No description available.

This study examined the effects of bilateral and unilateral deafness by measuring cortical auditory evoked potential (CAEP) responses in children at initial stages of bilateral cochlear implant (CI) use. We recorded cortical responses evoked by right and left CI stimulation in 127 children with early onset (< 12 months) deafness, with 72 children receiving the two devices in the same surgery (simultaneously implanted) and 55 children receiving the devices in separate procedures (sequentially implanted). Three different types of responses were identified in children with bilateral CIs. No significant effects of duration of deafness, age at implantation, or duration of unilateral CI use were found on response latencies and amplitudes within each type of cortical response, but there were clear differences in responses types between groups and ears. In the context of these findings, the effects of bilateral and unilateral deafness to the auditory pathways were discussed.

This study examined the effects of bilateral and unilateral deafness by measuring cortical auditory evoked potential (CAEP) responses in children at initial stages of bilateral cochlear implant (CI) use. We recorded cortical responses evoked by right and left CI stimulation in 127 children with early onset (< 12 months) deafness, with 72 children receiving the two devices in the same surgery (simultaneously implanted) and 55 children receiving the devices in separate procedures (sequentially implanted). Three different types of responses were identified in children with bilateral CIs. No significant effects of duration of deafness, age at implantation, or duration of unilateral CI use were found on response latencies and amplitudes within each type of cortical response, but there were clear differences in responses types between groups and ears. In the context of these findings, the effects of bilateral and unilateral deafness to the auditory pathways were discussed.

Thesis (M. Sc.)--University of Hong Kong, 1995. / Includes bibliographical references (leaves 72-75).

A complexidade da fisiologia da audição resulta da participação e interação de produtos de grande número de genes, razão pela qual a surdez hereditária exibe enorme heterogeneidade genética. Estudos moleculares nas duas últimas décadas permitiram a identificação de vários genes responsáveis por surdez; entretanto, muitos ainda restam ser identificados. A maioria dos estudos de mapeamento de genes de surdez até então conduzidos privilegiou estratégias que buscavam mutações de ponto. Outros mecanismos mutacionais, como deleções e duplicações, foram pouco investigados. Portanto, a contribuição das CNVs (Copy Number Variations) na surdez hereditária é pouco conhecida. O objetivo desse trabalho foi identificar novos genes que possam ter papel na etiologia da surdez sindrômica ou não-sindrômica por meio da investigação de microdeleções e microduplicações em pacientes com perda auditiva. Selecionamos 25 genes candidatos (CTTN, FGF3, FGF19, FOXC1, FOXF2, FOXQ1, IMMP2L, KIF5C, LRRN3, MAP1A, MYLK4, PPP3CA, SHANK2, SLC5A7, STRC, TMC1, TMC2, TMC3, TMC4, TMC5, TMC6, TMC7, TMC8, TPCN2 e TUBB2A) para a triagem de microrrearranjos por meio da técnica de MLPA (Multiplex Ligation-dependent Probe Amplification). Os genes candidatos foram selecionados a partir de rearranjos detectados em um estudo prévio realizado por meio de array-CGH (array-based Comparative Genomic Hybridization) em indivíduos com surdez sindrômica estudados em nosso laboratório, e também a partir de dados da literatura. Nossa casuística foi composta por 163 indivíduos, dos quais 74 são pacientes com surdez associada a outros sinais (sindrômicos), a maioria casos isolados, e 89 são pacientes com surdez não-sindrômica, propósitos de famílias em que segrega surdez de herança autossômica dominante ou recessiva. Desenhamos uma sonda sintética intragênica de MLPA para cada um dos genes candidatos. Foram detectadas seis deleções em TMC6 (3,7%), seis deleções e uma duplicação em STRC (4,3%) e uma duplicação em IMMP2L (0,6%). A triagem de alterações nesses três genes em 189 indivíduos fenotipicamente normais revelou quatro deleções em TMC6 (2,1%), oito deleções e três duplicações em STRC (5,8%) e três deleções em IMMP2L (1,6%). Todas as alterações em TMC6, tanto nos casos de surdez como nos controles, eram na realidade artefatos devidos a problemas de hibridação da sonda correspondente. No gene STRC, previamente já relacionado à surdez, os rearranjos nos indivíduos afetados devem se tratar de polimorfismos sem efeito fenotípico por serem muito frequentes na população. Contudo, é possível que haja nesses pacientes mutações adicionais