3-methylglutaconic aciduria (3-MGCA) is a biochemical finding in a diverse group of inherited metabolic disorders. Conditions manifesting 3-MGCA are classified into two major categories, primary and secondary. Primary 3-MGCAs involve two inherited enzymatic deficiencies affecting leucine catabolism, whereas secondary 3-MGCAs comprise a larger heterogeneous group of conditions that have in common compromised mitochondrial energy metabolism. Here, we report 3-MGCA in two siblings presenting with sensorineural hearing loss and neurological abnormalities associated with a novel, homozygous missense variant (c.1999C>G, p.Leu667Val) in the YME1L1 gene which encodes a mitochondrial ATP-dependent metalloprotease. We show that the identified variant results in compromised YME1L1 function, as evidenced by abnormal proteolytic processing of substrate proteins, such as OPA1 and PRELID1. Consistent with the aberrant processing of the mitochondrial fusion protein OPA1, we demonstrate enhanced mitochondrial fission and fragmentation of the mitochondrial network in patient-derived fibroblasts. Furthermore, our results indicate that YME1L1L667V is associated with attenuated activity of rate-limiting Krebs cycle enzymes and reduced mitochondrial respiration, which may explain the build-up of 3-methylglutaconic and 3-methylglutaric acid due to the diversion of acetyl-CoA, not efficiently processed in the Krebs cycle, towards the formation of 3-methylglutaconyl-CoA, the precursor of these metabolites. In summary, our findings classify YME1L1 deficiency as a new type of secondary 3-MGCA, thus expanding the genetic landscape and facilitating the diagnosis of inherited metabolic disorders featuring this biochemical phenotype.

• Klíčová slova
• 3‐methylglutaconic aciduria, YME1L1, inherited metabolic disorders, mitochondrial disorders, mitochondrial dysfunction, mitochondrial fragmentation,
• MeSH
• dítě MeSH
• fibroblasty metabolismus   MeSH
• glutaráty MeSH
• lidé MeSH
• metaloendopeptidasy * genetika   metabolismus   MeSH
• missense mutace MeSH
• mitochondriální dynamika MeSH
• mitochondriální proteiny * genetika   MeSH
• mitochondrie metabolismus   MeSH
• percepční nedoslýchavost genetika   MeSH
• sourozenci MeSH
• vrozené poruchy metabolismu * genetika   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• 3-methylglutaconic acid MeSH Prohlížeč
• glutaráty MeSH
• metaloendopeptidasy * MeSH
• mitochondriální proteiny * MeSH

OBJECTIVES: Arterial hypertension negatively influences the peripheral auditory system, causing sensorineural hearing loss. Much less is known about the detrimental effects of hypertension on the central auditory functions. METHODS: We tested 32 arterial hypertension patients and 32 age and sex-matched healthy volunteers with the expanded tonal audiometry (0.125-12.5 kHz), distortion product otoacoustic emissions (0.75-8 kHz), horizontal minimum audible angle test for eight azimuths with binaural stimulation and the random gap detection test. RESULTS: Peripheral hearing of the hypertensive patients was impaired in comparison with the controls within all audiometric frequencies (0.125-12.5 kHz) and within specific groups of frequencies. Distortion product otoacoustic emission results were significantly lower for frequencies 4 (P = 0.04) and 6 kHz (P < 0.001). The sound localization ability in the horizontal minimum audible angle test was significantly worse in the hypertensive patients in the 0°, 45°, 90°, 135°, and 270° azimuth when the interaural pure tone average (0.5-1-2 kHz) was set less than 20 dB hearing level (P < 0.05), and in the 0°, 90°, 225°, and 270°azimuth when the binaural pure tone average (0.5-1-2 kHz) was set 20 dB or less hearing level (P < 0.05). Gap detection thresholds in the random gap detection test did not differ between the two groups. CONCLUSION: Arterial hypertension is independently related to the damage of the peripheral part of the auditory system resulting in high-frequency hearing loss. Hypertensive disturbances of central auditory processing are more discrete and concern the spatial hearing resolution.

