Ototoxicidad y factores predisponentes / Ototoxicity and predisposing factors

Introducción: la pérdida auditiva inducida por fármacos ototóxicos se consideró un problema grave, frecuente, con repercusión en el quehacer diario de otorrinolaringólogos y pediatras. Se documentó ototoxicidad relacionada con aminoglucósidos y tratamientos antineoplásicos, salicilatos, quininas y algunos diuréticos. Objetivo: profundizar en los enfoques actuales más novedosos sobre ototoxicidad, factores de riesgo, predisposición genética y prevención. Métodos: estudio retrospectivo de la literatura escrita en idiomas español e inglés, de los reportes más interesantes y sugerentes publicados, sin límite de tiempo anterior, hasta Febrero de 2017, a través de búsqueda en línea por Internet, y bases de datos consultadas: Google, Cochrane y PubMed-Medline. Desarrollo: se obtuvo un total de más de 100 artículos. Los mecanismos exactos de ototoxicidad por aminoglucósidos y cisplatino, constituyeron un área activa de investigación. Se analizó la relación entre ototoxicidad y las caspasas 8,9 y 3, mediadores esenciales en la apoptosis de células ciliadas en la cóclea y la hipoacusia. Se describió la relación entre las mutaciones del gen MTRNR1, que codifica para la subunidad ribosomal 12s, y la pérdida auditiva por ototoxicidad. Se relacionó con hipoacusia y sordera mitocondrial no sindrómica, transmisión exclusivamente materna, e incremento en la susceptibilidad a la ototoxicidad por aminoglucósidos, factor clave predisponente. Consideraciones finales: los fármacos ototóxicos, inducen toxicidad coclear e hipoacusia bilateralmente simétrica, o asimétrica, en altas frecuencias, secundaria a destrucción irreversible de células ciliadas externas en el órgano de Corti. Nuevas investigaciones sobre cisplatino identifican la población susceptible, y pueden ofrecer alternativas de tratamiento menos agresivas. Se abordan criterios actuales sobre monitoreo audiológico y grados de ototoxicidad. La prevención implica una estricta (AU)

Introduction: hearing loss induced by ototoxic drugs was approached as a serious, frequent problem with an impact on the daily work of otolaryngologists and pediatricians. A review was conducted about the relationship of ototoxicity to aminoglycosides, antineoplastic treatments, salicylates, quinines and some diuretics. Objective: analyze the most updated current approaches about ototoxicity, risk factors, genetic predisposition and prevention. Methods: a retrospective review was conducted of the literature on the topic published in Spanish and English, as well as the most interesting and thought-provoking reports, from an open start date until February 2017, by means of a search on the Internet and in the databases Google, Cochrane and PubMed-MEDLINE. Results: more than 100 papers were obtained. The exact ototoxicity mechanisms by aminoglycosides and cisplatin were an area of active research. An analysis was made of the relationship between ototoxicity and caspases 8, 9 and 3, essential mediators in the apoptosis of ciliated cells in the cochlea, and hearing loss. A description is provided of the relationship between mutations of the MTRNR1 gene, which codifies for the ribosomal subunit 12s, and hearing loss by ototoxicity. A connection was established with hearing loss and mitochondrial nonsyndromic deafness, exclusively maternal transmission, and increased susceptibility to ototoxicity by aminoglycosides, a key predisposing factor. Final considerations: ototoxic drugs induce cochlear toxicity and bilaterally symmetric or asymmetric hearing loss at high frequencies, secondary to irreversible destruction of external ciliated cells in the organ of Corti. Recent research about cisplatin has identified the susceptible population, and may offer new, less aggressive treatment alternatives. Current criteria are presented about audiological surveillance and ototoxicity grades. Prevention implies strict surveillance(AU)

Mechanisms of Uniparental Mitochondrial DNA Inheritance in Cryptococcus neoformans

In contrast to the nuclear genome, the mitochondrial genome does not follow Mendelian laws of inheritance. The nuclear genome of meiotic progeny comes from the recombination of both parental genomes, whereas the meiotic progeny could inherit mitochondria from one, the other, or both parents. In fact, one fascinating phenomenon is that mitochondrial DNA in the majority of eukaryotes is inherited from only one particular parent. Typically, such unidirectional and uniparental inheritance of mitochondrial DNA can be explained by the size of the gametes involved in mating, with the larger gamete contributing towards mitochondrial DNA inheritance. However, in the human fungal pathogen Cryptococcus neoformans, bisexual mating involves the fusion of two isogamous cells of mating type (MAT) a and MATalpha, yet the mitochondrial DNA is inherited predominantly from the MATa parent. Although the exact mechanism underlying such uniparental mitochondrial inheritance in this fungus is still unclear, various hypotheses have been proposed. Elucidating the mechanism of mitochondrial inheritance in this clinically important and genetically amenable eukaryotic microbe will yield insights into general mechanisms that are likely conserved in higher eukaryotes. In this review, we highlight studies on Cryptococcus mitochondrial inheritance and point out some important questions that need to be addressed in the future.

Estudo de família brasileira portadora de deficiência auditiva sensorioneural não-sindrômica com herança mitocondrial / Study of a Brazilian family presenting non-syndromic hearing loss with mitochondrial inheritance

O presente estudo teve como objetivo descrever os achados audiológicos e genéticos de nove membros de uma família brasileira que apresenta a mutação no DNA mitocondrial. Todos os nove membros realizaram estudo genético, avaliação foniátrica e audiológica (audiometria tonal e logoaudiometria). O estudo genético revelou a presença de mutação mitocondrial A1555G no gene 12S rRNA (MT-RNR-1) do DNA mitocondrial em todos os sujeitos. Oito sujeitos apresentaram deficiência auditiva e somente um apresentou limiares auditivos normais até o término da realização do estudo. Os resultados audiológicos apontaram para perdas auditivas bilaterais, com prevalência das simétricas, de configurações e graus variados (de moderado a profundo) e pós-linguais. Progressão da perda auditiva foi observada em dois irmãos afetados. Não foi possível afirmar a época do início da perda auditiva por falta de informação dos sujeitos, no entanto, observou-se manifestação da perda em crianças e adultos. As mutações no DNA mitocondrial representam uma causa importante de perda auditiva, sendo imprescindível a realização do diagnóstico etiopatológico, a fim de retardar o início ou evitar a progressão da surdez.

We hereby report on the audiological and genetic findings in individuals from a Brazilian family, with the following mitochondrial mutation A1555G in the 12SrRNA gene (MT-RNR-1). Nine individuals underwent speech, audiologic (tonal audiometry and logoaudiometry) and genetic evaluations. Eight individuals among the A1555G carriers were affected by hearing impairment and one person had normal hearing thresholds till the end of the present study. The audiologic evaluation results indicated normal hearing thresholds all the way to bilateral profound hearing loss with post-lingual onset and variable configuration. Two affected siblings presented progressive hearing loss. It was impossible to precise the time of hearing loss onset; however, the impairment was present in both children and adults. The genetic study revealed the A1555G mitochondrial mutation in the 12SrRNA gene. Given the prevalence of mitochondrial mutations as a cause of hearing loss, it is fundamental to perform the etiopathologic diagnosis in order to postpone the onset or avoid hearing impairment progression. This kind of hearing impairment represents a challenge to the professionals since there are no physical traits that indicate genetic transmission.