Neurosensory Deafness Research Articles

IGF-1 deficiency causes atrophic changes associated with upregulation of VGluT1 and downregulation of MEF2 transcription factors in the mouse cochlear nuclei.

Insulin-like growth factor 1 (IGF-1) is a neurotrophic protein that plays a crucial role in modulating neuronal function and synaptic plasticity in the adult brain. Mice lacking the Igf1 gene exhibit profound deafness and multiple anomalies in the inner ear and spiral ganglion. An issue that remains unknown is whether, in addition to these peripheral abnormalities, IGF-1 deficiency also results in structural changes along the central auditory pathway that may contribute to an imbalance between excitation and inhibition, which might be reflected in abnormal auditory brainstem responses (ABR). To assess such a possibility, we evaluated the morphological and physiological alterations in the cochlear nucleus complex of the adult mouse. The expression and distribution of the vesicular glutamate transporter 1 (VGluT1) and the vesicular inhibitory transporter (VGAT), which were used as specific markers for labeling excitatory and inhibitory terminals, and the involvement of the activity-dependent myocyte enhancer factor 2 (MEF2) transcription factors in regulating excitatory synapses were assessed in a 4-month-old mouse model of IGF-1 deficiency and neurosensorial deafness (Igf1 (-/-) homozygous null mice). The results demonstrate decreases in the cochlear nucleus area and cell size along with cell loss in the cochlear nuclei of the deficient mouse. Additionally, our results demonstrate that there is upregulation of VGluT1, but not VGAT, immunostaining and downregulation of MEF2 transcription factors together with increased wave II amplitude in the ABR recording. Our observations provide evidence of an abnormal neuronal cytoarchitecture in the cochlear nuclei of Igf1 (-/-) null mice and suggest that the increased efficacy of glutamatergic synapses might be mediated by MEF2 transcription factors.

PO-0433 Improving Quality Of Care And Rehabilitation Of Children With High Perinatal Risk

Background and aims The neurological complication and delay of development occur in ne0nates of high perinatal group. Improve the level of patient satisfaction. Methods The developmental assessment was performed in 60 VLBW infants and in 21 children with FAS. There were used Albert scale (gross motor) and KID - RSDI scale (cognitive, fine motor, speech and language, social and adaptive development). Results The comorbidity of VLBW were following: retinopathy of newbon (10%); neurosensory deafness (3,3%), bronchopulmonary dysplasia (5%), congenital heart diseases (12,5%). The medical problems of FAS were intrauterine growth retardation (42,8%, p 0,05) at the first year of life, at the second year - 3,3 mo and 5,6 mo respectively (p Conclusions The delay of motor development on the first year of life predominates in very low birth weight infants, the cognitive delay of development on the second years predominates in children with fetal alcohol syndrome. There was a significant risk of important information getting missed.

PO-0463 Low Incidence Of Neurosensorial Deafness In Infants Treated With Hypothermia For Neonatal Hypoxic-ischaemic Encephalopathy Can Be Related To Avoidance Of Ototoxic Antibiotics

Background and aims Hypoxic-ischaemic encephalopathy is a risk factor for neurosensorial deafness. Incidences up to 10% were described by some groups. Hypothermia can alter drug metabolism leading to increased risk of toxic levels. We aim to evaluate the incidence and identify risk factors for deafness in our patients. Methods We studied all infants treated with hypothermia at our NICU in a 4-year period (2010–2013). Demographic and clinical data, including drug use and hearing screening result, were collected from our prospectively collected database. Hearing follow-up of children now over 24 months was also collected. Results 50/59 newborns treated survived (66% male, mean GA 39 weeks, mean BW 3121 g, median Apgar scores 2/4/5, 84% ventilated >4 days, 54% inotropes, 6% >2 anticonvulsants, 64% furosemide). Initial antibiotherapy was ampicilin+cefotaxime in 96%, vancomycin was used in 12% for late sepsis (toxic levels in 1/6 patients). Auditory evoked-potentials performed in 92%, acoustic otoemissions performed in 4%, no hearing screening test on 4%. Only 2 failed on hearing screening, one died and the other is being evaluated. On follow-up of 17 patients at 2 years, 16 have normal hearing and 1 is being treated for hearing loss due to glue ear. Conclusions Despite potential risk factors on our patients, the occurrence of deafness was rare. Our protocol that avoids the use of gentamicin as first line antibiotic therapy can explain the important difference in incidence when compared to other studies. When their use is unavoidable, close monitoring of ototoxic drug levels should be performed.

