Severe Sensorineural Deafness Research Articles

Slowly progressive d-bifunctional protein deficiency with survival to adulthood diagnosed by whole-exome sequencing

d-Bifunctional protein (DBP) deficiency is an autosomal recessive disorder of peroxisomal fatty acid oxidation caused by mutations in HSD17B4. It is typically fatal by the age of two years with symptom onset during the neonatal period, and survival until late childhood is rare. We herein report the case of a patient with DBP deficiency surviving until adulthood, who showed severe sensorineural deafness, disturbances in language acquisition, slowly progressive cerebellar ataxia, and peripheral neuropathy. This patient, in whom findings of prior investigations were nondiagnostic, had been followed up as having an early-onset spinocerebellar degeneration of unknown etiology. Whole-exome sequencing analysis at the age of 36 showed two heterozygous variants in the gene HSD17B4, which encodes DBP in this patient. A panel of peroxisomal investigations showed normal levels of very long chain fatty acids (VLCFAs) in plasma and elevated serum phytanic acid levels. Recently, an increasing number of patients with DBP deficiency surviving until adolescence/adulthood have been reported, in whom abnormalities in the levels of VLCFAs and other peroxisomal metabolites are marginal or nonexistent. Genetic analysis of HSD17B4 should be considered in adult patients with cerebellar ataxia, peripheral neuropathy, and pyramidal signs in addition to sensorineural auditory disturbance since childhood.

A novel biallelic splice site mutation of TECTA causes moderate to severe hearing impairment in an Algerian family

Congenital deafness is certainly one of the most common monogenic diseases in humans, but it is also one of the most genetically heterogeneous, which makes molecular diagnosis challenging in most cases. Whole-exome sequencing in two out of three Algerian siblings affected by recessively-inherited, moderate to severe sensorineural deafness allowed us to identify a novel splice donor site mutation (c.5272+1G > A) in the gene encoding α-tectorin, a major component of the cochlear tectorial membrane. The mutation was present at the homozygous state in the three affected siblings, and at the heterozygous state in their unaffected, consanguineous parents. To our knowledge, this is the first reported TECTA mutation leading to the DFNB21 form of hearing impairment among Maghrebian individuals suffering from congenital hearing impairment, which further illustrates the diversity of the genes involved in congenital deafness in the Maghreb.

The role of glial-specific Kir4.1 in normal and pathological states of the CNS.

Kir4.1 is an inwardly rectifying K(+) channel expressed exclusively in glial cells in the central nervous system. In glia, Kir4.1 is implicated in several functions including extracellular K(+) homeostasis, maintenance of astrocyte resting membrane potential, cell volume regulation, and facilitation of glutamate uptake. Knockout of Kir4.1 in rodent models leads to severe neurological deficits, including ataxia, seizures, sensorineural deafness, and early postnatal death. Accumulating evidence indicates that Kir4.1 plays an integral role in the central nervous system, prompting many laboratories to study the potential role that Kir4.1 plays in human disease. In this article, we review the growing evidence implicating Kir4.1 in a wide array of neurological disease. Recent literature suggests Kir4.1 dysfunction facilitates neuronal hyperexcitability and may contribute to epilepsy. Genetic screens demonstrate that mutations of KCNJ10, the gene encoding Kir4.1, causes SeSAME/EAST syndrome, which is characterized by early onset seizures, compromised verbal and motor skills, profound cognitive deficits, and salt-wasting. KCNJ10 has also been linked to developmental disorders including autism. Cerebral trauma, ischemia, and inflammation are all associated with decreased astrocytic Kir4.1 current amplitude and astrocytic dysfunction. Additionally, neurodegenerative diseases such as Alzheimer disease and amyotrophic lateral sclerosis demonstrate loss of Kir4.1. This is particularly exciting in the context of Huntington disease, another neurodegenerative disorder in which restoration of Kir4.1 ameliorated motor deficits, decreased medium spiny neuron hyperexcitability, and extended survival in mouse models. Understanding the expression and regulation of Kir4.1 will be critical in determining if this channel can be exploited for therapeutic benefit.

