Publications by authors named "Umberto Ambrosetti"

43 Publications

Sudden sensorineural hearing loss in children with dual positivity of serum anti-EBV IgM and anti-CMV IgM antibodies: a preliminary study.

Minerva Pediatr (Torino) 2021 Jun 21. Epub 2021 Jun 21.

Audiology Unit, Department of Specialist Surgical Sciences, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Background: Sudden sensorineural hearing loss (SSNHL) is rare in children, and its etiology remains largely unknown, although viral infections seem to play an important role. The aim of this study is to report 5 children who experienced permanent SSNHL and had dual positivity of serum anti-Epstein-Barr virus (EBV) IgM and anti-Cytomegalovirus (CMV) IgM antibodies.

Methods: The study was conducted in a third-level referral audiological center. The medical charts of children under age 14 who experienced SSNHL without hearing recovery between September 1, 2017 and August 31, 2020, were reviewed. These children had undergone diagnostic evaluations, including brain magnetic resonance imaging, serological testing, thrombophilia and autoimmunity screening, to find possible causes of SSNHL.

Results: In all 5 patients identified, anti-EBV IgM, anti-CMV IgM and anti-CMV IgG antibodies were detected by chemiluminescent immunoassay (CLIA) immediately after the diagnosis of SSNHL, which occurred from 2 to 4 weeks after the onset of symptoms attributable to primary EBV infection. No abnormalities were demonstrated by coagulation and immunologic tests. Brain magnetic resonance imaging showed normal findings.

Conclusions: This study suggests that primary EBV infection should be considered one of the most likely causes of SSNHL without any hearing recovery in children. Therefore, a routine audiological examination should be recommended for children with virologically confirmed primary EBV infection at approximately 3-4 weeks after onset of symptoms and then repeated with periodic follow-up. Further studies on a wider number of children affected by SSNHL might clarify the possible pathogenetic role of this dual serological positivity.
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http://dx.doi.org/10.23736/S2724-5276.21.06314-XDOI Listing
June 2021

Gene in Hereditary Non-syndromic Hearing Loss: Recurrence and Incomplete Penetrance of the p.C113Y Mutation in Northwest Africa.

Front Genet 2021 10;12:606630. Epub 2021 Feb 10.

Humanitas Clinical and Research Center-IRCCS, Rozzano, Italy.

Inherited hearing loss is extremely heterogeneous both clinically and genetically. In addition, the spectrum of deafness-causing genetic variants differs greatly among geographical areas and ethnicities. The identification of the causal mutation in affected families allows early diagnosis, clinical follow-up, and genetic counseling. A large consanguineous family of Moroccan origin affected by autosomal recessive sensorineural hearing loss (ARSNHL) was subjected to genome-wide linkage analysis and exome sequencing. Exome-wide variant analysis and prioritization identified the p.C113Y missense variant (rs768484124) as the most likely cause of ARSNHL in the family, falling within the unique significant (LOD score>3) linkage region on chromosome 5. Indeed, the same variant was previously reported in two Tunisian ARSNHL pedigrees. The variant is present in the homozygous state in all six affected individuals, but also in one normal-hearing sibling, suggesting incomplete penetrance. The mutation is absent in about 1,000 individuals from the Greater Middle East Variome study cohort, including individuals from the North African population, as well as in an additional seven deaf patients from the same geographical area, recruited and screened for mutations in the gene. This study represents the first independent replication of the involvement of in ARSNHL, highlighting the importance of the gene, and of the p.C113Y mutation, at least in the Northwest African population.
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http://dx.doi.org/10.3389/fgene.2021.606630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902881PMC
February 2021

Effects of COVID-19 Lockdown on Otitis Media With Effusion in Children: Future Therapeutic Implications.

Otolaryngol Head Neck Surg 2021 11 26;165(5):710-715. Epub 2021 Jan 26.

Audiology Unit, Department of Specialist Surgical Sciences, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Objective: To evaluate the role of social isolation during the lockdown due to the SARS-CoV-2 outbreak (severe acute respiratory syndrome coronavirus 2) in modifying the prevalence of otitis media with effusion (OME) and the natural history of chronic OME.

Study Design: Retrospective study.

Setting: Tertiary level referral audiologic center.

Methods: We assessed the prevalence of OME among children aged 6 months to 12 years who attended the outpatient clinic for hearing or vestibular disorders during 2 periods before the lockdown, May-June 2019 (n = 350) and January-February 2020 (n = 366), and the period immediately after the lockdown, May-June 2020 (n = 216). We also compared the disease resolution rates between a subgroup of children with chronic OME (n = 30) who were diagnosed in summer 2019 and reevaluated in May-June 2020 and a similar subgroup (n = 29) assessed in 2018-2019.

Results: The prevalence of OME in this clinic population was 40.6% in May-June 2019, 52.2% in January-February 2020, and 2.3% in May-June 2020. Children with chronic OME had a higher rate of disease resolution in May-June 2020 (93.3%) than those examined in May-June 2019 (20.7%, < .001).

Conclusion: Closure of schools and the physical distancing rules were correlated with a reduction in the prevalence of OME and favored the resolution of its chronic forms among children who attended the outpatient clinic. These data could suggest that in the presence of chronic OME, keeping young children out of group care settings for a period might be beneficial to allow for OME resolution.
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http://dx.doi.org/10.1177/0194599820987458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841252PMC
November 2021

Lights and Shadows in the Genetics of Syndromic and Non-Syndromic Hearing Loss in the Italian Population.

Genes (Basel) 2020 10 22;11(11). Epub 2020 Oct 22.

Institute for Maternal and Child Health-IRCCS "Burlo Garofolo", 34137 Trieste, Italy.