• MeSH
• audiometrie čistými tóny MeSH
• dospělí MeSH
• hypertenze komplikace   epidemiologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• otoakustické emise spontánní MeSH
• percepční nedoslýchavost epidemiologie   etiologie   MeSH
• studie případů a kontrol MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

A cardinal feature of the auditory pathway is frequency selectivity, represented in a tonotopic map from the cochlea to the cortex. The molecular determinants of the auditory frequency map are unknown. Here, we discovered that the transcription factor ISL1 regulates the molecular and cellular features of auditory neurons, including the formation of the spiral ganglion and peripheral and central processes that shape the tonotopic representation of the auditory map. We selectively knocked out Isl1 in auditory neurons using Neurod1Cre strategies. In the absence of Isl1, spiral ganglion neurons migrate into the central cochlea and beyond, and the cochlear wiring is profoundly reduced and disrupted. The central axons of Isl1 mutants lose their topographic projections and segregation at the cochlear nucleus. Transcriptome analysis of spiral ganglion neurons shows that Isl1 regulates neurogenesis, axonogenesis, migration, neurotransmission-related machinery, and synaptic communication patterns. We show that peripheral disorganization in the cochlea affects the physiological properties of hearing in the midbrain and auditory behavior. Surprisingly, auditory processing features are preserved despite the significant hearing impairment, revealing central auditory pathway resilience and plasticity in Isl1 mutant mice. Mutant mice have a reduced acoustic startle reflex, altered prepulse inhibition, and characteristics of compensatory neural hyperactivity centrally. Our findings show that ISL1 is one of the obligatory factors required to sculpt auditory structural and functional tonotopic maps. Still, upon Isl1 deletion, the ensuing central plasticity of the auditory pathway does not suffice to overcome developmentally induced peripheral dysfunction of the cochlea.

• Klíčová slova
• auditory behavior, auditory maps, auditory nuclei, inferior colliculus, spiral ganglion neurons,
• MeSH
• ganglion spirale * enzymologie   MeSH
• kochlea embryologie   inervace   MeSH
• myši MeSH
• neurogeneze * genetika   MeSH
• nucleus cochlearis * embryologie   MeSH
• proteiny s homeodoménou LIM * genetika   fyziologie   MeSH
• sluchová dráha * embryologie   MeSH
• transkripční faktory * genetika   fyziologie   MeSH
• vláskové buňky * fyziologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• insulin gene enhancer binding protein Isl-1 MeSH Prohlížeč
• proteiny s homeodoménou LIM * MeSH
• transkripční faktory * MeSH

Hearing depends on extracting frequency, intensity, and temporal properties from sound to generate an auditory map for acoustical signal processing. How physiology intersects with molecular specification to fine tune the developing properties of the auditory system that enable these aspects remains unclear. We made a novel conditional deletion model that eliminates the transcription factor NEUROD1 exclusively in the ear. These mice (both sexes) develop a truncated frequency range with no neuroanatomically recognizable mapping of spiral ganglion neurons onto distinct locations in the cochlea nor a cochleotopic map presenting topographically discrete projections to the cochlear nuclei. The disorganized primary cochleotopic map alters tuning properties of the inferior colliculus units, which display abnormal frequency, intensity, and temporal sound coding. At the behavioral level, animals show alterations in the acoustic startle response, consistent with altered neuroanatomical and physiological properties. We demonstrate that absence of the primary afferent topology during embryonic development leads to dysfunctional tonotopy of the auditory system. Such effects have never been investigated in other sensory systems because of the lack of comparable single gene mutation models.SIGNIFICANCE STATEMENT All sensory systems form a topographical map of neuronal projections from peripheral sensory organs to the brain. Neuronal projections in the auditory pathway are cochleotopically organized, providing a tonotopic map of sound frequencies. Primary sensory maps typically arise by molecular cues, requiring physiological refinements. Past work has demonstrated physiologic plasticity in many senses without ever molecularly undoing the specific mapping of an entire primary sensory projection. We genetically manipulated primary auditory neurons to generate a scrambled cochleotopic projection. Eliminating tonotopic representation to auditory nuclei demonstrates the inability of physiological processes to restore a tonotopic presentation of sound in the midbrain. Our data provide the first insights into the limits of physiology-mediated brainstem plasticity during the development of the auditory system.