que não puderam ser rastreadas e que poderiam contribuir ao fenótipo, em combinação com o rearranjo detectado, como já descrito em um caso da literatura. A duplicação em IMMP2L em uma paciente com surdez não-sindrômica, herdada da mãe igualmente afetada, mostrou-se a mais provavelmente relacionada ao fenótipo, pois o estudo complementar por meio de array-CGH revelou que o rearranjo inclui uma duplicação parcial da porção 3 de outro gene, DOCK4. O produto desse gene possui uma isoforma que se localiza nos estereocílios das células ciliadas e se liga a uma importante proteína relacionada à audição, a harmonina. Portanto, nossa hipótese é a de que a duplicação seja a causa da surdez na família e que DOCK4 seja um novo gene responsável por surdez. A associação de IMMP2L com surdez é menos provável devido ao grande número de CNVs não patogênicas já descritas que incluem partes desse gene. Estudos complementares são necessários para mapear a duplicação com mais precisão. Além disso, o rastreamento de mutações em DOCK4 em outras famílias com surdez pode vir a confirmar o possível papel desse gene na etiologia da surdez. / Several genes contribute to the complexity of physiology of hearing. Consequently, hereditary deafness is extremely heterogeneous from the genetic point of view. In the last two decades, several genes responsible for hereditary hearing loss have been identified, but a large number of genes remains to be found, as evidenced by the unexplained cases of inherited deafness. The search for point mutations in candidate genes after mapping based on linkage studies has been the main strategy in the identification of such genes. Other mutation mechanisms, such as deletions and duplications, have been rarely investigated, and the contribution of DNA copy number variants (CNVs) to hearing loss is not well known. This study aimed at identifying novel genes, which might play a role in the etiology of syndromic and non-syndromic deafness, through the search of gene microdeletions and microduplications. We selected 25 candidate genes (CTTN, FGF3, FGF19, FOXC1, FOXF2, FOXQ1, IMMP2L, KIF5C, LRRN3, MAP1A, MYLK4, PPP3CA, SHANK2, SLC5A7, STRC, TMC1, TMC2, TMC3, TMC4, TMC5, TMC6, TMC7, TMC8, TPCN2 and TUBB2A) based on their involvement in microimbalances detected by Array-based Comparative Genomic Hybridization (aCGH) in a previous study of a Brazilian sample of individuals with syndromic hearing loss from our laboratory and others reported in the literature. We studied 163 subjects, 74 of them presenting syndromic deafness, the majority were isolated cases, and 89 being probands of families in which nonsyndromic deafness had an autosomal dominant or recessive mode of inheritance. Gene deletions or duplications were screened by Multiplex Ligant-dependent Probe Amplification (MLPA) using one synthetic intragenic probe designed for each candidate gene. We detected six deletions in TMC6 (3,7%), six deletions and one duplication in STRC (4,3%), and one duplication in IMMP2L (0,6%). The screening of imbalances in these genes in a control sample of 189 hearing individuals revealed four deletions in TMC6 (2,1%), eight deletions and three duplications in STRC (5,8%) and three deletions in IMMP2L (1,6%). The imbalances found in TMC6, both in affected and control individuals, were in fact artifacts due to problems in the hybridization of the corresponding probe. As to the STRC gene, previously related to deafness, the imbalances are more likely to be 4 polymorphisms with no phenotypic effect. However, the possibility remains that additional undetected mutations in affected individuals contribute to their phenotype, in combination with the microrearrangement, as already reported in the literature. The duplication in IMMP2L in a non-syndromic patient, and also present in her affected mother, is most likely causative of deafness, since a complementary study performed with aCGH revealed that the rearrangement included a partial duplication of the 3 end of another gene, DOCK4. An isoform of the DOCK4 protein localizes to the stereocilia in the inner ear and interacts with harmonin, a protein already known to be involved in hearing. We hypothesize that this duplication may be the cause of deafness in the family and, this being the case, DOCK4 appears as a novel deafness gene. The causal association between IMMP2L and deafness is less plausible, because of the large number of reported non-pathogenic CNVs that include parts of this gene. Further studies are required to precisely map this duplication. In addition, the screening of mutations in DOCK4 in other families with hearing impairment is required to evaluate its possible role in the etiology of deafness.