Hearing loss (HL), both syndromic (SHL) and non-syndromic (NSHL), is the most common sensory disorder, affecting ~460 million people worldwide. More than 50% of the congenital/childhood cases are attributable to genetic causes, highlighting the importance of genetic testing in this class of disorders. Here we applied a multi-step strategy for the molecular diagnosis of HL in 125 patients, which included: (1) an accurate clinical evaluation, (2) the analysis of and genes, (3) the evaluation and deletions via Multiplex Ligation Probe Amplification (MLPA), (4) Whole Exome Sequencing (WES) in patients negative to steps 2 and 3. Our approach led to the characterization of 50% of the NSHL cases, confirming both the relevant role of the (20% of cases) and deletions (6% of cases), and the high genetic heterogeneity of NSHL. Moreover, due to the genetic findings, 4% of apparent NSHL patients have been re-diagnosed as SHL. Finally, WES characterized 86% of SHL patients, supporting the role of already know disease-genes. Overall, our approach proved to be efficient in identifying the molecular cause of HL, providing essential information for the patients' future management.
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http://dx.doi.org/10.3390/genes11111237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690429PMC
October 2020

Vestibular and audiological findings in the Alport syndrome.

Am J Med Genet A 2020 10 20;182(10):2345-2358. Epub 2020 Aug 20.

Audiology Unit, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.

Alport syndrome (AS) is caused by mutations in collagen IV, which is widespread in the basement membranes of many organs, including the kidneys, eyes, and ears. Whereas the effects of collagen IV changes in the cochlea are well known, no changes have been described in the posterior labyrinth. The aim of this study was to investigate both the auditory and the vestibular function of a group of individuals with AS. Seventeen patients, aged 9-52, underwent audiological tests including pure-tone and speech audiometry, immittance test and otoacoustic emissions and vestibular tests including video head impulse test, rotatory test, and vestibular evoked myogenic potentials. Hearing loss affected 25% of the males and 27.3% of the females with X-linked AS. It was sensorineural with a cochlear localization and a variable severity. 50% of the males and 45.4% of the females had a hearing impairment in the high-frequency range. Otoacoustic emissions were absent in about one-third of the individuals. A peripheral vestibular dysfunction was present in 75% of the males and 45.4% of the females, with no complaints of vertigo or dizziness. The vestibular impairment was compensated and the vestibulo-ocular reflex asymmetry was more evident in rotatory tests carried out at lower than higher speeds; a vestibular hypofunction was present in all hearing impaired ears although it was also found in subjects with normal hearing. A posterior labyrinth injury should be hypothesized in AS even when the patient does not manifest hearing disorders or evident signs of renal failure.
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http://dx.doi.org/10.1002/ajmg.a.61796DOI Listing
October 2020

Psychometric properties of the Italian Tinnitus Functional Index (TFI).

Acta Otorhinolaryngol Ital 2020 Jun;40(3):230-237

Audiology Unit, Department of Clinical Sciences and Community Health, University of Milan, Italy.

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http://dx.doi.org/10.14639/0392-100X-2432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416372PMC
June 2020

Primary Ciliary Dyskinesia: The Impact of Taste Receptor (TAS2R38) Gene Polymorphisms on Disease Outcome and Severity.

Int Arch Allergy Immunol 2020 13;181(9):727-731. Epub 2020 Jul 13.

Department of Medicine, Surgery and Health Sciences, University of Trieste, Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Trieste, Italy.

Background: Primary ciliary dyskinesia (PCD) is a rare genetic disease leading to recurrent respiratory infections of upper and lower airways. Chronic rhinosinusitis (CRS) and bronchiectasis are very common in PCD patients. Recently, it has been shown the presence of taste receptors in respiratory tract and the possible involvement of bitter taste receptor TAS2R38 gene in susceptibility to respiratory infections and rhinosinusitis.

Objective: Aim of this study was to evaluate the frequency of TAS2R38 polymorphisms in PCD patients and their possible correlations with clinical outcomes of the disease.

Methods: Genetic and phenotypic data of 35 PCD patients were collected. Clinical evaluation included neonatal respiratory distress (NRD) at birth, presence of situs inversus, CRS, and bronchiectasis. We also measured the number of respiratory infections per year and the relevant pathogens, Lund-Mackay score, FEV1, and modified Bhalla score. With regard to genetics data, 3 polymorphisms (rs1726866, rs713598, and rs10246939) within TAS2R38 gene were analyzed and the patients were classified as PAV/PAV, PAV/AVI, and AVI/AVI.

Results: A significant difference in the distribution of TAS2R38 haplotype between patients with and without NRD emerged (p value = 0.01). A lower percentage of PAV/PAV individuals showed frequent respiratory exacerbations (≥2/year) (p value = 0.04) compared to those with AVI/AVI and AVI/PAV haplotypes. Moreover, no patients homozygous for PAV/PAV haplotype presented chronic colonization by Pseudomonas aeruginosa, thus supporting the possible role of TAS2R38 gene in susceptibility to respiratory infections.

Conclusions: Here, we report, for the first time, a possible association of TAS2R38 polymorphisms with PCD phenotype.
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http://dx.doi.org/10.1159/000508938DOI Listing
February 2021

Early Magnetic Resonance Imaging for Patients With Idiopathic Sudden Sensorineural Hearing Loss in an Emergency Setting.

Otol Neurotol 2019 10;40(9):1139-1147

Otolaringology-Head and Neck surgery Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico.

Objective: The role of magnetic resonance (MR) imaging in idiopathic sudden sensorineural hearing loss (ISSHL) is controversial due to the inhomogeneity of clinical and MR protocols. The aim of this work is to relate early MR findings obtained immediately after the admission, with the clinical presentation, the audiological findings, and the outcomes of treatment.

Study Design: Prospective observational study.

Setting: Tertiary referral university center.

Patients: Forty-seven patients (22 M, 25 F; age: 54.4 ± 17.5 yr) consecutively referred to the Department of Emergency for ISSHL.

Interventions: All patients underwent the diagnostic and therapeutic work-up for ISSHL, and MR imaging within 72 hours from the admission, independently of the symptoms onset. All patients received the same treatment (systemic steroid therapy, intratympanic steroid injection, and hyperbaric oxygen therapy).

