Progressive Sensorineural Hearing Loss Research Articles

Clinical and genetic analysis of a patient with Perrault syndrome and additional neurological features

To explore the clinical, neuropathological and genetic characteristics of a patient with Perrault syndrome caused by TWNK mutation. Potential variation of the TWNK gene was detected by next-generation sequencing (NGS) and verified by Sanger sequencing. The patient has featured primary amenorrhoea and progressive sensorineural hearing loss since childhood. She also had gait anormaly, distal limb atrophy and weakness, and nystagmus. Further study confirmed sensory neuronopathy accompanied with upper and lower motor neuron involvement as well as cerebellum atrophy. NGS has identified two heterozygous variants of the TWNK gene, namely c.794G>A (p.Arg265His) and c.1181G>A (p.Arg394His). Sanger sequencing confirmed that c.1181G>A (p.Arg394His), a known pathogenic variant, was derived from her farther, while c.794G>A(p.Arg265His), a novel variant, was derived from her mother and likely pathogenic according to the ACMG guidelines. Perrault syndrome is a group of disorders with a high phenotypic heterogeneity. The compound heterozygous variation of c.794G>A (p.Arg265His) and c.1181G>A(p.Arg394His) of the TWNK gene may underlie Perrault syndrome in the patient.

PB1977 LATE DIAGNOSIS IN SYRIAN IMMIGRANT PATIENT; THIAMINE-RESPONSIVE MEGALOBLASTIC ANEMIA SYNDROME

Background: Thiamine-responsive megaloblastic anemia (TRMA) also known as Rogers syndrome was first described by Porter et al in 1969. It is characterized by diabetes mellitus, megaloblastic anemia and progressive sensorineural hearing loss. TRMA is a rare autosomal recessive disorder. Aims: This syndrome is seen especially in consanguineous marriages and isolated communities. İt has been reported in fewer than 80 families worldwide. Diagnosis relies on uncovering genetic variations (alleles) in the SLC19A2 gene, encoding for a high affinity thiamine transporter. This transporter is essentially present in hematopoietic stem cells, pancreaticc beta cells and inner ear cells, explaining the clinical manifestations of the disease. The disease is usually diagnosed in childhood period. Methods: We presented a 21-year-old patient who was diagnosed with TRMA with the findings of pancytopenia. Results: Case Report: A 21-year-old male patient was referred to our center upon the symptoms of fatigue, hearing loss and pancytopenia. He was emigrated from Syria to Turkey for years ago because of the Syrian War. Mother and father are first-degree relatives. He has hearing loss and inarticulated since hewas 1 year old. He was diagnosed as type 1 diabetes mellitus at 10 years old and treated with insulin. Erythrocyte transfusion had been performed several times due to the anemia. In laboratory tests; Wbc:2480 10^3 /μL, Hgb:4.3 g/dL Plt: 8000 10^3 /μL, MCV:81 fL, Glukoz: 345 mg/dL, Crea1nin:0,7 mg/dL, ldh:92 U/L, Ferri1n:1140 ug/L, VitB12: 702 ng/L, Folat: 5,2 ug/L were found. There was hepatomegaly and splenomegaly in abdominal ultrasonography. Megaloblastic changes were seen in peripheral blood smear, but there was no atypical cells. Bone marrow biopsy and flow cytometric evaluation were normal. Audiologic evaluation showed bilateral severe sensorineural hearing. Considering the laboratory test and clinical findings, a diagnosis of TRMA was suspected and the patient was started on thiamine hydrochloride (100 mg orally daily). An increase in leukocyte and platelet counts was observed on the 5th day of thiamine treatment. On the 10th day of treatment, an increase in hemoglobin level was observed. His pancytopenia was completely resolved. WBC: 7000 10^3 /μL, Hgb: 15 g/dL Plt: 234000 10^3 /μL, mcv: 91 were detected afer two months of treatment. At the same time genetic evaluation was initiated. Homozygous mutation in the SLC19A2 gene (c.242_243insA (p.Y81 ∗) (p.Tyr81 ∗) was detected as a result of genetic evaluation. Summary/Conclusion: Literature showed that the cases of TRMA are mostly diagnosed during childhood period. Our case was diagnosed at the age of 21. He is different from the others with this respect. Pancytopenia has been described several times in Rogers syndrome. There were serious cytopenia in our case at the time of diagnosis. Rapid improvement in cytopenia was seen afer the treatment with thiamine. In conclusion TRMA is a rare autosomal recessive disorder which typically has a clinical triad: megaloblastic anemia, diabetes mellitus and sensorineural hearing loss. Thiamine treatment should be continued for lifelong. Family screening should be done and genetic counseling should be offered when diagnosed.

