RESUMO
Dyskeratosis congenita (DC) is an inherited bone-marrow-failure disorder characterized by a triad of mucocutaneous features that include abnormal skin pigmentation, nail dystrophy, and oral leucoplakia. Despite the identification of several genetic variants that cause DC, a significant proportion of probands remain without a molecular diagnosis. In a cohort of eight independent DC-affected families, we have identified a remarkable series of heterozygous germline variants in the gene encoding thymidylate synthase (TYMS). Although the inheritance appeared to be autosomal recessive, one parent in each family had a wild-type TYMS coding sequence. Targeted genomic sequencing identified a specific haplotype and rare variants in the naturally occurring TYMS antisense regulator ENOSF1 (enolase super family 1) inherited from the other parent. Lymphoblastoid cells from affected probands have severe TYMS deficiency, altered cellular deoxyribonucleotide triphosphate pools, and hypersensitivity to the TYMS-specific inhibitor 5-fluorouracil. These defects in the nucleotide metabolism pathway resulted in genotoxic stress, defective transcription, and abnormal telomere maintenance. Gene-rescue studies in cells from affected probands revealed that post-transcriptional epistatic silencing of TYMS is occurring via elevated ENOSF1. These cell and molecular abnormalities generated by the combination of germline digenic variants at the TYMS-ENOSF1 locus represent a unique pathogenetic pathway for DC causation in these affected individuals, whereas the parents who are carriers of either of these variants in a singular fashion remain unaffected.
Assuntos
Disceratose Congênita , Timidilato Sintase , Disceratose Congênita/genética , Células Germinativas , Heterozigoto , Humanos , Nucleotídeos , Timidilato Sintase/deficiência , Timidilato Sintase/genéticaRESUMO
BACKGROUND: Primary ciliary dyskinesia (PCD) represents a group of rare hereditary disorders characterised by deficient ciliary airway clearance that can be associated with laterality defects. We aimed to describe the underlying gene defects, geographical differences in genotypes and their relationship to diagnostic findings and clinical phenotypes. METHODS: Genetic variants and clinical findings (age, sex, body mass index, laterality defects, forced expiratory volume in 1â s (FEV1)) were collected from 19 countries using the European Reference Network's ERN-LUNG international PCD Registry. Genetic data were evaluated according to American College of Medical Genetics and Genomics guidelines. We assessed regional distribution of implicated genes and genetic variants as well as genotype correlations with laterality defects and FEV1. RESULTS: The study included 1236 individuals carrying 908 distinct pathogenic DNA variants in 46 PCD genes. We found considerable variation in the distribution of PCD genotypes across countries due to the presence of distinct founder variants. The prevalence of PCD genotypes associated with pathognomonic ultrastructural defects (mean 72%, range 47-100%) and laterality defects (mean 42%, range 28-69%) varied widely among countries. The prevalence of laterality defects was significantly lower in PCD individuals without pathognomonic ciliary ultrastructure defects (18%). The PCD cohort had a reduced median FEV1 z-score (-1.66). Median FEV1 z-scores were significantly lower in CCNO (-3.26), CCDC39 (-2.49) and CCDC40 (-2.96) variant groups, while the FEV1 z-score reductions were significantly milder in DNAH11 (-0.83) and ODAD1 (-0.85) variant groups compared to the whole PCD cohort. CONCLUSION: This unprecedented multinational dataset of DNA variants and information on their distribution across countries facilitates interpretation of the genetic epidemiology of PCD and indicates that the genetic variant can predict diagnostic and phenotypic features such as the course of lung function.
Assuntos
Estudos de Associação Genética , Genótipo , Fenótipo , Humanos , Masculino , Feminino , Adulto , Criança , Adolescente , Adulto Jovem , Pessoa de Meia-Idade , Europa (Continente) , Sistema de Registros , Dineínas do Axonema/genética , Volume Expiratório Forçado , Pré-Escolar , Síndrome de Kartagener/genética , Síndrome de Kartagener/fisiopatologia , Variação Genética , Mutação , Idoso , Lactente , Proteínas do Citoesqueleto , ProteínasRESUMO
Primary ciliary dyskinesia (PCD) can be defined as a multiorgan ciliopathy with a dominant element of chronic airway disease affecting the nose, sinuses, middle ear, and in particular, the lower airways. Although most patients with PCD are diagnosed during preschool years, it is obvious that the chronic lung disease starts its course already from birth. The many faces of the clinical picture change, as does lung function, structural lung damage, the burden of infection, and of treatment throughout life. A markedly severe neutrophil inflammation in the respiratory tract seems pervasive and is only to a minimal extent ameliorated by a treatment strategy, which is predominantly aimed at bacterial infections. An ever-increasing understanding of the different aspects, their interrelationships, and possible different age courses conditioned by the underlying genotype is the focus of much attention. The future is likely to offer personalized medicine in the form of mRNA therapy, but to that end, it is of utmost importance that all patients with PCD be carefully characterized and given a genetic diagnosis. In this narrative review, we have concentrated on lower airways and summarized the current understanding of the chronic airway disease in this motile ciliopathy. In addition, we highlight the challenges, gaps, and opportunities in PCD lung disease research.
