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Hearing Disorders: HELP
Articles by Umberto Ambrosetti
Based on 19 articles published since 2010
(Why 19 articles?)
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Between 2010 and 2020, U. Ambrosetti wrote the following 19 articles about Hearing Disorders.
 
+ Citations + Abstracts
1 Article Diagnosis of congenital CMV infection via DBS samples testing and neonatal hearing screening: an observational study in Italy. 2019

Pellegrinelli, Laura / Galli, Cristina / Primache, Valeria / Alde', Mirko / Fagnani, Enrico / Di Berardino, Federica / Zanetti, Diego / Pariani, Elena / Ambrosetti, Umberto / Binda, Sandro. ·Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Via Carlo Pascal, 36, 20133, Milan, Italy. laura.pellegrinelli@unimi.it. · Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Via Carlo Pascal, 36, 20133, Milan, Italy. · Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano, Milan, Italy. · U.O.S.D di Audiologia, Fondazione I.R.C.C.S. Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy. ·BMC Infect Dis · Pubmed #31331274.

ABSTRACT: 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.

2 Article Next-generation sequencing identified SPATC1L as a possible candidate gene for both early-onset and age-related hearing loss. 2019

Morgan, Anna / Vuckovic, Dragana / Krishnamoorthy, Navaneethakrishnan / Rubinato, Elisa / Ambrosetti, Umberto / Castorina, Pierangela / Franzè, Annamaria / Vozzi, Diego / La Bianca, Martina / Cappellani, Stefania / Di Stazio, Mariateresa / Gasparini, Paolo / Girotto, Giorgia. ·Department of Medical Sciences, University of Trieste, Trieste, Italy. anna.morgan@burlo.trieste.it. · Department of Medical Sciences, University of Trieste, Trieste, Italy. · Sidra Medical and Research Center, Doha, Qatar. · Heart Science Centre, National Heart and Lung Institute, Imperial College London, London, UK. · UO Audiology, Fondazione IRCCS Ca Granda, Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy. · Audiology Unit, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy. · Ceinge Biotecnologie Avanzate, Naples, Italy; Istituto di Audiologia, Dipartimento di Neuroscienze, Scienze Riproduttive e Odontostomatologiche, Università di Napoli "Federico II", Naples, Italy. · Medical Genetics, Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Trieste, Italy. ·Eur J Hum Genet · Pubmed #30177775.

ABSTRACT: 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.

3 Article Whole-genome sequencing reveals new insights into age-related hearing loss: cumulative effects, pleiotropy and the role of selection. 2018

Vuckovic, Dragana / Mezzavilla, Massimo / Cocca, Massimiliano / Morgan, Anna / Brumat, Marco / Catamo, Eulalia / Concas, Maria Pina / Biino, Ginevra / Franzè, Annamaria / Ambrosetti, Umberto / Pirastu, Mario / Gasparini, Paolo / Girotto, Giorgia. ·Medical Sciences, Chirurgical and Health Department, University of Trieste, Trieste, Italy. dragana.vuckovic@burlo.trieste.it. · Medical Genetics, Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Trieste, Italy. dragana.vuckovic@burlo.trieste.it. · Medical Genetics, Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Trieste, Italy. · Medical Sciences, Chirurgical and Health Department, University of Trieste, Trieste, Italy. · Institute of Molecular Genetics, National Research Council of Italy, Pavia, Italy. · Ceinge Advanced Biotechnology, Naples, Italy. · Neuroscience, Reproductive and Odontology Sciences Department, University of Naples "Federico II", Naples, Italy. · UO Audiology, Fondazione IRCCS Ca Granda, Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy. · Audiology Unit, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy. · Institute of Population Genetics, National Research Council of Italy, Sassari, Italy. ·Eur J Hum Genet · Pubmed #29725052.

ABSTRACT: 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.

4 Article Effects of Tinnitus Retraining Therapy with Different Colours of Sound. 2017

Barozzi, Stefania / Ambrosetti, Umberto / Callaway, Susanna Løve / Behrens, Thomas / Passoni, Silvia / Bo, Luca Del. ·Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Via Pace, Milano, Italy. · Fondazione Ascolta e Vivi, Via Foppa Milano, Italy. · Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy. · Centre for Applied Audiology Research, Oticon A/S, Kongebakken, Smørum, Denmark. ·Int Tinnitus J · Pubmed #29336133.

ABSTRACT: 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.

