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1.
BMC Neurol ; 20(1): 314, 2020 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-32847546

RESUMO

BACKGROUND: Kartagener syndrome is an autosomal recessive inherited disorder of primary ciliary dyskinesia. Moyamoya syndrome refers to a moyamoya angiopathy associated with other neurological and/or extra-neurological symptoms, or due to a well identified acquired or inherited cause. We herein reported a case of a 48-year-old woman who was favored the diagnosis of Kartagener syndrome and moyamoya syndrome. The whole genome sequencing and bioinformatics analysis showed a homozygotic nonsense mutation in the dynein, axonemal, heavy chain (DNAH) 5 gene, and heterozygotic missense mutation in the DNAH11 gene. This is the first report of the co-occurrence of the two rare diseases. CASE PRESENTATION: A case of a 48-year-old woman was presented with hemiplegia and slurred speech. The magnetic resonance imaging of the brain confirmed acute cerebral infarction in the right basal ganglia region, semi-oval center, insular lobe, and frontal parietal lobe. The electrocardiogram showed inverted "P" waves in L1 and AVL on left-sided chest leads and computed tomography scan of the chest showed bronchiectasis changes, cardiac shadow and apex on the right side, and situs inversus of aortic arch position. The digital subtraction angiography showed inversion of the aortic arch, and bilateral internal carotid arteries are occluded from the ophthalmic segment. The clinical, radiological, and laboratory findings made the diagnosis of Kartagener syndrome and moyamoya syndrome. The whole genome sequencing and bioinformatics analysis showed a homozygotic nonsense mutation in DNAH5 gene, and heterozygotic missense mutation in the DNAH11 gene. CONCLUSION: The combined mutation of DNAH5 and DNAH11 may lead to the overlapping dysfunction of motile and nonmotile cilia, which contribute to the co-occurrence of Kartagener syndrome and moyamoya syndrome. Our report deserves further confirm by more case reports.


Assuntos
Dineínas do Axonema/genética , Síndrome de Kartagener/diagnóstico , Doença de Moyamoya/diagnóstico , Encéfalo/patologia , Feminino , Humanos , Síndrome de Kartagener/genética , Síndrome de Kartagener/patologia , Pessoa de Meia-Idade , Mutação , Mutação de Sentido Incorreto , Sequenciamento Completo do Genoma
2.
Laryngorhinootologie ; 99(5): 326-337, 2020 05.
Artigo em Alemão | MEDLINE | ID: mdl-32384558

RESUMO

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disease. First respiratory symptoms already occur within the first hours after birth. Major symptoms are an unexplained neonatal respiratory distress syndrome, situs inversus, persistant cough, and chronic nasal congestion, recurrent paranasal sinus disorders with or without polyps, bronchiectasis as well as male infertility. Diagnostics is complex and includes transmission electron microscopy, nasal NO assessment, high-speed video microscopy and genetic evaluations. This review gives an overview over the current diagnostic procedures and therapeutic options. The management of PCD is a multidisciplinary approach, which should be reserved to in highly specialized centers.


Assuntos
Síndrome de Kartagener , Tosse , Humanos , Síndrome de Kartagener/diagnóstico , Síndrome de Kartagener/genética , Síndrome de Kartagener/terapia , Masculino , Nariz
3.
Sci Rep ; 10(1): 3677, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-32111882

RESUMO

Situs inversus (SI), a left-right mirror reversal of the visceral organs, can occur with recessive Primary Ciliary Dyskinesia (PCD). However, most people with SI do not have PCD, and the etiology of their condition remains poorly studied. We sequenced the genomes of 15 people with SI, of which six had PCD, as well as 15 controls. Subjects with non-PCD SI in this sample had an elevated rate of left-handedness (five out of nine), which suggested possible developmental mechanisms linking brain and body laterality. The six SI subjects with PCD all had likely recessive mutations in genes already known to cause PCD. Two non-PCD SI cases also had recessive mutations in known PCD genes, suggesting reduced penetrance for PCD in some SI cases. One non-PCD SI case had recessive mutations in PKD1L1, and another in CFAP52 (also known as WDR16). Both of these genes have previously been linked to SI without PCD. However, five of the nine non-PCD SI cases, including three of the left-handers in this dataset, had no obvious monogenic basis for their condition. Environmental influences, or possible random effects in early development, must be considered.


