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1.
PLoS One ; 15(9): e0238913, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32915865

RESUMO

Hearing impairment was observed in patients with chronic kidney disease (CKD). Our purpose was to investigate the relationship between sensorineural hearing loss (SNHL) and associated comorbidities in the CKD population. We conducted a retrospective, population-based study to examine the risk of developing SNHL in patients with CKD. Population-based data from 2000-2010 from the Longitudinal Health Insurance Database of the Taiwan National Health Insurance Research Database was used in this study. The population sample comprised 185,430 patients who were diagnosed with CKD, and 556,290 without CKD to determine SNHL risk factors. Cox proportional hazard regression analysis demonstrated the CKD group had a significantly increased risk of SNHL compared with the non-CKD group [adjusted hazard ratio (HR), 3.42; 95% confidence interval (CI), 3.01-3.90, p < 0.001]. In the CKD group, the risk of SNHL (adjusted HR, 5.92) was higher among patients undergoing hemodialysis than among those not undergoing hemodialysis (adjusted HR, 1.40). Furthermore, subgroup analysis revealed an increased risk of SNHL in patients with CKD and comorbidities, including heart failure (adjusted HR, 7.48), liver cirrhosis (adjusted HR, 4.12), type 2 diabetes mellitus (adjusted HR, 3.98), hypertension (adjusted HR, 3.67), and chronic obstructive pulmonary disease (adjusted HR, 3.45). CKD is an independent risk of developing SNHL. Additionally, hemodialysis for uremia can increase the risk of SNHL. Cardiovascular, lung, liver, and metabolic comorbidities in CKD patients may further aggravate the risk of SNHL by inter-organ crosstalk. We should pay attention to SNHL in this high-risk population.


Assuntos
Perda Auditiva Neurossensorial/epidemiologia , Insuficiência Renal Crônica/complicações , Adolescente , Adulto , Comorbidade , Feminino , Perda Auditiva Neurossensorial/etiologia , Perda Auditiva Neurossensorial/patologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Taiwan/epidemiologia , Adulto Jovem
2.
J Comput Assist Tomogr ; 44(5): 704-707, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32842072

RESUMO

PURPOSE: Incomplete partition III (IP-III), characterized by congenital mixed or sensorineural hearing loss, is a rare genetic disease transmitted through X-linked mode of inheritance. Inner ear findings of IP-III have been well described and allow an immediate diagnosis to be made. Recently, an association between IP-III and distinct hypothalamic malformations has been reported in some of the patients with IP-III. The purpose of this study was to investigate the morphologic abnormalities of the hypothalamus in IP-III. MATERIALS AND METHODS: Magnetic resonance imaging studies of 8 subjects, including 1 set of brothers, who were diagnosed with IP-III based on their clinical and inner ear imaging findings, were analyzed. RESULTS: Of the 8 subjects, 7 demonstrated some degree of morphologic abnormality of the hypothalamus. Of these, 2 showed asymmetrical thickening, 1 showed symmetrical thickening, and 4 showed mass-like enlargement of the hypothalamus. Six of 7 subjects with hypothalamic abnormalities showed asymmetry in caudal extension of the abnormalities, which was more discernible on coronal oblique T2-weighted images. Clinically, none of the subjects had endocrinologic or neurologic symptoms. CONCLUSIONS: This retrospective analysis presents further magnetic resonance imaging evidence on the association between the rare IP-III malformations and the presence of hypothalamic morphologic abnormalities.


Assuntos
Orelha Interna , Doenças Genéticas Ligadas ao Cromossomo X , Perda Auditiva Neurossensorial , Hipotálamo , Adolescente , Adulto , Idoso , Pré-Escolar , Orelha Interna/anormalidades , Orelha Interna/diagnóstico por imagem , Orelha Interna/patologia , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico por imagem , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Perda Auditiva Neurossensorial/diagnóstico por imagem , Perda Auditiva Neurossensorial/patologia , Humanos , Hipotálamo/anormalidades , Hipotálamo/diagnóstico por imagem , Hipotálamo/patologia , Imagem por Ressonância Magnética , Masculino , Estudos Retrospectivos , Adulto Jovem
3.
J Laryngol Otol ; 134(7): 603-609, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32713375

RESUMO

OBJECTIVE: This study aimed to evaluate the association between cochlear nerve canal dimensions and semicircular canal abnormalities and to determine the distribution of bony labyrinth anomalies in patients with cochlear nerve canal stenosis. METHOD: This was a retrospective study in which high-resolution computed tomography images of paediatric patients with severe-to-profound sensorineural hearing loss were reviewed. A cochlear nerve canal diameter of 1.5 mm or less in the axial plane was classified as stenotic. Semicircular canals and other bony labyrinth morphology and abnormality were evaluated. RESULTS: Cochlear nerve canal stenosis was detected in 65 out of 265 ears (24 per cent). Of the 65 ears, 17 ears had abnormal semicircular canals (26 per cent). Significant correlation was demonstrated between cochlear nerve canal stenosis and semicircular canal abnormalities (p < 0.01). Incomplete partition type II was the most common accompanying abnormality of cochlear nerve canal stenosis (15 out of 65, 23 per cent). CONCLUSION: Cochlear nerve canal stenosis is statistically associated with semicircular canal abnormalities. Whenever a cochlear nerve canal stenosis is present in a patient with sensorineural hearing loss, the semicircular canal should be scrutinised for presence of abnormalities.


