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Purpose: To determine the utility of ophthalmology evaluation, dark-adapted threshold, and full-field electroretinogram for early detection of Usher syndrome in young patients with bilateral sensorineural hearing loss. Methods: We identified 39 patients with secure genetic diagnoses of Usher Syndrome. Visual acuity, spherical equivalent, fundus appearance, dark-adapted threshold, and full-field electroretinogram results were summarized and compared to those in a group of healthy controls with normal hearing. In those Usher patients with repeated measures, regression analysis was done to evaluate for change in visual acuity and dark-adapted threshold with age. Spherical equivalent and full-field electroretinogram responses from dark- and light-adapted eyes were evaluated as a function of age. Results: The majority of initial visual acuity and spherical equivalent results were within normal limits for age. Visual acuity and dark-adapted threshold worsened significantly with age in Usher type 1 but not in Usher type 2. At initial test, full-field electroretinogram responses from dark- and light-adapted eyes were abnormal in 53% of patients. Remarkably, nearly half of our patients (17% of Usher type 1 and 30% of Usher type 2) would have been missed by tests of retinal function alone if evaluated before age 10. Conclusions: Although there is an association of abnormal dark-adapted threshold and full-field electroretinogram at young ages in Usher patients, it appears that a small but important proportion of patients would not be detected by tests of retinal function alone. Thus, genetic testing is needed to secure a diagnosis of Usher syndrome.

Human cytomegalovirus (hCMV) is one of the most common causes of congenital infection in the post-rubella era, representing a major public health concern. Although most cases are asymptomatic in the neonatal period, congenital CMV (cCMV) disease can result in permanent impairment of cognitive development and represents the leading cause of non-genetic sensorineural hearing loss. Moreover, even if hCMV mostly causes asymptomatic or pauci-symptomatic infections in immunocompetent hosts, it may lead to severe and life-threatening disease in immunocompromised patients. Since immunity reduces the severity of disease, in the last years, the development of an effective and safe hCMV vaccine has been of great interest to pharmacologic researchers. Both hCMV live vaccines—e.g., live-attenuated, chimeric, viral-based—and non-living ones—subunit, RNA-based, virus-like particles, plasmid-based DNA—have been investigated. Encouraging data are emerging from clinical trials, but a hCMV vaccine has not been licensed yet. Major difficulties in the development of a satisfactory vaccine include hCMV’s capacity to evade the immune response, unclear immune correlates for protection, low number of available animal models, and insufficient general awareness. Moreover, there is a need to determine which may be the best target populations for vaccine administration. The aim of the present paper is to examine the status of hCMV vaccines undergoing clinical trials and understand barriers limiting their development.

Spermatogenesis-associated 5 like 1 (SPATA5L1) represents an orphan gene encoding a protein of unknown function. We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural hearing loss in 47 individuals from 28 (26 unrelated) families. In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy. Modeling indicated damaging effect of variants on the protein, largely via destabilizing effects on protein domains. Brain imaging revealed diminished cerebral volume, thin corpus callosum, and periventricular leukomalacia, and quantitative volumetry demonstrated significantly diminished white matter volumes in several individuals. Immunofluorescent imaging in rat hippocampal neurons revealed localization of Spata511 in neuronal and glial cell nuclei and more prominent expression in neurons. In the rodent inner ear, Spata511 is expressed in the neurosensory hair cells and inner ear supporting cells. Transcriptomic analysis performed with fibroblasts from affected individuals was able to distinguish affected from controls by principal components. Analysis of differentially expressed genes and networks suggested a role for SPATA5L1 in cell surface adhesion receptor function, intracellular focal adhesions, and DNA replication and mitosis. Collectively, our results indicate that bi-allelic SPATA5L1 variants lead to a human disease characterized by sensorineural hearing loss (SNHL) with or without a nonprogressive mixed neurodevelopmental phenotype.

Sensorineural hearing loss is a heterogeneous disease caused by mutations in many genes. However, in the presence of enlarged vestibular aqueduct, it is frequently associated with mutations in the solute carrier family 26 member 4 (SLC26A4), a gene causative of a syndromic form (Pendred) as well as a non-syndromic form of hearing loss (DFNB4). We describe a clinical case presenting bilateral sensorineural hearing loss and enlarged vestibular aqueduct in which a novel homozygous SLC26A4 mutation was identified. Despite a late diagnosis of hearing loss, a peculiar rehabilitation therapy strategy was identified that provided excellent results.