Main Outcome Measure(s): MR patterns, clinical, and laboratory findings.

Results: MR imaging was positive in 25 of 47 cases (53%), with a perfect agreement between clinical and MR examinations (Cohen K = 1) upon the affected ear. Three different radiological patterns were observed: labyrinthine haemorrhage (n = 5), acute inflammatory process (n = 14), isolated blood-labyrinth barrier breakdown (n = 6). By binary logistic regression, only vertigo was associated with a positive MR imaging [B = 2.8; p = 0.011; OR = 9.5 (95% CI: 2.2-40.8)] and the latter was the only variable associated with an unfavorable outcome [(B = 2.8; p = 0.02 OR = 12.8 (95% CI: 2.9-56.7)].

Conclusion: Patients affected by ISSHL with associated vertigo show a higher likelihood of having a positive MR imaging, which, in turn, seems to predict an unfavorable outcome.
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http://dx.doi.org/10.1097/MAO.0000000000002389DOI Listing
October 2019

Next generation sequencing study in a cohort of Italian patients with syndromic hearing loss.

Hear Res 2019 09 13;381:107769. Epub 2019 Jul 13.

Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Trieste, Italy; University of Trieste, Department of Medicine, Surgery and Health Sciences, Trieste, Italy.

Hearing loss (HL), one of the most common congenital disorder, affects about one child in 1000. Among the genetic forms of HL, ∼30% of the cases are associated with other signs or symptoms, leading to Syndromic Hearing Loss (SHL) with about 700 different forms described so far. In this report, we refer the clinical and molecular data of 38 Italian SHL unrelated patients, and their relatives, affected by the most common syndromes associated with HL (i.e., Usher, Pendred, Charge, Waardenburg, Alport, Stickler, Branchiootorenal and Microdeletions syndromes). Patients have been analysed using next-generation sequencing (NGS) and High Density (HD)-SNP array technologies. Data analysis led to the identification of nine novel and 27 known causative mutations in 12 genes and two microdeletions in chromosomes 1 and 10, respectively. In particular, as regards to Usher syndrome, that affects 32% of our patients, we were able to reach a molecular diagnosis in 83% of the cases and to identify in Northern Eastern Italy a very common USH2A gene mutation (39%) (c.11864G > A, p.(Trp3955*) which can be defined "Central-Eastern European allele." As regards to Alport syndrome, we were able to potentially reclassify a pathogenic allele in the COL4A3 gene, previously associated only with benign familial hematuria. In all the other cases, the genomic analysis allowed us to confirm the role of known causative genes and to identify several novel and known alleles. Overall, our results highlight the effectiveness of combining an accurate clinical characterization with the use of genomic technologies (NGS and SNP arrays) for the molecular diagnosis of SHL, with a clear positive impact in the management and treatment of all the patients.
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http://dx.doi.org/10.1016/j.heares.2019.07.006DOI Listing
September 2019

Diagnosis of congenital CMV infection via DBS samples testing and neonatal hearing screening: an observational study in Italy.

BMC Infect Dis 2019 Jul 22;19(1):652. Epub 2019 Jul 22.

Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Via Carlo Pascal, 36, 20133, Milan, Italy.

Background: Congenital Cytomegalovirus (cCMV) is the most common cause of non-genetic hearing loss in childhood. A newborn hearing screening program (NHSP) is currently running in Italy, but no universal cCMV nor statewide hearing-targeted CMV screening programs have been implemented yet. This observational monocentric study was aimed at estimating the rate of cCMV infections identified by CMV-DNA analysis on Dried Blood Spots (DBS) samples in deaf children identified via NHSP in Northern Italy in the period spanning from 2014 to 2018.

Methods: Children with a confirmed diagnosis of deafness and investigated for CMV-DNA by nucleic acid extraction and in-house polymerase-chain reaction (PCR) on stored newborns screening cards (DBS-test) were included in this study. Deafness was defined by a hearing threshold ≥20 decibel (dB HL) by Auditory Brainstem Responses (ABR); all investigated DBS samples were collected within 3 days of life.

Results: Overall, 82 children were included (median age: 3.4 months; lower-upper quartiles: 2-5.3 months; males: 60.9%). Most of them (70.7%) presented bilateral hearing loss with a symmetrical pattern in 79.3% of the cases. ABR thresholds were ≥ 70 dB HL (severe/profound deafness) in 46.5% of children. Among all tested children, 6.1% resulted positive for cCMV. The rate of severe/profound deafness was statistically higher in children with cCMV infection.

Conclusions: The addition of DBS-test to the NHSP allowed the identification, in their first months of life, of a cCMV infection in 6.1% of children who had failed NHS. The introduction of a targeted CMV screening strategy could help clinicians in the differential diagnosis and in the babies' management. DBS samples can be considered a "universal newborns biobank": their storage site and duration should be the subject of political decision-making.
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http://dx.doi.org/10.1186/s12879-019-4296-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6647195PMC
July 2019

Primary ciliary dyskinesia: can we identify patients with the most severe phenotype?

Minerva Med 2021 Aug 25;112(4):518-520. Epub 2019 Jun 25.

Unit of Audiology, Department of Clinical Sciences and Community Health, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, University of Milan, Milan, Italy -

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http://dx.doi.org/10.23736/S0026-4806.19.06054-3DOI Listing
August 2021

Genomic Studies in a Large Cohort of Hearing Impaired Italian Patients Revealed Several New Alleles, a Rare Case of Uniparental Disomy (UPD) and the Importance to Search for Copy Number Variations.

Front Genet 2018 21;9:681. Epub 2018 Dec 21.

Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy.