Assuntos
Perda Auditiva Neurossensorial/etiologia , Canais Semicirculares/anormalidades , Doenças do Nervo Vestibulococlear/complicações , Adolescente , Criança , Pré-Escolar , Nervo Coclear/diagnóstico por imagem , Nervo Coclear/patologia , Constrição Patológica , Feminino , Perda Auditiva Neurossensorial/diagnóstico por imagem , Perda Auditiva Neurossensorial/patologia , Humanos , Lactente , Masculino , Estudos Retrospectivos , Canais Semicirculares/diagnóstico por imagem , Canais Semicirculares/patologia , Tomografia Computadorizada por Raios X , Doenças do Nervo Vestibulococlear/diagnóstico por imagem , Doenças do Nervo Vestibulococlear/etiologia , Doenças do Nervo Vestibulococlear/patologia
5.
Hum Genet ; 139(10): 1325-1343, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32399598

RESUMO

Perrault syndrome is a rare heterogeneous condition characterised by sensorineural hearing loss and premature ovarian insufficiency. Additional neuromuscular pathology is observed in some patients. There are six genes in which variants are known to cause Perrault syndrome; however, these explain only a minority of cases. We investigated the genetic cause of Perrault syndrome in seven affected individuals from five different families, successfully identifying the cause in four patients. This included previously reported and novel causative variants in known Perrault syndrome genes, CLPP and LARS2, involved in mitochondrial proteolysis and mitochondrial translation, respectively. For the first time, we show that pathogenic variants in PEX6 can present clinically as Perrault syndrome. PEX6 encodes a peroxisomal biogenesis factor, and we demonstrate evidence of peroxisomal dysfunction in patient serum. This study consolidates the clinical overlap between Perrault syndrome and peroxisomal disorders, and highlights the need to consider ovarian function in individuals with atypical/mild peroxisomal disorders. The remaining patients had variants in candidate genes such as TFAM, involved in mtDNA transcription, replication, and packaging, and GGPS1 involved in mevalonate/coenzyme Q10 biosynthesis and whose enzymatic product is required for mouse folliculogenesis. This genomic study highlights the diverse molecular landscape of this poorly understood syndrome.


Assuntos
ATPases Associadas a Diversas Atividades Celulares/genética , Aminoacil-tRNA Sintetases/genética , Proteínas de Ligação a DNA/genética , Dimetilaliltranstransferase/genética , Endopeptidase Clp/genética , Farnesiltranstransferase/genética , Predisposição Genética para Doença , Geraniltranstransferase/genética , Disgenesia Gonadal 46 XX/genética , Perda Auditiva Neurossensorial/genética , Proteínas Mitocondriais/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Sequência de Bases , Criança , DNA Mitocondrial/genética , Feminino , Expressão Gênica , Disgenesia Gonadal 46 XX/diagnóstico , Disgenesia Gonadal 46 XX/patologia , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Ovário/metabolismo , Ovário/patologia , Linhagem , Peroxissomos/metabolismo , Peroxissomos/patologia
6.
BMC Med Genet ; 21(1): 79, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32295532

RESUMO

BACKGROUND: Congenital chloride diarrhea (CLD; OMIM 214700) is a rare autosomal recessive disorder caused by pathogenic variations in the solute carrier family 26 member A3 (SLC26A3) gene. Without salt substitution, this chronic diarrheal disorder causes severe dehydration and electrolyte disturbances. Homozygous variants in the nearby gene SLC26A4 disrupt anion exchange in the inner ear and the thyroid, causing Pendred syndrome (PDS; OMIM 274600), which is the most frequent form of syndromic deafness. CASE PRESENTATION: We report an unusual co-occurrence of two rare homozygous mutations in both the SLC26A3 and SLC26A4 genes, causing a rare combination of both CLD and PDS in two siblings. Although the clinical pictures were typical, the combined loss of these anion transporters might modulate the risk of renal injury associated with CLD. CONCLUSIONS: Familial presentation of two rare autosomal recessive disorders with loss of function of different SLC26 anion transporters is described. Independent homozygous variants in the SLC26A3 and SLC26A4 genes cause CLD and PDS in siblings, shedding light on co-occurrence of rare recessive traits in the progeny of consanguineous couples.