A complexidade da fisiologia da audição resulta da participação e interação de produtos de grande número de genes, razão pela qual a surdez hereditária exibe enorme heterogeneidade genética. Estudos moleculares nas duas últimas décadas permitiram a identificação de vários genes responsáveis por surdez; entretanto, muitos ainda restam ser identificados. A maioria dos estudos de mapeamento de genes de surdez até então conduzidos privilegiou estratégias que buscavam mutações de ponto. Outros mecanismos mutacionais, como deleções e duplicações, foram pouco investigados. Portanto, a contribuição das CNVs (Copy Number Variations) na surdez hereditária é pouco conhecida. O objetivo desse trabalho foi identificar novos genes que possam ter papel na etiologia da surdez sindrômica ou não-sindrômica por meio da investigação de microdeleções e microduplicações em pacientes com perda auditiva. Selecionamos 25 genes candidatos (CTTN, FGF3, FGF19, FOXC1, FOXF2, FOXQ1, IMMP2L, KIF5C, LRRN3, MAP1A, MYLK4, PPP3CA, SHANK2, SLC5A7, STRC, TMC1, TMC2, TMC3, TMC4, TMC5, TMC6, TMC7, TMC8, TPCN2 e TUBB2A) para a triagem de microrrearranjos por meio da técnica de MLPA (Multiplex Ligation-dependent Probe Amplification). Os genes candidatos foram selecionados a partir de rearranjos detectados em um estudo prévio realizado por meio de array-CGH (array-based Comparative Genomic Hybridization) em indivíduos com surdez sindrômica estudados em nosso laboratório, e também a partir de dados da literatura. Nossa casuística foi composta por 163 indivíduos, dos quais 74 são pacientes com surdez associada a outros sinais (sindrômicos), a maioria casos isolados, e 89 são pacientes com surdez não-sindrômica, propósitos de famílias em que segrega surdez de herança autossômica dominante ou recessiva. Desenhamos uma sonda sintética intragênica de MLPA para cada um dos genes candidatos. Foram detectadas seis deleções em TMC6 (3,7%), seis deleções e uma duplicação em STRC (4,3%) e uma duplicação em IMMP2L (0,6%). A triagem de alterações nesses três genes em 189 indivíduos fenotipicamente normais revelou quatro deleções em TMC6 (2,1%), oito deleções e três duplicações em STRC (5,8%) e três deleções em IMMP2L (1,6%). Todas as alterações em TMC6, tanto nos casos de surdez como nos controles, eram na realidade artefatos devidos a problemas de hibridação da sonda correspondente. No gene STRC, previamente já relacionado à surdez, os rearranjos nos indivíduos afetados devem se tratar de polimorfismos sem efeito fenotípico por serem muito frequentes na população. Contudo, é possível que haja nesses pacientes mutações adicionais que não puderam ser rastreadas e que poderiam contribuir ao fenótipo, em combinação com o rearranjo detectado, como já descrito em um caso da literatura. A duplicação em IMMP2L em uma paciente com surdez não-sindrômica, herdada da mãe igualmente afetada, mostrou-se a mais provavelmente relacionada ao fenótipo, pois o estudo complementar por meio de array-CGH revelou que o rearranjo inclui uma duplicação parcial da porção 3 de outro gene, DOCK4. O produto desse gene possui uma isoforma que se localiza nos estereocílios das células ciliadas e se liga a uma importante proteína relacionada à audição, a harmonina. Portanto, nossa hipótese é a de que a duplicação seja a causa da surdez na família e que DOCK4 seja um novo gene responsável por surdez. A associação de IMMP2L com surdez é menos provável devido ao grande número de CNVs não patogênicas já descritas que incluem partes desse gene. Estudos complementares são necessários para mapear a duplicação com mais precisão. Além disso, o rastreamento de mutações em DOCK4 em outras famílias