You ever heard of a child going deaf after a single dose of Gentamicin? It's more common than you think and it happens regrettably too late to do anything about it, as a single dose of gentamicin can cause permanent deafness in these children.
It happens in 1250 newborns every year in the United Kingdom.
These unfortunate children are 0.2 of the population, who carry a specific mitochondrial DNA mutation.
Remember, mitochondria have a circular DNA comprised of 16,569 base pairs (as opposed to the linear nuclear DNA, which is comprised of 3.3 billion base pairs). The mitochondrial DNA contains 37 genes, which code for 13 proteins, 22 tRNAs, and 2 ribosomal RNAs.
One of those two rRNAs is coded by a mitichondrial gene called MT-RNR1. If a child has a single nucleotide polymorphism, m.1555A>G (which means at the 1555th mitochondrial base pair, adenine has been replaced by guanine), he or she is exquisitely sensitive to the ototoxic effects of Gentamicin, and can develop permanent and catastrophic deafness after a single dose of gentamicin.
This is clearly a problem, as the UK, like many other countries, has guidelines which recommend that the empirical treatment of neonatal sepsis should be with a combination of gentamicin and benzylpenicillin. Moreover, NICE guidance also stipulate that any suspected sepsis must be treated within 1 hour of diagnosis, given its usually severe consequences.
But how do you test for a mitochondrial mutation within 1 hour? Standard genetic tests take hopelessly long.
Well, it seems that the pandemic has tought us a trick or two. At the Manchester Centre for Genomic Medicine, they have developed a point of care test (POCT) using the same technique used for COVID19- PCR amplification- that gives a result within 26 minutes of taking a gum swab from a newborn.
Those testing positive on the POCT are then confirmed with standard (old fashioned) Sanger sequencing and receive Cefotaxime rather than the combination of gentamicin and benzylpenicillin. No deafness!
And how does gentamicin cause deafness in this children? Well, gentamicin kills bacteria by binding to their 16S rRNA and preventing bacterial protein synthesis. In children who have the m1555A>G mutation in their MT-RNR1 mitochondrial gene, the normally eucaryotic 12S rRNA assumes a shape like the bacterial 16S rRNA, and thus binds to gentamicin.
The test has been provisionally approved by NICE, and is currently being piloted prior to a national rollout.
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