Outcomes of cochlear implantation in children with inner ear malformations.

To evaluate the surgical experience and auditory functions and progress of speech development of cochlear implantation in malformed ears. Between November 1995 and July 2017, thirty-seven patients (26 females and 11 males; mean age: 138.275 ± 96.24months) with diverse anomalies of the inner ear were retrospectively examined for surgical and audiological results. Speech Intelligibility Rating (SIR), Categories of Auditory Perception (CAP), Pure Tone Average (PTA), Speech Intelligibility Rating (SRT), and Word Discrimination Score (WDS) were the audiological tests used to evaluate the efficacy of CI in the malformed inner ears. CSF gusher was experienced by six patients (three with LVA (large vestibular aqueduct), one with IP (incomplete partition) I, and two with both IP II Mondini malformations and LVA). Two patients had transient facial paresis after surgery. All patients fully recovered within 6months. The postoperative PTA, SRT, and WDS test results showed significant differences between progressive and congenital sensorineural hearing loss (p values < 0.05 for all). On the other hand, the postoperative CAP and SIR test results revealed no significant differences between the two groups. According to etiology, the PTA and SRT values were significantly lower in common cavity patients than the LVA patients (p values < 0.01); no significant differences were found among the other etiological groups. Cochlear implantation is safe in children with inner ear malformations. However, the success rate is low compared to patients with normal anatomy in terms of audiological results; the most successful group of patients with inner ear malformation is large vestibular aqueduct.

Refined mapping of a gene for autosomal dominant progressive sensorineural hearing loss (DFNA5) to a 2-cM region, and exclusion of a candidate gene that is expressed in the cochlea.

A gene for an autosomal dominant form of progressive sensorineural hearing loss (DFNA5) was previously assigned by us to a 15-cM region on chromosome 7p15. In this study, the DFNA5 candidate region was refined to less than 2 cM, and completely cloned in a YAC contig. The HOXA1 gene located in 7p15 was considered to be a good candidate gene for DFNA5 as it harbours mutations leading to developmental defects of the inner ear in mice. However, the refinement of the candidate region of DFNA5 excludes the HOXA1 gene as a candidate for DFNA5. We cloned a novel candidate gene (CG1, candidate gene 1), which is expressed in human fetal cochlea, from the DFNA5 candidate region. The complete cDNA sequence of CG1, encoding a 423 amino acid protein of unknown function, was determined. Mutation analysis of the CG1 gene in DFNA5 patients, however, could not reveal a disease-causing mutation.

Annual hearing screening in girls with Turner Syndrome: Results from the first three years in Glasgow

