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1.
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
2.
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
4.
Genes (Basel) ; 10(7)2019 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-31336982

RESUMO

Labyrinthine aplasia, microtia, and microdontia (LAMM) is an autosomal recessive condition causing profound congenital deafness, complete absence of inner ear structures (usually Michel's aplasia), microtia (usually type 1) and microdontia. To date, several families have been described with this condition and a number of mutations has been reported. We report on eight further cases of LAMM syndrome including three novel mutations, c. 173T>C p.L58P; c. 284G>A p.(Arg95Gln) and c.325_327delinsA p.(Glu109Thrfs*18). Congenital deafness was the primary presenting feature in all affected individuals and consanguinity in all but two families. We compare the features in our patients to those previously reported in LAMM, and describe a milder, asymmetrical phenotype associated with FGF3 mutations.


Assuntos
Microtia Congênita/genética , Microtia Congênita/patologia , Orelha Interna/anormalidades , Fator 3 de Crescimento de Fibroblastos/genética , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/patologia , Anormalidades Dentárias/genética , Anormalidades Dentárias/patologia , Adulto , Pré-Escolar , Consanguinidade , Análise Mutacional de DNA , Surdez/congênito , Orelha Interna/patologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Fenótipo
5.
Int J Mol Sci ; 20(14)2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31340433

RESUMO

Lysyl oxidase like 3 (LOXL3) is a copper-dependent amine oxidase responsible for the crosslinking of collagen and elastin in the extracellular matrix. LOXL3 belongs to a family including other members: LOX, LOXL1, LOXL2, and LOXL4. Autosomal recessive mutations are rare and described in patients with Stickler syndrome, early-onset myopia and non-syndromic cleft palate. Along with an essential function in embryonic development, multiple biological functions have been attributed to LOXL3 in various pathologies related to amino oxidase activity. Additionally, various novel roles have been described for LOXL3, such as the oxidation of fibronectin in myotendinous junction formation, and of deacetylation and deacetylimination activities of STAT3 to control of inflammatory response. In tumors, three distinct roles were described: (1) LOXL3 interacts with SNAIL and contributes to proliferation and metastasis by inducing epithelial-mesenchymal transition in pancreatic ductal adenocarcinoma cells; (2) LOXL3 is localized predominantly in the nucleus associated with invasion and poor gastric cancer prognosis; (3) LOXL3 interacts with proteins involved in DNA stability and mitosis completion, contributing to melanoma progression and sustained proliferation. Here we review the structure, function and activity of LOXL3 in normal and pathological conditions and discuss the potential of LOXL3 as a therapeutic target in various diseases.


Assuntos
Aminoácido Oxirredutases/genética , Artrite/genética , Fissura Palatina/genética , Doenças do Tecido Conjuntivo/genética , Matriz Extracelular/genética , Perda Auditiva Neurossensorial/genética , Miopia/genética , Neoplasias/genética , Descolamento Retiniano/genética , Aminoácido Oxirredutases/química , Aminoácido Oxirredutases/metabolismo , Artrite/enzimologia , Artrite/patologia , Fissura Palatina/enzimologia , Fissura Palatina/patologia , Colágeno/química , Colágeno/genética , Colágeno/metabolismo , Doenças do Tecido Conjuntivo/enzimologia , Doenças do Tecido Conjuntivo/patologia , Elastina/química , Elastina/genética , Elastina/metabolismo , Transição Epitelial-Mesenquimal/genética , Matriz Extracelular/química , Matriz Extracelular/enzimologia , Regulação da Expressão Gênica , Perda Auditiva Neurossensorial/enzimologia , Perda Auditiva Neurossensorial/patologia , Humanos , Isoenzimas/química , Isoenzimas/genética , Isoenzimas/metabolismo , Miopia/enzimologia , Miopia/patologia , Neoplasias/enzimologia , Neoplasias/patologia , Especificidade de Órgãos , Descolamento Retiniano/enzimologia , Descolamento Retiniano/patologia , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Fatores de Transcrição da Família Snail/genética , Fatores de Transcrição da Família Snail/metabolismo
6.
Invest Ophthalmol Vis Sci ; 60(8): 3084-3090, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31323090