com surdez pode vir a confirmar o possível papel desse gene na etiologia da surdez. / Several genes contribute to the complexity of physiology of hearing. Consequently, hereditary deafness is extremely heterogeneous from the genetic point of view. In the last two decades, several genes responsible for hereditary hearing loss have been identified, but a large number of genes remains to be found, as evidenced by the unexplained cases of inherited deafness. The search for point mutations in candidate genes after mapping based on linkage studies has been the main strategy in the identification of such genes. Other mutation mechanisms, such as deletions and duplications, have been rarely investigated, and the contribution of DNA copy number variants (CNVs) to hearing loss is not well known. This study aimed at identifying novel genes, which might play a role in the etiology of syndromic and non-syndromic deafness, through the search of gene microdeletions and microduplications. We selected 25 candidate genes (CTTN, FGF3, FGF19, FOXC1, FOXF2, FOXQ1, IMMP2L, KIF5C, LRRN3, MAP1A, MYLK4, PPP3CA, SHANK2, SLC5A7, STRC, TMC1, TMC2, TMC3, TMC4, TMC5, TMC6, TMC7, TMC8, TPCN2 and TUBB2A) based on their involvement in microimbalances detected by Array-based Comparative Genomic Hybridization (aCGH) in a previous study of a Brazilian sample of individuals with syndromic hearing loss from our laboratory and others reported in the literature. We studied 163 subjects, 74 of them presenting syndromic deafness, the majority were isolated cases, and 89 being probands of families in which nonsyndromic deafness had an autosomal dominant or recessive mode of inheritance. Gene deletions or duplications were screened by Multiplex Ligant-dependent Probe Amplification (MLPA) using one synthetic intragenic probe designed for each candidate gene. We detected six deletions in TMC6 (3,7%), six deletions and one duplication in STRC (4,3%), and one duplication in IMMP2L (0,6%). The screening of imbalances in these genes in a control sample of 189 hearing individuals revealed four deletions in TMC6 (2,1%), eight deletions and three duplications in STRC (5,8%) and three deletions in IMMP2L (1,6%). The imbalances found in TMC6, both in affected and control individuals, were in fact artifacts due to problems in the hybridization of the corresponding probe. As to the STRC gene, previously related to deafness, the imbalances are more likely to be 4 polymorphisms with no phenotypic effect. However, the possibility remains that additional undetected mutations in affected individuals contribute to their phenotype, in combination with the microrearrangement, as already reported in the literature. The duplication in IMMP2L in a non-syndromic patient, and also present in her affected mother, is most likely causative of deafness, since a complementary study performed with aCGH revealed that the rearrangement included a partial duplication of the 3 end of another gene, DOCK4. An isoform of the DOCK4 protein localizes to the stereocilia in the inner ear and interacts with harmonin, a protein already known to be involved in hearing. We hypothesize that this duplication may be the cause of deafness in the family and, this being the case, DOCK4 appears as a novel deafness gene. The causal association between IMMP2L and deafness is less plausible, because of the large number of reported non-pathogenic CNVs that include parts of this gene. Further studies are required to precisely map this duplication. In addition, the screening of mutations in DOCK4 in other families with hearing impairment is required to evaluate its possible role in the etiology of deafness.