Severe manifestation of Bartter syndrome Type IV caused by a novel insertion mutation in the BSND gene

Bartter syndrome Type IV is a rare subtype of the Bartter syndromes that leads to both severe renal salt wasting and sensorineural deafness. This autosomal recessive disease is caused by mutations in the gene encoding barttin, BSND, an essential subunit of the ClC-K chloride channels expressed in renal and inner ear epithelia. Patients differ in the severity of renal symptoms, which appears to depend on the modification of channel function by the mutant barttin. To date, only a few BSND mutations have been reported, most of which are missense or nonsense mutations. In this study, we report the identification of the first insertion mutation, p.W102Vfs*7, in the BSND gene of a newborn girl with acute clinical symptoms including early-onset chronic renal failure. The results support previous data indicating that mutations that are predicted to abolish barttin expression are associated with a severe phenotype and early onset renal failure.

Adenylate kinase 2 deficiency limits survival and regulates various genes during larval stages of <I>Drosophila melanogaster</I>

Adenylate kinase isozyme 2 (AK2) is located in mitochondrial intermembrane space and regulates energy metabolism by reversibly converting ATP and AMP to 2 ADPs. We previously demonstrated that disruption of the Drosophila melanogaster AK2 gene (Dak2) resulted in growth arrest during the larval stage and subsequent death. Two other groups found that human AK2 mutations cause reticular dysgenesis, a form of severe combined immunodeficiency (SCID) that is associated with severe hematopoietic defects and sensorineural deafness. However, the mechanisms underlying differential outcomes of AK2 deficiency in Drosophila and human systems remain unknown. In this study, effects of tissue-specific inactivation of the Dak2 gene on Drosophila development were analyzed using RNAi-mediated gene knockdown. In addition, to investigate the roles of AK2 in the regulation of gene expression during development, microarray analysis was performed using RNA from first and second instar larvae of Dak2-deficient mutant and wild-type D. melanogaster. Knockdown of Dak2 in all germ layers caused cessation of growth and subsequent death of flies. Microarray analysis revealed that Dak2 deficiency downregulates various genes, particularly those involved in the proteasomal function and in mitochondrial translation machinery. These data indicate that adenine nucleotide interconversion by Dak2 is crucial for developmental processes of Drosophila melanogaster.

Supernumerary nostril together with patent ductus arteriosus, central incisor fusion and severe sensorineural deafness

Supernumerary nostril together with patent ductus arteriosus, central incisor fusion and severe sensorineural deafness

Cochlear implantation effect on deaf children with gap junction protein beta 2 gene mutation

Background The popularization and promotion of gene diagnosis technology makes it possible to detect deafness genes for children with congenital hearing impairment, and the proportion of gap junction protein beta 2 (GJB2) gene mutations in cochlear implant patients is 26.5%. We did follow-up evaluation on auditory rehabilitation effect for all 31 deaf children with GJB2 gene mutation after cochlear implantation to provide a reference for such patients. Methods Application of “the genetic deafness gene chip detection kit” and “gene complete sequence analysis” were applied to conduct detection on common genetic deafness gene mutation hotspots of the hearing impaired children with cochlear implantation. To conduct auditory rehabilitation effect evaluation on all 31 cases of patients with GJB2 genetic deafness after 3, 6 and 12 months of the operation respectively. The single factor repeated measure analysis of variance (ANOVA) was applied to analysis whether there were significant difference among the results of initial consonant of a Chinese syllable recognition at 3 different stages after the operation, the results of vowel of a Chinese syllable recognition at 3 different stages after the operation, and the results of two-syllable recognition at 3 different stages after the operation. Results The 235delC is the high-incidence mutational site in 31 cases of patients with GJB2 genetic deafness, and the total detection rate is up to 90.3% (28/31). There were significant differences in the initial consonant and the vowel of a Chinese syllable recognition rate, and the two-syllable recognition rates at 3, 6, and 12 months after the operation (P <0.01). Conclusion Cochlear implantation is a safe and effective measure for auditory reconstruction, enabling patients with GJB2 hereditary severe sensorineural deafness to achieve auditory speech recognition effectively.

