Голландские неонатологи за 30 минут выявляют генетический риск глухоты у недоношенных детей до начала лечения антибиотиками

In neonatology, every minute counts. When a premature infant is admitted to the ICU with symptoms suggestive of infection, waiting for microbiological results before starting antibiotic therapy is simply not an option. Gentamicin, a standard aminoglycoside antibiotic in this context, is administered rapidly, often as first-line therapy. It is precisely within this high-pressure therapeutic window that the initiative launched by Erasmus University Medical Center in Rotterdam, Netherlands, aligns well with the article’s broader theme: identifying, in less than half an hour, newborns carrying a genetic mutation that puts them at high risk for permanent hearing loss when treated with this antibiotic. A Vulnerability Encoded in Mitochondrial DNA It all hinges on a variant of the MT-RNR1 gene, which encodes 12S mitochondrial ribosomal RNA. In individuals carrying the m.1555A>G mutation, this RNA adopts a conformation that structurally resembles bacterial ribosomal RNA, the natural target of aminoglycosides. As a result, gentamicin can bind to the mitochondrial ribosomes of the hair cells in the inner ear with abnormally high affinity. The consequences are potentially devastating: profound and irreversible sensorineural hearing loss, sometimes occurring after a single dose. The prevalence of this variant is estimated at approximately 1 in 330 births. A seemingly modest figure, but one that takes on a whole new significance in a unit that admits 400-500 premature infants per year. Permanent hearing loss has significant personal and financial consequences. Now that a test exists to prevent it, I believe it is our ethical responsibility to use it, stated Ron H.N. van Schaik, PhD, professor of pharmacogenetics at Erasmus University Medical Center. Evidence From 751 Newborns The idea did not originate in Rotterdam. It was validated across the Channel as part of the PALOH study, published in 2022 in JAMA Pediatrics. In this prospective trial, conducted in two British neonatal units, 751 newborns were enrolled. A simple buccal swab was used to screen for the m.1555A>G variant using the Genedrive MT-RNR1-ID kit (a rapid point-of-care test). Results were available within 26 minutes. Three carrier newborns were identified, and none received an aminoglycoside. But the finding that drew the most attention from neonatologists was this: Before the test was introduced, antibiotics were given after an average of 55 minutes and 87 seconds. During the study, that time was 55 minutes and 18 seconds — a difference of less than 1 minute. In a setting long thought too time-sensitive for pharmacogenetics, the study showed that real-time implementation in intensive care was clinically feasible. International Recommendations Already in Place The link between MT-RNR1 variants and the ototoxicity of aminoglycosides is now sufficiently well documented to form the basis for official recommendations. The Clinical Pharmacogenetics Implementation Consortium identifies three risk variants — m.1555A>G, m.1494C>T, and m.1095T>C — and recommends avoiding aminoglycosides in carriers unless absolutely necessary for treatment. In the latter case, the duration of exposure should be minimized, with close therapeutic monitoring and hearing surveillance. In the UK, the National Institute for Health and Care Excellence (NICE) took a further step in 2023 by approving the use of the Genedrive test in newborns likely to receive an aminoglycoside, while recommending that positive results be confirmed by laboratory analysis and that data collection on its clinical impact continue. A Mutation That Also Affects the Family The pharmacogenetic aspect of this screening involves a distinctive feature that goes beyond the usual framework of antibiotic decision-making: The m.1555A>G variant is located in mitochondrial DNA, which is transmitted exclusively from mother to child. Detecting this variant in a premature infant may indicate a susceptibility shared by the child’s mother, maternal uncles and aunts, and maternal grandparents. NICE draws a logical conclusion from this: Parents must be informed of the implications of a positive result beyond just the affected child. This information may ultimately lead to changes in aminoglycoside prescribing practices throughout the maternal branch of the family. And in Belgium? To date, no Belgian national recommendation provides for systematic screening for MT-RNR1 variants prior to the administration of gentamicin in neonates. This does not preclude local initiatives at certain university hospitals, but the approach remains nonstandardized. The British experience, now extended by the Rotterdam initiative, clearly illustrates a structural shift in pharmacogenetics: It is no longer bound to come after a decision has been made. When a genotype can be determined in less than 30 minutes, it becomes a clinical tool in its own right, capable of being integrated into even the most restricted emergency protocols. For Belgian neonatal units, the question may no longer be whether this screening is feasible — the PALOH study has demonstrated that it is — but rather when it will become routine, provided that it is not too costly. This story was translated from MediQuality, part of the Medscape Professional Network.