Assuntos
Proteínas de Transporte/genética , Cílios/genética , Genes Recessivos , Proteínas de Membrana/genética , Penetrância , Situs Inversus/genética , Adolescente , Adulto , Feminino , Humanos , Síndrome de Kartagener/genética , Masculino , Pessoa de Meia-Idade
4.
Pediatr Pulmonol ; 55(2): 383-393, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31765523

RESUMO

BACKGROUND AND OBJECTIVE: Primary ciliary dyskinesia (PCD) is a rare and genetically heterogeneous disease and the severity of the disease related with genetic analysis has been described in some previous studies. The main aim of our study was to describe the clinical characteristics and laboratory findings of patients with genetically diagnosed PCD and to investigate the correlation between clinical, radiologic, and laboratory findings and genetic analyses of these patients. METHOD: This is a cohort study in which we analyzed the clinical characteristics, laboratory findings, and genetic results of 46 patients with genetically diagnosed PCD through whole-exome sequencing at our single center from a total of 265 patients with PCD within a 5-year period. RESULTS: Genetic analysis revealed pathogenic variants in DNAH5 (n = 12 individuals, 12 families), CCDC40 (n = 9 individuals, six families), RSPH4A (n = 5 individuals, three families), DNAH11 (n = 4 individuals, four families), HYDIN (n = 5 individuals, five families), CCNO (n = 4 individuals, four families), DNAI1 (n = 2 individuals, one family), ARMC4 (n = 2 individuals, two families), TTC25 (n = 1), DNAH1 (n = 1), and CCDC39 (n = 1) genes. Although not statistically significant, the age at diagnosis was lower (median: 3 years; range, 6 months-4 years) in patients with CCNO pathogenic variants due to the early reporting of symptoms, and the median body mass index (BMI) and BMI z scores were lower in patients at 18.7 and 16 kg/m2 , and -0.78 and -1.2 with CCDC40 and CCNO pathogenic variants, respectively. The median forced expiratory flow in 1 second (FEV1%), forced vital capacity (FVC%), and forced expiratory flow (FEF)25-75% were 53%, 64%, and 28%, respectively; these parameters were also lower in the CCDC40 group than in the other groups. There was no significant correlation between the genetic results and symptoms, radiologic findings, and microbiologic data of patients with PCD. CONCLUSION: In PCD, there was significant heterogeneity of lung disease, patients who had pathogenic variants in CCNO presented earlier, and those with CCDC40 and CCNO had worse lung disease, and poorer nutritional status compared with the other subgroups. We hope that whole genotype-phenotype and clinical relationships will be identified in PCD.


Assuntos
Síndrome de Kartagener/genética , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , DNA Glicosilases/genética , Feminino , Testes Genéticos , Genótipo , Humanos , Lactente , Masculino , Mutação , Fenótipo , Proteínas/genética , Turquia
5.
Cells ; 8(8)2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31443223

RESUMO

Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disorder characterized by dysfunction of motile cilia causing ineffective mucus clearance and organ laterality defects. In this study, two unrelated Portuguese children with strong PCD suspicion underwent extensive clinical and genetic assessments by whole-exome sequencing (WES), as well as ultrastructural analysis of cilia by transmission electron microscopy (TEM) to identify their genetic etiology. These analyses confirmed the diagnostic of Kartagener syndrome (KS) (PCD with situs inversus). Patient-1 showed a predominance of the absence of the inner dynein arms with two disease-causing variants in the CCDC40 gene. Patient-2 showed the absence of both dynein arms and WES disclosed two novel high impact variants in the DNAH5 gene and two missense variants in the DNAH7 gene, all possibly deleterious. Moreover, in Patient-2, functional data revealed a reduction of gene expression and protein mislocalization in both genes' products. Our work calls the researcher's attention to the complexity of the PCD and to the possibility of gene interactions modelling the PCD phenotype. Further, it is demonstrated that even for well-known PCD genes, novel pathogenic variants could have importance for a PCD/KS diagnosis, reinforcing the difficulty of providing genetic counselling and prenatal diagnosis to families.