5 Article Cilia and Ear. 2017

Piatti, Gioia / De Santi, Maria Margherita / Torretta, Sara / Pignataro, Lorenzo / Soi, Daniela / Ambrosetti, Umberto. ·1 Department of Pathophysiology and Transplantation, University of Milan, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Division of Bronchopneumology, Milan, Italy. · 2 Department of Human Pathology and Oncology, University of Siena, Siena, Toscana, Italy. · 3 Department of Clinical Sciences and Community Health, University of Milan, Division of Otolaryngology, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Lombardia, Italy. · 4 Department of Clinical Sciences and Community Health, University of Milan, Division of Audiology, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Lombardia, Italy. ·Ann Otol Rhinol Laryngol · Pubmed #28290230.

ABSTRACT: 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.

6 Article First independent replication of the involvement of LARS2 in Perrault syndrome by whole-exome sequencing of an Italian family. 2016

Soldà, Giulia / Caccia, Sonia / Robusto, Michela / Chiereghin, Chiara / Castorina, Pierangela / Ambrosetti, Umberto / Duga, Stefano / Asselta, Rosanna. ·Department of Biomedical Sciences, Humanitas University, Milan, Italy. · Humanitas Clinical and Research Center, Milan, Italy. · Department of Biomedical and Clinical Sciences "Luigi Sacco", Università degli Studi di Milano - LITA Vialba, Milan, Italy. · UO Audiologia, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy. · Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano, Milan, Italy. ·J Hum Genet · Pubmed #26657938.

ABSTRACT: 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.

7 Article Risk factors for idiopathic sudden sensorineural hearing loss and their association with clinical outcome. 2015

Passamonti, Serena M / Di Berardino, Federica / Bucciarelli, Paolo / Berto, Valentina / Artoni, Andrea / Gianniello, Francesca / Ambrosetti, Umberto / Cesarani, Antonio / Pappalardo, Emanuela / Martinelli, Ida. ·A. Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico and University of Milan, Italy. Electronic address: seremap@gmail.com. · Audiology Unit, Department of Clinical Sciences and Community Health, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico and University of Milan, Italy. · A. Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico and University of Milan, Italy. ·Thromb Res · Pubmed #25619439.

ABSTRACT: 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.

8 Article Usher syndrome: an effective sequencing approach to establish a genetic and clinical diagnosis. 2015

Lenarduzzi, S / Vozzi, D / Morgan, A / Rubinato, E / D'Eustacchio, A / Osland, T M / Rossi, C / Graziano, C / Castorina, P / Ambrosetti, U / Morgutti, M / Girotto, G. ·Department of Medical Sciences, University of Trieste, Italy. · Institute for Maternal and Child Health-IRCCS "Burlo Garofolo", Trieste, Italy. · Department of Genetics, University of Bologna, Policlinico S. Orsola-Malpighi, Bologna, Italy. · UO Audiology, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy. · UO Audiology, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy; Audiology Unit, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy. · Department of Medical Sciences, University of Trieste, Italy. Electronic address: giorgia.girotto@burlo.trieste.it. ·Hear Res · Pubmed #25575603.

ABSTRACT: Usher syndrome is an autosomal recessive disorder characterized by retinitis pigmentosa, sensorineural hearing loss and, in some cases, vestibular dysfunction. The disorder is clinically and genetically heterogeneous and, to date, mutations in 11 genes have been described. This finding makes difficult to get a precise molecular diagnosis and offer patients accurate genetic counselling. To overcome this problem and to increase our knowledge of the molecular basis of Usher syndrome, we designed a targeted resequencing custom panel. In a first validation step a series of 16 Italian patients with known molecular diagnosis were analysed and 31 out of 32 alleles were detected (97% of accuracy). After this step, 31 patients without a molecular diagnosis were enrolled in the study. Three out of them with an uncertain Usher diagnosis were excluded. One causative allele was detected in 24 out 28 patients (86%) while the presence of both causative alleles characterized 19 patients out 28 (68%). Sixteen novel and 27 known alleles were found in the following genes: USH2A (50%), MYO7A (7%), CDH23 (11%), PCDH15 (7%) and USH1G (2%). Overall, on the 44 patients the protocol was able to characterize 74 alleles out of 88 (84%). These results suggest that our panel is an effective approach for the genetic diagnosis of Usher syndrome leading to: 1) an accurate molecular diagnosis, 2) better genetic counselling, 3) more precise molecular epidemiology data fundamental for future interventional plans.