Supernumerary nostril together with patent ductus arteriosus, central incisor fusion and severe sensorineural deafness

Supernumerary nostril is an extremely rare congenital anomaly of duplication. It can be unilateral or bilateral, and it sometimes occurs in the presence of other congenital deformities. The supernumerary nostril in association with patent ductus arteriosus is even rarer, with only two cases reported so far. We are reporting a case of supernumerary nostril in association with patent ductus arteriosus, central incisor fusion and severe sensorineural deafness, which happens to be the first case of its kind to be reported.

Brown‐Vialetto‐Van Laere and Fazio Londe syndromes: defects of riboflavin transport with biochemical similarities to multiple acyl‐CoA dehydrogenation defects (MADD)

Riboflavin-responsive defects of electron transfer were firstdescribed in the 1980s as mild variant forms of MADD orglutaric acidemia type II (Gregersen et al 1982; Amendt andRhead 1986). Some of these patients were shown to havedefects in ETF and ETF dehydrogenase but a number ofpatients remained in whom the biochemical and moleculardefects remained elusive (Roettger et al 1992). It was pos-tulated that these patients may have defect(s) of riboflavintransport or abnormalities in downstream flavin metabolismto form the active FAD/FMN cofactors required for facili-tating electron transfer. Treatment of some of these patientswith high dose riboflavin tended to normalize the abnormalmetabolite profiles. Treatment with high dose riboflavin wasalso subjectively claimed to improve the clinical phenotype,a difficult judgment given the mild and intermittent natureof the phenotype. The phenotype of most of the cases ofriboflavin-responsive MADD was that of stress-inducedmyopathy (de Visser et al 1986; DiDonato et al 1989).Recently, the genetic basis for Brown-Vialetto-Van Laeresyndrome(BVVLS) wasidentified asapreviouslyunknownopen reading frame C20orf54 (Green et al 2010). This genewas subsequently shown to encode a riboflavin transporterand the gene is now renamed SLC52A3 encoding humanriboflavin transporter 2 (hRFT2). At around the same time, adominantly inherited mutation in SLC52A1encoding humanriboflavin transporter 1 (hRFT1) was identified in theclinically normal mother of a neonate with complex neuro-logical disease and a MADD metabolite profile whichresponded dramatically to riboflavin therapy. It is presumedthat the neonate was riboflavin deficient secondarily to thematernal haploinsufficiency and from increased riboflavindemand during pregnancy (Ho et al 2011). Bosch and cow-orkersandothersextendedthephenotypeofSLC52A3defectsto include patients with Fazio Londe syndrome, which waspreviouslyconsideredtobeanoverlappingclinicalphenotypebut without a molecular basis (Bosch et al 2011). Anand andcoworkers added an additional riboflavin-responsive BVVLScase to the data base (Anand et al 2012). In this volume ofJIMD, Haack et al 2012, demonstrating the power of wholeexome sequencing identified disease-causing mutations in athird riboflavin transporter in an individual with BVVLS.They identified mutations in SLC52A2 and exquisitely dem-onstrate a functional defect of hRFT3, the gene product. Thispresent case also highlights the likely mechanisms of diseasephenotype in BVVLS.The clinical phenotype of BVVLS is not what wewould immediately associate with defects of electrontransfer such as MADD. For this reason, it is importantfor investigators to recognize this phenotype as it wouldappear that these defects of riboflavin transport areeminently treatable with high dose riboflavin therapy.BVVLS is rare and has been reported in about 60patients in total but may be under diagnosed. It presentsprimarily with a severe sensorineural deafness. The ageof onset is from infancy to the third decade. During therelentless progress, lower motor neuron limb signs leadto neuropathy and are accompanied by cerebellar ataxia,optic atrophy, retinal pigmentary changes, mental retar-dation and psychiatric abnormalities. Death is usually aresult of diaphragmatic paralysis (Dipti et al 2005).