RESUMO

Purpose: To report molecular genetic findings in six probands with congenital hereditary endothelial dystrophy (CHED) variably associated with hearing loss (also known as Harboyan syndrome). Furthermore, we developed a cellular model to determine if disease-associated variants induce aberrant SLC4A11 pre-mRNA splicing. Methods: Direct sequencing of the entire SLC4A11 coding region was performed in five probands. In one individual, whole genome sequencing was undertaken. The effect of c.2240+5G>A on pre-mRNA splicing was evaluated in a corneal endothelial-like (CE-like) cell model expressing SLC4A11. CE-like cells were derived from autologous induced pluripotent stem cells (iPSCs) via neural crest cells exposed to B27, PDGF-BB, and DKK-2. Total RNA was extracted, and RT-PCR was performed followed by Sanger and a targeted next generation sequencing (NGS) approach to identify and quantify the relative abundance of alternatively spliced transcripts. Results: In total, 11 different mutations in SLC4A11 evaluated as pathogenic were identified; of these, c.1237G>A, c.2003T>C, c.1216+1G>A, and c.2240+5G>A were novel. The c.2240+5G>A variant was demonstrated to result in aberrant pre-mRNA splicing. A targeted NGS approach confirmed that the variant introduces a leaky cryptic splice donor site leading to the production of a transcript containing an insertion of six base pairs with the subsequent introduction of a premature stop codon (p.Thr747*). Furthermore, a subset of transcripts comprising full retention of intron 16 also were observed, leading to the same functionally null allele. Conclusions: This proof-of-concept study highlights the potential of using CE-like cells to investigate the pathogenic consequences of SLC4A11 disease-associated variants.


Assuntos
Proteínas de Transporte de Ânions/genética , Antiporters/genética , Distrofias Hereditárias da Córnea/genética , Epitélio Posterior/patologia , Regulação da Expressão Gênica , Perda Auditiva Neurossensorial/genética , Células-Tronco Pluripotentes Induzidas/citologia , RNA/genética , Adolescente , Adulto , Idoso , Proteínas de Transporte de Ânions/biossíntese , Antiporters/biossíntese , Diferenciação Celular , Células Cultivadas , Criança , Pré-Escolar , Distrofias Hereditárias da Córnea/metabolismo , Distrofias Hereditárias da Córnea/patologia , Epitélio Posterior/metabolismo , Feminino , Perda Auditiva Neurossensorial/metabolismo , Perda Auditiva Neurossensorial/patologia , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Masculino , Pessoa de Meia-Idade , Linhagem , Precursores de RNA , Processamento de RNA , Adulto Jovem
7.
Am J Otolaryngol ; 40(4): 473-477, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31060752

RESUMO

OBJECTIVE: Enlargement of the vestibular aqueduct (EVA) is one of the most common congenital malformations in pediatric patients presenting with sensorineural or mixed hearing loss. The relationship between vestibular aqueduct (VA) morphology and hearing loss across sex is not well characterized. This study assesses VA morphology and frequency-specific hearing thresholds with sex as the primary predictor of interest. MATERIALS AND METHODS: A retrospective, longitudinal, and repeated-measures study was used. 47 patients at an academic tertiary care center with hearing loss and a record of CT scan of the internal auditory canal were candidates, and included upon meeting EVA criteria after confirmatory measurements of vestibular aqueduct midpoint and operculum widths. Audiometric measures included pure-tone average and frequency-specific thresholds. RESULTS: Of the 47 patients (23 female and 24 male), 79 total ears were affected by EVA; the median age at diagnosis was 6.60 years. After comparing morphological measurements between sexes, ears from female patients were observed to have a greater average operculum width (3.25 vs. 2.70 mm for males, p = 0.006) and a greater average VA midpoint width (2.80 vs. 1.90 mm for males, p = 0.004). After adjusting for morphology, male patients' ears had pure-tone average thresholds 17.6 dB greater than female patients' ears (95% CI, 3.8 to 31.3 dB). CONCLUSIONS: Though females seem to have greater enlargement of the vestibular aqueduct, this difference does not extend to hearing loss. Therefore, our results indicate that criteria for EVA diagnoses may benefit from re-evaluation. Further exploration into morphological and audiometric discrepancies across sex may help inform both clinician and patient expectations.