Assuntos
Cílios/ultraestrutura , Síndrome de Kartagener/genética , Síndrome de Kartagener/patologia , Dineínas do Axonema/genética , Criança , Dineínas/genética , Feminino , Testes Genéticos , Humanos , Masculino , Mutação , Portugal , Proteínas/genética , Sequenciamento Completo do Exoma/métodos
6.
J Assist Reprod Genet ; 36(8): 1683-1700, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31273583

RESUMO

PROPOSE: To study CCDC103 expression profiles and understand how pathogenic variants in CCDC103 affect its expression profile at mRNA and protein level. METHODS: To increase the knowledge about the CCDC103, we attempted genotype-phenotype correlations in two patients carrying novel homozygous (missense and frameshift) CCDC103 variants. Whole-exome sequencing, quantitative PCR, Western blot, electron microscopy, immunohistochemistry, immunocytochemistry, and immunogold labelling were performed to characterize CCDC103 expression profiles in reproductive and somatic cells. RESULTS: Our data demonstrate that pathogenic variants in CCDC103 gene negatively affect gene and protein expression in both patients who presented absence of DA on their axonemes. Further, we firstly report that CCDC103 is expressed at different levels in reproductive tissues and somatic cells and described that CCDC103 protein forms oligomers with tissue-specific sizes, which suggests that CCDC103 possibly undergoes post-translational modifications. Moreover, we reported that CCDC103 was restricted to the midpiece of sperm and is present at the cytoplasm of the other cells. CONCLUSIONS: Overall, our data support the CCDC103 involvement in PCD and suggest that CCDC103 may have different assemblies and roles in cilia and sperm flagella biology that are still unexplored.


Assuntos
Axonema/patologia , Transtornos da Motilidade Ciliar/genética , Infertilidade Masculina/patologia , Síndrome de Kartagener/genética , Proteínas Associadas aos Microtúbulos/genética , Mutação , Cauda do Espermatozoide/patologia , Axonema/genética , Transtornos da Motilidade Ciliar/patologia , Dineínas/metabolismo , Feminino , Humanos , Infertilidade Masculina/etiologia , Síndrome de Kartagener/patologia , Masculino , Pessoa de Meia-Idade , Reprodução , Situs Inversus/genética , Situs Inversus/patologia , Cauda do Espermatozoide/metabolismo
7.
Neumol. pediátr. (En línea) ; 14(2): 76-80, jul. 2019. ilus
Artigo em Espanhol | LILACS | ID: biblio-1014992

RESUMO

Primary ciliary dyskinesia is a congenital disorder due to abnormal motile ciliary function, especially in the airway epithelium. The mucociliary clearance is impaired, producing reoccurring respiratory tract infections, usually resulting in bronchiectasis as an adult. Patients also have frequent ear and sinus infections and almost 50% of them have situs inversus. Diagnosis of primary ciliary dyskinesia is difficult because there is not a single gold standard test, resulting in the need of a multi-test approach. Until recently in our country we only had transmission electron microscopy, but nasal nitric oxide and high speed video microscopy are now available. In this article we will detail the most important clinical characteristics that make us suspect the presence of primary ciliary dyskinesia at different ages and the methods available for its diagnosis.


La discinesia ciliar primaria es una enfermedad congénita debida a una alteración del movimiento normal de los cilios, especialmente a nivel del epitelio respiratorio. Esto se traduce en una alteración del clearance mucociliar lo que predispone al paciente a tener infecciones respiratorias repetidas, terminando en la aparición de bronquiectasias en la edad adulta. También son frecuentes las infecciones repetidas de oídos y cavidades perinasales. La presencia de situs inverso puede verse en hasta en 50% de los pacientes con esta enfermedad. El diagnóstico de discinesia ciliar primaria es difícil ya que no existe un examen que sea considerado patrón de oro, por lo que se requiere la realización de distintos exámenes. En nuestro país hasta hace poco tiempo solo contábamos con la microscopía electrónica, pero recientemente se ha sumado la medición de óxido nítrico nasal y la videomicroscopía de alta velocidad. En el presente artículo se detallarán las características clínicas más importantes que hacen sospechar la presencia de DCP en las distintas edades y los métodos disponibles para su diagnóstico.