Intraventricular Hemorrhage and Neurodevelopmental Outcomes in Extreme Preterm Infants

Not many large studies have reported the true impact of lower-grade intraventricular hemorrhages in preterm infants. We studied the neurodevelopmental outcomes of extremely preterm infants in relation to the severity of intraventricular hemorrhage. A regional cohort study of infants born at 23 to 28 weeks' gestation and admitted to a NICU between 1998 and 2004. Primary outcome measure was moderate to severe neurosensory impairment at 2 to 3 years' corrected age defined as developmental delay (developmental quotient >2 SD below the mean), cerebral palsy, bilateral deafness, or bilateral blindness. Of the 1472 survivors assessed, infants with grade III-IV intraventricular hemorrhage (IVH; n = 93) had higher rates of developmental delay (17.5%), cerebral palsy (30%), deafness (8.6%), and blindness (2.2%). Grade I-II IVH infants (n = 336) also had increased rates of neurosensory impairment (22% vs 12.1%), developmental delay (7.8% vs 3.4%), cerebral palsy (10.4% vs 6.5%), and deafness (6.0% vs 2.3%) compared with the no IVH group (n = 1043). After exclusion of 40 infants with late ultrasound findings (periventricular leukomalacia, porencephaly, ventricular enlargement), isolated grade I-II IVH (n = 296) had increased rates of moderate-severe neurosensory impairment (18.6% vs 12.1%). Isolated grade I-II IVH was also independently associated with a higher risk of neurosensory impairment (adjusted odds ratio 1.73, 95% confidence interval 1.22-2.46). Grade I-II IVH, even with no documented white matter injury or other late ultrasound abnormalities, is associated with adverse neurodevelopmental outcomes in extremely preterm infants.

Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study

A single course of antenatal corticosteroid therapy is recommended for pregnant women at risk of preterm birth between 24 and 33 weeks' gestational age. However, 50% of women remain pregnant 7 to 14 days later, leading to the question of whether additional courses should be given to women remaining at risk for preterm birth. The Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study (MACS) was an international randomized clinical trial that compared multiple courses of antenatal corticosteroids with a single course in women at risk of preterm birth. To determine the effects of single vs multiple courses of antenatal corticosteroid therapy on death or neurodevelopmental disability (neuromotor, neurosensory, or neurocognitive/neurobehavioral function) at 5 years of age in children whose mothers participated in MACS. Our secondary aims were to determine the effect on height, weight, head circumference, blood pressure, intelligence, and specific cognitive (visual, spatial, and language) skills. Cohort follow-up study of children seen between June 2006 and May 2012 at 55 centers. In total, 1724 women (2141 children) were eligible for the study, of whom 1728 children (80.7% of the 2141 eligible children) participated and 1719 children contributed to the primary outcome. Single and multiple courses of antenatal corticosteroid therapy. The primary outcome was death or survival with a neurodevelopmental disability in 1 of the following domains: neuromotor (nonambulatory cerebral palsy), neurosensory (blindness, deafness, or need for visual/hearing aids), or neurocognitive/neurobehavioral function (abnormal attention, memory, or behavior). There was no significant difference between the groups in the risk of death or neurodevelopmental disability: 217 of 871 children (24.9%) in the multiple-courses group vs 210 of 848 children (24.8%) in the single-course group (odds ratio, 1.02 [95% CI, 0.81 to 1.29]; P = .84). Multiple courses, compared with a single course, of antenatal corticosteroid therapy did not increase or decrease the risk of death or disability at 5 years of age. Because of a lack of strong conclusive evidence of short-term or long-term benefits, it remains our opinion that multiple courses not be recommended in women with ongoing risk of preterm birth. clinicaltrials.gov Identifier: NCT00187382.