Assuntos
Audiometria , Perda Auditiva Neurossensorial/patologia , Perda Auditiva Neurossensorial/fisiopatologia , Audição , Caracteres Sexuais , Aqueduto Vestibular/anormalidades , Aqueduto Vestibular/patologia , Criança , Limiar Diferencial , Feminino , Perda Auditiva Neurossensorial/etiologia , Humanos , Estudos Longitudinais , Masculino , Estudos Retrospectivos , Centros de Atenção Terciária , Fatores de Tempo
8.
J Int Adv Otol ; 15(1): 77-82, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31058598

RESUMO

OBJECTIVES: Capture the human inner-ear malformation types in 3D by segmenting the inner-ear structures from clinical CT (computed tomography) and MR (magnetic resonance) image datasets. Volumetric analysis was done to find the variations in the volume of cochlear part alone from complete inner-ear followed by 3D printing from the 3D segmented models. MATERIALS AND METHODS: Using 3D slicer freeware, the complete inner-ear structures were segmented from anonymized CT and MR image by setting a tight grey-scale threshold to avoid capturing unwanted structures followed by volumetric analysis of the cochlear part alone. 3D printing was done using Form labs desktop 3D printer. RESULTS: We identified 2x normal anatomy (NA) cochlea, 1x enlarged vestibular aqueduct syndrome (EVAS), 3x incomplete partition (IP) type-I, 4x IP type-II, 3x IP type-III, 5x common cavity (CC) and 5x cochlear hypoplasia (CH). 3D segmented models along with the 3D printed models showed huge variation in size, shape and the anatomy among the image data-sets analyzed. Volumetric analysis showed that on average, volume of CC was above 150mm3, volume of CH fell below 80mm3, Volume of NA, EVAS and IP-I were all around 85-105mm3 whereas the volume of IP-II was around 50mm3. CONCLUSION: Visualizing human inner-ear malformation types in 3D both as computer models and as 3D printed models is a whole-new experience as demonstrated in this study. The volumetric analysis showed a huge variation among the volume of cochlear part alone among the malformation types.


Assuntos
Cóclea/anormalidades , Orelha Interna/anormalidades , Orelha Interna/diagnóstico por imagem , Impressão Tridimensional/instrumentação , Cóclea/diagnóstico por imagem , Simulação por Computador , Perda Auditiva Neurossensorial/diagnóstico por imagem , Perda Auditiva Neurossensorial/patologia , Humanos , Imagem por Ressonância Magnética/métodos , Osso Temporal/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Aqueduto Vestibular/anormalidades , Aqueduto Vestibular/diagnóstico por imagem , Aqueduto Vestibular/patologia
9.
J Clin Neurosci ; 65: 6-10, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31072738

RESUMO

Aim of this paper is to investigate the presence of White Matter Lesions (WMLs) in subjects affected by Sudden Sensorineural Hearing Loss (SSNHL) and possibly to evaluate the significance of WMLs in SSNHL patients. A total of 64 patients (cases) affected by SSNHL were included in this case-control study. Hearing tests were performed at SSNHL onset, after 7 days and after 30 days. Cerebral MRI sequences were performed to rule out retrocochlear pathology, and WMLs were evaluated if present. MRI control group included 32 subjects, without hearing loss, affected by pituitary adenoma, who underwent cerebral MRI of follow-up. WML presence in those affected by SSNHL resulted having a similar distribution to that of the control group; however, we observed complete hearing recovery in 42,9% of patients without WML and in 11,6% of patients with WML >1 (p = 0,017*). The incidence of WML in patients with SSNHL was not different compared to that of the control group; however, MRI could have a prognostic role for SSNHL patients, as the presence of WMLs can been linked to a poorer hearing recovery rate.


