Clinical Information

Aminoglycosides (tobramycin, streptomycin, and gentamicin, etc) are a group of broad-spectrum antibiotics commonly prescribed for infections caused by Gram-negative bacteria. In the United States alone, approximately 4 million courses of aminoglycosides are administered each year with approximately 2% to 5% of patients treated developing clinically significant hearing loss. Mitochondrial gene RNR1 (MT-RNR1) variants m.1555A>G and m.1494C>T are the most common variants associated with aminoglycoside-induced ototoxicity. Hearing loss associated with aminoglycoside exposure can occur even after a single dose and may be bilateral, irreversible, and often severe to profound. Avoidance of aminoglycoside antibiotics reduces the risk of developing hearing loss for individuals carrying one of these 2 variants.

The severity and onset of hearing loss in individuals with the associated pathogenic mitochondrial variants range from profound congenital deafness to mild to moderate late-onset hearing loss. Evidence demonstrates that this variance can often be explained by variant load in an individual. In contrast to variants in nuclear genes, which are present in either 0, 1, or 2 copies, mitochondrial variants can be present in any fraction of the total organelles, a phenomenon known as heteroplasmy. Penetrance of hearing loss without exposure to aminoglycosides is thought to be a function of the degree of heteroplasmy, with a correlation between higher fraction of altered mitochondria and higher penetrance. Hearing loss is believed to be 100% penetrant in homoplasmic individuals who receive aminoglycoside antibiotics.