Novel mutations of SLC26A4 in Chinese patients with nonsyndromic hearing loss

Conclusions: This study demonstrated high prevalence of GJB2, SLC26A4, and mtDNA A1555G mutations in Chinese patients with nonsyndromic hearing loss and discovered eight novel mutations in SLC26A4. Most of these novel mutations were predicted pathogenic variants. Objectives: Nonsyndromic hearing loss is the most common neurosensory deafness where the majority of patients have highly diversified genetic defects. This study aimed to define the genetic profile of deafness in a Chinese population with potential to discover novel mutations. Methods: A total of 227 segregating deaf students and 200 individuals with normal hearing were enrolled. With the Sanger sequencing chemistry, direct sequencing was performed on entire coding regions of GJB2, GJB3, SLC26A4, and mtDNA m.C1494T and m.A1555G. Results: Direct sequencing analysis revealed that 53 (23.35%) of 227 patients carried at least 1 mutant allele in GJB2, 40 (17.62%) patients in SLC26A4, 5 (2.20%) patients in mtDNA A1555G, and 1 (0.44%) patient in mtDNA C1494T mutations. Four patients carried three unclassified mutations in GJB3 genes. Overall 38 mutant variants were detected in this cohort of patients, including 8 novel mutations in SLC26A4. The eight novel variants were six missense substitutions (p.V163L, p.G222S, p.A456D, p.N457I, p.C466Y, p.F667L), one nonsense mutation (p.W472X), and one frameshift (p.Asn612Ilefs×23).

Intragenic ILRAPL1 deletion in a male patient with intellectual disability, mild dysmorphic signs, deafness, and behavioral problems

Intellectual disability affects approximately 2% of the population, with affected males outnumbering affected female, partly due to disturbances involving X-linked genes. To date >90 genes associated with X-linked intellectual disability have been identified and, among these, IL1RAPL1 (interleukin 1 receptor accessory protein-like 1), was first described and mapped to Xp21.3-22.1 in 1999. Intragenic deletions of IL1RAPL1, only rarely identified, have mostly been associated with nonspecific intellectual disability (IDX) and autism spectrum disorder. Array-CGH analysis performed in our patient with intellectual disability, mild dysmorphic signs and changes in behavior identified a 285 Kb deletion in chromosome Xp21.3-21.2, with breakpoints lying in IL1RAPL1 gene intron 2 and intron 3. This is the first patient reported in literature with deletion of only exon 3 of IL1RAPL1 gene. Our patient also exhibits bilateral progressive neurosensorial deafness, which has not been previously associated with IL1RAPL1 mutations.

Síndrome de rubéola congénita en diecisiete hospitales del Perú, 1998-2000

Objetivo: Determinar la presencia de casos de síndrome de rubéola congénita (SRC) en Hospitales Nacionales e Institutos Especializados del Perú. Diseño: Transversal, descriptivo. Material y Métodos: Se revisó historias clínicas de niños hospitalizados entre enero de 1998 y junio de 2000 en 17 hospitales ubicados en 7 departamentos del Perú, niños que presentaron cuando menos alguno de los siguientes diagnósticos: catarata o glaucoma congénitos, retinitis pigmentosa, malformación cardíaca congénita o sordera neurosensorial. Resultados: De 91 102 diagnósticos de egresos hospitalarios en niños menores de 12 años, 361 cumplían con los criterios de inclusión para el estudio; de ellos, 187 (51,8%) tuvieron sospecha de síndrome de rubéola congénita (SRC), 35 (9,7%) fueron casos probables y 5 (1,4%) confirmados. Las principales manifestaciones clínicas fueron cardiovasculares (93,6%), del sistema nervioso central (29,6%) y oculares (18,6%); 11% de los niños tuvo más de una manifestación clínica. Conclusión: Existe evidencia de niños con SRC que han sido hospitalizados en 17 hospitales en el Perú.