• Klíčová slova
• Neurod1 mutation, auditory pathway, cochlear nucleus, inferior colliculus, plasticity, sensory topographical map,
• MeSH
• chování zvířat fyziologie   MeSH
• colliculus inferior anatomie a histologie   fyziologie   MeSH
• ganglion spirale cytologie   fyziologie   MeSH
• mapování mozku MeSH
• mezencefalon embryologie   fyziologie   MeSH
• myši knockoutované MeSH
• myši MeSH
• nucleus cochlearis anatomie a histologie   fyziologie   MeSH
• sluch fyziologie   MeSH
• sluchová percepce genetika   fyziologie   MeSH
• těhotenství MeSH
• transkripční faktory bHLH genetika   fyziologie   MeSH
• úleková reakce genetika   fyziologie   MeSH
• vestibulární aparát anatomie a histologie   fyziologie   MeSH
• vnímání výšky zvuku fyziologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• Neurod1 protein, mouse MeSH Prohlížeč
• transkripční faktory bHLH MeSH

OBJECTIVES: Smoking is a strong addiction, that affects a huge number of people worldwide, including the young ones. Due to composition of cigarette smoke, which contains nicotine and other chemical substances, lots of harmful effects on human health were described. Apart from the influence on other organs smoking is associated with hearing loss. METHODS: The literature review was conducted using PubMed and the combination of the following words: smoking, hearing impairment and hearing loss. RESULTS: The total number of 585 articles published in the recent 10 years were analysed. The review results show a strong association of hearing loss with smoking, both active and passive. As the main reason for hearing loss, a damage to outer hair cells was identified. Hearing loss in such cases is basically sensorineural and usually affects high frequencies. It was also observed that the risk of hearing loss increases with time of smoking. Smoking cessation reduces the risk of hearing loss associated with smoking. This article is a review of the literature that summarizes the results of studies aiming to analyse the influence of smoking on human hearing. CONCLUSIONS: As smoking causes serious health problems, public health policies in societies should promote primary prevention as well as smoking cessation (secondary prevention) to diminish the total burden of healthcare systems.

• Klíčová slova
• cochlear dysfunction, hearing impairment, hearing loss, otoacoustic emissions, smoking,
• MeSH
• kouření * škodlivé účinky   epidemiologie   MeSH
• lidé MeSH
• nedoslýchavost * chemicky indukované   epidemiologie   MeSH
• odvykání kouření MeSH
• rizikové faktory MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

• Klíčová slova
• ACOUSTIC NERVE *, AUDIOMETRY *, INFANT *, INFANT, NEWBORN *, NEUROLOGIC MANIFESTATIONS *, PREGNANCY *, PREGNANCY COMPLICATIONS, INFECTIOUS *, SYPHILIS, CONGENITAL *, VESTIBULAR FUNCTION TESTS *,
• MeSH
• audiometrie * MeSH
• dítě MeSH
• infekční komplikace v těhotenství * MeSH
• kojenec MeSH
• komplikace těhotenství * MeSH
• lidé MeSH
• nervus cochlearis * MeSH
• neurologické manifestace * MeSH
• novorozenec MeSH
• syfilis * MeSH
• těhotenství MeSH
• vestibulární funkční testy * MeSH
• vrozená syfilis * MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• novorozenec MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Different types of spiral ganglion neurons (SGNs) are essential for auditory perception by transmitting complex auditory information from hair cells (HCs) to the brain. Here, we use deep, single cell transcriptomics to study the molecular mechanisms that govern their identity and organization in mice. We identify a core set of temporally patterned genes and gene regulatory networks that may contribute to the diversification of SGNs through sequential binary decisions and demonstrate a role for NEUROD1 in driving specification of a Ic-SGN phenotype. We also find that each trajectory of the decision tree is defined by initial co-expression of alternative subtype molecular controls followed by gradual shifts toward cell fate resolution. Finally, analysis of both developing SGN and HC types reveals cell-cell signaling potentially playing a role in the differentiation of SGNs. Our results indicate that SGN identities are drafted prior to birth and reveal molecular principles that shape their differentiation and will facilitate studies of their development, physiology, and dysfunction.