Assuntos
Transtornos da Motilidade Ciliar , Ciliopatias , Doença Pulmonar Obstrutiva Crônica , Pré-Escolar , Transtornos da Motilidade Ciliar/genética , Transtornos da Motilidade Ciliar/terapia , Genótipo , HumanosRESUMO
Primary ciliary dyskinesia (PCD) presents with symptoms early in life and the disease course may be progressive, but longitudinal data on lung function are scarce. This multinational cohort study describes lung function trajectories in children, adolescents and young adults with PCD. We analysed data from 486 patients with repeated lung function measurements obtained between the age of 6 and 24â years from the International PCD Cohort and calculated z-scores for forced expiratory volume in 1â s (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio using the Global Lung Function Initiative 2012 references. We described baseline lung function and change of lung function over time and described their associations with possible determinants in mixed-effects linear regression models. Overall, FEV1, FVC and FEV1/FVC z-scores declined over time (average crude annual FEV1 decline was -0.07 z-scores), but not at the same rate for all patients. FEV1 z-scores improved over time in 21% of patients, remained stable in 40% and declined in 39%. Low body mass index was associated with poor baseline lung function and with further decline. Results differed by country and ultrastructural defect, but we found no evidence of differences by sex, calendar year of diagnosis, age at diagnosis, diagnostic certainty or laterality defect. Our study shows that on average lung function in PCD declines throughout the entire period of lung growth, from childhood to young adult age, even among patients treated in specialised centres. It is essential to develop strategies to reverse this tendency and improve prognosis.
Assuntos
Transtornos da Motilidade Ciliar , Humanos , Criança , Adolescente , Adulto Jovem , Adulto , Estudos de Coortes , Capacidade Vital , Volume Expiratório Forçado , PulmãoRESUMO
Ciliopathies are clinically and genetically heterogeneous diseases. We studied three patients from two independent families presenting with features of Joubert syndrome: abnormal breathing pattern during infancy, developmental delay/intellectual disability, cerebellar ataxia, molar tooth sign on magnetic resonance imaging scans, and polydactyly. We identified biallelic loss-of-function (LOF) variants in CBY1, segregating with the clinical features of Joubert syndrome in the families. CBY1 localizes to the distal end of the mother centriole, contributing to the formation and function of cilia. In accordance with the clinical and mutational findings in the affected individuals, we demonstrated that depletion of Cby1 in zebrafish causes ciliopathy-related phenotypes. Levels of CBY1 transcript were found reduced in the patients compared with controls, suggesting degradation of the mutated transcript through nonsense-mediated messenger RNA decay. Accordingly, we could detect CBY1 protein in fibroblasts from controls, but not from patients by immunofluorescence. Furthermore, we observed reduced ability to ciliate, increased ciliary length, and reduced levels of the ciliary proteins AHI1 and ARL13B in patient fibroblasts. Our data show that CBY1 LOF-variants cause a ciliopathy with features of Joubert syndrome.
Assuntos
Anormalidades Múltiplas/genética , Proteínas de Transporte/genética , Cerebelo/anormalidades , Ciliopatias/genética , Anormalidades do Olho/genética , Doenças Renais Císticas/genética , Mutação/genética , Proteínas Nucleares/genética , Retina/anormalidades , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/patologia , Adolescente , Animais , Cerebelo/diagnóstico por imagem , Cerebelo/patologia , Criança , Pré-Escolar , Cílios/metabolismo , Cílios/patologia , Ciliopatias/diagnóstico por imagem , Ciliopatias/patologia , Anormalidades do Olho/diagnóstico por imagem , Anormalidades do Olho/patologia , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Homozigoto , Humanos , Lactente , Recém-Nascido , Doenças Renais Císticas/diagnóstico por imagem , Doenças Renais Císticas/patologia , Imageamento por Ressonância Magnética , Masculino , Linhagem , Fenótipo , Retina/diagnóstico por imagem , Retina/patologia , Receptor Smoothened/metabolismo , Adulto Jovem , Peixe-Zebra/genéticaRESUMO
Primary ciliary dyskinesia (PCD) is a rare disease causing motile cilia dysfunction, recurrent airway infection, and bronchiectasis. Airway infection management strategies are borrowed from cystic fibrosis. The aim of this study is to describe the management of airway infection with Pseudomonas aeruginosa ( PA) in children and adults with PCD across European centers. An online survey questionnaire was sent electronically using SurveyMonkey® to 55 PCD centers in 36 European countries. Fifty-two responded from 43 centers in 26 countries, a response rate of 70%. Most (89%) countries did not have written guidelines for PCD management. Airway sampling for infection detection at each clinic visit was more likely when follow-up was frequent. Eighty-seven percent of centers chose to treat the first PA isolate, most prescribing combined oral ciprofloxacin and inhaled colistimethate sodium (43%, n = 18). The preferred treatment for chronic infection with PA was nebulized colistimethate in 51% ( n = 22). In summary, considerable variation exists across European centers in the frequency of patient follow-up and airway sampling for infection, treatment goals, and the management of PA infection. Few centers had written guidelines for PCD management. Clinical trials to determine optimal treatment of PA in PCD patients are urgently needed.
