Case study
Absence of hypersensitivity to the ototoxic effect of gentamicin in a patient carrying the 1555A>G mutation in the MT-RNR1 gene
Ausencia de hipersensibilidad al efecto ototóxico de la gentamicina en un paciente portador de la mutación 1555A>G en el gen MT-RNR1
a Servicio de Anestesiología y Reanimación, Otorrinolaringología, Hospital Universitario Marqués de Valdecilla Hospital, Santander, Cantabria, Spain
b Servicio de Radiodiagnóstico, Hospital Universitario Marqués de Valdecilla, Santander, Cantabria, Spain
c Servicio de Otorrinolaringología, Hospital Universitario Marqués de Valdecilla, Santander, Cantabria, Spain
d IDIVAL, Santander, Cantabria, Spain
e Facultad de Medicina, Universidad de Cantabria, Santander, Spain
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The pure tone audiometry performed is shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>. At the age of 16 he was admitted to hospital following a motorbike accident, in which he fractured his right clavicle. During admission he was treated intravenously with 2<span class="elsevierStyleHsp" style=""></span>g cefazolin every 8<span class="elsevierStyleHsp" style=""></span>h and 120<span class="elsevierStyleHsp" style=""></span>mg gentamicin every 12<span class="elsevierStyleHsp" style=""></span>h, up to a total of 10 doses of gentamicin. The patient did not notice any change in hearing as a consequence of this episode. Five years later the patient was seen in an ENT consultation, as six months earlier his mother had undergone a genetic study, which found her to be a carrier of the 1555A<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>G mutation, and an offer was made to extend the study to more members of the family. The pure-tone audiometry performed at this consultation did not show any variations from the previous test (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). The patient was found to be a carrier of this mutation.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Discussion</span><p id="par0010" class="elsevierStylePara elsevierViewall">Aminoglycoside ototoxicity is a common cause of acquired deafness. Administration of aminoglycosides at high doses and for prolonged periods results in cochlear and vestibular damage in most individuals. However, there is a genetic component that determines greater susceptibility to the ototoxic effect of low doses of these antibiotics.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Aminoglycosides exert their bactericidal effect by binding to 16S ribosomal ribonucleic acid (rRNA) in the 30S subunit of the bacterial ribosome, which hinders protein synthesis.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> In humans, mitochondrial ribosomes are more similar to bacterial ribosomes than cytoplasmic ribosomes.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> It appears that the 1555A<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>G mutation increases the similarity between human 12S rRNA and bacterial 16S rRNA, leading to an increase in aminoglycoside binding affinity, which would alter protein synthesis in mitochondria.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Aminoglycosides reach high concentrations in the endolymph and perilymph, which would explain the onset of adverse reactions in the inner ear.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> The aminoglycoside most frequently described as responsible for hearing loss in individuals that carry the 1555A<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>G gene is streptomycin.<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4,6–8</span></a> In some cases it has been linked to dihydrostreptomycin,<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> or to isepamycin,<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> while numerous studies do not establish the aminoglycoside involved.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,8,11–13</span></a> Aminoglycosides are divided into two groups according to the type of central aminocyclitol ring they possess (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">Once inside bacteria, all aminoglycosides inhibit protein synthesis, although there are differences between them according to the type of central ring they contain. The ribosome binding sites vary between them, as evidenced by the lack of competition between aminoglycosides from both groups.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> The explanation for our patient’s hearing loss not progressing after treatment with gentamicin treatment could be that the 1555A<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>G mutation does not affect the site where gentamicin interacts with the mitochondrial ribosome, and therefore does not increase susceptibility to the ototoxic effect of this aminoglycoside. However, for isepamicin, which is a derivative of gentamicin, two cases of worsening hearing have been reported.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The fact that our patient had no change in hearing despite treatment with 10 doses of gentamicin, and that this mutation has been found in 1 in 500 Caucasians in 3 different studies,<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15–17</span></a> (in other words, it is a relatively frequent mutation), and that almost all published cases of patients with this mutation and aminoglycoside ototoxicity have been related to streptomycin dihydrostreptomycin,<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18–20</span></a> despite the much more frequent use of gentamicin in daily clinical practice, makes us suspect that hypersensitivity to the ototoxic effect of aminoglycosides in carriers of the 1555A<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>G mutation of the MT-RNR1 gene may be variable depending on the type of aminoglycoside. Studies in large series of patients with this mutation are needed to help clarify which type of aminoglycosides are involved in the development of hearing loss in these patients and to identify other factors that could modify the hearing phenotype of these patients.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Conflict of interests</span><p id="par0025" class="elsevierStylePara elsevierViewall">The authors have no conflict of interests to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Clinical case" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Discussion" ] 2 => array:2 [ "identificador" => "sec0015" "titulo" => "Conflict of interests" ] 3 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2023-01-17" "fechaAceptado" => "2023-03-11" "multimedia" => array:2 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 691 "Ancho" => 1508 "Tamanyo" => 109874 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0265" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Audiograms (airway) of the patient, at 8 and 21 years of age.</p>" ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0270" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Aminocyclitol central ring: streptidine \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Streptomycin, dihydrostreptomycin, spectinomycin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Aminocyclitol central ring: 2-deoxystreptamine Kanamycin family: kanamycin, amikacin, tobramycin, dibekacin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Gentamycin family: gentamycin, sisomycin, netilmicin, isepamicin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neomycin family: neomycin, paromomycin \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3359377.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Classification of aminoglycosides.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:20 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Unique inheritance of streptomycin-induced deafness" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "K. 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