A genome-wide association study of a rage-related misophonia symptom and the genetic link with audiological traits, psychiatric disorders, and personality

Introduction: People with misophonia experience strong negative emotional responses to sounds and associated stimuli—mostly human produced—to an extent that it may cause impairment in social functioning. The exact nature of the disorder remains a matter of ongoing research and debate. Here, we investigated the genetic etiology of misophonia to understand contributing genetic factors and shed light on individual differences in characteristics that are related to the disorder. Methods: For misophonia, we used an unpublished genome-wide association study (GWAS) from genetic service provider 23andMe, Inc., on a self-report item probing a single common misophonic symptom: the occurrence of rage when others produce eating sounds. First, we used gene-based and functional annotation analyses to explore neurobiological determinants of the rage-related misophonia symptom. Next, we calculated genetic correlations (r G) of this rage-related misophonia symptom GWAS with a wide range of traits and disorders from audiology (tinnitus, hearing performance, and hearing trauma), psychiatry, neurology, and personality traits. Results: The rage-related misophonia symptom was significantly correlated with tinnitus, major depression disorder (MDD), post-traumatic stress disorder (PTSD), and generalized anxiety disorder (GAD; 0.12 < r G < 0.22). Stronger genetic correlations (0.21 < r G < 0.42) were observed for two clusters of personality traits: a guilt/neuroticism and an irritability/sensitivity cluster. Our results showed no genetic correlation with attention deficit and hyperactivity disorder, obsessive-compulsive disorder, and psychotic disorders. A negative correlation with autism spectrum disorder (ASD) was found, which may be surprising given the previously reported comorbidities and the sensory sensitivity reported in ASD. Clustering algorithms showed that rage-related misophonia consistently clustered with MDD, generalized anxiety, PTSD, and related personality traits. Discussion: We conclude that—based on the genetics of a common misophonia symptom—misophonia most strongly clusters with psychiatric disorders and a personality profile consistent with anxiety and PTSD

Aminoglycoside- and glycopeptide-induced ototoxicity in children: a systematic review

Background: Ototoxicity has been reported after administration of aminoglycosides and glycopeptides. Objectives: To identify available evidence for the occurrence and determinants of aminoglycoside- and glycopeptide-related ototoxicity in children. Materials and methods: Systematic electronic literature searches that combined ototoxicity (hearing loss, tinnitus and/or vertigo) with intravenous aminoglycoside and/or glycopeptide administration in children were performed in PubMed, EMBASE and Cochrane Library databases. Studies with sample sizes of ≥50 children were included. The QUIPS tool and Cochrane criteria were used to assess the quality and risk of bias of included studies. Results: Twenty-nine aminoglycoside-ototoxicity studies met the selection criteria (including 7 randomized controlled trials). Overall study quality was medium/low. The frequency of hearing loss within these studies ranged from 0%-57%, whereas the frequency of tinnitus and vertigo ranged between 0%-53% and 0%-79%, respectively. Two studies met the criteria on glycopeptide-induced ototoxicity and reported hearing loss frequencies of 54% and 55%. Hearing loss frequencies were higher in gentamicin-treated children compared to those treated with other aminoglycosides. In available studies aminoglycosides had most often been administered concomitantly with platinum agents, diuretics and other co-medication. Conclusions: In children the reported occurrence of aminoglycoside/glycopeptide ototoxicity highly varies and seems to depend on the diagnosis, aminoglycoside subtype and use of co-administered medication. More research is needed to investigate the prevalence and determinants of aminoglycoside/glycopeptide ototoxicity. Our results indicate that age-dependent audiological examination may be considered for children frequently treated with aminoglycosides/glycopeptides especially if combined with other ototoxic medication

Local application of sodium thiosulfate as an otoprotectant for cisplatin-exposed patients - a narrative literature review to explore the potential benefit for children with cancer