Hereditary hearing loss (HHL) is a common disorder characterized by a huge genetic heterogeneity. The definition of a correct molecular diagnosis is essential for proper genetic counseling, recurrence risk estimation, and therapeutic options. From 20 to 40% of patients carry mutations in gene, thus, in more than half of cases it is necessary to look for causative variants in the other genes so far identified (~100). In this light, the use of next-generation sequencing technologies has proved to be the best solution for mutational screening, even though it is not always conclusive. Here we describe a combined approach, based on targeted re-sequencing (TRS) of 96 HHL genes followed by high-density SNP arrays, aimed at the identification of the molecular causes of non-syndromic HHL (NSHL). This strategy has been applied to study 103 Italian unrelated cases, negative for mutations in , and led to the characterization of 31% of them (i.e., 37% of familial and 26.3% of sporadic cases). In particular, TRS revealed and genes as major players in the Italian population. Furthermore, two missense variants in 1 have been identified and investigated through protein modeling and molecular dynamics simulations, confirming their likely pathogenic effect. Among the selected patients analyzed by SNP arrays (negative to TRS, or with a single variant in a recessive gene) a molecular diagnosis was reached in ~36% of cases, highlighting the importance to look for large insertions/deletions. Moreover, copy number variants analysis led to the identification of the first case of uniparental disomy involving gene. Overall, taking into account the contribution of , plus the results from TRS and SNP arrays, it was possible to reach a molecular diagnosis in ~51% of NSHL cases. These data proved the usefulness of a combined approach for the analysis of NSHL and for the definition of the epidemiological picture of HHL in the Italian population.
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http://dx.doi.org/10.3389/fgene.2018.00681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309105PMC
December 2018

Next-generation sequencing identified SPATC1L as a possible candidate gene for both early-onset and age-related hearing loss.

Eur J Hum Genet 2019 01 3;27(1):70-79. Epub 2018 Sep 3.

Department of Medical Sciences, University of Trieste, Trieste, Italy.

Hereditary hearing loss (HHL) and age-related hearing loss (ARHL) are two major sensory diseases affecting millions of people worldwide. Despite many efforts, additional HHL-genes and ARHL genetic risk factors still need to be identified. To fill this gap a large genomic screening based on next-generation sequencing technologies was performed. Whole exome sequencing in a 3-generation Italian HHL family and targeted re-sequencing in 464 ARHL patients were performed. We detected three variants in SPATC1L: a nonsense allele in an HHL family and a frameshift insertion and a missense variation in two unrelated ARHL patients. In silico molecular modelling of all variants suggested a significant impact on the structural stability of the protein itself, likely leading to deleterious effects and resulting in truncated isoforms. After demonstrating Spatc1l expression in mice inner ear, in vitro functional experiments were performed confirming the results of the molecular modelling studies. Finally, a candidate-gene population-based statistical study in cohorts from Caucasus and Central Asia revealed a statistically significant association of SPATC1L with normal hearing function at low and medium hearing frequencies. Overall, the amount of different genetic data presented here (variants with early-onset and late-onset hearing loss in addition to genetic association with normal hearing function), together with relevant functional evidence, likely suggest a role of SPATC1L in hearing function and loss.
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http://dx.doi.org/10.1038/s41431-018-0229-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303261PMC
January 2019

Whole-genome sequencing reveals new insights into age-related hearing loss: cumulative effects, pleiotropy and the role of selection.

Eur J Hum Genet 2018 08 30;26(8):1167-1179. Epub 2018 Apr 30.

Medical Sciences, Chirurgical and Health Department, University of Trieste, Trieste, Italy.

Age-related hearing loss (ARHL) is the most common sensory disorder in the elderly. Although not directly life threatening, it contributes to loss of autonomy and is associated with anxiety, depression and cognitive decline. To search for genetic risk factors underlying ARHL, a large whole-genome sequencing (WGS) approach has been carried out in a cohort of 212 cases and controls, both older than 50 years to select genes characterized by a burden of variants specific to cases or controls. Accordingly, the total variation load per gene was compared and two groups were detected: 375 genes more variable in cases and 371 more variable in controls. In both cases, Gene Ontology analysis showed that the largest enrichment for biological processes (fold > 5, p-value = 0.042) was the "sensory perception of sound", suggesting cumulative genetic effects were involved. Replication confirmed 141 genes, while additional analysis based on natural selection led to a prioritization of 21 genes. The majority of them (20 out of 21) showed positive expression in mouse cochlea cDNA and were associated with two functional pathways. Among them, two genes were previously associated with hearing (CSMD1 and PTRPD) and re-sequenced in a large Italian cohort of ARHL patients (N = 389). Results led to the identification of six coding variants not detected in cases so far, suggesting a possible protective role, which requires investigation. In conclusion, we show that this multistep strategy (WGS, selection, expression, pathway analysis and targeted re-sequencing) can provide major insights into the molecular characterization of complex diseases such as ARHL.
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http://dx.doi.org/10.1038/s41431-018-0126-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6057993PMC
August 2018

Effects of Tinnitus Retraining Therapy with Different Colours of Sound.

Int Tinnitus J 2017 Dec 1;21(2):139-143. Epub 2017 Dec 1.

Fondazione Ascolta e Vivi, Via Foppa Milano, Italy.

Background: In Tinnitus Retraining Therapy (TRT) sound stimulation is conventionally performed with low-level broadband sound generators; since the patient has to receive it for many hours in a day, it is important that the sound is tolerable and agreeable to the patient. A clinical trial was undertaken to evaluate the effect of different colour sound generators on tinnitus. The colour of a sound refers to the power spectrum of the signal. The sound generators used in this study provide the option to choose the preferred or most acceptable sound among white, red and pink noise.

Methods And Findings: Changes in Tinnitus Handicap Inventory and Numeric Rating Scales were measured in 20 patients after 3 and 6 months following the fitting of ear-level multi-colour sound generators. The outcomes were compared to a similar group of 20 participants receiving the same management except through conventional white noise sound generators. Significant improvements were obtained in both groups following 3 and 6 months after fitting. No significant difference was found between the two groups using one or the other type of sound. Two thirds of the patient preferred white noise, making it the most appealing amongst the options. The rest of the patients indicated red noise as the preferred sound given that it reminded them of soothing noises like shower or rainfall. No one chose pink noise.