Assuntos
Humanos , Recém-Nascido , Pré-Escolar , Adulto , Síndrome de Kartagener/diagnóstico , Síndrome de Kartagener/genética , Síndrome de Kartagener/terapia , Cílios/ultraestrutura , Biópsia , Algoritmos , Testes Genéticos , Microscopia de Vídeo , Microscopia Eletrônica de Transmissão , Óxido Nítrico/análise
8.
Neumol. pediátr. (En línea) ; 14(2): 81-85, jul. 2019.
Artigo em Espanhol | LILACS | ID: biblio-1014999

RESUMO

At present, there is no specific treatment for primary ciliary dyskinesia, nor controlled and randomized clinical trials to determine how the management and monitoring of these patients should be considered. The therapeutic options are extrapolated from other diseases, such as cystic fibrosis, or non-cystic fibrosis bronchiectasis. However, the implementation of specific groups of experts, both in the USA (PDC-foundation) and in Europe (BESTCILIA or BEAT-PD), are helping to increase knowledge of the disease, opening research channels and seeking new treatments. Until we have therapies capable of correcting the basic defect of the disease, the pillars of treatment are the daily cleansing of the airways and aggressive antibiotherapy against respiratory infections. Multidisciplinary care in specialized centers where pulmonary function is monitored and the infection is prevented and treated will improve, as in cystic fibrosis, the results of patients.


En la actualidad no existe un tratamiento específico para la discinesia ciliar primaria, ni se cuenta con ensayos clínicos controlados y randomizados que permitan determinar cómo debe plantearse el manejo y seguimiento de estos pacientes. Las opciones terapéuticas son extrapoladas de otras enfermedades, como la fibrosis quística, o las bronquiectasias no fibrosis quística. Sin embargo, la puesta en marcha de grupos específicos de expertos, tanto en USA (PDC-foundation) como en Europa (BESTCILIA o BEAT-PD), están permitiendo incrementar el conocimiento de la enfermedad, abriendo vías de investigación y buscando nuevos tratamientos. Hasta contar con terapias capaces de corregir el defecto básico de la enfermedad, los pilares del tratamiento son la limpieza diaria de las vías aéreas y la antibioterapia agresiva frente a las infecciones respiratorias. La atención multidisciplinar en centros especializados donde se monitorice la función pulmonar y se prevengan y traten las infecciones mejorará, como en la fibrosis quística, los resultados de los pacientes.


Assuntos
Humanos , Síndrome de Kartagener/diagnóstico , Síndrome de Kartagener/fisiopatologia , Síndrome de Kartagener/genética , Síndrome de Kartagener/terapia , Infecções Respiratórias/tratamento farmacológico , Seguimentos , Pneumopatias/fisiopatologia , Pneumopatias/terapia , Pneumopatias Fúngicas
9.
J Hum Genet ; 64(8): 711-719, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31186518

RESUMO

Primary ciliary dyskinesia (PCD) is a rare phenotypically and genetically heterogeneous disorder resulting from abnormal cilia ultrastructure and function. Few studies have reported the phenotype and genetic characteristics of PCD caused by mutations in DNAAF3. In this study, four PCD patients with DNAAF3 mutations underwent extensive clinical assessments, cilia ultrastructural and motion evaluations. All patients presented with situs inversus totalis, neonatal respiratory distress, and sinusitis; however, they did not have recurrent infections of the lower airways. The nasal nitric oxide level of these patients was markedly reduced. The respiratory cilia were found to be uniformly immotile, with their dynein arms defects. A total of 7 (5 novel) variants in DNAAF3 were identified and cosegregated in their families by Trio-based whole-exome sequencing. As the first report on DNAAF3 mutations in PCD patients in China, our study not only contributes to a deeper appreciation of the phenotypic characteristics of patients with DNAAF3 mutations but also expands the spectrum of DNAAF3 mutations and may contribute to the genetic diagnosis of and counseling for PCD.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Síndrome de Kartagener/diagnóstico , Síndrome de Kartagener/genética , Proteínas Associadas aos Microtúbulos/genética , Mutação , Fenótipo , Biomarcadores , Criança , Cílios/metabolismo , Cílios/ultraestrutura , Consanguinidade , Análise Mutacional de DNA , Feminino , Imunofluorescência , Loci Gênicos , Testes Genéticos , Humanos , Imuno-Histoquímica , Lactente , Síndrome de Kartagener/metabolismo , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , Óxido Nítrico/metabolismo , Linhagem , Mucosa Respiratória , Tomografia Computadorizada por Raios X
10.
Sci Rep ; 9(1): 8693, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31213628