Assuntos
Ciprofloxacina/administração & dosagem , Colistina/análogos & derivados , Síndrome de Kartagener/complicações , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/isolamento & purificação , Administração Oral , Adolescente , Adulto , Antibacterianos/administração & dosagem , Criança , Colistina/administração & dosagem , Progressão da Doença , Quimioterapia Combinada , Europa (Continente)/epidemiologia , Feminino , Humanos , Incidência , Síndrome de Kartagener/epidemiologia , Masculino , Infecções por Pseudomonas/complicações , Infecções por Pseudomonas/epidemiologia , Inquéritos e Questionários , Resultado do Tratamento , Adulto JovemRESUMO
Primary ciliary dyskinesia (PCD) has been considered a relatively mild disease, especially compared to cystic fibrosis (CF), but studies on lung function in PCD patients have been few and small.This study compared lung function from spirometry of PCD patients to normal reference values and to published data from CF patients. We calculated z-scores and % predicted values for forced expiratory volume in 1â s (FEV1) and forced vital capacity (FVC) using the Global Lung Function Initiative 2012 values for 991 patients from the international PCD Cohort. We then assessed associations with age, sex, country, diagnostic certainty, organ laterality, body mass index and age at diagnosis in linear regression models. Lung function in PCD patients was reduced compared to reference values in both sexes and all age groups. Children aged 6-9â years had the smallest impairment (FEV1 z-score -0.84 (-1.03 to -0.65), FVC z-score -0.31 (-0.51 to -0.11)). Compared to CF patients, FEV1 was similarly reduced in children (age 6-9â years PCD 91% (88-93%); CF 90% (88-91%)), but less impaired in young adults (age 18-21â years PCD 79% (76-82%); CF 66% (65-68%)). The results suggest that PCD affects lung function from early in life, which emphasises the importance of early standardised care for all patients.
Assuntos
Transtornos da Motilidade Ciliar/fisiopatologia , Pulmão/fisiopatologia , Adolescente , Adulto , Fatores Etários , Índice de Massa Corporal , Criança , Pré-Escolar , Fibrose Cística/fisiopatologia , Feminino , Volume Expiratório Forçado , Humanos , Lactente , Recém-Nascido , Internacionalidade , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Valores de Referência , Estudos Retrospectivos , Fatores Sexuais , Espirometria , Capacidade Vital , Adulto JovemRESUMO
OBJECTIVE: The aim and objective of this study was to assess the knowledge and views of parents on transitional and adolescent care in young adults with epilepsy, and to develop a transitional and adolescent program for epilepsy. METHODS: Data were collected from questionnaires completed by parents during focus groups exploring transitional care and inherent issues for young adults, aged 12-18years, with epilepsy. The questionnaire assessed the current knowledge and views of parents of children with epilepsy on transitional care, and following a presentation on "Transition in Epilepsy" (including themes such as self-advocacy, independent healthcare behavior, sexual health, psychosocial support, educational and vocational planning, health and lifestyle issues) assessed feedback on the proposed model of care in transitional and adolescent care. RESULTS: Data were collected from 34 parents; the majority of parents, 74% (n=25), wish their children to be transitioned and transferred over to the adult epilepsy sites at the age of 18years. Over 82% (n=28) of parents believe the concept of transition should be introduced between the ages of 12-16years. CONCLUSION: This quality improvement initiative identified the need for transitional care to begin at an early age. This study engaged parents in a process to improve adolescent and transitional care for adolescents with epilepsy. This study also highlights the importance of introducing a detailed preparatory phase for a transitional and adolescent care in epilepsy.
