Correspondence
Prevalence of Mitochondrial 1555A→G Mutation in European Children
N Engl J Med 2009; 360:640-642February 5, 2009
- Article
To the Editor:
Aminoglycoside antibiotics are used worldwide to treat gram-negative sepsis. Since these drugs are ototoxic and nephrotoxic, drug levels are closely monitored. However, their effect on patients with the mitochondrial DNA mutation m.1555A→G is dramatic. Carriers of this mutation have permanent, profound hearing loss after receiving aminoglycosides, even when drug levels are within the therapeutic range.1,2 A review of previous studies indicates that after aminoglycoside exposure, penetrance of deafness in this population is close to 100%.3
Estimates of the prevalence of the m.1555A→G mutation have been hampered because of the small numbers of patients in such studies, many of which have involved the ascertainment of either one or a few patients. We genotyped the m.1555A→G variant in the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort, a cohort of children who were not selected for hearing loss (www.bristol.ac.uk/alspac).4 Pure-tone audiometry and tympanometry were performed prospectively in children at ages 7 and 9 years. Of 9371 children who were tested, 18 had the m.1555A→G mutation, providing a population prevalence of 1 in 520, or 0.19% (95% confidence interval, 0.10 to 0.28) (for details, see the Supplementary Appendix, available with the full text of this letter at NEJM.org). The children with the mutation all had hearing thresholds in the clinically normal range at 9 years, indicating that only genetic testing could have revealed those at risk for deafness (Figure 1Figure 1
Results of Pure-Tone Audiometry in Children with the m.1555A→G Genotype.). (See the Supplementary Appendix for details regarding hearing thresholds and tympanometry results for the entire cohort.)None of the children had a history of admission to a neonatal intensive care unit, where children most commonly receive aminoglycosides. This finding is consistent with a lack of penetrance of the mutation in this cohort.
On the basis of a mutation frequency of 0.19% in this population, genetic screening before aminoglycoside administration is cost-effective when balanced against the costs of lifelong deafness or the need for cochlear implantation.5 In this issue of the Journal, a letter by Vandebona et al.6 reports a prevalence of 0.21% for the m.1555A→G mutation in an aging population of European descent, but the prevalence of the mutation in non-European populations is unknown. Clearly, robust studies involving other ethnic groups are required to determine whether screening is appropriate.
On the basis of our findings, we recommend that elective genetic testing be performed on a case-by-case basis to prevent hearing loss, although in an acute, life-threatening situation, the best interests of the patient may require the administration of aminoglycosides before the results of genetic testing are available. Children with leukemia and patients with tuberculosis could be tested at diagnosis, and those allergic to beta-lactam antibiotics could be tested in the surgical outpatient department. Universal screening of neonates would not be effective in preventing 100% of deafness related to m.1555A→G, since admission to a neonatal intensive care unit usually occurs before such screening could take place. Screening all pregnant women for the mutation would be an alternative approach, since the mutation is maternally inherited and is almost always homoplasmic. Such an approach would not detect low levels of heteroplasmy.
Maria Bitner-Glindzicz, F.R.C.P., Ph.D.
Marcus Pembrey, F.R.C.P., F.Med.Sci.
Andrew Duncan, Ph.D.
UCL Institute of Child Health, London WC1N 1EH, United Kingdom
mbitnerg@ich.ucl. ac. uk Jon Heron, Ph.D.
Susan M. Ring, Ph.D.
Amanda Hall, Ph.D.
University of Bristol, Bristol BS8 1TH, United KingdomShamima Rahman, F.R.C.P.C.H., Ph.D.
MRC Centre for Neuromuscular Diseases, London WC1N 3BG, United KingdomSupported by a grant from Sparks, the Children's Medical Research Charity. The U.K. Medical Research Council, the Wellcome Trust, and the University of Bristol provide core support for ALSPAC.
6 References1
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Full Text | Web of Science | Medline
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