RESUMO

Primary Ciliary Dyskinesia (PCD) is underdiagnosed in Brazil. We enrolled patients from an adult service of Bronchiectasis over a two-year period in a cross-sectional study. The inclusion criteria were laterality disorders (LD), cough with recurrent infections and the exclusion of other causes of bronchiectasis. Patients underwent at least two of the following tests: nasal nitric oxide, ciliary movement and analysis of ciliary immunofluorescence, and genetic tests (31 PCD genes + CFTR gene). The clinical characterization included the PICADAR and bronchiectasis scores, pulmonary function, chronic Pseudomonas aeruginosa (cPA) colonization, exhaled breath condensate (EBC) and mucus rheology (MR). Forty-nine of the 500 patients were diagnosed with definite (42/49), probable (5/49), and clinical (2/49) PCD. Twenty-four patients (24/47) presented bi-allelic pathogenic variants in a total of 31 screened PCD genes. A PICADAR score > 5 was found in 37/49 patients, consanguinity in 27/49, LD in 28/49, and eight PCD sibling groups. FACED diagnosed 23/49 patients with moderate or severe bronchiectasis; FEV1 ≤ 50% in 25/49 patients, eight patients had undergone lung transplantation, four had been lobectomized and cPA+ was determined in 20/49. The EBC and MR were altered in all patients. This adult PCD population was characterized by consanguinity, severe lung impairment, genetic variability, altered EBC and MR.


Assuntos
Síndrome de Kartagener/diagnóstico , Pneumopatias/diagnóstico , Infecções por Pseudomonas/diagnóstico , Adulto , Idoso , Brasil/epidemiologia , Comorbidade , Estudos Transversais , Feminino , Testes Genéticos , Humanos , Síndrome de Kartagener/epidemiologia , Síndrome de Kartagener/genética , Pneumopatias/epidemiologia , Pneumopatias/genética , Masculino , Pessoa de Meia-Idade , Prevalência , Infecções por Pseudomonas/epidemiologia , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/isolamento & purificação , Pseudomonas aeruginosa/fisiologia , Índice de Gravidade de Doença , Adulto Jovem
11.
Arch Argent Pediatr ; 117(3): e292-e296, 2019 06 01.
Artigo em Espanhol | MEDLINE | ID: mdl-31063320

RESUMO

Kartagener Syndrome is an inherited autosomal recessive disorder characterized by primary ciliary dyskinesia and the triad of situs inversus viscerum, chronic sinus disease and bronchiectasis. Its prevalence varies from 1/15 000 to 1/30 000 but it is estimated that a lot of patients with primary ciliary dyskinesia have not been diagnosed as such. Its clinical presentation is non-specific and heterogeneous, and there is not a single, gold standard, diagnostic test. The diagnosis is often delayed because of these reasons and limitations and no availability of diagnostic tests. Early diagnosis and treatment change patient's prognosis. In addition, Scientific Societies have published recent diagnostic algorithm to evaluate the patient with suspected primary ciliary dyskinesia. Therefore, it is important to keep up to date with all the latest articles. We present the case of a newborn with this syndrome diagnosed by genetic analysis in a secondary care hospital.


Assuntos
Síndrome de Kartagener/diagnóstico , Transtornos da Motilidade Ciliar/diagnóstico , Diagnóstico Diferencial , Feminino , Humanos , Recém-Nascido , Síndrome de Kartagener/genética , Síndrome de Kartagener/fisiopatologia
12.
Intern Med ; 58(16): 2383-2386, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31118369

RESUMO

A 33-year-old woman presented with a productive cough from childhood. She had suffered from repeated bacterial pneumonia. Her clinical and imaging findings revealed chronic sinusitis, bronchiectasis and situs inversus. We suspected primary ciliary dyskinesia (PCD) and performed a bronchial mucosal biopsy. The ciliary beat pattern according to high-speed video microscopy was complete loss. Electron microscopic findings of cilia showed defect of outer dynein arm (ODA). A genetic examination detected compound heterozygous mutations of DNAH5 that encode ODA components. There are few reports of genetic mutation analyses in Japanese PCD patients. We herein report a PCD patient with DNAH5 mutations and review the related literature.