• MeSH
• buněčná diferenciace genetika   MeSH
• ganglion spirale * MeSH
• myši MeSH
• neurony * metabolismus   MeSH
• RNA metabolismus   MeSH
• vláskové buňky metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• RNA MeSH

OBJECTIVE: Chronic otitis media (COM) is a common middle ear disease in children and young adults. Dysfunction of the Eustachian tube and bacterial infection are the main causes. This pilot study aimed to describe and compare bacteriomes of the middle ear in children and young adults with serious forms of COM, such as cholesteatoma and retraction pocket (RP) of the tympanic membrane, with bacteriomes in healthy middle ears. STUDY DESIGN: Observational study. SETTING: Clinical practice in a tertiary center. From January 1, 2021 to August 31, 2022. Patients aged 0 to 20 years. METHODS: In this case-control study, middle ears were swabbed during surgery on children with cholesteatoma (N = 23) or RP (N = 26) and on children indicated for cochlear implant (N = 15, controls). Genomic DNA extraction was followed by creation of a 16S ribosomal DNA gene library and sequencing on a MiSeq instrument. Samples with relative abundance of at least one bacterial genus >20% were considered positive for the specific genus. RESULTS: Bacterial diversity was generally low in the middle ear samples from patients with COM, with DNA content from 1 or 2 bacteria usually dominating in the sample. A significant difference in positivity for one or more bacterial genera was observed between patients with cholesteatoma or RP (38.8%) versus patients indicated for cochlear implants (6.7%). CONCLUSION: While middle ear bacteriomes in cases of cholesteatoma and RP differed from those of controls, findings in the 2 pathological conditions were similar. These results support the statement that the RP could be a precholesteatoma stage.

• Klíčová slova
• bacteriome, children, cholesteatoma, chronic otitis media, middle ear, retraction pocket,
• Publikační typ
• časopisecké články MeSH

GABAB receptors are G-protein coupled receptors for the inhibitory neurotransmitter GABA. Functional GABAB receptors are formed as heteromers of GABAB1 and GABAB2 subunits, which further associate with various regulatory and signaling proteins to provide receptor complexes with distinct pharmacological and physiological properties. GABAB receptors are widely distributed in nervous tissue, where they are involved in a number of processes and in turn are subject to a number of regulatory mechanisms. In this review, we summarize current knowledge of the cellular distribution and function of the receptors in the inner ear and auditory pathway of the mammalian brainstem and midbrain. The findings suggest that in these regions, GABAB receptors are involved in processes essential for proper auditory function, such as cochlear amplifier modulation, regulation of spontaneous activity, binaural and temporal information processing, and predictive coding. Since impaired GABAergic inhibition has been found to be associated with various forms of hearing loss, GABAB dysfunction could also play a role in some pathologies of the auditory system.

• Klíčová slova
• GABAB receptor, auditory, hearing loss, neuronal excitability, synaptic transmission, tinnitus,
• MeSH
• buněčná membrána MeSH
• GABA MeSH
• hluchota * MeSH
• kognice MeSH
• receptory GABA-B * MeSH
• savci MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• GABA MeSH
• receptory GABA-B * MeSH