Thesis (MSc)--University of Stellenbosch, 2004. / ENGLISH ABSTRACT: The most common inherited sensory disorder that affects I in 1 000 children is severe hearing loss. In developed countries, about a third of cases have a genetic origin, 80% of which are autosomal recessive forms (DFNB). Before 1993 few genes causing hearing loss had been identified, but since then a large number of genes related to this problem have been identified. Studies indicate that the DFNBI locus, located at position 13q11-12, contributes to 20% of all childhood deafness and may have a carrier rate as high as 2.8%. There are two genes linked to DFNB 1, GJB2 and GJB6, which are the major genetic cause of non-syndromic autosomal recessive deafness. GJB2 and GJB6 encode the connexin proteins connexin 26 and 30 (Cx26 and Cx30), respectively. The specific aim of this study was to determine the role of GJB2 and GJB6 in deafness within the South African population, since there are no published results involving South African patients with non-syndromic autosomal recessive deafness. This study therefore involved the identification of mutations within the coding region of the GJB2 and GJB6 genes in the South African population and the determination of their specific allele frequencies. Another aim of this study was to analyse the effectiveness of three single-strand conformation polymorphic (SSCP) gel electrophoresis systems in the detection of GJB2 mutations, for use in a standardised diagnostic program. A total of 44 families were recruited and divided into either the familial or sporadic study group, which consisted of 16 and 28 families, respectively. Control samples were also screened from 50 Caucasians and 50 Mixed Ancestry individuals collected from the general population. To achieve the aims of this study, polymerase chain reaction (PCR) amplification followed by automated DNA sequencing of the coding regions of GJB2 and GJB6 was performed. The three SSCP systems that were tested for their effectiveness in detecting mutations within the coding region of GJB2 included mini polyacrylamide, SSCP-urea and two buffer gel electrophoresis systems. In total, six previously reported mutations (35delG, 312de1l4, W24X, M34T, V37I and W44X), a novel mutation (N62I), and four benign polymorphisms (V27I, A40A, R127H and V153I) were detected in GJB2. In the GJB6 gene only the S199T polymorphism was observed. It was determined that the most common mutations found within the Caucasian and Mixed Ancestry populations of South Africa were 35delG and 312de1l4 of GJB2. An overall detection rate of 35.227% was achieved in non-syndromic autosomal recessive deafness amongst this patient cohort. It was also observed that none of the SSCP gel electrophoresis systems were effective at detecting all of the GJB2 mutations. This could change if the systems were specifically optimised for the cornmon mutations that were identified. This study therefore, provides information that can be used in the formulation of a screenmg program for non-syndromic autosomal recessive deafness specific to the South African population. Further research should be conducted involving other genes, in addition other population groups of South Africa to provide a more comprehensive genetic diagnostic and counselling tool. / AFRIKAANSE OPSOMMING: Die mees algemene oorerflike sensoriese steuring wat 1 in 1 000 kinders affekteer is ernstige gehoorverlies. In ontwikkelde lande het omtrent een-derde van die gevalle 'n genetiese oorsprong, waarvan 80% outosomaal resessiewe vorms is (DFNB). Tot en met 1993 is min gene wat gehoorverlies veroorsaak geïdentifiseer, maar sedertdien is 'n groot aantal gene gelokaliseer en verskeie is ook al gekloneer. Studies toon dat die DFNB 1 loci, wat in posisie 13q 11-12 gevind word, 20% van doofheid in kinders veroorsaak, en dit het 'n draer frekwensie van so hoog as 2.8%. Twee gene wat koppeling met DFNBI toon, GJB2 en GJB6, is die vernaamste genetiese oorsaak van nie-sindromise autosomaal resessiewe doofheid. GJB2 en GJB6 koder vir die connexin proteïne 26 en 30 (Cx26 en Cx30), onderskeidelik. Die spesifieke doel van hierdie studie is om die rol van GJR2 en GJB6 in doofheid binne die Suid- Afrikaanse populasie te bepaal, aangesien daar tans nog geen gepubliseerde