Assuntos
Encéfalo/patologia , Perda Auditiva Neurossensorial/patologia , Substância Branca/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Orelha/inervação , Orelha/patologia , Feminino , Perda Auditiva Neurossensorial/etiologia , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto Jovem
10.
Ann Otol Rhinol Laryngol ; 128(6_suppl): 61S-68S, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31092027

RESUMO

OBJECTIVES: The aims of this study were to clarify the clinical value of the bony cochlear nerve canal (BCNC) and internal auditory canal (IAC) in children with bilateral sensorineural hearing loss (b-SNHL) and to reveal the correlation between these parameters and outcomes after cochlear implantation (CI). METHODS: Ninety-four ears with b-SNHL that received CI and 100 ears with normal hearing were enrolled. Parameters of IAC and pre- and post-CI categories of auditory performance scores were analyzed. RESULTS: The width of the BCNC and the width, height, and length of the IAC were shorter in the b-SNHL group. BCNC and IAC width were associated with b-SNHL. The calculated cutoff values for BCNC and IAC width were 2.055 mm in the BCNC and 4.245 mm in the IAC, setting the sensitivity to 90%. Patients with narrow BCNCs and IACs had significantly worse post-CI auditory performance. CONCLUSIONS: BCNC and IAC widths were narrower in children with b-SNHL than in normal-hearing children. Narrow BCNC and IAC width had a negative impact on post-CI outcomes. The proposed cutoff values for BCNC and IAC width were meaningful when predicting the auditory outcome after CI, especially considering both.


Assuntos
Implante Coclear , Orelha Interna/patologia , Perda Auditiva Neurossensorial/terapia , Fatores Etários , Limiar Auditivo , Estudos de Casos e Controles , Criança , Pré-Escolar , Nervo Coclear , Feminino , Perda Auditiva Neurossensorial/patologia , Humanos , Masculino , Valor Preditivo dos Testes , Resultado do Tratamento
11.
BMC Endocr Disord ; 19(1): 52, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31113413

RESUMO

BACKGROUND: Hypothyroidism, one of the prevalent endocrine disorders worldwide, has a broad spectrum of clinical manifestations, from an asymptomatic condition to myxedema coma. Although the majority of patients with hypothyroidism have minor clinical symptoms, which are recovered with levothyroxine treatment, some patients occasionally do experience fatal complications. Here we report, for the first time, the case of a patient who had hypothyroidism with simultaneous occurrence of rhabdomyolysis with acute kidney injury, moderate pericardial effusion, and sudden sensorineural hearing loss. CASE PRESENTATION: A 57-year-old man with a previous history of dyslipidemia and untreated hypothyroidism was admitted to the hospital due to shortness of breath, lethargy, lower extremity discomfort, and unilateral hearing loss. Laboratory results revealed rhabdomyolysis with acute kidney injury and severe hypothyroidism. We detected cardiomegaly without lung parenchymal infiltration on chest radiography and moderate pericardial effusion on transthoracic echocardiography. We performed pure tone audiometry and identified profound unilateral sensorineural hearing loss. Aggressive fluid resuscitation, levothyroxine treatment, and systemic and intratympanic steroid therapy alleviated the patient's severe hypothyroidism, rhabdomyolysis, and pericardial effusion; however, sensorineural hearing loss was not fully recovered. CONCLUSIONS: Early recognition of life-threatening complications is important in patients with severe hypothyroidism to prevent adverse outcomes. This case suggests that hypothyroidism should be considered in patients who have rhabdomyolysis with acute kidney disease and pericardial effusion. Moreover, sudden sensorineural hearing loss should be kept in mind as a rare complication of hypothyroidism.


Assuntos
Perda Auditiva Neurossensorial/patologia , Hipotireoidismo/patologia , Derrame Pericárdico/patologia , Rabdomiólise/patologia , Perda Auditiva Neurossensorial/complicações , Humanos , Hipotireoidismo/complicações , Masculino , Pessoa de Meia-Idade , Derrame Pericárdico/complicações , Prognóstico , Rabdomiólise/complicações
12.
Ann Otol Rhinol Laryngol ; 128(8): 749-754, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30971097