Contiguous deletion of SLC6A8 and BAP31 in a patient with severe dystonia and sensorineural deafness

We report here a 6-year-old boy exhibiting severe dystonia, profound intellectual and developmental disability with liver disease, and sensorineural deafness. A deficient creatine peak in brain 1H-MR spectroscopy and high ratio of creatine/creatinine concentration in his urine lead us to suspect a creatine transporter (solute carrier family 6, member 8; SLC6A8) deficiency, which was confirmed by the inability to take up creatine into fibroblasts. We found a large ~19kb deletion encompassing exons 5–13 of SLC6A8 and exons 5–8 of the B-cell receptor-associated protein (BAP31) gene. This case is the first report in which the SLC6A8 and BAP31 genes are both deleted. The phenotype of BAP31 mutations has been reported only as a part of Xq28 deletion syndrome or contiguous ATP-binding cassette, sub-family D, member 1 (ABCD1)/DXS1375E (BAP31) deletion syndrome [MIM ID #300475], where liver dysfunction and sensorineural deafness have been suggested to be attributed to the loss of function of BAP31. Our case supports the idea that the loss of BAP31 is related to liver dysfunction and hearing loss.

Report of a further family with dominant deafness‐onychodystrophy (DDOD) syndrome

Deafness and onychodystrophy is a presumed autosomal dominant condition previously reported in five families. We report on a three-generation family with three affected members with absent finger and toenails, finger-like thumbs, and severe sensorineural deafness. In the hands, the first and fifth digits had absent nails and bulbous swelling of the distal phalanx. The second, third, and fourth digits were relatively spared. In the feet,there were hypoplastic great toenails and absent nails on second to fifth toes. Intelligence was normal. In addition to deafness and onychodystrophy, other features in this family included subtle facial dysmorphism in two individuals, cutis aplasia in one individual, epilepsy in one individual, and sudden infant death in two family members, one of whom had deafness and onychodystrophy and one who did not. A full autopsy of both infants did not reveal a cause. SNP microarray analysis of one family member showed no evidence of copy number change. This family's condition fits within the spectrum of dominant deafness-onychodystrophy syndrome (DDOD) and further characterises this rare condition.

Connexin 26 (GJB2) mutations as a cause of the KID syndrome with hearing loss

KID syndrome (MIM 148210) is an ectodermal dysplasia characterized by the occurrence of localized erythematous scaly skin lesions, keratitis and severe bilateral sensorineural deafness. KID syndrome is inherited as an autosomic dominant disease, due to mutations in the gene encoding gap junction protein GJB2 (connexin 26, Cx26). Cx26 is a component of gap junction channels in the epidermis and in the stria vascularis of the cochlea. These channels play a role in the coordinated exchange of molecules and ions occurring in a wide spectrum of cellular activities. In this paper we describe two patients with Cx26 mutations cause cell death by the alteration of protein trafficking, membrane localization and probably interfering with intracellular ion concentrations. We discuss the pathogenesis of both the hearing and skin phenotypes.

Connexin 26 (GJB2) mutations, causing KID Syndrome, are associated with cell death due to calcium gating deregulation

The autosomic dominant KID Syndrome (MIM 148210), due to mutations in GJB2 (connexin 26, Cx26), is an ectodermal dysplasia with erythematous scaly skin lesions, keratitis and severe bilateral sensorineural deafness. The Cx26 protein is a component of gap junction channels in epithelia, including the cochlea, which coordinates the exchange of molecules and ions. Here, we demonstrate that different Cx26 mutants (Cx26D50N and Cx26G11E) cause cell death in vitro by the alteration of intra-cellular calcium concentrations. These results help to explain the pathogenesis of both the hearing and skin phenotypes, since calcium is also a potent regulator of the epidermal differentiation process.

