by A. L. Del Tredici

Pathway‘s drug response panel includes aminoglycoside antibiotics and risk of hearing loss.  This phenotype may be of particular interest to couples planning a pregnancy.

The 1555 mutation and risk of antibiotic-induced hearing loss

For more than 60 years, aminoglycoside antibiotics such as streptomycin, gentamicin, neomycin, paromomycin, kanamycin, amikacin, netilmicin and tobramycin have been widely used, and continue to be used, especially in developing countries, for the treatment of severe bacterial infections. However, aminoglycoside use also carries the risk of hearing loss (also known as ototoxicity).

Pathway tests for a mtDNA mutation, called 1555A>G, which is the most frequent cause of inherited aminoglycoside-induced ototoxicity. The “1555 mutation” occurs in all ethnic groups and has been found to occur in approximately 1 of every 500 people of European descent (PMID 19196684, PMID 19196685). Newborn screening for the 1555 mutation has been suggested in China, where aminoglycoside antibiotics are more commonly used (PMID 21324532, PMID 21329993).

Pathway screens for a mutation in mtDNA, called 1555A>G, which is the most frequent cause of inherited aminoglycoside-induced hearing loss.

There are other mutations that are associated with antibiotic-induced hearing loss, but the 1555 mutation is the most prevalent. Carriers of the 1555 mtDNA mutation who undergo even a single course of aminoglycoside antibiotic therapy can suffer a severe and irreversible loss of hearing (PMID 20301595).

There is no report of a 1555 mutation carrier receiving aminoglycosides and not suffering a significant loss of hearing.

For individuals that carry the 1555 mutation, the recommended action is simple. Avoid aminoglycoside antibiotics. There are many alternatives to aminoglycoside antibiotics, and your physician can decide which is best for you.

There is no report of a 1555 mutation carrier receiving aminoglycosides and not suffering a significant loss of hearing.

However, individuals who carry the 1555 mutation and avoid aminoglycoside antibiotics are still at some risk of hearing loss.A few 1555A>G carriers who were not exposed to aminoglycoside antibiotics have developed hearing loss, suggesting that there might also be other environmental or genetic “triggers” that cause hearing loss in carriers (PMID 20301595).

Why is the 1555 mutation important for prospective mothers?

If you are female and pregnant or planning a pregnancy, we encourage you to be tested for this mutation. If you are female and your test results show that you carry the 1555 mutation, your child is likely to inherit the mutation.

In the US, aminoglycoside antibiotics are often prescribed in the neonatal intensive care unit to treat newborns with bacterial infections (PMID 15846011). For a newborn that carries the 1555 mutation, the risk of hearing loss can be avoided, simply by prescribing a different type of antibiotic (PMID 19192037).

Male carriers, on the other hand, will not pass the 1555 mutation on to their children. The 1555 mutation is mitochondrial and thus is transmitted maternally.

How does the 1555 mutation and aminoglycoside use cause hearing loss?

Aminoglycoside antibiotics wield their antibacterial effects by binding to bacterial ribosomes, the protein making machinery in cells, and thus disrupting protein synthesis in the bacteria.  Even though these antibiotics are usually administered so that all the cells in the body are exposed, they tend to accumulate in the fluids of the inner ear (PMID 3044302).

The 1555 mutation occurs in a molecule that is part of the mitochondrial ribosomes in the hair cells of the inner ear – these are the cells that sense sound vibrations, and allow you to hear. The 1555 mutation permits aminoglycoside antibiotics to bind to hair cell mitochondrial ribosomes, where they disrupt protein synthesis (PMID 19687236, PMID 18308926). The disruption in protein synthesis leads to the death of the hair cells in the inner ear, and eventually, irreversible hearing loss.

Genetic testing can help you or your child avoid hearing loss

Testing for the 1555 mutation is not currently part of any standard newborn or fetal screening test.  Pathway’s test for the 1555 mutation can give you actionable information about your risk of aminoglycoside-induced hearing loss. If you are female, testing for the 1555 mutation can also give you information about your child’s risk of aminoglycoside-induced hearing loss.

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