Results: Patient with a known MT-RNR1 genotype requiring aminoglycoside antibiotics

A five-year-old girl presents with gram-negative sepsis from a chest infection. She was diagnosed with cystic fibrosis during newborn screening and underwent genomic testing, which identified the MT-RNR1 1555A>G genetic variant. This predisposes her to aminoglycoside-induced hearing loss.

• In high doses, or with protracted dosing regimens, aminoglycosides are known to cause nephrotoxicity and ototoxicity, the latter of which can manifest as either vestibulotoxicity (balance disturbance) or cochleotoxicity (hearing loss).
• Variants in the MT-RNR1 gene can predispose an individual to ototoxicity after just a single dose of an aminoglycoside.
• Recent Clinical Pharmacogenetic Implementation Consortium (CPIC) guidelines have identified three MT-RNR1 variants that can cause aminoglycoside-induced hearing loss, meaning that aminoglycosides should be avoided:
  • 1555A>G (by far the most common MT-RNR1 variant, and therefore the most clinically relevant, with a population prevalence of around 1 in 500 in the UK);
  • 1494C>T; and
  • 1095T>C.

• The most recent CPIC guideline advises that any individual with the m.1555A>G, m.1494C>T or m.1095T>C variants should avoid aminoglycoside antibiotics unless the risk of permanent hearing loss is outweighed by the severity of infection and the lack of safe or effective alternative antimicrobial therapies.
• The clinician needs to consider the patient’s genotype in the context of their wider medical history, their concurrent medicines and the availability of safe and effective alternatives.
• Following the identification of a pharmacogenetic contraindication to aminoglycoside therapy, suitable alternative therapies should be discussed with the local microbiology and/or infectious diseases team where appropriate.
• MT-RNR1 variants are subject to mitochondrial inheritance, so families should be counselled that the variant may have been inherited from the patient’s mother (unless it arose de novo), and that female patients who have the variant will pass it on to all of their children. Families can be referred to their local clinical genetics service for counselling about the risk to relatives.

For clinicians

• Medicines and Healthcare products Regulatory Agency: Drug safety update: Aminoglycosides (gentamicin, amikacin, tobramycin, and neomycin): Increased risk of deafness in patients with mitochondrial mutations
• National Library of Medicine: Gentamicin therapy and MT-RNR1 genotype

References:

• McDermott JH, Wolf J, Hoshitsuki K and others. ‘Clinical Pharmacogenetics Implementation Consortium Guideline for the use of aminoglycosides based on MT-RNR1 genotype’. Clinical Pharmacology & Therapeutics 2022: volume 111, issue 2, pages 366–372. DOI: 10.1002/cpt.2309