Assuntos
Antiportadores de Cloreto-Bicarbonato/genética , Diarreia/congênito , Bócio Nodular/genética , Perda Auditiva Neurossensorial/genética , Erros Inatos do Metabolismo/genética , Transportadores de Sulfato/genética , Diarreia/diagnóstico , Diarreia/genética , Diarreia/patologia , Feminino , Genes Recessivos/genética , Testes Genéticos , Bócio Nodular/diagnóstico , Bócio Nodular/patologia , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/patologia , Humanos , Lactente , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/patologia , Mutação , Linhagem , Gravidez , Doenças Raras/diagnóstico , Doenças Raras/genética , Doenças Raras/patologia , Irmãos
7.
Mol Immunol ; 121: 28-37, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32151906

RESUMO

INTRODUCTION: H Syndrome is an autosomal recessive (AR) disease caused by defects in SLCA29A3 gene. This gene encodes the equilibrative nucleoside transporter, the protein which is highly expressed in spleen, lymph node and bone marrow. Autoinflammation and autoimmunity accompanies H Syndrome (HS). AIM: The aim was to further elucidate the mechanisms of disease by molecular studies in a patient with SLC29A3 gene defect. PATIENT AND METHODS: Mitochondrial dysfunction, lysosomal integrity, cytokine response in response to stimulation with different pattern recognition receptor ligands, and circulating cell-free mitochondrial-DNA(ccf-mtDNA) level in plasma were analyzed compared to controls to understand the cellular triggers of autoinflammation. RNA sequencing (RS) analyses were also performed in monocytes before/after culture with lipopolysaccharide. RESULTS: Patient had progressive destructive arthropathy in addition to clinical findings due to combined immunodeficiency. Pure red cell aplasia (PRCA), vitiligo, diabetes, multiple autoantibody positivity, lymphopenia, increased acute phase reactants were present. Recent thymic emigrants (RTE), naïve T cells were decreased, effector memory CD4 + T cells, nonclassical inflammatory monocytes were increased. Patient's peripheral blood mononuclear cells secreted more IL-1ß and IL-6, showed lysosomal disruption and significant mitochondrial dysfunction compared to healthy controls. Plasma ccf-mtDNA level was significantly elevated compared to age-matched controls (p < 0.05). RNA sequencing studies revealed decreased expression of NLR Family Caspase Recrument-Domain Containing 4(NLRC4), 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4(PFKFB4), serine dehydratase(SDS), heparan sulfate(Glucosamine) 3-O-sulfotransferase 1(HS3ST1), neutral cholesterol ester hydrolase 1 (NCEH1), and interleukin-8 (IL-8) in patient's monocytes compared to controls. Longstanding PRCA, which is possibly autoimmune, resolved after initiating monthly intravenous immunoglobulins (IVIG) and low dose steroids to the patient. CONCLUSION: Although autoinflammation and autoimmunity are reported in HS, by functional analyses we here show in the present patient that over-active inflammasome pathway in HS might be related with mitochondrial and lysosomal dysfunction. Increased plasma ccf-mtDNA may be used as a biomarker of inflammasomopathy in HS. HS should be included in the classification of primary immunodeficiency diseases.


Assuntos
Autoimunidade/genética , Contratura/genética , Perda Auditiva Neurossensorial/genética , Histiocitose/genética , Síndromes de Imunodeficiência/genética , Proteínas de Transporte de Nucleosídeos/genética , Adolescente , Contratura/tratamento farmacológico , Contratura/imunologia , Contratura/patologia , Glucocorticoides/uso terapêutico , Perda Auditiva Neurossensorial/tratamento farmacológico , Perda Auditiva Neurossensorial/imunologia , Perda Auditiva Neurossensorial/patologia , Histiocitose/tratamento farmacológico , Histiocitose/imunologia , Histiocitose/patologia , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Síndromes de Imunodeficiência/tratamento farmacológico , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/patologia , Inflamassomos/imunologia , Lisossomos/imunologia , Lisossomos/patologia , Masculino , Mitocôndrias/imunologia , Mitocôndrias/patologia , Resultado do Tratamento
8.
J Neurosci ; 40(15): 2976-2992, 2020 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-32152201