9 Article The expanding spectrum of PRPS1-associated phenotypes: three novel mutations segregating with X-linked hearing loss and mild peripheral neuropathy. 2015

Robusto, Michela / Fang, Mingyan / Asselta, Rosanna / Castorina, Pierangela / Previtali, Stefano C / Caccia, Sonia / Benzoni, Elena / De Cristofaro, Raimondo / Yu, Cong / Cesarani, Antonio / Liu, Xuanzhu / Li, Wangsheng / Primignani, Paola / Ambrosetti, Umberto / Xu, Xun / Duga, Stefano / Soldà, Giulia. ·Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy. · BGI-Shenzhen, Shenzhen, China. · Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, UO Audiologia, Milan, Italy. · Division of Neuroscience, Institute of Experimental Neurology, San Raffaele Scientific Institute, Milan, Italy. · Laboratory of Medical Genetics, Molecular Genetic Sector, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy. · Haemostasis Research Center, Institute of Internal Medicine and Geriatrics, Catholic University School of Medicine, Rome, Italy. ·Eur J Hum Genet · Pubmed #25182139.

ABSTRACT: 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.

10 Article Genome-wide association analysis demonstrates the highly polygenic character of age-related hearing impairment. 2015

Fransen, Erik / Bonneux, Sarah / Corneveaux, Jason J / Schrauwen, Isabelle / Di Berardino, Federica / White, Cory H / Ohmen, Jeffrey D / Van de Heyning, Paul / Ambrosetti, Umberto / Huentelman, Matthew J / Van Camp, Guy / Friedman, Rick A. ·1] Center for Medical Genetics, University of Antwerp, Antwerp, Belgium [2] StatUa Center for Statistics, University of Antwerp, Antwerp, Belgium. · Center for Medical Genetics, University of Antwerp, Antwerp, Belgium. · Neurogenomics Division, The Translational Genomics Research Institute, Phoenix, AZ, USA. · 1] Center for Medical Genetics, University of Antwerp, Antwerp, Belgium [2] StatUa Center for Statistics, University of Antwerp, Antwerp, Belgium [3] Neurogenomics Division, The Translational Genomics Research Institute, Phoenix, AZ, USA. · 1] Audiology Unit, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy [2] Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. · Cell Biology and Genetics Division, House Research Institute, Los Angeles, CA, USA. · Department of Otolaryngology, University Hospital of Antwerp, Edegem, Belgium. ·Eur J Hum Genet · Pubmed #24939585.

ABSTRACT: 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.

11 Article Emerging ciliopathies: are respiratory cilia compromised in Usher syndrome? 2014

Piatti, G / De Santi, M M / Brogi, M / Castorina, P / Ambrosetti, U. ·Department of Pathophysiology and Transplantation, University of Milan, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Italy. Electronic address: gioia.piatti@unimi.it. · Department of Human Pathology and Oncology, University of Siena, Italy. · Department of Clinical Sciences and Community, University of Milan, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Italy. ·Am J Otolaryngol · Pubmed #24602455.

ABSTRACT: PURPOSE: Usher syndrome is a ciliopathy involving photoreceptors and cochlear hair cells (sensory cilia): since sensory and motor ciliopathies can overlap, we analysed the respiratory cilia (motile) in 17 patients affected by Usher syndrome and 18 healthy control subject. PATIENTS AND METHODS: We studied the mucociliary transport time with the saccharine test, ciliary motility and ultrastructure of respiratory cilia obtained by nasal brushing; we also recorded the classical respiratory function values by spirometry. RESULTS: All enrolled subjects showed normal respiratory function values. The mean mucociliary transport time with saccharine was 22.33 ± 17.96 min, which is in the range of normal values. The mean ciliary beat frequency of all subjects was 8.81 ± 2.18 Hz, which is a value approaching the lower physiological limit. None of the classical ciliary alterations characterizing the "ciliary primary dyskinesia" was detected, although two patients showed alterations in number and arrangement of peripheral microtubules and one patient had abnormal ciliary roots. CONCLUSIONS: Respiratory cilia in Usher patients don't seem to have evident ultrastructural alterations, as expected, but the fact that the ciliary motility appeared slightly reduced could emphasize that a rigid distinction between sensory and motor ciliopathies may not reflect what really occurs.

12 Article Public awareness of ear and hearing management as measured using a specific questionnaire. 2013

Di Berardino, Federica / Forti, Stella / Iacona, Elisabetta / Orlandi, Giovanna P / Ambrosetti, Umberto / Cesarani, Antonio. ·Audiology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Pace 9, 20122 Milan, Italy. ·Eur Arch Otorhinolaryngol · Pubmed #22350429.

ABSTRACT: 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.