Peroxisomal biogenesis disorders (PBD) are rare autosomal recessive disorders with various degrees of severity caused by hypomorphic mutations in 13 different peroxin (PEX) genes. In this study, we report the clinical and molecular characterization of a 9-years-old female presenting an apparently isolated pre-lingual sensorineural hearing loss (SNHL) and early onset Retinitis Pigmentosa (RP) that may clinically overlap with Usher syndrome. Genetic testing by clinical exome sequencing identified two variants in PEX1: the missense variant c.274G > C; p.(Val92Leu) that was already reported in a PBD patient, and the variant c.2140_2145dup; p.(Ser714_Gln715dup) which is a novel, non-frameshift variant, absent in control databases. On the basis of the molecular analysis, a thorough clinical examination revealed nail and dental abnormalities, a mild cognitive impairment, learning disabilities and poor feeding, apart from the retinal and audiological features initially identified. The clinical and molecular findings led us to the diagnosis of a mild form of PBD. This study further emphasizes that mild forms of PBD can be a differential diagnosis of Usher syndrome and suggests that patients with mild cognitive impairment associated to visual and hearing loss should perform a comprehensive mutation screening that includes PEX genes.

Objective: To evaluate the frequency of GJB2 mutations and their correlation with phenotype in Sicilian non-syndromic sensorineural hearing loss (NSHL) patients. Design: Sequencing of the coding region, basal promoter, exon 1, and donor splice site of the GJB2 gene; screening for the presence of the two common GJB6 deletions. Study sample: A cohort of 102 Sicilian NSHL patients. Results: Fifteen different mutations in GJB2 and seventeen different genotypes were detected. No GJB6 mutations were found. The hearing impairment was profound in the 64.72% of probands (mean PTA 0.25 – 4 kHz of 88.82 26.52 dB HL). A total of 81.37% of patients harboured at least one c.35delG allele; c.167delT and c.-23 1G A were identifi ed in 10.78% and the 9.8% of patients respectively; c.35delG homozygotes presented more severe hearing impairment (75.59% of profound hearing loss) and a higher mean PTA 0.25 – 4 kHz (96.79 21.11 dB HL) with respect to c.35delG/non-c.35delG and c.35delG/Wt patients (P 0.05). Conclusions: This work underlines the role of c.35delG, c.167delT and c.-23 1G A as the most frequent causes of NSHL in Sicily. The c.35delG frequency found is similar to those reported in other populations of the Mediterranean area. The analysis of genetic and audiologic data confi rmed a variability in the phenotype associated to a single genotype.