BackgroundHearing loss is prevalent in girls with Turner Syndrome (TS). A number of cross-sectional studies have confirmed that conductive hearing loss due to middle ear disease and permanent, progressive sensorineural hearing loss are both very common and often unrecognised in TS. Hearing screening has been suggested by many authors and is recommended in some recent national audiology guidelines (every 3–5 years in an international consensus statement, every 1–2 years in the USA and every year in the UK). The effectiveness of such regular hearing screening has not been assessed before. Study aims and methodsIn January 2016 we began a programme of annual hearing screening for all girls attending the West of Scotland TS clinic. We have collected data on age, karyotype, ear and hearing symptoms, otoscopy findings, audiometric test results and subsequent outcomes for the first three years of our programme. Our aim is to assess whether this screening programme is an effective use of resources, with a worthwhile rate of detecting new otological problems and without an excessive additional workload for the audiology department. ResultsTwenty-six girls participated in the screening programme and 8 of these had no hearing issues or ear abnormalities at any time over the 3 years. Two girls had cholesteatoma, 4 had tympanic membrane retractions and/or perforations, and 9 had OME (of which 6 were transient and 3 persistent, with 2 of these requiring treatment). One cholesteatoma, one perforation and one persistent OME were already known about but all other diagnoses were new as a result of the screening programme. Five girls have persistent conductive hearing loss (plus another 6 who had a transient episode of conductive loss due to middle ear fluid) and 6 have some degree of sensorineural hearing loss (3 purely sensorineural, 3 mixed). At the time that a hearing loss was diagnosed, the parents had concerns about the hearing in 4 cases and no concerns in 12. Six girls have been fitted with hearing aids since we started the screening programme, each for different indications (sensorineural hearing loss in two cases, and one case each of persistent OME, post cholesteatoma surgery, tympanic membrane perforation and unilateral tympanic membrane retraction respectively). Two girls have had ear surgery as a result of referral from the programme (one for ventilation tubes, one for cholesteatoma). ConclusionsThe screening programme has picked up ear disease in 69% of girls with TS with only a small additional workload for the audiology department. The ongoing detection of new problems in the second and third years of the programme attests to the value of continued regular hearing screening for girls with TS.

Characterizing P2X2 Mutants Associated with Progressive Sensorineural Hearing Loss (DFNA41)

P2X receptors are trimeric ion channels that open in response to extracellular ATP. Each subunit is comprised of intracellular N- and C-termini, a large extracellular domain containing the ATP binding site and two transmembrane (TM) helices that form a pore that is permeable to cations. P2X2 receptors are hypothesized to play a role in cochlear adaptation to elevated sound levels and protection from overstimulation. Whole-exome sequencing and linkage analysis of individuals with dominantly inherited progressive sensorineural hearing loss (DFNA41) revealed three different mutations of human P2X2 (hP2X2) receptor: V60L, D201Y, and G353R. To investigate the effects of mutations, recombinant hP2X2 receptors were expressed in HEK 293 cells and macroscopic currents were measured with the whole-cell patch clamp technique. We find that the G353R mutation lowers the apparent affinity for activation by ATP and produces a pronounced inward rectification, with large inward currents being observed only below −80 mV. In contrast, expression of the V60L mutation produces measurable constitutive currents with little rectification. To verify that the constitutive currents observed with V60L arise from the mutant receptor, we inserted a Cys into the pore-lining TM2 helix and observed robust and irreversible inhibition by thiol-reactive methanethiosulfonates (MTS). Interestingly, larger MTS reagents reacted more slowly with the V60L construct compared to control, suggesting that the mutation produces a structural alteration in the pore. Finally, the D201Y mutant channel does not respond to ATP and appears to be non-functional. Taken together, our results suggest that all three mutations greatly diminish or ablate ATP-activated currents at physiological voltages, and that the V60L also produces constitutively active channels. It will be interesting to further explore how these perturbations give rise to severe progression of hearing loss.

Histopathology of the Inner Ear in Charcot-Marie-Tooth Syndrome Caused by a Missense Variant (p.Thr65Ala) in the MPZ Gene

Charcot-Marie-Tooth (CMT) syndrome is a clinically and genetically heterogeneous group of neuropathies affecting both peripheral motor and sensory nerves. Progressive sensorineural hearing loss, vestibular abnormalities, and dysfunction of other cranial nerves have been described. This is the second case report of otopathology in a patient with CMT syndrome. Molecular genetic testing of DNA obtained at autopsy revealed a missense variant in the MPZ gene (p.Thr65Ala), pathogenic for an autosomal-dominant form of CMT1B. The temporal bones were also prepared for light microscopy by hematoxylin and eosin and Gömöri trichome stains, and immunostaining for anti-myelin protein zero. Pathology was consistent with a myelinopathy of the auditory, vestibular, and facial nerves bilaterally. The pathophysiology of cranial nerve dysfunction in CMT is unknown. Findings in the current case suggested, at least in cranial nerves 7 and 8, that a myelinopathy may be causative.

Immunoided otological diseases: when to suspect, how to diagnose and treat?