\ua9 2025 The Authors. Background: Ototoxicity is a highly prevalent, serious, and irreversible side effect in cisplatin-treated childhood cancer patients, which can significantly impact speech-language development, psychosocial development, and quality of life. In this respect, the development and implementation of reliable and safe otoprotectants is urgently needed. Sodium thiosulfate (STS*) is an otoprotective drug, recently approved for intravenous administration in cisplatin-treated children with non-disseminated cancer. Intratympanic STS application has been developed as a potential strategy to reduce systemic exposure. To explore potential opportunities for this approach, we have reviewed available literature addressing efficacy, safety, and pharmacokinetics of local STS administration. Methods: A PubMed search, focused on clinical and pre-clinical efficacy, safety, and pharmacokinetics of local STS application in cisplatin-exposed subjects of all ages was performed. Findings: From 256 studies, ten studies met the inclusion criteria, including seven preclinical studies, and three clinical studies. Four studies (two preclinical, two clinical) which included pharmacokinetic data, showed that locally administered STS was associated with low systemic serum STS levels. Preclinical studies in guinea pigs showed a significant protective effect on outer hair cell loss or hearing function. However, two clinical trials in adults did not show convincing evidence of otoprotection, by locally administered STS. Interpretation: Preclinical studies suggest a potential benefit of locally administered STS, however clinical evidence for a significant otoprotective effect is not yet available. The burden and potential sequalae of repeated intratympanic procedures in children, together with the low level of evidence of efficacy, currently limited to pre-clinical data, suggests that further study and potentially improved technology to apply local STS is required for childhood cancer patients receiving cisplatin

Comparison of cisplatin-induced hearing loss in different durations of infusion and volume of hydration schedules in head and neck squamous cell carcinoma patients treated with cisplatin-based chemoradiation

INTRODUCTION: Head and neck squamous cell carcinoma (HNSCC) patients treated with cisplatin-based chemoradiation often suffer from cisplatin-induced hearing loss (CIHL). To prevent toxicities, patients receive hydration before and after cisplatin infusions. This study evaluated cisplatin-induced hearing loss between a long and short duration of infusion and volume of hydration schedule (DIVHS). METHODS: Between 2019 and 2023, 161 patients were included in two Dutch hospitals. Patients received either weekly cisplatin (Cis40qw, n = 77) or triweekly cisplatin (Cis1003q3w, n = 88). Two different short and long DIVHS were used in each cisplatin regimen. Pure tone audiometry was performed at baseline and three months after chemoradiation. Pure tone averages (PTA) were calculated for PTA 1-2-4 kHz and PTA 8-10-12.5 kHz. CIHL was assessed using mean threshold shift. RESULTS: In the Cis40qw group, the mean threshold shift at PTA 1-2-4 kHz was 3.1 dB in the short and 4.7 dB in the long DIVHS (p = 0.37). In the Cis100q3w cohort, the mean threshold shift was 5.3 dB in the short and 7.1 dB in the long DIVHS (p = 0.36). At PTA 8-10-12.5 kHz, the mean threshold shifts of the Cis40qw groups were 11.8 dB in the short versus 15.4 dB in the long DIVHS (p = 0.30). In the Cis100q3w cohort, the mean threshold shift was 19.9 dB in the short compared to 19.4 dB in the long DIVHS (p = 0.85). CONCLUSION: This study found no significant difference in CIHL between different DIVHS during cisplatin-based chemoradiation in HNSCC patients

The association between skeletal muscle mass and sensorineural hearing loss upon cisplatin-based chemoradiotherapy in patients with head and neck squamous cell carcinoma

Introduction: Patients with head and neck squamous cell carcinoma(HNSCC) treated with cisplatin-based chemoradiotherapy (CRT) frequentlyexperience irreversible sensorineural hearing loss (SNHL). Patients with lowlumbar skeletal muscle index (LSMI) may experience higher serum peak dos-ages of cisplatin. This study investigated whether pre-treatment low LSMI isassociated with increased SNHL upon cisplatin-based CRT.Materials and methods: LSMI was assessed using routine pre-treatment CTscans. Pure tone audiometry was performed at baseline and at follow-up toassess treatment-related SNHL. Linear mixed models were used to reveal apotential association between the continuous variable LSMI and SNHL.Results: This retrospective cohort study included 81 patients and found a significantassociation between low LSMI and increased treatment-related SNHL at pure tone fre-quencies vital for the perception of speech (averaged of 1, 2, and 4 kHz) (p = 0.048).Conclusions: HNSCC patients with low LSMI suffer increased treatment-related SNHL upon cisplatin-based CRT.Otorhinolaryngolog

TCERG1L allelic variation is associated with cisplatin-induced hearing loss in childhood cancer, a PanCareLIFE study.

