Mohr-Tranebjaerg syndrome (MTS) is a rare X-linked recessive neurodegenerative disorder caused by pathogenic variants in the TIMM8A gene. TIMM8A, also known as Deafness-Dystonia Peptide-1 (DDP1) is a mitochondrial intermembrane space protein involved in the import and insertion of hydrophobic membrane proteins from the cytoplasm into the mitochondrial inner membrane. MTS typically presents early-onset progressive hearing loss, dystonia, visual impairment, and cognitive decline. Here, we report a case of a male adolescent with a previously undescribed variant in TIMM8A, associated with progressive dystonia but no hearing loss, highlighting the clinical variability of MTS. A 16-year-old male was referred for genetic evaluation due to a 6-year history of progressive dystonia, motor coordination difficulties, and iron deposits in the basal ganglia detected by brain MRI. Family history revealed mild motor abnormalities in his maternal uncle and recurrent muscle spasms in his mother. Whole-exome sequencing (WES) identified a c.98_101dupAGCA variant in TIMM8A in hemizygosity, classified as likely pathogenic. This variant causes a frameshift leading to a truncated protein. The patient inherited the variant from his mother, who is heterozygous for the mutation. Although the patient lacks the characteristic early-onset hearing loss seen in MTS, his neurological presentation and the imaging findings are consistent with the syndrome. This case underscores the phenotypic heterogeneity of Mohr-Tranebjaerg syndrome, where patients may present with prominent neurological symptoms such as dystonia without the hallmark auditory dysfunction. The identification of a novel TIMM8A variant expands the mutational spectrum of this rare disorder and provides insights into genotype-phenotype correlations. The absence of hearing loss in this patient raises important questions about the variability in the expression of the mutated TIMM8A. This report highlights a novel TIMM8A mutation associated with Mohr-Tranebjaerg syndrome, presenting primarily with dystonia and iron accumulation in the basal ganglia. The findings contribute to the understanding of the clinical spectrum of MTS and emphasize the importance of genetic testing in patients with unexplained progressive neurological symptoms.

This study aims to explore the presence of contralateral suppression of otoacoustic emissions (CS-OAEs) in unilateral cochlear implant (CI) users with auditory neuropathy spectrum disorder (ANSD). We enrolled three unilateral CI users with bilateral ANSD and stable otoacoustic emissions in the nonimplanted ear, exhibiting diverse postsynaptic ANSD backgrounds including cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss syndrome, Optic Atrophy Plus Syndrome, and Spinocerebellar Ataxia. Measurements of transient-evoked otoacoustic emissions (TEOAEs) were conducted both with and without contralateral electrical stimulation (CES) across five frequency bands. CES was delivered via a CI using a direct audio input cable connected to a computer. In order to elicit a response, broad-band noise is applied and presented at a comfortable level. Minor amplitude reductions (between 0.2 and 0.6 dB SPL) were observed in TEOAEs with CES across different frequencies for each subject. Despite these changes, there was no prominent suppression effect observed, which emphasizes the differences in CS-OAE responses among individuals with postsynaptic ANSD. The absence of significant CS-OAE suppression suggests that direct electrical stimulation through CES may not consistently engage the efferent auditory system in patients with postsynaptic ANSD characteristics. It is essential to broaden the study population to encompass a more diverse range of ANSD presentations in order to confirm the effectiveness of CES in stimulating efferent pathways.

Dominant optic atrophy (DOA) is one of the most prevalent forms of hereditary optic neuropathies and is mainly caused by heterozygous variants in OPA1, encoding a mitochondrial dynamin-related large GTPase. The clinical spectrum of DOA has been extended to a wide variety of syndromic presentations, called DOAplus, including deafness as the main secondary symptom associated to vision impairment. To date, the pathophysiological mechanisms underlying the deafness in DOA remain unknown. To gain insights into the process leading to hearing impairment, we have analyzed the Opa1delTTAG mouse model that recapitulates the DOAplus syndrome through complementary approaches combining morpho-physiology, biochemistry, and cellular and molecular biology. We found that Opa1delTTAG mutation leads an adult-onset progressive auditory neuropathy in mice, as attested by the auditory brainstem response threshold shift over time. However, the mutant mice harbored larger otoacoustic emissions in comparison to wild-type littermates, whereas the endocochlear potential, which is a proxy for the functional state of the stria vascularis, was comparable between both genotypes. Ultrastructural examination of the mutant mice revealed a selective loss of sensory inner hair cells, together with a progressive degeneration of the axons and myelin sheaths of the afferent terminals of the spiral ganglion neurons, supporting an auditory neuropathy spectrum disorder (ANSD). Molecular assessment of cochlea demonstrated a reduction of Opa1 mRNA level by greater than 40%, supporting haploinsufficiency as the disease mechanism. In addition, we evidenced an early increase in Sirtuin 3 level and in Beclin1 activity, and subsequently an age-related mtDNA depletion, increased oxidative stress, mitophagy as well as an impaired autophagic flux. Together, these results support a novel role for OPA1 in the maintenance of inner hair cells and auditory neural structures, addressing new challenges for the exploration and treatment of OPA1-linked ANSD in patients.

CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) syndrome is a rare genetic disorder caused by the heterozygous mutation, c.2452G > A, in the ATP1A3 gene. CAPOS syndrome involves a characteristic episode in which neuropathy develops after a fever in childhood, and here, we describe the case of a patient with CAPOS syndrome. The patient had repeated episodes of a fever around 74 months of age. Although he could speak at 23 months of age, he presented with hearing difficulty after the fever. Pure-tone audiometry revealed moderate-to-severe bilateral sensorineural hearing loss, and auditory brainstem response (ABR) showed poor response in the both ears. Auditory stead-state response (ASSR) produced relatively consistent results compared to pure-tone audiometry. A mutation in the ATP1A3 gene was detected through genetic testing. In CAPOS syndrome, a genetic mutation leads to desynchronization during neural firing. We believe that this desynchronization in neural firing is responsible for the lack of response in the ABR and the presence of a response in the ASSR. In this patient, we attribute the response detection in ASSR to its greater tolerance for errors in the timing of neural firing compared to ABR.

We studied a patient with mitochondrial DNA depletion in skeletal muscle and a multiorgan phenotype, including fatal encephalomyopathy, retinopathy, optic atrophy, and sensorineural hearing loss. Instead of pathogenic variants in the mitochondrial maintenance genes, we identified previously unpublished variant in DHX16 gene, a de novo heterozygous c.1360C>T (p. Arg454Trp). Variants in DHX16 encoding for DEAH-box RNA helicase have previously been reported only in five patients with a phenotype called as neuromuscular oculoauditory syndrome including developmental delay, neuromuscular symptoms, and ocular or auditory defects with or without seizures. We performed functional studies on patient-derived fibroblasts and skeletal muscle revealing, that the DHX16 expression was decreased. Clinical features together with functional data suggest, that our patient's disease is associated with a novel pathogenic DHX16 variant, and mtDNA depletion could be a secondary manifestation of the disease.