Assuntos
Dineínas do Axonema/genética , Transtornos da Motilidade Ciliar/complicações , Transtornos da Motilidade Ciliar/genética , Síndrome de Kartagener/diagnóstico , Síndrome de Kartagener/genética , Situs Inversus/complicações , Adulto , Análise Mutacional de DNA , Feminino , Humanos , Japão , Mutação
13.
Am J Respir Cell Mol Biol ; 61(3): 312-321, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30896965

RESUMO

Primary ciliary dyskinesia (PCD) is a genetically and phenotypically heterogeneous disease caused by mutations in over 40 different genes. Individuals with PCD caused by mutations in RSPH1 (radial spoke head 1 homolog) have been reported to have a milder phenotype than other individuals with PCD, as evidenced by a lower incidence of neonatal respiratory distress, higher nasal nitric oxide concentrations, and better lung function. To better understand genotype-phenotype relationships in PCD, we have characterized a mutant mouse model with a deletion of Rsph1. Approximately 50% of cilia from Rsph1-/- cells appeared normal by transmission EM, whereas the remaining cilia revealed a range of defects, primarily transpositions or a missing central pair. Ciliary beat frequency in Rsph1-/- cells was significantly lower than in control cells (20.2 ± 0.8 vs. 25.0 ± 0.9 Hz), and the cilia exhibited an aberrant rotational waveform. Young Rsph1-/- animals demonstrated a low rate of mucociliary clearance in the nasopharynx that was reduced to zero by about 1 month of age. Rsph1-/- animals accumulated mucus in the nasal cavity but had a lower bacterial burden than animals with a deletion of dynein axonemal intermediate chain 1 (Dnaic1-/-). Thus, Rsph1-/- mice display a PCD phenotype similar to but less severe than that observed in Dnaic1-/- mice, similar to what has been observed in humans. The results suggest that some individuals with PCD may not have a complete loss of mucociliary clearance and further suggest that early diagnosis and intervention may be important to maintain this low amount of clearance.


Assuntos
Proteínas de Ligação a DNA/genética , Síndrome de Kartagener/genética , Depuração Mucociliar/genética , Fenótipo , Animais , Axonema/genética , Cílios/genética , Humanos , Camundongos , Mutação/genética , Deleção de Sequência/genética
14.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(3): 225-228, 2019 Mar 10.
Artigo em Chinês | MEDLINE | ID: mdl-30835351

RESUMO

OBJECTIVE: To explore the clinical and genetic features of a child with primary ciliary dyskinesia. METHODS: Genomic DNA of the child and her parents was extracted and subjected to targeted gene capture and next generation sequencing. Suspected mutation was verified by Sanger sequencing, with its nature and impact predicted by Bioinformatic analysis. RESULTS: Clinical manifestations of the child mainly included severe pneumonia, bronchiectasia, nasosinusitis and pneumothorax. DNA sequencing showed that she has carried compound heterozygous mutations of the CCNO gene, namely c.848T>C (p.L283P) and c.262_263 insGGCCCGGCCC (p.Q88Rfs*51), which were respectively inherited from her mother and father. CONCLUSION: The child was diagnosed with primary ciliary dyskinesia caused by the compound heterozygous mutations of the CCNO gene.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Síndrome de Kartagener , Sequência de Bases , Feminino , Humanos , Síndrome de Kartagener/genética , Masculino , Mutação , Análise de Sequência de DNA
15.
Paediatr Respir Rev ; 29: 19-22, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30792130

RESUMO

Primary ciliary dyskinesia (PCD), also known as immotile-cilia syndrome, is a rare genetic disease that is inherited in an autosomal recessive manner. Several studies have explored certain aspects of PCD in the Arab world, yet much is still lacking in terms of identifying the different characteristics of this disease. In this paper, we aim to briefly cover those studies published about PCD in Arab countries, as well as to provide recommendations and guidelines for future studies.


Assuntos
Transtornos da Motilidade Ciliar/etnologia , Mundo Árabe , Árabes/genética , Transtornos da Motilidade Ciliar/diagnóstico , Transtornos da Motilidade Ciliar/genética , Transtornos da Motilidade Ciliar/terapia , Consanguinidade , Humanos , Síndrome de Kartagener/diagnóstico , Síndrome de Kartagener/etnologia , Síndrome de Kartagener/genética , Síndrome de Kartagener/terapia , Kuweit , Oriente Médio , Guias de Prática Clínica como Assunto , Catar , Pesquisa , Arábia Saudita , Emirados Árabes Unidos , Iêmen
16.
Am J Respir Crit Care Med ; 199(2): 190-198, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30067075