Conclusions: TRT with different colour sound generators is effective in reducing the discomfort caused by tinnitus in normal hearing patients. Enabling the patients to choose their preferred sound after short trial periods achieved higher patient satisfaction. This practice could help tailor individualized treatment for each patient.
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http://dx.doi.org/10.5935/0946-5448.20170026DOI Listing
December 2017

Cilia and Ear.

Ann Otol Rhinol Laryngol 2017 Apr 12;126(4):322-327. Epub 2017 Feb 12.

4 Department of Clinical Sciences and Community Health, University of Milan, Division of Audiology, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Lombardia, Italy.

Objective: To investigate the prevalence of otological complications derived from primary ciliary dyskinesia (PCD) in adulthood.

Methods: Twenty-three patients with diagnosed PCD underwent medical history aimed at recording the presence of ear, nose, and throat manifestations (ENT) and any surgical treatments. The ENT objectivity was annotated, and then patients were subjected to audiometric test, tympanometry, registration of otoacoustic emission, and vestibular evaluation.

Results: Otitis media with chronic middle ear effusion (OME) during childhood was reported in 52% of the subjects, no patient had undergone ear surgery, and only 2 patients had an episode of otitis in the last year. Eleven of 23 patients showed normal hearing, 11 had a conductive hearing impairment, and 1 showed a severe sensorineural hearing loss unrelated to the syndrome. The bilateral stapedial reflex was only found in all cases of normoacusia and type A tympanogram, distortion product otoacoustic emissions (DPOAE) were present in 8 patients, and no patient had vestibular alterations.

Conclusion: Our study confirms a very frequent prevalence of OME in PCD during childhood. Careful monitoring of otological complications of the syndrome is always desirable, also given the high presence in adults of other manifestations in the upper airways, such as chronic rhinosinusitis and nasal polyposis.
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http://dx.doi.org/10.1177/0003489417691299DOI Listing
April 2017

First independent replication of the involvement of LARS2 in Perrault syndrome by whole-exome sequencing of an Italian family.

J Hum Genet 2016 Apr 10;61(4):295-300. Epub 2015 Dec 10.

Department of Biomedical Sciences, Humanitas University, Milan, Italy.

Perrault syndrome (MIM #233400) is a rare autosomal recessive disorder characterized by ovarian dysgenesis and primary ovarian insufficiency in females, and progressive hearing loss in both genders. Recently, mutations in five genes (HSD17B4, HARS2, CLPP, LARS2 and C10ORF2) were found to be responsible for Perrault syndrome, although they do not account for all cases of this genetically heterogeneous condition. We used whole-exome sequencing to identify pathogenic variants responsible for Perrault syndrome in an Italian pedigree with two affected siblings. Both patients were compound heterozygous for two novel missense variants within the mitochondrial leucyl-tRNA synthetase (LARS2): NM_015340.3:c.899C>T(p.Thr300Met) and c.1912G>A(p.Glu638Lys). Both variants cosegregated with the phenotype in the family. p.Thr300 and p.Glu638 are evolutionarily conserved residues, and are located, respectively, within the editing domain and immediately before the catalytically important KMSKS motif. Homology modeling using as template the E. coli leucyl-tRNA synthetase provided further insights on the possible pathogenic effects of the identified variants. This represents the first independent replication of the involvement of LARS2 mutations in Perrault syndrome, contributing valuable information for the further understanding of this disease.
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http://dx.doi.org/10.1038/jhg.2015.149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4817218PMC
April 2016

Risk factors for idiopathic sudden sensorineural hearing loss and their association with clinical outcome.

Thromb Res 2015 Mar 7;135(3):508-12. Epub 2015 Jan 7.

A. Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico and University of Milan, Italy.

Background: Sudden sensorineural hearing loss (ISSHL) is idiopathic in 85% of cases and cochlear micro-thrombosis has been hypothesized as pathogenic mechanism. The role of thrombophilia and cardiovascular risk factors in ISSHL is controversial and whether these risk factors influence the clinical outcome of ISSHL is unknown.

Methods: and patients To investigate the role of thrombophilia and cardiovascular risk factors in ISSHL and to evaluate their influence on clinical outcome of the disease, 118 patients with a first episode of ISSHL and 415 healthy controls were investigated. Thrombophilia screening included measurements of antithrombin, protein C, protein S, factor V Leiden, prothrombin G20210A, antiphospholipid antibodies, fibrinogen, factor VIII and homocysteine.

Results: Deficiencies of antithrombin, protein C or S taken together, high factor VIII and hyperhomocysteinemia were significantly associated with ISSHL (OR [95%CI]: 7.55 [1.05-54.47], 2.91 [1.31-6.44] and 2.69 [1.09-6.62], respectively), whereas no association was found with the remaining thrombophilia markers. A 2-fold increased risk of poor clinical outcome was observed for every 5 μmol/L increase of fasting homocysteine levels (adjusted OR [95%CI]) 2.13 [1.02-4.44]) until levels of approximately 15 μmol/L, then the risk increased slowly. Cardiovascular risk factors (arterial hypertension, hyperlipidemia, diabetes and smoking) were associated with an increased risk of ISSHL (OR [95%CI] 1.88 [1.17-3.03]) and with a poor clinical outcome (OR [95%CI] 2.22 [0.93-5.26]).

Conclusions: Hyperhomocysteinemia, high factor VIII and, with more uncertainty, deficiencies of antithrombin, protein C or S and cardiovascular risk factors increase the risk of ISSHL. Hyperhomocysteinemia and cardiovascular risk factors are associated with a poor clinical outcome of ISSHL.
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http://dx.doi.org/10.1016/j.thromres.2015.01.001DOI Listing
March 2015

The expanding spectrum of PRPS1-associated phenotypes: three novel mutations segregating with X-linked hearing loss and mild peripheral neuropathy.