Objectives: MYH9-related disease (MYH9-RD) is an autosomal-dominant disorder deriving from mutations in MYH9, the gene for the nonmuscle myosin heavy chain (NMMHC)-IIA. MYH9-RD has a complex phenotype including congenital features, such as thrombocytopenia, and noncongenital manifestations, namely sensorineural hearing loss (SNHL), nephropathy, cataract, and liver abnormalities. The disease is caused by a limited number of mutations affecting different regions of the NMMHC-IIA protein. SNHL is the most frequent noncongenital manifestation of MYH9-RD. However, only scarce and anecdotal information is currently available about the clinical and audiometric features of SNHL of MYH9-RD subjects. The objective of this study was to investigate the severity and propensity for progression of SNHL in a large series of MYH9-RD patients in relation to the causative NMMHC-IIA mutations. Design: This study included the consecutive patients diagnosed with MYH9-RD between July 2007 and March 2012 at four participating institutions. A total of 115 audiograms were analyzed from 63 patients belonging to 45 unrelated families with different NMMHCIIA mutations. Cross-sectional analyses of audiograms were performed. Regression analysis was performed, and age-related typical audiograms (ARTAs) were derived to characterize the type of SNHL associated with different mutations. Results: Severity of SNHL appeared to depend on the specific NMMHCIIA mutation. Patients carrying substitutions at the residue R702 located in the short functional SH1 helix had the most severe degree of SNHL, whereas patients with the p.E1841K substitution in the coiled-coil region or mutations at the nonhelical tailpiece presented a mild degree of SNHL even at advanced age. The authors also disclosed the effects of different amino acid changes at the same residue: for instance, individuals with the p.R702C mutation had more severe SNHL than those with the p.R702H mutation, and the p.R1165L substitution was associated with a higher degree of hearing loss than the p.R1165C. In general, mild SNHL was associated with a fairly flat audiogram configuration, whereas severe SNHL correlated with downsloping configurations. ARTA plots showed that the most progressive type of SNHL was associated with the p.R702C, the p.R702H, and the p.R1165L substitutions, whereas the p.R1165C mutation correlated with a milder, nonprogressive type of SNHL than the p.R1165L. ARTA for the p.E1841K mutation demonstrated a mild degree of SNHL with only mild progression, whereas the ARTA for the mutations at the nonhelical tailpiece did not show any substantial progression. Conclusions: These data provide useful tools to predict the progression and the expected degree of severity of SNHL in individual MYH9-RD patients, which is especially relevant in young patients. Consequences in clinical practice are important not only for appropriate patient counseling but also for development of customized, genotype-driven clinical management. The authors recently reported that cochlear implantation has a good outcome in MYH9-RD patients; thus, stricter follow-up and earlier intervention are recommended for patients with unfavorable genotypes. Fil: Verver, Eva J.J.. University of Utrecht; Países Bajos Fil: Topsakal, Vedat. University of Utrecht; Países Bajos Fil: Kunst, Henricus P. M.. Radboud University Medical Centre; Países Bajos Fil: Huygen, Patrick L. M.. Radboud University Medical Centre; Países Bajos Fil: Heller, Paula Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Pujol Moix, Nuria. Universitat Autònoma de Barcelona; España Fil: Savoia, Anna. Università degli Studi di Trieste; Italia. Istituti di Ricovero e Cura a Carattere Scientifico; Italia Fil: Benazzo, Marco. Fondazione Policlinico San Matteo; Italia. Istituti di Ricovero e Cura a Carattere Scientifico; Italia Fil: Fierro, Tiziana. Università di Perugia; Italia Fil: Grolman, Wilko. University of Utrecht; Países Bajos Fil: Gresele, Paolo. Università di Perugia; Italia Fil: Pecci, Alessandro. Fondazione Policlinico San Matteo; Italia. Istituti di Ricovero e Cura a Carattere Scientifico; Italia. Università degli Studi di Pavia; Italia

Objective To determine the feasibility and effectiveness of well-infant nursery hearing screening programme for the early identification of hearing impairment, based on transient evoked otoacoustic emission (TEOAE) with a high “screen sensitivity” reducing the number of more expensive secondary level exams. Methods The newborns were screened by non-specialist health workers in well babies nursery at the twentieth day of life for 6 years consecutive. Based on PASS/FAIL criteria and presence/absence of audiological risk factors the newborns were divided into four groups each one with its personal step programme: G1 – PASS without risk factor, free to go home; G2 – PASS with risk factor, retest at the age of 7 months; G3 – FAIL without risk factor, re-screening after 2 weeks for a maximum of four times before audiology assessment; G4 – FAIL with risk factor, retest after 2 weeks. Results The coverage rate increased progressively from 89.8% to 92%. The referral rate was 1.51% after second stage with a specificity value of 98.78%. The four-stage screening performed for G3 reduced the numbers of global audiology assessment to 0.91% with a final global specificity of 99.4 ± 0.4%. Conclusion Less than 1% of infants underwent audiological assessment; the false positives resulted 0.62% with hearing loss global incidence of 2.95/1000 and a mean age of confirmation of 3.5 months of age. It is reasonable to think that this screening programme could be implement to overall 42 Western Sicily birth centres within few years.