Keratitis, Ichthyosis and Deafness (KID) Syndrome – a Case Report

Abstract Keratitis, ichthyosis and deafness (KID) syndrome is a rare congenital ectodermal dysplasia characterized by ichthyosiform hyperkeratosis of the skin, neurosensory hearing loss and vascularizing keratitis. It is inherited as an autosomal dominant trait, now known to be due to mutations in the connexin gene. This paper presents a case of a 20-year-old male patient with erythrokeratodermia and mild scaling since birth. He presented mild hearing impairment at the age of two and often suffered from eye inflammations. On admission, his clinical picture was typical of KID syndrome with erythrokeratodermia, neurosensory deafness, vascularizing keratitis, alopecia, palmoplantar keratosis, and nail dystrophy. The patient also had a history of recurrent infections, especially bacterial and candidal infections of the skin, auditory canals and eyes. Despite extensive skin, ocular, ear and hair manifestations, his physical and psychomotor growth and development were normal. Adjuvant balneotherapy in Prolom Spa, along with emollient creams, significantly reduced cutaneous manifestations in our patient.

Keratitis, congenital ichthyosis, and neurosensory deafness syndrome with tinea capitis and severe kerion formation

Keratitis, congenital ichthyosis, and neurosensory deafness syndrome with tinea capitis and severe kerion formation

Prevalence of the 35delG mutation in the GJB2 gene in two samples of non-syndromic deaf subjects from Chile

Hearing loss is the most common inherited sensorial deficiency in humans; about 1 in 1000 children suffer from severe or profound hearing loss at birth. Mutations in the GJB2 gene are the most common cause of prelingual, non-syndromic autosomal recessive deafness in many populations; the c.35delG mutation is the most common in Caucasian populations. The frequency of the c.35delG mutation was estimated in two samples of deaf patients from Santiago, Chile. Unrelated non-syndromic sensorioneural deaf patients were examined: Group 1 consisted of 47 unrelated individuals with neurosensory deafness referred to the Chilean Cochlear Implant Program; Group 2 included 66 school children with prelingual deafness attending special education institutions for deaf people. Individuals with profound to moderate isolated neurosensory hearing loss with unknown etiology were included. The presence of the c.35delG mutation was evaluated by the allele-specific polymerase chain reaction method (PCR), and in some cases it was confirmed by direct DNA sequencing of the coding region of the GJB2 gene. Deaf relatives were present in 20.3% of the cases. We found 19.5% (22/113) patients with the c.35delG mutation, 6 of them homozygous; these rates are similar to frequencies found in other Latin American countries.

Sporadic myopathy, myoclonus, leukoencephalopathy, neurosensory deafness, hypertrophic cardiomyopathy and insulin resistance associated with the mitochondrial 8306 T>C MTTK mutation

We report a new T8306C transition in the D-stem of the MTTK gene of a 67-year-old man who manifested severe adult onset myopathy, myoclonus, leukoencephalopathy, neurosensory hypoacusis, hypertrophic cardiomyopathy and insulin resistance. No other family member was affected, suggesting that our patient was a sporadic case. The T8306C mutation was heteroplasmic in several tissues of the proband, while it was absent from his asymptomatic siblings. Single fibre analysis confirmed the segregation of higher mutational load in cytochrome c oxidase-deficient fibres. The mutation T8306C is predicted to disrupt a highly conserved base pair and was not found in more than 120 controls. This finding broadens the phenotypic and molecular spectrum of mitochondrial tRNALys associated disorders.

