathogenic mutation that can predispos e to aminoglycoside ototoxicity. It demonstrates the clinical relevance of taking a family history before administering aminoglycosides to any patient . In addition, it would be desirable for sporadic patients with aminoglycos ide-induced hearing loss to be screened with molecular tests for the presen ce of the 1555 and 961 mutations. Such screening could significantly decrea se the prevalence of aminoglycoside-induced hearing loss. Copyright (C) 199 9 by W.B. Saunders Company.