The inner ear may be damaged by several autoimmune mechanisms, the most frequent manifestation being progressive sensorineural hearing loss with good responsiveness to immunosuppressants. Eiff work is justified by the need for further studies relating to sensorineural hearing loss mediated (DNSI), since the pathophysiology of this disease entity per obscure manece but positive response to immunosuppressive therapy enhances the existence of immunological mechanisms and autoimmune diseases. The overall objective of this work was to perform a literature review on sensorineural hearing loss immune-mediated-DNSI, focusing on the presentation forms and clinical manifestations, identifying the possible pathophysiological mechanisms involved in internal ear involvement. The specific focus was to establish a protocol to be followed to conduct a suspected case of DNSI, from diagnosis to treatment. The results found in the consulted literature show that the inner ear may be located within the organ-specific disease groups, or, more commonly, as a compromised organ within the systemic form, and hearing damage may be the first symptom. The index of inner ear impairment in systemic au toimunes is variable. It can be concluded that the hearing loss is neurossensoria may occur in patients with autoimmune disease and should always be taken in cases of hearing loss without apparent cause and the knowledge of autoimmune diseases and their correlation with the sensorineural hearing loss contributed significantly to the demystification of this type of hearing loss, allowing the institution of specific treatment.

Inner ear and retrocochlear pathology on magnetic resonance imaging for sudden and progressive asymmetrical sensorineural hearing loss.

In sudden and asymmetrical progressive sensorineural hearing loss (SNHL), magnetic resonance imaging (MRI) is required to evaluate retrocochlear pathology and, with recent advances in MRI techniques, inner ear pathology. Given the limited literature regarding inner ear pathology associated with SNHL, we aimed to assess the incidence of retrocochlear and inner ear pathology, and congenital malformation on MRI in sudden SNHL (SSNHL) and progressive SNHL. A total of 987 acoustic neuroma (AN) protocol MRI internal acoustic meatus studies performed at our institution to investigate SNHL between January 2013 and December 2015 inclusive were identified. Following categorization for indication of SSNHL versus progressive asymmetrical SNHL, MRIs with retrocochlear or inner ear abnormality, congenital malformation or other otology-related abnormality were identified, and further data were collected for these patients including patient demographics, associated symptomatology, management and outcomes. In SSNHL, aetiological abnormality on MRI was identified for 6.9% patients with AN present on 4% overall. 3.2% of MRIs for progressive asymmetrical SNHL identified a causative lesion with 2.3% of scans overall diagnosing AN. The incidence of congenital inner ear malformation on MRI in the setting of SSNHL and progressive asymmetrical SNHL are 1.7% and 0.6%, respectively. This is the first retrospective study of inner ear MRI abnormalities in both SSNHL and progressive asymmetrical SNHL in Australia and one of the largest cohorts published in the literature to date. MRI must be performed in the setting of SNHL to ensure aforementioned and rarer causative lesions are identified.

Therapeutic potential of the mitochondria-targeted antioxidant MitoQ in mitochondrial-ROS induced sensorineural hearing loss caused by Idh2 deficiency

Mitochondrial NADP+-dependent isocitrate dehydrogenase 2 (IDH2) is a major NADPH-producing enzyme which is essential for maintaining the mitochondrial redox balance in cells. We sought to determine whether IDH2 deficiency induces mitochondrial dysfunction and modulates auditory function, and investigated the protective potential of an antioxidant agent against reactive oxygen species (ROS)-induced cochlear damage in Idh2 knockout (Idh2−/−) mice. Idh2 deficiency leads to damages to hair cells and spiral ganglion neurons (SGNs) in the cochlea and ultimately to apoptotic cell death and progressive sensorineural hearing loss in Idh2−/− mice. Loss of IDH2 activity led to decreased levels of NADPH and glutathione causing abnormal ROS accumulation and oxidative damage, which might trigger apoptosis signal in hair cells and SGNs in Idh2−/− mice. We performed ex vivo experiments to determine whether administration of mitochondria-targeted antioxidants might protect or induce recovery of cells from ROS-induced apoptosis in Idh2-deficient mouse cochlea. MitoQ almost completely neutralized the H2O2-induced ototoxicity, as the survival rate of Idh2−/− hair cells were restored to normal levels. In addition, the lack of IDH2 led to the accumulation of mitochondrial ROS and the depolarization of ΔΨm, resulting in hair cell loss. In the present study, we identified that IDH2 is indispensable for the functional maintenance and survival of hair cells and SGNs. Moreover, the hair cell degeneration caused by IDH2 deficiency can be prevented by MitoQ, which suggests that Idh2−/− mice could be a valuable animal model for evaluating the therapeutic effects of various antioxidant candidates to overcome ROS-induced hearing loss.