Hereditary deafness in Kirov oblast: Estimation of the incidence rate and DNA diagnosis in children

Genetic analysis of hereditary deafness (HD) has been performed in the city of Kirov and ten rural districts of Kirov oblast (administrative region). The analysis employed the methods used in audiology, medical genetic counseling, and DNA diagnosis. Deafness has been established to be hereditary in 143 children from 100 unrelated families. The incidence rates of isolated and syndromic HDs in the period studied (1995-2001) have been estimated at 1.25 and 0.36 per 1000 newborns, respectively, the total incidence rate of all HD forms being 1.61 per 1000 newborns (1 case per 621 newborns). DNA analysis for the detection of seven frequent mutations in the genes GJB2 (the 35delG, 167delT, 235delC, and M34T mutations), GJB6 (the del(GJB6-D13S1854) and del(GJB6-D13S1830) mutations), and TMC1 (the R34X mutation) has been performed in families with isolated neurosensory deafness. Molecular genetic analysis has detected mutations in 51 children (48.6%); in 54 children (51.4%), no mutations have been found. The following genotypes have been identified in children with HD: 35delG/35delG in 32 probands (30.5%), 35delG/+ in 16 probands (15.2%), 35delG/235delC in 1 proband (0.95%), M34T/+ in 1 proband (0.95%), and M34T/35delG in 1 proband (0.95%). The 167delT mutation has not been found. The frequency of the 35delG mutation in the GJB2 gene has been estimated to be 39.05%. In the group with a family history of HD, mutations have been found in 66.7% of patients; in the group without a family history of HD, in 37.5% of patients. No mutation has been found in the GJB6 or TMC1 gene. Molecular genetic analysis has been performed in a family with clinically diagnosed Treacher Collins-Franceschetti syndrome. Sequencing has been used to find the 748-69C>T polymorphism in intron 6 (in the homozygous state) and the 3635C>G mutation in exon 23 leading to the substitution of glycine for alanine at position 1176 of the amino acid sequence (Ala1176Gly, in the heterozygous state), which have not been described before.

Age-related functional and structural retinal modifications in the Igf1−/− null mouse

BackgroundMutations in the gene encoding human insulin-like growth factor-I (IGF-I) cause syndromic neurosensorial deafness. To understand the precise role of IGF-I in retinal physiology, we have studied the morphology and electrophysiology of the retina of the Igf1−/− mice in comparison with that of the Igf1+/− and Igf1+/+ animals during aging. MethodsSerological concentrations of IGF-I, glycemia and body weight were determined in Igf1+/+, Igf1+/− and Igf1−/− mice at different times up to 360days of age. We have analyzed hearing by recording the auditory brainstem responses (ABR), the retinal function by electroretinographic (ERG) responses and the retinal morphology by immunohistochemical labeling on retinal preparations at different ages. ResultsIGF-I levels are gradually reduced with aging in the mouse. Deaf Igf1−/− mice had an almost flat scotopic ERG response and a photopic ERG response of very small amplitude at postnatal age 360days (P360). At the same age, Igf1+/− mice still showed both scotopic and photopic ERG responses, but a significant decrease in the ERG wave amplitudes was observed when compared with those of Igf1+/+ mice. Immunohistochemical analysis showed that P360 Igf1−/− mice suffered important structural modifications in the first synapse of the retinal pathway, that affected mainly the postsynaptic processes from horizontal and bipolar cells. A decrease in bassoon and synaptophysin staining in both rod and cone synaptic terminals suggested a reduced photoreceptor output to the inner retina. Retinal morphology of the P360 Igf1+/− mice showed only small alterations in the horizontal and bipolar cell processes, when compared with Igf1+/+ mice of matched age. ConclusionsIn the mouse, IGF-I deficit causes an age-related visual loss, besides a congenital deafness. The present results support the use of the Igf1−/− mouse as a new model for the study of human syndromic deaf-blindness.