RESUMO

Hepatocyte growth factor (HGF) is a multifunctional protein that signals through the MET receptor. HGF stimulates cell proliferation, cell dispersion, neuronal survival, and wound healing. In the inner ear, levels of HGF must be fine-tuned for normal hearing. In mice, a deficiency of HGF expression limited to the auditory system, or an overexpression of HGF, causes neurosensory deafness. In humans, noncoding variants in HGF are associated with nonsyndromic deafness DFNB39 However, the mechanism by which these noncoding variants causes deafness was unknown. Here, we reveal the cause of this deafness using a mouse model engineered with a noncoding intronic 10 bp deletion (del10) in Hgf Male and female mice homozygous for del10 exhibit moderate-to-profound hearing loss at 4 weeks of age as measured by tone burst auditory brainstem responses. The wild type (WT) 80 mV endocochlear potential was significantly reduced in homozygous del10 mice compared with WT littermates. In normal cochlea, endocochlear potentials are dependent on ion homeostasis mediated by the stria vascularis (SV). Previous studies showed that developmental incorporation of neural crest cells into the SV depends on signaling from HGF/MET. We show by immunohistochemistry that, in del10 homozygotes, neural crest cells fail to infiltrate the developing SV intermediate layer. Phenotyping and RNAseq analyses reveal no other significant abnormalities in other tissues. We conclude that, in the inner ear, the noncoding del10 mutation in Hgf leads to developmental defects of the SV and consequently dysfunctional ion homeostasis and a reduction in the EP, recapitulating human DFNB39 nonsyndromic deafness.SIGNIFICANCE STATEMENT Hereditary deafness is a common, clinically and genetically heterogeneous neurosensory disorder. Previously, we reported that human deafness DFNB39 is associated with noncoding variants in the 3'UTR of a short isoform of HGF encoding hepatocyte growth factor. For normal hearing, HGF levels must be fine-tuned as an excess or deficiency of HGF cause deafness in mouse. Using a Hgf mutant mouse with a small 10 bp deletion recapitulating a human DFNB39 noncoding variant, we demonstrate that neural crest cells fail to migrate into the stria vascularis intermediate layer, resulting in a significantly reduced endocochlear potential, the driving force for sound transduction by inner ear hair cells. HGF-associated deafness is a neurocristopathy but, unlike many other neurocristopathies, it is not syndromic.


Assuntos
Cóclea/fisiopatologia , Potenciais Evocados Auditivos do Tronco Encefálico/genética , Perda Auditiva Neurossensorial/genética , Fator de Crescimento de Hepatócito/genética , Crista Neural/crescimento & desenvolvimento , Estria Vascular/patologia , Animais , Contagem de Células , Orelha Interna/anormalidades , Feminino , Células Ciliadas Auditivas , Perda Auditiva Neurossensorial/patologia , Homeostase , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Crista Neural/patologia , Sondas RNA
9.
BMC Med Genet ; 21(1): 27, 2020 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-32039712

RESUMO

BACKGROUND: Stickler syndrome is the most common genetic cause of rhegmatogenous retinal detachment (RRD) in children, and has a high risk of blindness. Type I (STL1) is the most common subtype, caused by COL2A1 mutations. This study aims to analyze the mutation spectrum of COL2A1 and further elucidate the genotype-phenotype relationships in the East Asian populations with STL1, which is poorly studied at present. METHODS: By searching MEDLINE, Web of Science, CNKI, Wanfang Data, HGMD and Clinvar, all publications associated with STL1 were collected. Then, they were carefully screened to obtain all reported STL1-related variants in COL2A1 and clinical features in East Asian patients with STL1. RESULTS: There were 274 COL2A1 variants identified in 999 patients with STL1 from 466 unrelated families, and more than half of them were truncation mutations. Of the 107 STL1 patients reported in the East Asian population, it was found that patients with truncation mutations had milder systemic phenotypes, whereas patients with splicing mutations had severer phenotypes. In addition, several recurrent variants (c.3106C > T, c.1833 + 1G > A, c.2710C > T and c.1693C > T) were found. CONCLUSIONS: Genotype-phenotype correlations should certainly be studied carefully, contributed to making personalized follow-up plans and predicting prognosis of this disorder. Genome editing holds great potential for treating inherited diseases caused by pathogenic mutations. In this study, several recurrent variants were found, providing potential candidate targets for genetic manipulation in the future.


Assuntos
Artrite/genética , Doenças do Tecido Conjuntivo/genética , Análise Mutacional de DNA , Perda Auditiva Neurossensorial/genética , Mutação/genética , Descolamento Retiniano/genética , Artrite/epidemiologia , Artrite/patologia , Doenças do Tecido Conjuntivo/epidemiologia , Doenças do Tecido Conjuntivo/patologia , Oftalmopatias Hereditárias , Estudos de Associação Genética , Perda Auditiva Neurossensorial/epidemiologia , Perda Auditiva Neurossensorial/patologia , Humanos , Fenótipo , Descolamento Retiniano/epidemiologia , Descolamento Retiniano/patologia
10.
BMC Med Genet ; 21(1): 35, 2020 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-32066420

RESUMO

BACKGROUND: We report a large family with four successive generations, presenting with a complex phenotype of severe congenital neutropenia (SCN), partially penetrant monocytosis, and hearing loss of varying severity. METHODS: We performed whole exome sequencing to identify the causative variants. Sanger sequencing was used to perform segregation analyses on remaining family members. RESULTS: We identified and classified a pathogenic GFI1 variant and a likely pathogenic variant in MYO6 which together explain the complex phenotypes seen in this family. CONCLUSIONS: We present a case illustrating the benefits of a broad screening approach that allows identification of oligogenic determinants of complex human phenotypes which may have been missed if the screening was limited to a targeted gene panel with the assumption of a syndromic disorder. This is important for correct genetic diagnosis of families and disentangling the range and severity of phenotypes associated with high impact variants.