Eur J Hum Genet 2015 Jun 3;23(6):766-73. Epub 2014 Sep 3.

Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy.

Next-generation sequencing is currently the technology of choice for gene/mutation discovery in genetically-heterogeneous disorders, such as inherited sensorineural hearing loss (HL). Whole-exome sequencing of a single Italian proband affected by non-syndromic HL identified a novel missense variant within the PRPS1 gene (NM_002764.3:c.337G>T (p.A113S)) segregating with post-lingual, bilateral, progressive deafness in the proband's family. Defects in this gene, encoding the phosphoribosyl pyrophosphate synthetase 1 (PRS-I) enzyme, determine either X-linked syndromic conditions associated with hearing impairment (eg, Arts syndrome and Charcot-Marie-Tooth neuropathy type X-5) or non-syndromic HL (DFNX1). A subsequent screening of the entire PRPS1 gene in 16 unrelated probands from X-linked deaf families led to the discovery of two additional missense variants (c.343A>G (p.M115V) and c.925G>T (p.V309F)) segregating with hearing impairment, and associated with mildly-symptomatic peripheral neuropathy. All three variants result in a marked reduction (>60%) of the PRS-I activity in the patients' erythrocytes, with c.343A>G (p.M115V) and c.925G>T (p.V309F) affecting more severely the enzyme function. Our data significantly expand the current spectrum of pathogenic variants in PRPS1, confirming that they are associated with a continuum disease spectrum, thus stressing the importance of functional studies and detailed clinical investigations for genotype-phenotype correlation.
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http://dx.doi.org/10.1038/ejhg.2014.168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4270732PMC
June 2015

Genome-wide association analysis demonstrates the highly polygenic character of age-related hearing impairment.

Eur J Hum Genet 2015 Jan 18;23(1):110-5. Epub 2014 Jun 18.

Cell Biology and Genetics Division, House Research Institute, Los Angeles, CA, USA.

We performed a genome-wide association study (GWAS) to identify the genes responsible for age-related hearing impairment (ARHI), the most common form of hearing impairment in the elderly. Analysis of common variants, with and without adjustment for stratification and environmental covariates, rare variants and interactions, as well as gene-set enrichment analysis, showed no variants with genome-wide significance. No evidence for replication of any previously reported genes was found. A study of the genetic architecture indicates for the first time that ARHI is highly polygenic in nature, with probably no major genes involved. The phenotype depends on the aggregated effect of a large number of SNPs, of which the individual effects are undetectable in a modestly powered GWAS. We estimated that 22% of the variance in our data set can be explained by the collective effect of all genotyped SNPs. A score analysis showed a modest enrichment in causative SNPs among the SNPs with a P-value below 0.01.
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http://dx.doi.org/10.1038/ejhg.2014.56DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4266741PMC
January 2015

Chronic cerebrospinal venous insufficiency in Ménière disease.

Phlebology 2015 May 4;30(4):274-9. Epub 2014 Mar 4.

Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano, Milan, Italy Audiology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Objectives: The aim of this study was to focus on patients suffering from cochleo-vestibular disorder with and without Ménière disease (MD) in order to verify whether chronic cerebrospinal drainage abnormalities could play a role in the etiopathogenesis of endolymphatic hydrops.

Methods: Fifty-two volunteers were enrolled and subdivided into two groups: 24 definite MD and 28 not-MD. Both magnetic resonance venography imaging with contrast-enhanced imaging of the venous cerebrospinal system (MRV) and venous echo-color Doppler (ECD) were performed.

Results: MRV showed abnormalities in 83% of MD and 57% of not-MD subjects (p < 0.001). Asymmetrical cervical venous flow, assessed by MRV, was confirmed by ECD in 62.5% of MD but in only 21.5% of not-MD subjects (p<0.001).

Conclusion: Chronic cerebrospinal venous insufficiency might be the anatomical background, which provides a predisposing factor for the development of endolymphatic hydrops in MD patients.
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http://dx.doi.org/10.1177/0268355514526871DOI Listing
May 2015

Auditory late potentials in normal-hearing adult subjects with Down's syndrome.

Otol Neurotol 2012 Sep;33(7):1113-7

Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano, Milan, Italy.

Objective: Several studies have demonstrated that adult subjects with Down's syndrome (DS) and hearing impairments show significantly delayed latencies in auditory late potentials (ALPs). The aim of this study was to investigate whether the differences were still present in ALPs in an adult DS population with normal hearing, taking into consideration sex, handedness, and head size.

Study Design: Prospective study.

Setting: Audiology unit of the hospital Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Patients: Sixteen normal-hearing adult DS subjects referred to the health monitoring program for DS patients of Vivi Down Onlus Association in Milan, Italy (7 male subjects with a mean age of 26 ± 7.74 yr and 9 female subjects with a mean age of 28 ± 8.63 yr) and 16 controls (7 male subjects with a mean age of 26 ± 7.74 yr and 9 female subjects with a mean age of 28 ± 8.86 yr) matched for sex, age, and handedness.

Main Outcome Measure: The 2 negative peaks, N1 and N2, and the 2 positive peaks, P1 and P2, of ALP.

Results: ALP N1 and P2 components were well defined in all subjects. The P1 and N2 components were less evident than the others. There were significant delayed latencies in the DS group with respect to the control subjects for P1, N1, P2, and N2 components.

Conclusion: Our study demonstrated that ALP longer latencies are present in adult DS participants even when they have a normal hearing threshold, regardless of handedness and head size.
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http://dx.doi.org/10.1097/MAO.0b013e3182659d02DOI Listing
September 2012

Audiological findings in Williams syndrome: a study of 69 patients.

Am J Med Genet A 2012 Apr 12;158A(4):759-71. Epub 2012 Mar 12.

Audiologic Unit, Department of Specialized Surgical Sciences, University of Milan, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy.