Background: Wolfram Syndrome type 2 (WFS2) is considered a phenotypic and genotypic variant of WFS, whose minimal criteria for diagnosis are diabetes mellitus and optic atrophy. The disease gene for WFS2 is . The clinical phenotype of WFS2 differs from WFS1 for the absence of diabetes insipidus and psychiatric disorders, and for the presence of bleeding upper intestinal ulcers and defective platelet aggregation. After the first report of consanguineous Jordanian patients, no further cases of WFS2 have been reported worldwide. We describe the first Caucasian patient affected by WFS2. Case presentation: The proband was a 17 year-old girl. She presented diabetes mellitus, optic neuropathy, intestinal ulcers, sensorineural hearing loss, and defective platelet aggregation to ADP. Genetic testing showed a novel homozygous intragenic deletion of in the proband. Her brother and parents carried the heterozygous mutation and were apparently healthy, although they showed subclinical defective platelet aggregation. Long runs of homozygosity analysis from SNP-array data did not show any degree of parental relationship, but the microsatellite analysis confirmed the hypothesis of a common ancestor. Conclusion: Our patient does not show optic atrophy, one of the main diagnostic criteria for WFS, but optic neuropathy. Since the "asymptomatic" optic atrophy described in Jordanian patients is not completely supported, we could suppose that the ocular pathology in Jordanian patients was probably optic neuropathy and not optic atrophy. Therefore, as optic atrophy is required as main diagnostic criteria of WFS, it might be that the so-called WFS2 could not be a subtype of WFS. In addition, we found an impaired aggregation to ADP and not to collagen as previously reported, thus it is possible that different experimental conditions or inter-patient variability can explain different results in platelet aggregation. Further clinical reports are necessary to better define the clinical spectrum of this syndrome and to re-evaluate its classification. Background: Wolfram Syndrome type 2 (WFS2) is considered a phenotypic and genotypic variant of WFS, whose minimal criteria for diagnosis are diabetes mellitus and optic atrophy. The disease gene for WFS2 is . The clinical phenotype of WFS2 differs from WFS1 for the absence of diabetes insipidus and psychiatric disorders, and for the presence of bleeding upper intestinal ulcers and defective platelet aggregation. After the first report of consanguineous Jordanian patients, no further cases of WFS2 have been reported worldwide. We describe the first Caucasian patient affected by WFS2. Case presentation: The proband was a 17 year-old girl. She presented diabetes mellitus, optic neuropathy, intestinal ulcers, sensorineural hearing loss, and defective platelet aggregation to ADP. Genetic testing showed a novel homozygous intragenic deletion of in the proband. Her brother and parents carried the heterozygous mutation and were apparently healthy, although they showed subclinical defective platelet aggregation. Long runs of homozygosity analysis from SNP-array data did not show any degree of parental relationship, but the microsatellite analysis confirmed the hypothesis of a common ancestor. Conclusion: Our patient does not show optic atrophy, one of the main diagnostic criteria for WFS, but optic neuropathy. Since the "asymptomatic" optic atrophy described in Jordanian patients is not completely supported, we could suppose that the ocular pathology in Jordanian patients was probably optic neuropathy and not optic atrophy. Therefore, as optic atrophy is required as main diagnostic criteria of WFS, it might be that the so-called WFS2 could not be a subtype of WFS. In addition, we found an impaired aggregation to ADP and not to collagen as previously reported, thus it is possible that different experimental conditions or inter-patient variability can explain different results in platelet aggregation. Further clinical reports are necessary to better define the clinical spectrum of this syndrome and to re-evaluate its classification.

Sudden sensorineural hearing loss (SSNHL), is an important otological disorder that affects up to 5-20 in 100,000 people. It is characterized by a rapid loss of the hearing, usually unilateral, with a sensorineural hearing loss greater than 30 dB over three consecutive frequencies, in less than 72 hours and can be associated with tinnitus and vertigo. It is a real sensorineural emergency that can become a permanent handicap if not adequately treated. Because of patients recovering rapidly or seeking no medical attention, the true figure might be higher, even if delaying SHL diagnosis and treatment may decrease the effectiveness of treatment. Sudden Hearing Loss can occur at any age but usually affects between 50 and 60 years old and the youngest patients affected are among 20-30 years old. There are not significantly differences in the prevalence between men and women[1-3]. Several pathophysiological mechanisms have been proposed to explain SHL (infective, vascular, and immune disease), but only 10 to 15 percent of the people have an identifiable cause; the majority of cases in fact remain 'idiopathic'[4].Because no specific cause is identified, the treatments are heterogeneous and can be considered empiric; on one hand therapies' aim is to correct the primary risk factors (smoke, diabetes, hypertension, previous viral or bacterial infections), on the other hand the purpose is to act on the main etiopathogenetic hypotheses (viral infection, immunologic, vascular compromise).