RESUMO

OBJECTIVES: The cochlear aqueduct is a bony duct connecting the scala tympani with the subarachnoid space. Given the pathophysiology of otosclerosis, including bone resorption and new bone deposition, we hypothesize that the cochlear aqueduct in otosclerotic ears is narrowed. METHODS: A retrospective review of patients with otosclerosis who have undergone high-resolution computed tomography (HRCT) of the temporal bone was completed. The control cohort included 20 patients with the diagnosis of noise-induced hearing loss, without the diagnosis of otosclerosis. Uniform measurements of cochlear aqueduct dimensions were performed using the axial plane. RESULTS: The otosclerosis cohort included 25 males and 52 females with mean age of 52.2 ± 17.6 years. The control group included 10 males and 10 females with mean age of 64.0 ± 18.5 years. The mean cochlear aqueduct length, width mid canal, aperture base, aperture widest diameter, and funnel diameter in millimeters were 12.19 ± 1.66, 0.68 ± 0.28, 4.21 ± 1.67, 3.23 ± 1.47, and 2.70 ± 1.05 in the ears with otosclerotic foci and 11.57 ± 1.66, 0.69 ± 0.29, 2.56 ± 1.59, 2.77 ± 1.67, and 2.58 ± 1.03 in control group, respectively. Statistical difference was seen in length of cochlear aqueduct, aperture base, and aperture widest diameters (P = .017, <.001, .007). CONCLUSIONS: The length of the cochlear aqueduct and the funnel width are statistically longer in the otosclerotic population compared to control. The width of the cochlear aqueduct is not statistically different.


Assuntos
Aqueduto da Cóclea/diagnóstico por imagem , Aqueduto da Cóclea/patologia , Otosclerose/diagnóstico por imagem , Otosclerose/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Pesos e Medidas Corporais , Feminino , Perda Auditiva Neurossensorial/diagnóstico por imagem , Perda Auditiva Neurossensorial/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tomografia Computadorizada por Raios X
13.
Medicina (Kaunas) ; 55(3)2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-30934652

RESUMO

The term congenital hypopigmentary disorders refers to a wide group of heterogeneous hereditary diseases, clinically characterized by inborn pigmentary defects of the iris, hair, and/or skin. They include Gray Hair Syndromes (GHSs), a rare group of autosomal recessive genodermatosis hallmarked by inborn silvery gray hair. GHSs encompass Griscelli, Chediak⁻Higashi, Elejalde, and Cross syndromes, which are all characterized by a broad spectrum of severe multisystem disorders, including neurological, ocular, skeletal, and immune system impairment. In this manuscript, we describe in detail the clinical, trichoscopic, and genetic features of a rare case of Griscelli syndrome; moreover, we provide an overview of all the GHSs known to date. Our report highlights how an accurate clinical examination with noninvasive methods, like trichoscopy, may play a crucial rule in diagnosis of rare and potentially lethal genetic syndromes such as Griscelli syndrome, in which timely diagnosis and therapy may modify the clinical course, quality of life, and likelihood of survival.


Assuntos
Transtornos da Pigmentação/diagnóstico , Transtornos da Pigmentação/genética , Doenças Raras/diagnóstico , Doenças Raras/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/imunologia , Anormalidades Múltiplas/patologia , Adulto , Síndrome de Chediak-Higashi/diagnóstico , Síndrome de Chediak-Higashi/genética , Síndrome de Chediak-Higashi/imunologia , Síndrome de Chediak-Higashi/patologia , Pré-Escolar , Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/imunologia , Anormalidades Craniofaciais/patologia , Diagnóstico Diferencial , Feminino , Cabelo/anormalidades , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/imunologia , Perda Auditiva Neurossensorial/patologia , Humanos , Hipertricose/induzido quimicamente , Iris/anormalidades , Masculino , Mutação , Síndromes Neurocutâneas/diagnóstico , Síndromes Neurocutâneas/genética , Síndromes Neurocutâneas/imunologia , Síndromes Neurocutâneas/patologia , Piebaldismo/diagnóstico , Piebaldismo/genética , Piebaldismo/imunologia , Piebaldismo/patologia , Transtornos da Pigmentação/imunologia , Transtornos da Pigmentação/patologia , Qualidade de Vida , Doenças Raras/imunologia , Doenças Raras/patologia , Anormalidades da Pele , Proteínas rab27 de Ligação ao GTP/genética
14.
Mol Genet Genomic Med ; 7(5): e639, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30924321