A comparative study of age-related hearing loss in wild type and insulin-like growth factor I deficient mice

Insulin-like growth factor-I (IGF-I) belongs to the family of insulin-related peptides that fulfils a key role during the late development of the nervous system. Human IGF1 mutations cause profound deafness, poor growth and mental retardation. Accordingly, Igf1−/− null mice are dwarfs that have low survival rates, cochlear alterations and severe sensorineural deafness. Presbycusis (age-related hearing loss) is a common disorder associated with aging that causes social and cognitive problems. Aging is also associated with a decrease in circulating IGF-I levels and this reduction has been related to cognitive and brain alterations, although there is no information as yet regarding the relationship between presbycusis and IGF-I biodisponibility. Here we present a longitudinal study of wild type Igf1+/+ and null Igf1−/− mice from 2 to 12 months of age comparing the temporal progression of several parameters: hearing, brain morphology, cochlear cytoarchitecture, insulin-related factors and IGF gene expression and IGF-I serum levels. Complementary invasive and non-invasive techniques were used, including auditory brainstem-evoked response (ABR) recordings and in vivo MRI brain imaging. Igf1−/− null mice presented profound deafness at all the ages studied, without any obvious worsening of hearing parameters with aging. Igf1+/+ wild type mice suffered significant age-related hearing loss, their auditory thresholds and peak I latencies augmenting as they aged, in parallel with a decrease in the circulating levels of IGF-I. Accordingly, there was an age-related spiral ganglion degeneration in wild type mice that was not evident in the Igf1 null mice. However, the Igf1−/− null mice in turn developed a prematurely aged stria vascularis reminiscent of the diabetic strial phenotype. Our data indicate that IGF-I is required for the correct development and maintenance of hearing, supporting the idea that IGF-I-based therapies could contribute to prevent or ameliorate age-related hearing loss.

Schizencephaly in LEOPARD Syndrome

We report on a 2-year-old boy with facial dysmorphism, multiple lentigines, and hypertrophic cardiomyopathy. Mutation analyses of the patient and his mother revealed a Y279G mutation in exon 7 of the PTPN11 gene. The presence of LEOPARD syndrome was confirmed by a genetic study and clinical phenotypes. Since age 18 months, the patient had manifested frequent seizures that were poorly controlled by multiple anticonvulsants. Neurologic examinations indicated severe developmental delay and sensorineural deafness. Brain imaging demonstrated open-lip schizencephaly in the right frontoparietal area. Central nervous system anomalies are rarely reported in this disease. To the best of our knowledge, this is the first report of LEOPARD syndrome with associated schizencephaly. Psychomotor retardation is not uncommon in LEOPARD syndrome. We advocate brain-imaging studies of patients with LEOPARD syndrome and neurologic abnormalities such as developmental delay or epilepsy.

Susac's syndrome: Intratympanic therapy for hearing loss and a review of the literature

Two cases of Susac's Syndrome are presented with a discussion of treatment modalities for the associated severe sensorineural deafness. Patients were managed with high dose oral steroids, anticoagulants and immunosuppressive drugs. The addition of intratympanic methylprednisolone injections were added to one patient's regimen with initial improvement but subsequent relapse and progression to profound deafness. The management of Susac's syndrome is difficult and still in need of innovative methods as the standard treatment continues to be ineffective in the long term.

Disease-Causing Dysfunctions of Barttin in Bartter Syndrome Type IV

Bartter syndrome type IV is an inherited human condition characterized by severe renal salt wasting and sensorineural deafness. The causal gene, BSND, encodes barttin, an accessory subunit of chloride channels located in the kidney and inner ear. Barttin modulates the stability, cell surface localization, and function of ClC-K channels; distinct mutations cause phenotypes of varying severity. For definition of the molecular basis of this diversity, the functional consequences of six disease-causing mutations (R8L, R8W, G10S, Q32X, G47R, and E88X) on ClC-K channel properties were studied by heterologous expression in renal cell lines, electrophysiology, confocal imaging, and biochemical analysis. Three missense mutations (R8L, R8W, and G10S) eliminated the function of ClC-K/barttin channels but did not prevent the insertion of the channels into the surface membrane. Another mutant that produces a mild renal phenotype (G47R) was capable of performing all functions of wild-type barttin but bound to ClC-K channels less effectively. The nonsense mutation E88X affected epithelial sorting, leading to equal amounts of barttin inserting into the basolateral and apical membranes, contrasting with the preferential apical insertion of wild-type barttin. Last, the nonsense mutation Q32X allowed barttin to associate with ClC-K channels but prevented surface membrane insertion and channel activation. These results demonstrate that Bartter syndrome type IV can be caused by various derangements in the function of barttin, likely contributing to the diversity of observed phenotypes.