Endolymphatic Sac Tumors

Tumors of the endolymphatic sac are rare and can be found in patients with Von Hippel Lindau disease. They most often develop within the intrapetrosal part of the sac but can sometimes be located in the distal part. Their growth is slow and they spread in two directions: laterally toward the external and middle ear and in the direction of the jugular foramen and medially into the ponto-cerebellar angle. The symptoms are usually auditive, with a constant neurosensorial deafness of sudden onset in 50 % of cases and sometimes associated with a tinnitus and dizziness. The varieties with medial extension result in a cerebellopontine angle syndrome. Diagnosis is made by imaging (CT scan and MRI) that reveals a heterogeneous tumor between the lateral sinus and the internal auditory meatus, hypervascularized showing contrast, with cystic zones and associated with bone lysis. Histological examination of a papillary cystadenoma is performed and the differential diagnosis is essentially made with a papillary of the choroïd plexus. They require total surgical excision in order to avoid possible recurrence and can be performed by retrosigmoïd approach, or more ideally, by transpetrosal approach.

Two Portuguese Cochlear Implanted Dizygotic Twins: A Case Report

Individual's hearing performance after cochlear implant (CI) is variable and depends on different factors such as etiology of deafness, age at implantation, and social/family hearing environment. Here we report the case of dizygotic twins, boy and girl, presenting with neurosensorial profound deafness prior CI (age of implantation = 3.5 years old). Both parents have severe/profound deafness, since childhood, and use sign language as primary mode of communication. Clinical and genetic characterization was performed, as well as the assessment of the auditory and oral (re)habilitation after CI, applying a battery of audiological, speech, and language tests. The twin girl and the father were homozygous for the c.35delG mutation in the GJB2 gene, while the twin boy and the mother were compound heterozygotes, both monoallelic for c.35delG and for the deletion del(GJB6-D13S1830) in the GJB6 gene. The remaining hearing impaired relatives were c.35delG homozygotes. The genetic cause of deafness was thus identified in this family. Some noteworthy differences were observed regarding twins' auditory and oral performance after CI. Subsequent follow-up of these children allowed us to conclude that those differences were most likely due to the different environment in which the twins have been living than to their different GJB2/GJB6 genotypes.

Insomnio y anormalidades conductuales como manifestaciones iniciales en una paciente con síndrome de Sanfilippo

Mucopolysaccharidoses are a heterogeneous group of diseases characterized by a genetic abnormality of the enzymes that participate in the metabolism of glucosamines in lysosomes. The most frequent findings in affected patients are the presence of coarse facial features associated with eye, bone and heart involvement; hepatosplenomegaly, skin infiltration, and umbilical and inguinal hernias. Neurological manifestations may vary from normal intellect, delay in psychomotor development, to progressive severe neurological deterioration. Clinical manifestations of mucopolysaccharidosis III or Sanfilippo disease are the paradigm of the accumulation of glycosaminoglycans in the central nervous system; however the lack of visceral involvement frequently delays diagnosis. We describe the neurological findings after a 5 year course of the disease in a patient with insomnia, neurosensory deafness, self-aggression, and neurological regression. Multiple hereditary and acquired disorders were discarded during the progress of the disease, but it was at the age of eight years when a lysosomal disorder was suspected; a quantification of urinary glycosaminoglycans was done, which confirmed the diagnosis of Sanfilippo syndrome.

Nonsense Mutations in FGF8 Gene Causing Different Degrees of Human Gonadotropin-Releasing Deficiency