Genetic background of Meniere’s disease

Meniere’s disease (MD) as an inner ear disorder including such symptoms as recurrent vertigo attacks, tinnitus, fluctuating or progressive sensorineural hearing loss. Its relatively frequent familial incidence implicates a genetic background. An autosomal dominant inheritance was commonly observed with a few exceptions. It was established that Meniere’s disease is not a monogenic disorder. Instead a group of genes of genomic and mitochondrial genes was established as determinants of hearing loss. Another group of genes was associated with inner ear (vestibulum, labyrinth, endolymph) alterations followed by dizziness and tinnitus. Altogether, many studies suggest a multigenic interaction to predispose to develop Meniere’s disease.

Amylose rénale faisant découvrir un syndrome périodique associé à la cryopyrine

Cryopyrin associated periodic syndrome is a rare auto inflammatory disease including three clinical entities with a common genetic cause. Among these three entities, Muckle-Wells syndrome is described as an intermediate phenotype associated with a progressive sensorineural hearing loss and AA amyloidosis. The present case reports a renal AA amyloidosis associated with an IgA nephropathy, revealing a Muckle-Wells syndrome. The case is reported of a 38-years-old patient who presented a renal failure revealed concomitantly with a macroscopic hematuria exploration. Urological investigations were performed with negative results. The patient had no particular background except urticarial rashes, unlabeled inflammatory rheumatism and a grandmother's amyloidosis. Renal biopsy revealed glomerular, vascular and interstitial AA amyloidosis associated to an IgA nephropathy. This amyloidosis was known to be a part of Muckle-Wells syndrome, and a NLRP3 gene study confirmed the diagnosis. Cryopyrin associated periodic syndrome is a rare disease and the clinical diagnosis suspicion need genetic confirmation. AA amyloidosis is known to happen in Muckle-Wells syndrome. Other occasional renal impairments are described in this syndrome whereas the IgA nephropathy association remains poorly characterized.

Hearing loss

Hearing loss affects one in six people in the UK and is a significant disease burden. In addition to communication problems, there is also an association with depression and dementia....

Cerebellar Ataxia with Progressive Optic Atrophy and Deafness (CAPOS Syndrome): A Rare Case Report

CAPOS syndrome (cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss) is a rare autosomal dominant disorder caused by ATP1A3 mutation. Fever triggered cerebellar dysfunction along with progressive optic atrophy and sensorineural deafness are typical features. Herein, we report a 20-year-old female with multiple fever induced cerebellar dysfunction with partial improvement. Pendular nystagmus and optic atrophy were prominent which were also present in patient’s younger sister. As there was progressive sensorineural hearing loss and areflexia, CAPOS syndrome was diagnosed. Though specific therapy is yet to be developed, acetazolamide, cochlear implantation, visual aid and family screening may improve quality of life. Bangladesh Journal of Neuroscience 2018; Vol. 34 (2): 110-114

Cochlear implantation in children with CHARGE syndrome: a report of eight cases.