Ocular features of CHARGE syndrome

To detail the presence and severity of ocular and cranial nerve abnormalities found in individuals with CHARGE syndrome in a distinct geographic area. Nine individuals with CHARGE syndrome from Maritime Canada identified from a Canadian database were prospectively examined. Structural and sensorial defects associated with functional visual deficits were defined with ophthalmic and neurological evaluation. Consistent with current diagnostic criteria and the literature, colobomas were the major ophthalmic manifestation. These were typically bilateral chorioretinal colobomas involving the optic nerve. All subjects had bilateral severe sensorineural deafness (cranial nerve VIII), and 8 of 9 (89%) had facial nerve (cranial nerve VII) involvement (7 of 9 had unilateral involvement; 1 of 9 had bilateral involvement). Unique to this group of participants were the findings of anisometropia in 8 of the 9 (89%) patients, severe myopic astigmatism in 13 of the 18 eyes (72%), and limited elevation in adduction in 3 of 9 (33%) participants. Associated findings were strabismus, cataracts, microcornea, keratopathy, staphyloma, reduced stereopsis, superior visual field defects, and reduced visual acuity. The presence of coloboma plus another CHARGE feature warrants further investigation, including genetic screening for the CHD7 gene. Early recognition and management of sensory problems (visual, auditory, and vestibular) are crucial to ensure best psychomotor and cognitive development.

蝸牛耳硬化症例に対する人工内耳の問題

Most cases of otosclerosis show pathological changes only around the oval window. On the other hand, it is known that cavernous changes extending to the cochlea induce progressive sensorineural deafness. Three patients with severe bilateral deafness and severe cochlear otosclerosis as diagnosed by CT underwent cochlear implantation. The postoperative hearing abilities were satisfactory in two of the three patients at one year after the operation. However, one patient with advanced otosclerosis suffered from the complication of facial nerve stimulation two months later after the cochlear implantation. His available cochlear implant electrodes gradually decreased due to the facial nerve stimulation and at last the cochlear implant was no longer beneficial for reacquisition of his hearing ability. His CT densitometry revealed marked degradation of the CT value in the cochlear basal turn circumference in comparison with that in other patients showing good courses after the cochlear implantation. In conclusion, a cochlear implant operation is valuable in patients with severe sensorineural deafness with cochlear otosclerosis. However, we should cautious in performing cochlear implantation in patients with severe demineralization of the cochlear optic capsule.

Postasphyxial Hypoxic-Ischemic Encephalopathy in Neonates

To construct and validate a model and derive a simple rule that is usable in any birth location for the prediction of outcome of term infants with severe asphyxia. Retrospective cohort study. Regional outborn neonatal intensive care unit. Infants with postintrapartum asphyxial hypoxic-ischemic encephalopathy (n = 375). Clinical and laboratory predictors available at age 4 hours. A logistic regression model was developed and internally validated (with random sampling and based on the year of birth) for severe adverse outcome, which was defined as death or severe disability (severe cerebral palsy, severe developmental delay, sensorineural deafness, or cortical blindness singly or in combination). A simple prediction rule was derived from 3 variables. Complete data were available for 302 (92%) of the 345 infants with known outcomes (204 infants with severe adverse outcome). Six independent predictors of outcomes were identified. Using the 3 most significant predictors (chest compressions, age at onset of respiration, and base deficit), severe adverse outcome rates were 46% (95% confidence interval, 33%-58%) with none of the 3 predictors, 64% (95% confidence interval, 54%-73%) with any 1 predictor, 76% (95% confidence interval, 66%-85%) with any 2 predictors, and 93% (95% confidence interval, 81%-99%) with all of the 3 predictors present. The internal validations revealed a robust model. This predictive model for neonatal hypoxic-ischemic encephalopathy provides a sliding scale of probabilities that could be used for prognostication and to design eligibility criteria for decision making including neuroprotective therapy.