RESUMO

BACKGROUND: Warsaw Breakage Syndrome (WABS) is an ultra rare cohesinopathy caused by biallelic mutation of DDX11 gene. It is clinically characterized by pre and postnatal growth delay, microcephaly, hearing loss with cochlear hypoplasia, skin color abnormalities, and dysmorphisms. METHODS: Mutational screening and functional analyses (protein expression and 3D-modeling) were performed in order to investigate the presence and pathogenicity of DDX11 variant identified in our patients. RESULTS: We report the clinical history of two sisters affected by WABS with a pathological mytomicin C test carrying compound heterozygous mutations (c.2507T > C / c.907_920del) of the DDX11 gene. The pathogenicity of this variant was confirmed in the light of a bioinformatic study and protein three-dimensional modeling, as well as expression analysis. CONCLUSION: These findings further extend the clinical and molecular knowledge about the WABS showing a possible mild phenotype without major malformations or intellectual disability.


Assuntos
Anormalidades Múltiplas/genética , Manchas Café com Leite/genética , RNA Helicases DEAD-box/genética , DNA Helicases/genética , Perda Auditiva Neurossensorial/genética , Fenótipo , Anormalidades Múltiplas/patologia , Manchas Café com Leite/patologia , Linhagem Celular , Células Cultivadas , Criança , Pré-Escolar , Feminino , Perda Auditiva Neurossensorial/patologia , Humanos , Mutação , Síndrome
15.
Am J Hematol ; 94(6): 667-677, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30916803

RESUMO

MYH9-related disease (MYH9-RD) is a rare, autosomal dominant disorder caused by mutations in MYH9, the gene encoding the actin-activated motor protein non-muscle myosin IIA (NMIIA). MYH9-RD patients suffer from bleeding syndromes, progressive kidney disease, deafness, and/or cataracts, but the impact of MYH9 mutations on other NMIIA-expressing tissues remains unknown. In human red blood cells (RBCs), NMIIA assembles into bipolar filaments and binds to actin filaments (F-actin) in the spectrin-F-actin membrane skeleton to control RBC biconcave disk shape and deformability. Here, we tested the effects of MYH9 mutations in different NMIIA domains (motor, coiled-coil rod, or non-helical tail) on RBC NMIIA function. We found that MYH9-RD does not cause clinically significant anemia and that patient RBCs have normal osmotic deformability as well as normal membrane skeleton composition and micron-scale distribution. However, analysis of complete blood count data and peripheral blood smears revealed reduced hemoglobin content and elongated shapes, respectively, of MYH9-RD RBCs. Patients with mutations in the NMIIA motor domain had the highest numbers of elongated RBCs. Patients with mutations in the motor domain also had elevated association of NMIIA with F-actin at the RBC membrane. Our findings support a central role for motor domain activity in NMIIA regulation of RBC shape and define a new sub-clinical phenotype of MYH9-RD.


Assuntos
Actinas , Membrana Eritrocítica , Eritrócitos Anormais , Perda Auditiva Neurossensorial , Mutação , Cadeias Pesadas de Miosina , Trombocitopenia/congênito , Actinas/genética , Actinas/metabolismo , Membrana Eritrocítica/genética , Membrana Eritrocítica/metabolismo , Membrana Eritrocítica/patologia , Eritrócitos Anormais/metabolismo , Eritrócitos Anormais/patologia , Feminino , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/metabolismo , Perda Auditiva Neurossensorial/patologia , Humanos , Masculino , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Trombocitopenia/genética , Trombocitopenia/metabolismo , Trombocitopenia/patologia
16.
Ann Otol Rhinol Laryngol ; 128(8): 689-695, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30913906

RESUMO

INTRODUCTION: Sensorineural hearing loss frequently has been described in patients with leukemia, and in fact, hearing loss may be the presenting symptom of this disease. However, the pathogenesis of sensorineural hearing loss in leukemia is not well understood. OBJECTIVE: To describe the temporal bone histopathology in 1 patient with leukemia and sensorineural hearing loss. METHODS: The histopathology of the temporal bones of 1 patient with chronic myelomonocytic leukemia who suffered well-documented bilateral sequential profound sensorineural hearing loss 4 months before death was investigated using light microscopy. RESULT: There was evidence of ischemic necrosis of the neuroepithelium and intravascular fibrin micro-thrombi suggestive of intravascular coagulation in the cochlea and vestibular labyrinth. CONCLUSION: Intravascular coagulation may be a contributing factor in the commonly reported finding of hemorrhage in the cochlea in leukemia and may play a role in the pathogenesis of sensorineural loss in some cases of leukemia.