To report neuroradiologic findings, surgical strategies and clinical and audiological results in a series of children with CHARGE syndrome (CS) who had been evaluated for cochlear implantation (CI). Retrospective case series. Tertiary referral university hospital. Eight profoundly deafened children with CS were included. Routine audiometric measurements, speech perception categories and speech intelligibility ratings were performed pre- and post-operatively. Neuroradiological and intraoperative findings, surgical planning, and post-operative complications were analyzed. Six children were profoundly deaf from birth and 2 had progressive hearing loss to profound levels. Cochlear nerve deficiency (CND) was noted in 5 out of the 6 patients with congenital sensorineural hearing loss (SNHL). Seven children underwent CI. Surgery was performed using standard transmastoid facial recess approach in 3 ears, subtotal petrosectomy in 3, and transmastoid single-slit labyrinthotomy in one. Temporary facial palsy occurred in one patient. In the group of patients with congenital SNHL, 2 children benefitted from CI and developed spoken language; the remaining 3 children obtained improved access to environmental sounds and used signs and gestures as their main mode of communication. The two patients with progressive SNHL had preoperative verbal language and continued to use verbal language after CI. The constant presence of temporal bone anomalies in children with CS requires surgical expertise in performing non-standard approaches for safe and effective CI. Patients with progressive SNHL and normal cochlear nerves had satisfactory results with CI. Limited benefits have been observed in presence of CND.

Vestibular Dysfunction in Patients With Superficial Siderosis of the Central Nervous System

To describe the vestibular function in patients with superficial siderosis of the central nervous system (SSCN). Retrospective analysis. Tertiary referral center. Ten consecutive patients with SSCN. This study is the largest case series of SSCN in which detailed neuro-otological findings, including electronystagmography recording, video head impulse test (vHIT), and posturography, were described. Audiological and neuro-otological examinations, including pure-tone audiometry, distortion product otoacoustic emissions, speech audiometry, auditory brainstem responses, electronystagmography recording, vHIT, and posturography. Pure-tone average, DP level, maximum speech discrimination score, interpeak latency between auditory brainstem responses waves I and V, eye tracking test, examination of optokinetic nystagmus, caloric response, visual suppression, vestibulo-ocular reflex gains, total center of pressure path length, and Romberg's ratio. Audiological examinations suggested that the sensorineural hearing loss was of a cochlear etiology in 3 ears, a retrocochlear etiology in 11 ears, and a combined cochlear and retrocochlear etiology in 6 ears. Neuro-otological examinations revealed that eight out of nine patients had cerebellar disorders, while all patients also had peripheral vestibular dysfunction. In addition to cerebellar disorders, SSCN patients suffer from severe peripheral vestibular dysfunction, which can exacerbate the patient's imbalance. When otolaryngologists encounter patients with distinctly progressive sensorineural hearing loss and imbalance, they should include SSCN in the differential diagnosis and perform neuro-otological examinations, including an electronystagmography recording and vHIT and brain magnetic resonance imaging.

Longitudinal hearing loss in Wolfram syndrome

BackgroundWolfram syndrome (WFS) is a rare autosomal recessive disease with clinical manifestations of diabetes mellitus (DM), diabetes insipidus (DI), optic nerve atrophy (OA) and sensorineural hearing loss (SNHL). Although SNHL is a key symptom of WFS, there is limited information on its natural history using standardized measures. Such information is important for clinical care and determining its use as an outcome measure in clinical trials.MethodsStandardized audiologic measures, including pure-tone testing, tympanometry, speech perception, and the unaided Speech Intelligibility Index (SII) were assessed in patients with confirmed WFS annually. Mixed model analyses were used to examine main effects of age, time or interactions for pure tone average (PTA), high frequency average (HFA) and SII.ResultsForty WFS patients were evaluated between 1 and 6 times. Mean age at initial enrollment was 13.5 years (SD = 5.6). Patients were classified as having normal hearing (n = 10), mild-to-severe (n = 24) or profound SNHL (n = 6). Mean age of diagnosis for SNHL was 8.3 years (SD = 5.1) with 75% prevalence. HFA worsened over time for both ears, and SII worsened over time in the worse ear, with greater decline in both measures in younger patients. Average estimated change over 1 year for all measures was in the subclinical range and power analyses suggest that 100 patients would be needed per group (treatment vs. placebo) to detect a 60% reduction in annual change of HFA over 3 years. If trials focused on just those patients with SNHL, power estimates suggest 55 patients per group would be sufficient.ConclusionsMost patients had a slow progressive SNHL emerging in late childhood. Change over time with standard audiologic tests (HFA, SII) was small and would not be detectable for at least 2 years in an individual. Relatively large sample sizes would be necessary to detect significant impact on hearing progression in a clinical trial. Hearing function should be monitored clinically in WFS to provide appropriate intervention. Because SNHL can occur very early in WFS, audiologists and otolaryngologists should be aware of and refer for later emerging symptoms.