Assuntos
Síndrome Congênita de Insuficiência da Medula Óssea/genética , Proteínas de Ligação a DNA/genética , Perda Auditiva Neurossensorial/genética , Cadeias Pesadas de Miosina/genética , Neutropenia/congênito , Fatores de Transcrição/genética , Adulto , Idoso , Síndrome Congênita de Insuficiência da Medula Óssea/complicações , Síndrome Congênita de Insuficiência da Medula Óssea/diagnóstico , Síndrome Congênita de Insuficiência da Medula Óssea/fisiopatologia , Exoma/genética , Feminino , Doenças Genéticas Inatas/complicações , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/fisiopatologia , Perda Auditiva Neurossensorial/complicações , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Neutropenia/complicações , Neutropenia/diagnóstico , Neutropenia/genética , Neutropenia/fisiopatologia , Linhagem , Fenótipo , Sequenciamento Completo do Exoma
11.
PLoS One ; 15(1): e0225368, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31971949

RESUMO

Single Nucleotide Polymorphisms (SNPs) are the most common candidate mutations in human beings that play a vital role in the genetic basis of certain diseases. Previous studies revealed that Solute Carrier Family 26 Member 4 (SLC26A4) being an essential gene of the multi-faceted transporter family SLC26 facilitates reflexive movement of Iodide into follicular lumen through apical membrane of thyrocyte. SLC26A4 gene encodes Pendred protein, a membrane glycoprotein, highly hydrophobic in nature, present at the apical membrane of thyrocyte functioning as transporter of iodide for thyroid cells. A minor genetic variation in SLC26A4 can cause Pendred syndrome, a syndrome associated with thyroid glands and deafness. In this study, we performed in-silico analysis of 674 missense SNPs of SLC26A4 using different computational platforms. The bunch of tools including SNPNEXUS, SNAP-2, PhD-SNP, SNPs&GO, I-Mutant, ConSurf, and ModPred were used to predict 23 highly confident damaging and disease causing nsSNPs (G209V, G197R, L458P, S427P, Q101P, W472R, N392Y, V359E, R409C, Q235R, R409P, G139V, G497S, H723R, D87G, Y127H, F667C, G334A, G95R, S427C, R291W, Q383H and E384G) that could potentially alter the SLC26A4 gene. Moreover, protein structure prediction, protein-ligand docking and Molecular Dynamics simulation were performed to confirm the impact of two evident alterations (Y127H and G334A) on the protein structure and function.


Assuntos
Biologia Computacional , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Transportadores de Sulfato/genética , Surdez/genética , Surdez/patologia , Bócio Nodular/genética , Bócio Nodular/patologia , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/patologia , Humanos , Ligantes , Simulação de Dinâmica Molecular , Mutação/genética , Ligação Proteica , Conformação Proteica , Relação Estrutura-Atividade , Transportadores de Sulfato/química
12.
J Cutan Pathol ; 47(2): 146-149, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31437319

RESUMO

Sweet syndrome is rare in the pediatric population and usually responds well to treatment, resolving without sequelae. Marshall syndrome is a rare pediatric skin disease characterized by loss of elastic tissue (cutis laxa) secondary to acquired, localized neutrophilic dermatitis without any internal organ involvement. Only few cases of Marshall syndrome (acquired cutis laxa type II) have been reported. Systemic steroids and dapsone show excellent results in Sweet syndrome. Although there is no satisfactory treatment for cutis laxa, dapsone can be used in the acute phase for control of swelling.


Assuntos
Catarata/tratamento farmacológico , Colágeno Tipo XI/deficiência , Anormalidades Craniofaciais/tratamento farmacológico , Cútis Laxa , Dapsona/administração & dosagem , Perda Auditiva Neurossensorial/tratamento farmacológico , Osteocondrodisplasias/tratamento farmacológico , Síndrome de Sweet , Catarata/metabolismo , Catarata/patologia , Pré-Escolar , Colágeno Tipo XI/metabolismo , Anormalidades Craniofaciais/metabolismo , Anormalidades Craniofaciais/patologia , Cútis Laxa/tratamento farmacológico , Cútis Laxa/metabolismo , Cútis Laxa/patologia , Feminino , Perda Auditiva Neurossensorial/metabolismo , Perda Auditiva Neurossensorial/patologia , Humanos , Osteocondrodisplasias/metabolismo , Osteocondrodisplasias/patologia , Síndrome de Sweet/tratamento farmacológico , Síndrome de Sweet/metabolismo , Síndrome de Sweet/patologia
13.
Eur Radiol ; 30(1): 99-109, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31338653

