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Abstract
Background The mitochondrial DNA mutation m.1555A>G predisposes to permanent idiosyncratic aminoglycoside-induced deafness that is independent of dose. Research suggests that in some families, m.1555A>G may cause non-syndromic deafness, without aminoglycoside exposure, as well as reduced hearing thresholds with age (age-related hearing loss).
Objectives To determine whether adults with m.1555A>G have impaired hearing, a factor that would inform the cost–benefit argument for genetic testing prior to aminoglycoside administration.
Design Population-based cohort study.
Setting UK.
Participants Individuals from the British 1958 birth cohort.
Measurements Hearing thresholds at 1 and 4 kHz at age 44–45 years; m.1555A>G genotyping.
Results 19 of 7350 individuals successfully genotyped had the m.1555A>G mutation, giving a prevalence of 0.26% (95% CI 0.14% to 0.38%) or 1 in 385 (95% CI 1 in 714 to 1 in 263). There was no significant difference in hearing thresholds between those with and without the mutation. Single-nucleotide polymorphism analysis indicated that the mutation has arisen on a number of different mitochondrial haplogroups.
Limitations No data were collected on aminoglycoside exposure. For three subjects, hearing thresholds could not be predicted because information required for modelling was missing.
Conclusions In this cohort, hearing in those with m.1555A>G is not significantly different from the general population and appears to be preserved at least until 44–45 years of age. Unbiased ascertainment of mutation carriers provides no evidence that this mutation alone causes non-syndromic hearing impairment in the UK. The findings lend weight to arguments for genetic testing for this mutation prior to aminoglycoside administration, as hearing in susceptible individuals is expected to be preserved well into adult life. Since global use of aminoglycosides is likely to increase, development of a rapid test is a priority.
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This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
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Footnotes
To cite: Rahman S, Ecob R, Costello H, et al. Hearing in 44–45-year-olds with m.1555A>G, a genetic mutation predisposing to aminoglycoside-induced deafness: a population-based cohort study. BMJ Open 2012;2:e000411. doi:10.1136/bmjopen-2011-000411
Funding This work was supported by a grant from Sparks, the Children's Medical Research Charity and by a Summer Studentship from the Royal National Institute for Deaf People (now Action on Hearing Loss). Research at the University College London Institute of Child Health and Great Ormond Street Hospital for Children National Health Service Trust benefits from R&D funding received from the National Health Service Executive. MB-G and SR are supported by Great Ormond Street Hospital Children's Charity. The researchers were independent of the funders. The organisations responsible for funding had no role in the design or conduct of the study or in collection, analysis and interpretation of data or preparation, review or approval of this manuscript. The authors had full access to all data and had final responsibility for the decision to submit for publication.
Competing interests None.
Ethics approval SouthEast Multi-Centre Research Ethics Committee.
Contributors SR and MB-G were responsible for inception and design of the study, for data collation, analysis of the molecular genetic data and writing the manuscript. RE and AD were responsible for statistical analysis of the audiometric data. HC, MGS and AJD were responsible for confirmation of mutation status and GeneChip analysis, which was performed by KP. DS was responsible for data linkage and AF helped to formulate the hypothesis. All authors read and approved the final version and were involved in critical revision of the manuscript. SR and MB-G are guarantors.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Complete mitochondrial DNA resequence data of all 19 individuals with the m.1555A>G mutation are attached as a supplementary file.