The aim of this study was to investigate, in a clinical setting, the auditory function of a group of individuals affected by Williams syndrome (WS). Sixty-nine patients with WS, aged 2-30, underwent comprehensive audiological testing including air/bone conduction behavioral audiometry, speech audiometry, tympanometry and measurement of the acoustic reflex, transient evoked otoacoustic emissions and brainstem auditory evoked responses. Hearing loss, defined by a pure-tone average above 15 dB HL, affected 22.6% of the patients studied with traditional audiometry and was mostly slight in severity. Hearing loss was conductive in 9.4% of patients, mainly children with otitis media with effusion, and sensorineural in 13.2% of patients. However, 30% of the ears studied had a hearing impairment in the high frequency range (high-frequency pure-tone audiometry above 15 dB HL), higher in participants above 15 years (46.15%) than in the younger ones (23.45%). Contralateral stapedial reflexes were present in all patients with A-type tympanograms. Transient otoacoustic emissions were absent in 44% of the ears of patients with normal hearing. Brainstem auditory evoked responses fell within normal ranges thus confirming the absence of retrocochlear dysfunction. Although hearing loss does not seem to be frequent, a cochlear fragility, especially in the high frequency range, related to outer hair cells is characteristic of WS. Therefore we strongly recommend monitoring patients affected by WS using annual audiometric tests and performing otoacoustic emissions in order to identify a subclinical cochlear dysfunction which might benefit from an audiological follow up before the possible onset of hearing loss.
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http://dx.doi.org/10.1002/ajmg.a.35241DOI Listing
April 2012

Public awareness of ear and hearing management as measured using a specific questionnaire.

Eur Arch Otorhinolaryngol 2013 Feb 17;270(2):449-53. Epub 2012 Feb 17.

Audiology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Pace 9, 20122 Milan, Italy.

Public awareness of audiological issues has never been measured in the general public even if the World Health Organization (WHO) has detected a common urgent need for action to prevent and manage ear diseases and hearing loss. The aim of this study was to measure urban community citizens' awareness of managing and preventing ear disease and hearing loss using a specific questionnaire. A questionnaire was formulated on the basis of WHO material concerning the major specific audiological issues and attitudes, focusing in particular on four domains: (1) knowledge of infant hearing loss, (2) correct management of the ears including cleaning and treating, (3) focus on the effect of overexposure to loud sounds and noise, (4) underestimated ear symptoms leading to diagnostic delay. 254 volunteers were enrolled in this cross-sectional study by a team of medical doctors and audiologists stationed in a mobile unit that visited different areas of Milan, Italy. More than 80% of correct responses were given to almost all of the statements by the interviewees, although certain important knowledge was found to be lacking. The proposed audiological questionnaire seems to be a suitable tool to evaluate the public awareness of ear and hearing management. The results showed a need for continued development of comprehensive hearing conservation programs, focused on hearing aid management and early infant hearing loss identification as well as noise exposure.
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http://dx.doi.org/10.1007/s00405-012-1961-3DOI Listing
February 2013

A novel mutation within the MIR96 gene causes non-syndromic inherited hearing loss in an Italian family by altering pre-miRNA processing.

Hum Mol Genet 2012 Feb 28;21(3):577-85. Epub 2011 Oct 28.

Dipartimento di Biologia e Genetica per Scienze Mediche, Università degli Studi di Milano, Milan, Italy.

The miR-96, miR-182 and miR-183 microRNA (miRNA) family is essential for differentiation and function of the vertebrate inner ear. Recently, point mutations within the seed region of miR-96 were reported in two Spanish families with autosomal dominant non-syndromic sensorineural hearing loss (NSHL) and in a mouse model of NSHL. We screened 882 NSHL patients and 836 normal-hearing Italian controls and identified one putative novel mutation within the miR-96 gene in a family with autosomal dominant NSHL. Although located outside the mature miR-96 sequence, the detected variant replaces a highly conserved nucleotide within the companion miR-96*, and is predicted to reduce the stability of the pre-miRNA hairpin. To evaluate the effect of the detected mutation on miR-96/mir-96* biogenesis, we investigated the maturation of miR-96 by transient expression in mammalian cells, followed by real-time reverse-transcription polymerase chain reaction (PCR). We found that both miR-96 and miR-96* levels were significantly reduced in the mutant, whereas the precursor levels were unaffected. Moreover, miR-96 and miR-96* expression levels could be restored by a compensatory mutation that reconstitutes the secondary structure of the pre-miR-96 hairpin, demonstrating that the mutation hinders precursor processing, probably interfering with Dicer cleavage. Finally, even though the mature miR-96 sequence is not altered, we demonstrated that the identified mutation significantly impacts on miR-96 regulation of selected targets. In conclusion, we provide further evidence of the involvement of miR-96 mutations in human deafness and demonstrate that a quantitative defect of this miRNA may contribute to NSHL.
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http://dx.doi.org/10.1093/hmg/ddr493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3259013PMC
February 2012

Four-year follow-up of diagnostic service in USH1 patients.

Invest Ophthalmol Vis Sci 2011 Jun 8;52(7):4063-71. Epub 2011 Jun 8.

Laboratoire de Génétique Moléculaire, Montpellier, France.

Purpose: The purpose of this study was to establish the mutation spectrum of an Usher type I cohort of 61 patients from France and to describe a diagnostic strategy, including a strategy for estimating the pathogenicity of sequence changes.

Methods: To optimize the identification of Usher (USH)-causative mutations, taking into account the genetic heterogeneity, preliminary haplotyping at the five USH1 loci was performed to prioritize the gene to be sequenced, as previously described. Coding exons and flanking intronic sequences were sequenced and, where necessary, semiquantitative PCR and multiplex ligation-dependent probe amplification (MLPA) were performed to detect large genomic rearrangements.

Results: Four years ' experience confirms that the chosen approach provides an efficient diagnostic service. Sixty-one patients showed an abnormal genotype in one of the five USH1 genes. Genetic heterogeneity was confirmed, and, although MYO7A remains the major gene, involvement of other genes is considerable. Distribution of missense, splicing, premature termination codons (PTCs; due to point substitution and small deletions/ or insertions), and large genomic alterations was determined among the USH genes and clearly highlights the need to pay special attention to the diagnostic approach and interpretation, depending on the mutated gene.