RESUMO

RATIONALE: In primary ciliary dyskinesia, factors leading to disease heterogeneity are poorly understood. OBJECTIVES: To describe early lung disease progression in primary ciliary dyskinesia and identify associations between ultrastructural defects and genotypes with clinical phenotype. METHODS: This was a prospective, longitudinal (5 yr), multicenter, observational study. Inclusion criteria were less than 19 years at enrollment and greater than or equal to two annual study visits. Linear mixed effects models including random slope and random intercept were used to evaluate longitudinal associations between the ciliary defect group (or genotype group) and clinical features (percent predicted FEV1 and weight and height z-scores). MEASUREMENTS AND MAIN RESULTS: A total of 137 participants completed 732 visits. The group with absent inner dynein arm, central apparatus defects, and microtubular disorganization (IDA/CA/MTD) (n = 41) were significantly younger at diagnosis and in mixed effects models had significantly lower percent predicted FEV1 and weight and height z-scores than the isolated outer dynein arm defect (n = 55) group. Participants with CCDC39 or CCDC40 mutations (n = 34) had lower percent predicted FEV1 and weight and height z-scores than those with DNAH5 mutations (n = 36). For the entire cohort, percent predicted FEV1 decline was heterogeneous with a mean (SE) decline of 0.57 (0.25) percent predicted/yr. Rate of decline was different from zero only in the IDA/MTD/CA group (mean [SE], -1.11 [0.48] percent predicted/yr; P = 0.02). CONCLUSIONS: Participants with IDA/MTD/CA defects, which included individuals with CCDC39 or CCDC40 mutations, had worse lung function and growth indices compared with those with outer dynein arm defects and DNAH5 mutations, respectively. The only group with a significant lung function decline over time were participants with IDA/MTD/CA defects.


Assuntos
Cílios/genética , Cílios/ultraestrutura , Síndrome de Kartagener/genética , Criança , Estudos de Coortes , Feminino , Genótipo , Humanos , Síndrome de Kartagener/fisiopatologia , Estudos Longitudinais , Pulmão/fisiopatologia , Masculino , Mutação/genética , Fenótipo , Estudos Prospectivos , Testes de Função Respiratória
17.
Am J Hum Genet ; 103(6): 995-1008, 2018 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-30471718

RESUMO

Dysfunction of motile monocilia, altering the leftward flow at the embryonic node essential for determination of left-right body asymmetry, is a major cause of laterality defects. Laterality defects are also often associated with reduced mucociliary clearance caused by defective multiple motile cilia of the airway and are responsible for destructive airway disease. Outer dynein arms (ODAs) are essential for ciliary beat generation, and human respiratory cilia contain different ODA heavy chains (HCs): the panaxonemally distributed γ-HC DNAH5, proximally located ß-HC DNAH11 (defining ODA type 1), and the distally localized ß-HC DNAH9 (defining ODA type 2). Here we report loss-of-function mutations in DNAH9 in five independent families causing situs abnormalities associated with subtle respiratory ciliary dysfunction. Consistent with the observed subtle respiratory phenotype, high-speed video microscopy demonstrates distally impaired ciliary bending in DNAH9 mutant respiratory cilia. DNAH9-deficient cilia also lack other ODA components such as DNAH5, DNAI1, and DNAI2 from the distal axonemal compartment, demonstrating an essential role of DNAH9 for distal axonemal assembly of ODAs type 2. Yeast two-hybrid and co-immunoprecipitation analyses indicate interaction of DNAH9 with the ODA components DNAH5 and DNAI2 as well as the ODA-docking complex component CCDC114. We further show that during ciliogenesis of respiratory cilia, first proximally located DNAH11 and then distally located DNAH9 is assembled in the axoneme. We propose that the ß-HC paralogs DNAH9 and DNAH11 achieved specific functional roles for the distinct axonemal compartments during evolution with human DNAH9 function matching that of ancient ß-HCs such as that of the unicellular Chlamydomonas reinhardtii.


Assuntos
Dineínas do Axonema/genética , Cílios/genética , Dineínas/genética , Mutação/genética , Axonema/genética , Transtornos da Motilidade Ciliar/genética , Humanos , Síndrome de Kartagener/genética , Fenótipo
18.
Intern Med J ; 48(10): 1252-1254, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30288904

RESUMO

Primary ciliary dyskinesia is an uncommon, inherited condition causing progressive suppurative airway lung disease with subsequent bronchiectasis, chronic rhinitis-sinusitis, deafness and reduced fertility. Diagnosis is often delayed by lack of awareness of the condition in the medical community and limited access to the few centres in Australia able to do full diagnostic testing. This report details the late diagnosis of primary ciliary dyskinesia in two adults who have had long-standing interactions with medical services but in whom the diagnosis was never considered or even dismissed. Greater awareness of the condition will reduce time to diagnosis, prevent administration of ineffective therapy and allow earlier institution of targeted therapy.