FGFR1 mutations cause isolated hypogonadotropic hypogonadism (IHH) with or without olfactory abnormalities, Kallmann syndrome, and normosmic IHH respectively. Recently, missense mutations in FGF8, a key ligand for fibroblast growth factor (FGF) receptor 1 in the ontogenesis of GnRH, were identified in IHH patients, thus establishing FGF8 as a novel locus for human GnRH deficiency. Our objective was to analyze the clinical, hormonal, and molecular findings of two familial IHH patients due to FGF8 gene mutations. The entire coding region of the FGF8 gene was amplified and sequenced in two well-phenotyped IHH probands and their relatives. Two unique heterozygous nonsense mutations in FGF8 (p.R127X and p.R129X) were identified in two unrelated IHH probands, which were absent in 150 control individuals. These two mutations, mapped to the core domain of FGF8, impact all four human FGF8 isoforms, and lead to the deletion of a large portion of the protein, generating nonfunctional FGF8 ligands. The p.R127X mutation was identified in an 18-yr-old Kallmann syndrome female. Her four affected siblings with normosmic IHH or delayed puberty also carried the p.R127X mutation. Additional developmental anomalies, including cleft lip and palate and neurosensorial deafness, were also present in this family. The p.R129X mutation was identified in a 30-yr-old man with familial normosmic IHH and severe GnRH deficiency. We identified the first nonsense mutations in the FGF8 gene in familial IHH with variable degrees of GnRH deficiency and olfactory phenotypes, confirming that loss-of-function mutations in FGF8 cause human GnRH deficiency.

Nonsense Mutations inFGF8Gene Causing Different Degrees of Human Gonadotropin-Releasing Deficiency

FGFR1 mutations cause isolated hypogonadotropic hypogonadism (IHH) with or without olfactory abnormalities, Kallmann syndrome, and normosmic IHH respectively. Recently, missense mutations in FGF8, a key ligand for fibroblast growth factor receptor (FGFR) 1 in the ontogenesis of GnRH, were identified in IHH patients, thus establishing FGF8 as a novel locus for human GnRH deficiency. Our objective was to analyze the clinical, hormonal, and molecular findings of two familial IHH patients due to FGF8 gene mutations. The entire coding region of the FGF8 gene was amplified and sequenced in two well-phenotyped IHH probands and their relatives. Two unique heterozygous nonsense mutations in FGF8 (p.R127X and p.R129X) were identified in two unrelated IHH probands, which were absent in 150 control individuals. These two mutations, mapped to the core domain of FGF8, impact all four human FGF8 isoforms, and lead to the deletion of a large portion of the protein, generating nonfunctional FGF8 ligands. The p.R127X mutation was identified in an 18-yr-old Kallmann syndrome female. Her four affected siblings with normosmic IHH or delayed puberty also carried the p.R127X mutation. Additional developmental anomalies, including cleft lip and palate and neurosensorial deafness, were also present in this family. The p.R129X mutation was identified in a 30-yr-old man with familial normosmic IHH and severe GnRH deficiency. We identified the first nonsense mutations in the FGF8 gene in familial IHH with variable degrees of GnRH deficiency and olfactory phenotypes, confirming that loss-of-function mutations in FGF8 cause human GnRH deficiency.

Comparison of different aminoglycoside antibiotic treatments to refine ototoxicity studies in adult mice

Hearing and balance receptors in the inner ear are highly susceptible to damage caused by a wide variety of toxic substances, including aminoglycosides. This class of antibiotics is commonly used in medicine, even though they may produce irreversible bilateral neurosensorial deafness. To identify potential ototoxic agents and novel therapeutic targets, it is necessary to generate standardized animal models of aminoglycoside ototoxicity, which will also serve to explore otic cell repair and regeneration. Although the mouse is the species most often used in biomedical research, due to the genetic information and genetically-modified strains available, there are few standard models of aminoglycoside ototoxicity in adult mice. Most protocols to produce ototoxicity in adult mice employ high doses of aminoglycosides for long periods of time, which causes systemic toxicity, side-effects and high mortality rates. Here, we compare the effects of systemic treatment with four different, yet common, aminoglycoside antibiotics in two mouse strains, evaluating their effects on mortality, cochlear morphology and auditory brainstem responses. Our data indicate that gentamicin and neomycin caused high mortality in the adult mouse without significantly changing the auditory threshold. Amikacin produced a tolerable rate of mortality but at doses that did not exhibit ototoxicity. Finally, intramuscular injection of kanamycin in C57BL/6JOlaHsd mice induced significant dose-dependent bilateral hearing loss with a moderate rate of mortality and less discomfort than following subcutaneous administration.