Incidence and associated risk factors for platinum-induced ototoxicity in pediatric patients

ObjectivesPlatinum-based chemotherapy is effective against a variety of pediatric malignancies. Unfortunately, the use of cisplatin and carboplatin can lead to permanent and progressive sensorineural hearing loss which can affect the quality of life of cancer survivors. The objectives of this study were to evaluate the incidence of platinum-induced ototoxicity in children and analyze potential risk factors. MethodsProspective cohort study. All pediatric patients receiving chemotherapy with cisplatin and/or carboplatin from 01/2012 until 10/2017 were included. Hearing evaluations were performed before every chemotherapy cycle, and following the end of chemotherapy, with auditory brainstem response, otoacoustic emissions and/or audiometry. Demographics, cumulative doses, cranial irradiation and exposure to other ototoxic agents were analyzed. ResultsTwenty-eight patients were included, with a mean age of 7.2 years at the beginning of chemotherapy (range 5 months–15 years 2 months); twenty-one patients received cisplatin, four received carboplatin, and three received both agents. Twelve patients had cranial irradiation and seven received another ototoxic medication. The most frequent malignancies were germ cell tumors, medulloblastoma and gliomas. Sensorineural hearing loss occurred in 28.6% of the patients with a mean follow-up period of 21.5 months (range: 1–53 months). All patients evaluated with audiometry had ≥ Chang 2b ototoxicity. Risk factors include age less than 5 years, cranial irradiation, and cisplatin cumulative dose greater than 400 mg/m2. ConclusionSensorineural hearing loss is a potential side effect of platinum-based chemotherapy. Pediatric patients receiving cisplatin chemotherapy with a cumulative dose exceeding 400 mg/m2, cranial irradiation as well as patients younger than 5 years are at greater risk of developing hearing loss.

Mutation of IFNLR1, an interferon lambda receptor 1, is associated with autosomal-dominant non-syndromic hearing loss

Background Hereditary sensorineural hearing loss is a genetically heterogeneous disorder.Objectives This study was designed to explore the genetic etiology of deafness in a large Chinese family with autosomal dominant, nonsyndromic,...

High-level heteroplasmy for the m.7445A>G mitochondrial DNA mutation can cause progressive sensorineural hearing loss in infancy

ObjectiveHearing loss caused by mutation of mitochondrial DNA typically develops in late childhood or early adulthood, but rarely in infancy. We report the investigation of a patient to determine the cause of his early onset hearing loss. Materials and methodsThe proband was a boy aged 1 year and 2 months at presentation. Newborn hearing screening test by automated auditory brainstem response generated “pass” results for both ears. His reaction to sound deteriorated by 9 months. Average pure tone threshold at 0.5, 1, and 2 kHz was 55 dB by conditioned orientation response audiometry. His father had congenital hearing loss, and his mother had progressive hearing loss since childhood.Invader assays and Sanger sequencing were performed to investigate genetic causes of the hearing loss in the proband, and heteroplasmy was assessed by PCR-restriction fragment length polymorphism, Sanger sequencing, and pyrosequencing. Additionally, mitochondrial function was evaluated by measurement of the oxygen consumption rate of patient skin fibroblasts. ResultsAn m.7445A > G mitochondrial DNA mutation and a heterozygous c.235delC (p.L79Cfs*3) mutation of GJB2 were detected in the proband. His mother carried the m.7445A > G mitochondrial DNA mutation, and his father was a compound heterozygote for GJB2 mutations (c.[235delC]; [134G > A; 408C > A]). Tissue samples from both the proband and his mother exhibited a high degree of heteroplasmy. Fibroblasts from the proband exhibited markedly reduced oxygen consumption rates. These data indicate that the proband had impaired mitochondrial function, resulting in hearing loss. ConclusionThis research demonstrates that hearing loss in a proband who presented in infancy and that of his mother resulted from a high level of heteroplasmy for the m.7445A > G mitochondrial DNA mutation, indicating that this alteration can cause hearing loss in infancy.