RESUMO

AIM: We investigated if loop characteristics correlate with audio-vestibular symptoms or hemifacial spasm in patients with a vascular loop in the root entry zone (VII and VIII) and in the internal auditory canal. MATERIALS AND METHODS: A retrospective, multicenter study analyzed 2622 consecutive magnetic resonance imaging (MRI) scans of the cerebellopontine angle of patients with asymmetric audio-vestibular symptom or hemifacial spasm; patients' symptoms were confirmed by clinical tests. MRIs displaying vascular loops visible in the axial view were analyzed using multiplanar reconstruction. We evaluated (1) depth of penetration of the loop into the internal auditory canal (IAC); (2) largest diameter of the vessel; (3) nerve(s) involved in the vascular impingement, position of the loop relative to such nerve(s) and number of contacts between vessel and nerve(s); (4) length of such contact. The loop metrics described above were correlated with the patients' audio-vestibular symptoms and hemifacial spasm. RESULTS: Three hundred ninety-nine patients displayed a loop visible in the MRI axial view and out of them only 118 displayed a direct contact between loop and nerve. The cochlear nerve was involved in a contact in 57.7%. Loops in direct nerve contact had a calibre > 0.85 mm, were located in the middle portion of the IAC, and correlated with vertigo (p = 0.002), tinnitus (p = 0.003), and hemifacial spasm (p < 0.001). Asymmetric sensorineural hearing loss (SNHL) correlated with number of contacts (p < 0.001) and length of contact (p < 0.05). The contact was asymptomatic in 41.5% of patients. CONCLUSION: Loop characteristics may help predict whether a vascular impingement is responsible for a symptom and guide the physician to select the best treatment. KEY POINTS: • A vascular loop in the internal auditory canal was observed in 18-20% of the patients in this study; whether a loop can be responsible for a compressive syndrome is still unclear in particular referred to the vestibulocochlear nerve. • Compression by a loop on the facial nerve causes hemifacial spasm; compression by a loop on the cochlear or vestibular nerve may cause audio-vestibular symptoms. • In patients with a loop, the loop calibre, the loop position, and the number of loop-nerve(s) assessed via the multiplanar MRI reconstruction technique may help assess whether the patient will manifest audio-vestibular symptoms or hemifacial spasm.


Assuntos
Perda Auditiva Neurossensorial/etiologia , Espasmo Hemifacial/etiologia , Síndromes de Compressão Nervosa/complicações , Adulto , Idoso , Orelha Interna/irrigação sanguínea , Orelha Interna/inervação , Nervo Facial/patologia , Feminino , Perda Auditiva Neurossensorial/patologia , Espasmo Hemifacial/patologia , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Síndromes de Compressão Nervosa/patologia , Estudos Retrospectivos , Zumbido/etiologia , Zumbido/patologia , Doenças Vestibulares/complicações , Doenças Vestibulares/patologia , Vestíbulo do Labirinto/irrigação sanguínea , Vestíbulo do Labirinto/patologia
15.
BMC Med Genet ; 20(1): 198, 2019 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-31852434

RESUMO

BACKGROUND: Perrault syndrome is a genetically heterogenous, very rare disease, characterized clinically by sensorineural hearing loss, ovarian dysfunction and neurological symptoms. We present the case of a 33 years old female patient with TWNK-associated Perrault syndrome. The TWNK gene is coding the mitochondrial protein Twinkle and currently there are only two reports characterizing the phenotype of TWNK-associated Perrault syndrome. None of these publications reported about special brain MRI alterations and neuropathological changes in the muscle and peripheral nerves. CASE PRESENTATION: Our patients with TWNK-dependent Perrault syndrome had severe bilateral hypoacusis, severe ataxia, polyneuropathy, lower limb spastic paraparesis with pyramidal signs, and gonadal dysgenesis. Psychiatric symptoms such as depression and paranoia were present as well. Brain MRI observed progressive cerebellar hyperintensive signs associated with cerebellar, medulla oblongata and cervical spinal cord atrophy. Light microscopy of the muscle biopsy detected severe neurogenic lesions. COX staining was centrally reduced in many muscle fibers. Both muscle and sural nerve electron microscopy detected slightly enlarged mitochondria with abnormal cristae surrounded by lipid vacuoles. In the sural nerve, dystrophic axons had focally uncompacted myelin lamellae present. Genetic investigation revealed multiple mtDNA deletion and compound heterozygous mutations of the TWNK gene (c.1196 A > G, c.1358 G > A). CONCLUSION: This study demonstrates that TWNK associated Perrault syndrome has a much broader phenotype as originally published. The coexistence of severe hypoacusis, spastic limb weakness, ataxia, polyneuropathy, gonadal dysgensia, hyperintense signals in the cerebellum and the presence of the mtDNA multiple deletion could indicate the impairment of the TWNK gene. This is the first report about pyramidal tract involvement and cerebellar MRI alteration associated with TWNK-related Perrault syndrome.