Assuntos
Síndrome de Kartagener/diagnóstico , Administração dos Cuidados ao Paciente/métodos , Adulto , Idade de Início , Austrália , Diagnóstico Tardio , Diagnóstico Diferencial , Feminino , Aconselhamento Genético , Humanos , Síndrome de Kartagener/genética , Síndrome de Kartagener/fisiopatologia , Masculino , Pessoa de Meia-Idade , Depuração Mucociliar/fisiologia , Encaminhamento e Consulta , Irmãos
19.
PLoS One ; 13(10): e0205422, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30300419

RESUMO

Primary ciliary dyskinesia (PCD) is a rare inherited autosomal recessive or X-linked disorder that mainly affects lungs. Dysfunction of respiratory cilia causes symptoms such as chronic rhinosinusitis, coughing, rhinitis, conductive hearing loss and recurrent lung infections with bronchiectasis. It is now well known that pathogenic genetic changes lead to ciliary dysfunction. Here we report usage of clinical-exome based NGS approach in order to reveal underlying genetic causes in cohort of 21 patient with diagnosis of PCD. By detecting 18 (12 novel) potentially pathogenic genetic variants, we established the genetic cause of 11 (9 unrelated) patients. Genetic variants were detected in six PCD disease-causing genes, as well as in SPAG16 and SPAG17 genes, that were not detected in PCD patients so far, but were related to some symptoms of PCD. The most frequently mutated gene in our cohort was DNAH5 (27.77%). Identified variants were in homozygous, compound heterozygous and trans-heterozygous state. For detailed characterization of one novel homozygous genetic variant in DNAI1 gene (c. 947_948insG, p. Thr318TyrfsTer11), RT-qPCR and Western Blot analysis were performed. Molecular diagnostic approach applied in this study enables analysis of 29 PCD disease-causing and related genes. It resulted in mutation detection rate of 50% and enabled discovery of twelve novel mutations and pointed two possible novel PCD candidate genes.


Assuntos
Variação Genética , Síndrome de Kartagener/diagnóstico , Adolescente , Adulto , Dineínas do Axonema/química , Dineínas do Axonema/genética , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Mutação da Fase de Leitura , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Síndrome de Kartagener/genética , Masculino , Proteínas dos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/genética , Estrutura Terciária de Proteína , Análise de Sequência de DNA , Adulto Jovem
20.
Am J Respir Crit Care Med ; 197(12): e24-e39, 2018 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-29905515

RESUMO

BACKGROUND: This document presents the American Thoracic Society clinical practice guidelines for the diagnosis of primary ciliary dyskinesia (PCD). TARGET AUDIENCE: Clinicians investigating adult and pediatric patients for possible PCD. METHODS: Systematic reviews and, when appropriate, meta-analyses were conducted to summarize all available evidence pertinent to our clinical questions. Evidence was assessed using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for diagnosis and discussed by a multidisciplinary panel with expertise in PCD. Predetermined conflict-of-interest management strategies were applied, and recommendations were formulated, written, and graded exclusively by the nonconflicted panelists. Three conflicted individuals were also prohibited from writing, editing, or providing feedback on the relevant sections of the manuscript. RESULTS: After considering diagnostic test accuracy, confidence in the estimates for each diagnostic test, relative importance of test results studied, desirable and undesirable direct consequences of each diagnostic test, downstream consequences of each diagnostic test result, patient values and preferences, costs, feasibility, acceptability, and implications for health equity, the panel made recommendations for or against the use of specific diagnostic tests as compared with using the current reference standard (transmission electron microscopy and/or genetic testing) for the diagnosis of PCD. CONCLUSIONS: The panel formulated and provided a rationale for the direction as well as for the strength of each recommendation to establish the diagnosis of PCD.


Assuntos
Cílios/patologia , Técnicas e Procedimentos Diagnósticos/normas , Síndrome de Kartagener/diagnóstico , Síndrome de Kartagener/genética , Guias de Prática Clínica como Assunto , Estudos de Coortes , Estudos Transversais , Predisposição Genética para Doença , Humanos , Estudos Prospectivos , Estudos Retrospectivos , Sensibilidade e Especificidade , Sociedades Médicas , Estados Unidos
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