resultate omtrent Suid- Afrikaanse pasiënte met nie-sindromiese outosomaal resessiewe doofheid is nie. Hierdie studie handel dus oor die identifikasie van mutasies wat binne die koderende areas van die GJR2 en GJB6 gene voorkom in die Suid-Afrikaanse populasie, asook oor die bepaling van hulle spesifieke alleel frekwensies. Verder het hierdie studie ten doelom die effektiwiteit van drie enkel-string konformasie polimorfisme (SSCP) gel-elektroforese metodes in die opsporing van GJB2 mutasies te analiseer met die oog op toekomstige gebruik in 'n gestandardiseerde diagnostiese program. Altesaam 44 families is ingesamel en gekategoriseer in familiële of sporadiese studie-groepe met 16 en 28 families onderskeidelik. Kontrole monsters van 50 Kaukasiese en 50 Gemengde Herkoms individule uit die algemene populasie is ook getoets. Om die doeleindes van die studie te bereik is PKR amplifikasie en outomatiese DNS volgordebepaling van die koderende area van GJB2 en GJR6 gedoen. Die drie SSCP sisteme wat getoets is vir hulle effektiwiteit in die identifisering van mutasies in die koderende area van GJB2 sluit in mini poli-akrielamied, urea en twee-buffer gel elektroforese sisteme. In totaal is ses gerapporteerde mutasies (35delG, 312de114, W24X, M34T, V37I en W44X), 'n nuwe mutasie (N62I), en vier onskadelike polimorfismes (V27I, A40A, R127H en V153I) opgespoor in GJB2, maar in GJB6 is net die S199T polimorfisme waargeneem. Uit die resultate kon afgelei word dat 35deiG en 312de114 van GJB2 die mees algemene mutasies binne die Kaukasiese en Gemengde Herkoms bevolkings van Suid Afrika is. Die total ontdekking standaard van 35.227%· vir nie-sindromise autosomaal resessiewe doofheid tussen herdie patient kohort was bereik. Verder is waargeneem dat geen van die SSCP gel elektroforese metodes effektief was om al die mutasies van GJB2 op te spoor nie. Die situasie kan egter verander as die sisteme spesifiek geoptimiseer word vir die algemene mutasies wat gevind is. Hierdie studie verskaf dus inligting wat gebruik kan word in die verskaffing van 'n diagnostise program vir nie-sindromise outosomaal resessiewe doofheid wat spesifiek is vir die Suid- Afrikaanse populasie. Verdere navorsing wat ander gene en ander populasie groepe van Suid-Afrika insluit, behoort egter uitgevoer te word om uiteindelik 'n meer uitgebreide genetiese diagnostiese en raadgewing diens daar te stel.

No description available.

Nasality is a common resonance disorder present in the speech of severely hearing impaired individuals (Hudgins, 1934). The likely cause has been attributed to structural or functional abnormalities of the velopharyngeal mechanism as well as deviations in pitch and loudness. In addition, hearing impaired individuals speak at a slower rate than normal hearing individuals which has been shown to exacerbate the presence of nasality in their speech (Colton & Cooker, 1968). The purpose of this study was to determine whether deliberate increases in speaking rate would serve to decrease the amount of nasality in the speech of severely hearing impaired individuals. The participants were 11 severe to profoundly hearing impaired students, ranging in age from 12 to 19 years (mean = 16 years). Each participant provided a baseline speech sample (R1) followed by three training sessions during which participants were trained to increase their speaking rate. Following the training sessions, a second speech sample was obtained (R2). Acoustic and perceptual analysis pf the speech samples obtained at R1 and R2 were undertaken. The acoustic analysis focused on changes in first and second formant frequency bandwidth (BW1 & BW2). The perceptual analysis involved 21 naïve listeners rating the speech samples (at R1 & R2) for perceived nasality. Findings indicated a significant increase in speaking rate at R2. In addition, a significantly narrower BW2 frequency and lower perceptual rating score was obtained at R2 across all participants, suggesting a considerable decrease in nasality as speaking rate increases. The influences of speaking rate changes on the functioning of the velopharyngeal mechanism are discussed. In addition, the clinical implications of the findings are explored.

Thesis (Ed.D.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / 2031-01-01