Assuntos
DNA Helicases/genética , Disgenesia Gonadal 46 XX/genética , Perda Auditiva Neurossensorial/genética , Proteínas Mitocondriais/genética , Fenótipo , Adulto , Feminino , Disgenesia Gonadal 46 XX/diagnóstico por imagem , Disgenesia Gonadal 46 XX/patologia , Perda Auditiva Neurossensorial/diagnóstico por imagem , Perda Auditiva Neurossensorial/patologia , Humanos , Imagem por Ressonância Magnética , Mutação
16.
Trends Hear ; 23: 2331216519886707, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31722636

RESUMO

There is increasing evidence that hearing-impaired (HI) individuals do not use the same listening strategies as normal-hearing (NH) individuals, even when wearing optimally fitted hearing aids. In this perspective, better characterization of individual perceptual strategies is an important step toward designing more effective speech-processing algorithms. Here, we describe two complementary approaches for (a) revealing the acoustic cues used by a participant in a /d/-/g/ categorization task in noise and (b) measuring the relative contributions of these cues to decision. These two approaches involve natural speech recordings altered by the addition of a "bump noise." The bumps were narrowband bursts of noise localized on the spectrotemporal locations of the acoustic cues, allowing the experimenter to manipulate the consonant percept. The cue-weighting strategies were estimated for three groups of participants: 17 NH listeners, 18 HI listeners with high-frequency loss, and 15 HI listeners with flat loss. HI participants were provided with individual frequency-dependent amplification to compensate for their hearing loss. Although all listeners relied more heavily on the high-frequency cue than on the low-frequency cue, an important variability was observed in the individual weights, mostly explained by differences in internal noise. Individuals with high-frequency loss relied slightly less heavily on the high-frequency cue relative to the low-frequency cue, compared with NH individuals, suggesting a possible influence of supra-threshold deficits on cue-weighting strategies. Altogether, these results suggest a need for individually tailored speech-in-noise processing in hearing aids, if more effective speech discriminability in noise is to be achieved.


Assuntos
Perda Auditiva de Alta Frequência/patologia , Perda Auditiva Neurossensorial/patologia , Pessoas com Deficiência Auditiva/estatística & dados numéricos , Percepção da Fala , Adulto , Idoso , Sinais (Psicologia) , Feminino , Auxiliares de Audição , Humanos , Masculino , Pessoa de Meia-Idade , Ruído , Adulto Jovem
17.
Laryngoscope ; 129(11): 2574-2579, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31633822

RESUMO

OBJECTIVE: To investigate the relations of monoallelic (M1), biallelic (M2), or the absence of mutations (M0) in SLC26A4 to inner ear morphology and hearing levels in individuals with Pendred syndrome (PS) or nonsyndromic enlarged vestibular aqueduct (NSEVA) associated with hearing loss. METHODS: In a cohort of 139 PS/NSEVA individuals, 115 persons from 95 unrelated families had full genetic sequencing of SLC26A4, and 113 had retrievable images for re-assessment of inner ear morphology. The association between the number of mutant alleles in SLC26A4, inner ear morphology (including endolymphatic sac size and protein content on magnetic resonance imaging), and hearing level (pure tone average) was explored. RESULTS: Biallelic SLC26A4 mutations (M2) occurred in three-quarters of the cohort and was invariably associated with poor hearing; in 87%, it was associated with incomplete partition type II of the cochlea as well as enlarged endolymphatic sac and vestibular aqueduct. M1 or M0 individuals exhibited a greater variability in inner ear morphology. Endolymphatic sac size and presence of "high-protein" sac contents were significantly higher in M2 individuals compared to M1 and M0 individuals. CONCLUSION: The number of SLC26A4 mutations is associated with severity and variability of inner ear morphology and hearing level in individuals with PS or NSEVA. M2 individuals have poorer hearing and present largely incomplete partition type II of the cochleas with enlarged endolymphatic sacs, whereas individuals with M1 and no detectable SLC26A4 mutations have less severe hearing loss and more diverse inner ear morphology. LEVEL OF EVIDENCE: 4. Laryngoscope, 129:2574-2579, 2019.