Assuntos
Perda Auditiva Neurossensorial/etiologia , Leucemia Mielomonocítica Crônica/complicações , Leucemia Mielomonocítica Crônica/patologia , Idoso , Cóclea/patologia , Perda Auditiva Neurossensorial/patologia , Humanos , Masculino , Osso Temporal/patologia , Vestíbulo do Labirinto/patologia
17.
Nat Commun ; 10(1): 427, 2019 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-30683875

RESUMO

Adeno-associated virus (AAV) has been successfully used to deliver gene therapy to improve auditory function in mouse models of hereditary hearing loss. Many forms of hereditary hearing loss have mutations which affect the cochlear hair cells, the mechanosensory cells which allow for sound detection and processing. While most conventional AAVs infect inner hair cells (IHCs) with various efficiencies, they infect outer hair cells (OHCs) and supporting cells at lower levels in the cochlea. Here we examine the infection patterns of two synthetic AAVs (AAV2.7m8 and AAV8BP2) in the mouse inner ear. AAV2.7m8 infects both IHCs and OHCs with high efficiency. In addition, AAV2.7m8 infects inner pillar cells and inner phalangeal cells with high efficiency. Our results suggest that AAV2.7m8 is an excellent viral vector for inner ear gene therapy targeting cochlear hair cells and supporting cells, and it will likely greatly expand the potential applications for inner ear gene therapy.


Assuntos
Dependovirus/genética , Terapia Genética/métodos , Vetores Genéticos/metabolismo , Células Ciliadas Auditivas Internas/metabolismo , Perda Auditiva Neurossensorial/terapia , Miosinas/genética , Animais , Animais Recém-Nascidos , Dependovirus/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Genes Reporter , Vetores Genéticos/química , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células Ciliadas Auditivas Internas/patologia , Células Ciliadas Auditivas Externas/metabolismo , Células Ciliadas Auditivas Externas/patologia , Audição/genética , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/metabolismo , Perda Auditiva Neurossensorial/patologia , Camundongos , Miosinas/metabolismo
18.
Can J Vet Res ; 83(1): 11-16, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30670897

RESUMO

The objective of this study was to evaluate any otopathologic changes in temporal bone specimens from dogs with deafness related to cochleosaccular (Scheibe) dysplasia (CSD). We used the canine temporal bone collections of the Otopathology Laboratory at the University of Minnesota and of the Massachusetts Eye and Ear Infirmary at Harvard University in Boston. Our morphometric analysis included measuring the areas of the stria vascularis and the spiral ligament and counting the number of spiral ganglion cells. In addition, we noted the presence of the organ of Corti and cochlear hair cells, assessed the location of Reissner's membrane and the saccular membrane, and counted the number of both Type I and Type II vestibular hair cells in the macule of the saccule and vestibular ganglion cells. In the group of specimens from dogs with cochleosaccular dysplasia, we observed generalized degeneration in the cochlea and a significantly decreased number of Type I and Type II vestibular hair cells and vestibular ganglion cells. As hereditary deafness is presently untreatable with known therapeutic methods, dogs with cochleosaccular dysplasia should not be considered for breeding. Future therapeutic approaches, such as stem cell therapies, should be designed to target all the elements of the cochlea in addition to the saccule as it was found that both are affected in dogs with CSD.


Assuntos
Cóclea/patologia , Doenças do Cão/patologia , Perda Auditiva Neurossensorial/veterinária , Osso Temporal/patologia , Animais , Doenças do Cão/genética , Cães , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/patologia , Células Ganglionares da Retina
19.
Int J Pediatr Otorhinolaryngol ; 118: 147-151, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30634102