13 Article Audiological findings in Williams syndrome: a study of 69 patients. 2012

Barozzi, Stefania / Soi, Daniela / Comiotto, Elisabetta / Borghi, Anna / Gavioli, Chiara / Spreafico, Emanuela / Gagliardi, Chiara / Selicorni, Angelo / Forti, Stella / Ambrosetti, Umberto / Cesarani, Antonio / Brambilla, Daniele. ·Audiologic Unit, Department of Specialized Surgical Sciences, University of Milan, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy. stefania.barozzi@unimi.it ·Am J Med Genet A · Pubmed #22411878.

ABSTRACT: 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.

14 Article A novel mutation within the MIR96 gene causes non-syndromic inherited hearing loss in an Italian family by altering pre-miRNA processing. 2012

Soldà, Giulia / Robusto, Michela / Primignani, Paola / Castorina, Pierangela / Benzoni, Elena / Cesarani, Antonio / Ambrosetti, Umberto / Asselta, Rosanna / Duga, Stefano. ·Dipartimento di Biologia e Genetica per Scienze Mediche, Università degli Studi di Milano, Milan, Italy. giulia.solda@unimi.it ·Hum Mol Genet · Pubmed #22038834.

ABSTRACT: 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.

15 Article Four-year follow-up of diagnostic service in USH1 patients. 2011

Roux, Anne-Françoise / Faugère, Valérie / Vaché, Christel / Baux, David / Besnard, Thomas / Léonard, Susana / Blanchet, Catherine / Hamel, Christian / Mondain, Michel / Gilbert-Dussardier, Brigitte / Edery, Patrick / Lacombe, Didier / Bonneau, Dominique / Holder-Espinasse, Muriel / Ambrosetti, Umberto / Journel, Hubert / David, Albert / Lina-Granade, Geneviève / Malcolm, Sue / Claustres, Mireille. ·Laboratoire de Génétique Moléculaire, Montpellier, France. anne-francoise.roux@inserm.fr ·Invest Ophthalmol Vis Sci · Pubmed #21436283.

ABSTRACT: 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.

16 Article GJB2 and MTRNR1 contributions in children with hearing impairment from Northern Cameroon. 2011

Trotta, Luca / Iacona, Elisabetta / Primignani, Paola / Castorina, Pierangela / Radaelli, Chiara / Del Bo, Luca / Coviello, Domenico / Ambrosetti, Umberto. ·Laboratory of Medical Genetics, Molecular Genetic Sector, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. ·Int J Audiol · Pubmed #21114417.

ABSTRACT: 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.

17 Article Tinnitus sound therapy with open ear canal hearing aids. 2010

Forti, S / Crocetti, A / Scotti, A / Costanzo, S / Pignataro, L / Ambrosetti, U / Del Bo, L. ·Audiology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. ·B-ENT · Pubmed #21090162.

ABSTRACT: OBJECTIVE: The aims of this study were to evaluate the efficacy of open ear canal hearing aids in tinnitus treatment and to investigate the influence of gender, age, medication usage, tinnitus cause, tinnitus perception side, tinnitus pitch, pure tone audiometry, distortion product otoacoustic emissions, and minimal masking level on outcome. METHODOLOGY: One hundred tinnitus patients were evaluated by the tinnitus handicap inventory (THI) at the beginning of the study and after nine months of treatment. All subjects were submitted to counselling and sound enrichment from the simple sound amplification provided by the open ear canal hearing aids. RESULTS: Initial mean THI score was 54.22 (+/- 20.37) and final mean score was 28.32 (+/- 16.50), p < 0.0001. No statistically significant correlations were found between THI value reduction and the studied parameters. CONCLUSION: Open ear canal hearing aids were useful in all tinnitus patients with mild hearing loss.

18 Article Tinnitus patients lost to follow-up. 2010

Forti, Stella / Ambrosetti, Umberto / Crocetti, Andrea / Del Bo, Luca. ·Audiology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. aut_est@yahoo.it ·Int J Audiol · Pubmed #21070123.

ABSTRACT: 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.

19 Article Cochlear implantation in adolescents with prelinguistic deafness. 2010

Arisi, Elena / Forti, Stella / Pagani, Davide / Todini, Loredana / Torretta, Sara / Ambrosetti, Umberto / Pignataro, Lorenzo. ·Department of Specialist Surgical Sciences, University of Milan, Milan, Italy. elena.arisi@gmail.com ·Otolaryngol Head Neck Surg · Pubmed #20493349.

ABSTRACT: 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.