In children with cancer, the heterogeneity in ototoxicity occurrence after similar treatment suggests a role for genetic susceptibility. Using a genome-wide association study (GWAS) approach, we identified a genetic variant in TCERG1L (rs893507) to be associated with hearing loss in 390 non-cranial irradiated, cisplatin-treated children with cancer. These results were replicated in two independent, similarly treated cohorts (n = 192 and 188, respectively) (combined cohort: P = 5.3 × 10-10, OR 3.11, 95% CI 2.2-4.5). Modulating TCERG1L expression in cultured human cells revealed significantly altered cellular responses to cisplatin-induced cytokine secretion and toxicity. These results contribute to insights into the genetic and pathophysiological basis of cisplatin-induced ototoxicity

The association between skeletal muscle mass and sensorineural hearing loss upon cisplatin-based chemoradiotherapy in patients with head and neck squamous cell carcinoma

INTRODUCTION: Patients with head and neck squamous cell carcinoma (HNSCC) treated with cisplatin-based chemoradiotherapy (CRT) frequently experience irreversible sensorineural hearing loss (SNHL). Patients with low lumbar skeletal muscle index (LSMI) may experience higher serum peak dosages of cisplatin. This study investigated whether pre-treatment low LSMI is associated with increased SNHL upon cisplatin-based CRT. MATERIALS AND METHODS: LSMI was assessed using routine pre-treatment CT scans. Pure tone audiometry was performed at baseline and at follow-up to assess treatment-related SNHL. Linear mixed models were used to reveal a potential association between the continuous variable LSMI and SNHL. RESULTS: This retrospective cohort study included 81 patients and found a significant association between low LSMI and increased treatment-related SNHL at pure tone frequencies vital for the perception of speech (averaged of 1, 2, and 4 kHz) (p = 0.048). CONCLUSIONS: HNSCC patients with low LSMI suffer increased treatment-related SNHL upon cisplatin-based CRT

A Retrospective Evaluation of Ototoxicity Monitoring in a Cohort of Pediatric Patients With Solid Tumors, Treated in the Dutch National Cancer Center

INTRODUCTION: Ototoxicity is an adverse effect of childhood cancer treatment with a negative impact on speech-language development and quality of life. This study aimed to retrospectively assess ototoxicity monitoring in a national cohort of pediatric patients with solid tumors, examining the frequency and determinants associated with hearing loss (HL). METHODS: This retrospective cohort study included 305 patients treated between 2015 and 2020 at the Princess Máxima Center. Patients receiving platinum agents, head and neck radiotherapy, and/or ear-nose-throat surgery were analyzed. Electronic patient files provided demographic, clinical, and audiological data. HL was defined as Muenster ≥ 2b or SIOP ≥ 2 grade. Associations between clinical characteristics and HL occurrence were analyzed using logistic regression analysis. RESULTS: Audiological monitoring was performed at baseline (62.6%), during treatment (79.0%), and at the end of treatment (82.1%). Post treatment, 51.2% and 36.5% experienced Muenster and SIOP-defined HL, respectively. Multivariable analyses revealed that age at diagnosis (OR 0.9, 95% CI 0.9-1.0), total cumulative dose cisplatin per 100 mg/m 2 (OR 1.6, 95% CI 1.4-2.0), and vincristine treatment (OR 3.3, 95% CI 1.4-7.8) remained significantly associated with Muenster grade ≥ 2b HL. Age at diagnosis in years (OR 0.9, 95% CI 0.8-1.0), total cumulative dose cisplatin per 100 mg/m 2 (OR 1.5, 95% CI 1.2-1.8), and male sex (OR 2.7, 95% CI 1.4-5.3) were associated with SIOP ≥ 2 HL. CONCLUSION: This study shows that more than half of the children treated with ototoxic cancer therapies develop HL by the end of treatment. Therefore, audiological monitoring during and after treatment is essential. Improved insight into clinical determinants aids in identifying patients at high risk for HL, who may benefit from prevention strategies that are currently being implemented