RESUMO

OBJECTIVE: To investigate any meaningful differences in hearing between patients with unilateral and bilateral enlarged vestibular aqueduct (EVA). EVA is a common radiological finding in children presenting with hearing loss. We hope to provide insight into the pathogenesis of EVA and provide further guidelines for unilateral EVA management. We hypothesized that hearing loss in unilateral EVA would be similar to that seen in bilateral EVA. METHODS: A longitudinal retrospective study design was used. Three measures of hearing, pure tone average (PTA) word recognition score (WRS) and speech awareness threshold (SAT) and radiologic morphologies were tested for difference across unilateral versus bilateral ear EVA status. Linear mixed effects models were used to identify differences while accounting for time and multiple measurements per ear. RESULTS: Using Cincinnati criteria, 89 ears fit inclusion criteria, 75 of which were from patients with bilateral EVA compared to 14 ears from patients with unilateral EVA. No significant differences across bilateral status were observed in audiological measurements. Models showed that speech recognition threshold (SRT) (p = 0.925), word recognition score (WRS)(p = 0.521) and pure tone average (PTA) of air and bone conduction from 250 to 4000 Hz (p = 0.281-0.933) were not statistically different with respect to bilateral status. Wilcoxon rank-sum tests showed no statistical difference in vestibular aqueduct width or operculum size (VA)(p = 0.234, p = 0.623). Each year after the first audiogram was associated with significantly greater SRT (p = 0.003) decreased WRS (0.014) and increased PTA (0.003.). Greater midpoint width was associated with significantly lower SRT (p = 0.004) WRS (<0.001) and PTA (<0.001.) CONCLUSION: Our results indicate no statistically significant difference in hearing ability with respect to bilateral EVA status, suggesting that unilateral EVA patients require close follow-up. Our results also demonstrate the progressive nature of EVA and a relationship between VA midpoint width and hearing loss severity.


Assuntos
Surdez/etiologia , Perda Auditiva Neurossensorial/etiologia , Perda Auditiva Unilateral/etiologia , Aqueduto Vestibular/anormalidades , Audiometria de Tons Puros , Condução Óssea , Criança , Pré-Escolar , Feminino , Audição , Perda Auditiva Neurossensorial/complicações , Perda Auditiva Neurossensorial/diagnóstico por imagem , Perda Auditiva Neurossensorial/patologia , Humanos , Estudos Longitudinais , Masculino , Estudos Retrospectivos , Teste do Limiar de Recepção da Fala , Síndrome , Aqueduto Vestibular/diagnóstico por imagem , Aqueduto Vestibular/patologia
20.
Eur J Hum Genet ; 27(3): 369-377, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30568244

RESUMO

Stickler syndrome is a genetic disorder that can lead to joint problems, hearing difficulties and retinal detachment. Genes encoding collagen types II, IX and XI are usually responsible, but some families have no causal variant identified. We investigate a variant in the gene encoding growth factor BMP4 in a family with Stickler syndrome with associated renal dysplasia. Next generation sequencing of the coding region of COL2A1, COL11A1 and a panel of genes associated with congenital anomalies of the kidney and urinary tract (CAKUT) was performed. A novel heterozygous BMP4 variant causing a premature stop codon, c. 130G>T, p.(Gly44Ter), which segregated with clinical features of Stickler syndrome in multiple family members, was identified. No variant affecting gene function was detected in COL2A1 or COL11A1. Skin fibroblasts were cultured with and without emetine, and the mRNA extracted and analysed by Sanger sequencing to assess whether the change was causing nonsense-mediated decay. Nonsense-mediated decay was not observed from the extracted BMP4 mRNA. BMP4 is a growth factor known to contribute to eye development in animals, and gene variants in humans have been linked to microphthalmia/anophthalmia as well as CAKUT. The variant identified here further demonstrates the importance of BMP4 in eye development. This is the first report of a BMP4 DNA variant causing Stickler syndrome, and we suggest BMP4 be added to standard diagnostic gene panels for this condition.


Assuntos
Artrite/genética , Proteína Morfogenética Óssea 4/genética , Doenças do Tecido Conjuntivo/genética , Perda Auditiva Neurossensorial/genética , Rim/anormalidades , Mutação com Perda de Função , Descolamento Retiniano/genética , Adulto , Artrite/patologia , Proteína Morfogenética Óssea 4/metabolismo , Células Cultivadas , Doenças do Tecido Conjuntivo/patologia , Feminino , Perda Auditiva Neurossensorial/patologia , Humanos , Masculino , Linhagem , Fenótipo , Descolamento Retiniano/patologia
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