Assuntos
Bócio Nodular/genética , Perda Auditiva Neurossensorial/genética , Transportadores de Sulfato/genética , Aqueduto Vestibular/anormalidades , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Criança , Cóclea/patologia , Orelha Interna/patologia , Saco Endolinfático/patologia , Feminino , Bócio Nodular/patologia , Audição/genética , Perda Auditiva Neurossensorial/patologia , Testes Auditivos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Estudos Retrospectivos , Aqueduto Vestibular/patologia , Adulto Jovem
18.
Hum Genomics ; 13(1): 53, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31640787

RESUMO

BACKGROUND: Dysfunction in inwardly rectifying potassium channel Kir4.1 has been implicated in SeSAME syndrome, an autosomal-recessive (AR), rare, multi-systemic disorder. However, not all neurological, intellectual disability, and comorbid phenotypes in SeSAME syndrome can be mechanistically linked solely to Kir4.1 dysfunction. METHODS: We therefore performed whole-exome sequencing and identified additional genetic risk-elements that might exert causative effects either alone or in concert with Kir4.1 in a family diagnosed with SeSAME syndrome. RESULTS: Two variant prioritization pipelines based on AR inheritance and runs of homozygosity (ROH), identified two novel homozygous variants in KCNJ10 and PI4KB and five rare homozygous variants in PVRL4, RORC, FLG2, FCRL1, NIT1 and one common homozygous variant in HSPA6 segregating in all four patients. The novel mutation in KCNJ10 resides in the cytoplasmic domain of Kir4.1, a seat of phosphatidylinositol bisphosphate (PIP2) binding. The mutation altered the subcellular localization and stability of Kir4.1 in patient-specific lymphoblastoid cells (LCLs) compared to parental controls. Barium-sensitive endogenous K+ currents in patient-specific LCLs using whole-cell patch-clamp electrophysiology revealed membrane depolarization and defects in inward K+ ion conductance across the membrane, thereby suggesting a loss-of-function effect of KCNJ10 variant. CONCLUSION: Altogether, our findings implicate the role of new genes in SeSAME syndrome without electrolyte imbalance and thereby speculate the regulation of Kir4.1 channel activity by PIP2 and integrin-mediated adhesion signaling mechanisms.


Assuntos
Perda Auditiva Neurossensorial/genética , Deficiência Intelectual/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Canais de Potássio Corretores do Fluxo de Internalização/genética , Convulsões/genética , Adolescente , Adulto , Criança , Feminino , Perda Auditiva Neurossensorial/patologia , Homozigoto , Humanos , Deficiência Intelectual/patologia , Masculino , Mutação/genética , Fenótipo , Convulsões/patologia , Sequenciamento Completo do Exoma , Adulto Jovem
20.
Mol Genet Genomic Med ; 7(11): e967, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31478598

RESUMO

BACKGROUND: X-linked deafness-4 (DFNX4) caused by functional loss of SMPX is a nonsyndromic form of progressive hearing loss with post-lingual onset. Herein, we describe a male neonate from an ethnic Han Chinese family who presented with congenital deafness. METHODS: The proband and the family members were subjected to comprehensively hearing screen. Genetic testing was carried out using whole-exome sequencing (WES). The result was verified by Sanger sequencing. Functional characterization of the identified variant was completed by reverse transcription PCR (RT-PCR), Sanger sequencing, and fluorogenic quantitative PCR (qPCR). RESULTS: The proband was diagnosed with progressive sensorineural hearing loss. The proband's mother showed normal hearing at present. The proband's maternal grandmother exhibited mild HL since the age of 50. Using whole-exome sequencing (WES), we identified a donor splice-site variant (NM_014332.2: c.132 + 1G>A) in the SMPX gene in the proband. The mother and maternal grandmother were both carriers, which suggested a X-linked inheritance of the condition in the family. RT-PCR and Sanger sequencing revealed that four alternative splice pairs within intron 3 have led to four aberrant RNAs transcripts, including two non-canonical splice-pairs (GC-AG and CT-AG). The variant generated a novel frameshift variant, creating a premature termination codon (PTC) upstream of a newly formed splice site (p.Met45Glyfs*16). SMPX mRNA expression assay showed that the PTC has caused degradation of mRNA via nonsense-mediated mRNA decay (NMD). CONCLUSION: This is the first study to report a SMPX (DFNX4) splicing variant in a Chinese family. These findings, especially congenital deafness, contributed to existing knowledge regarding the genotypic and phenotypic spectrum of SMPX-associated hearing loss.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X/etiologia , Perda Auditiva Neurossensorial/congênito , Perda Auditiva Neurossensorial/etiologia , Proteínas Musculares/genética , Polimorfismo de Nucleotídeo Único , Sítios de Splice de RNA , Processamento de RNA/genética , Sequenciamento Completo do Exoma/métodos , Criança , Pré-Escolar , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Perda Auditiva Neurossensorial/patologia , Humanos , Íntrons , Masculino , Pessoa de Meia-Idade , Prognóstico
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