Conclusions: Over the 4 years of a diagnostic service offering USH1 patient testing, pathogenic genotypes were identified in most cases (>90%). The complexity and heterogeneity of mutations reinforces the need for a comprehensive approach. Because 32% of the mutations are newly described, the results show that a screening strategy based on known mutations would have solved less than 55% of the cases.
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http://dx.doi.org/10.1167/iovs.10-6869DOI Listing
June 2011

GJB2 and MTRNR1 contributions in children with hearing impairment from Northern Cameroon.

Int J Audiol 2011 Feb 29;50(2):133-8. Epub 2010 Nov 29.

Laboratory of Medical Genetics, Molecular Genetic Sector, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Objective: the aim of this work was to evaluate the possible different impacts of genetic and environmental factors in childhood deafness in northern Cameroon. GJB2 mutations are responsible for more than half of all cases of prelingual nonsyndromic recessive deafness in Caucasians, representing the most important deafness-causing factor in the industrialized world. Other genes such as MTRNR1 are also involved. In sub-Saharan Africa, environmental factors seem to dominate genetic contributions, but few studies on the etiology of deafness in Africa are available for comparison.

Design: prospective cross sectional study.

Study Sample: we performed a molecular screen of the GJB2 and MTRNR1 genes in 70 deaf children and 67 unaffected controls in Maroua (Cameroon) and a literature analysis focused on deafness epidemiology in developing countries.

Results: no GJB2 mutations emerged, and only a single MTRNR1 variant that may be pathogenic was found.

Conclusion: environmental factors turn out to be more relevant than genetic factor in the Maroua population.
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http://dx.doi.org/10.3109/14992027.2010.537377DOI Listing
February 2011

Tinnitus patients lost to follow-up.

Int J Audiol 2010 Dec;49(12):877-80

Audiology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Tinnitus patients without hearing loss or hyperacusis often start tinnitus retraining therapy but do not return to the tinnitus clinic for follow-up visits. The aim of this study was to evaluate how these 'missing patients' feel and whether they still use their sound generators after they discontinue retraining therapy. We interviewed 269 tinnitus patients by phone who never returned to the clinic after receiving initial counseling and a generator for sound enrichment. Twenty-six percent did not have tinnitus anymore, 30.5% still used the sound generator to treat their tinnitus, and 43.5% did not use their sound generator but still suffered from tinnitus. This study suggests that therapists need to contact missing patients periodically to follow their improvement, encourage them, and decide on new therapeutic approaches as necessary.
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http://dx.doi.org/10.3109/14992027.2010.505583DOI Listing
December 2010

Cochlear implantation in adolescents with prelinguistic deafness.

Otolaryngol Head Neck Surg 2010 Jun;142(6):804-8

Department of Specialist Surgical Sciences, University of Milan, Milan, Italy.

Objective: The aims of this study were to examine auditory function in a group of adolescents with prelingual deafness who received cochlear implants (CI) and to identify poor-outcome predictors in order to define reliable prognostic indicators useful in selecting patients for CI.

Study Design: Prospective study.

Setting: The study was conducted in the Audiology Unit of Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.

Subjects And Methods: The study involved 45 adolescents (mean age at implantation: 13.4 +/- 2.6 years, range: 11-18) with profound congenital hearing impairment with a follow-up of three years. Preimplantation and postimplantation auditory performance and speech perception were evaluated using the mean score of three hearing and speech perception tests (vowel-consonant-vowel [VCV], identification of disyllabic words, and recognition of short sentences) performed in auditory-only listening conditions.

Results: Significant improvements in all speech perception tests were observed after CI. However, 15 cases were considered "poor performers" (i.e., the auditory performance of these patients was less than 30 percent). The diagnosis of deafness in these subjects was significantly delayed (18.07 +/- 6.25 and 34.4 +/- 10.26 months in good and poor performers, respectively, P = 0.006), and their hearing threshold was significantly lower than in the good users group. The mean age at CI was 12.8 +/- 2.33 and 14.53 +/- 2.70 years in good and poor performers, respectively (P = ns).

Conclusion: CI was shown to be a useful device with the ability to reverse the adverse consequences of hearing loss, particularly for prelingual adolescents who receive implantation early in life and who present a hearing threshold of 100 dB or better both at diagnosis and at surgery.
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http://dx.doi.org/10.1016/j.otohns.2010.02.016DOI Listing
June 2010

Analysis of the GJB2 and GJB6 genes in Italian patients with nonsyndromic hearing loss: frequencies, novel mutations, genotypes, and degree of hearing loss.

Genet Test Mol Biomarkers 2009 Apr;13(2):209-17

Laboratorio di Genetica Medica, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena-Milano, Milan, Italy.

Mutations in the GJB2 gene, which encodes the gap-junction protein connexin 26, are the most common cause of nonsyndromic hearing loss (NSHL) and account for about 32% of cases. We analyzed 734 patients and identified mutations in 474/1468 chromosomes. Thirty-six different mutations and five polymorphisms were found in 269 NSHL subjects. Our data confirm 35delG as the most frequent GJB2 mutation in the Italian population, accounting for about 68% of all the mutated GJB2 alleles analyzed. We also identified two novel variants: the V156I mutation and the C>A change at nucleotide 684 in the 3'UTR of the gene. The GJB6 gene deletion, del(GJB6-D13S1830), which can cause HL in combination with GJB2 mutations in trans, was identified in three patients, while the del(GJB6-D13S1854) was not observed in our cohort of patients. We collected audiometric data from 200 patients with biallelic DFNB1 mutations or with dominant mutation in GJB2 to determine the degree of HL to correlate the genotypes with the audiological phenotypes.
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http://dx.doi.org/10.1089/gtmb.2008.0086DOI Listing
April 2009
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