Assuntos
Atenção à Saúde/métodos , Epilepsia/tratamento farmacológico , Conhecimentos, Atitudes e Prática em Saúde , Melhoria de Qualidade , Qualidade da Assistência à Saúde/normas , Transição para Assistência do Adulto/normas , Adolescente , Adulto , Atitude do Pessoal de Saúde , Criança , Feminino , Acessibilidade aos Serviços de Saúde , Humanos , Masculino , Pais/psicologia , Satisfação do Paciente , Inquéritos e Questionários , Transição para Assistência do Adulto/organização & administração , Adulto JovemRESUMO
Chronic respiratory disease can affect growth and nutrition, which can influence lung function. We investigated height, body mass index (BMI), and lung function in patients with primary ciliary dyskinesia (PCD).In this study, based on the international PCD (iPCD) Cohort, we calculated z-scores for height and BMI using World Health Organization (WHO) and national growth references, and assessed associations with age, sex, country, diagnostic certainty, age at diagnosis, organ laterality and lung function in multilevel regression models that accounted for repeated measurements.We analysed 6402 measurements from 1609 iPCD Cohort patients. Height was reduced compared to WHO (z-score -0.12, 95% CI -0.17 to -0.06) and national references (z-score -0.27, 95% CI -0.33 to -0.21) in male and female patients in all age groups, with variation between countries. Height and BMI were higher in patients diagnosed earlier in life (p=0.026 and p<0.001, respectively) and closely associated with forced expiratory volume in 1 s and forced vital capacity z-scores (p<0.001).Our study indicates that both growth and nutrition are affected adversely in PCD patients from early life and are both strongly associated with lung function. If supported by longitudinal studies, these findings suggest that early diagnosis with multidisciplinary management and nutritional advice could improve growth and delay disease progression and lung function impairment in PCD.
Assuntos
Estatura , Índice de Massa Corporal , Transtornos da Motilidade Ciliar/fisiopatologia , Estado Nutricional , Adolescente , Adulto , Distribuição por Idade , Criança , Pré-Escolar , Progressão da Doença , Feminino , Humanos , Lactente , Recém-Nascido , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Valores de Referência , Testes de Função Respiratória , Estudos Retrospectivos , Adulto JovemRESUMO
Data on primary ciliary dyskinesia (PCD) epidemiology is scarce and published studies are characterised by low numbers. In the framework of the European Union project BESTCILIA we aimed to combine all available datasets in a retrospective international PCD cohort (iPCD Cohort).We identified eligible datasets by performing a systematic review of published studies containing clinical information on PCD, and by contacting members of past and current European Respiratory Society Task Forces on PCD. We compared the contents of the datasets, clarified definitions and pooled them in a standardised format.As of April 2016 the iPCD Cohort includes data on 3013 patients from 18 countries. It includes data on diagnostic evaluations, symptoms, lung function, growth and treatments. Longitudinal data are currently available for 542 patients. The extent of clinical details per patient varies between centres. More than 50% of patients have a definite PCD diagnosis based on recent guidelines. Children aged 10-19â years are the largest age group, followed by younger children (≤9â years) and young adults (20-29â years).This is the largest observational PCD dataset available to date. It will allow us to answer pertinent questions on clinical phenotype, disease severity, prognosis and effect of treatments, and to investigate genotype-phenotype correlations.
Assuntos
Síndrome de Kartagener/diagnóstico , Síndrome de Kartagener/fisiopatologia , Adolescente , Adulto , Criança , Pré-Escolar , Europa (Continente) , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Estudos Retrospectivos , Literatura de Revisão como Assunto , Índice de Gravidade de Doença , Adulto JovemRESUMO
Protracted bacterial bronchitis is a common cause of persistent, wet cough in pre-school children. The condition has been described relatively recently, and knowledge of the diagnosis may be an aid to making the correct assessment of children with chronic cough, helping to ensure that the symptoms are not misinterpreted and treated as asthma.
Assuntos
Bronquite , Tosse/etiologia , Antibacterianos/uso terapêutico , Bronquite/complicações , Bronquite/diagnóstico , Bronquite/tratamento farmacológico , Bronquite/microbiologia , Criança , Pré-Escolar , Diagnóstico Diferencial , HumanosRESUMO
Primary ciliary dyskinesia (PCD) is a rare disease, but causes symptoms that resemble far more common respiratory diseases. Late diagnosis is common, when damage to the respiratory system has already occurred. This article aims to elucidate the condition and the diagnostic methods available. The article is based on literature searches in PubMed and the author's own experience of patient treatment and clinical research.
Assuntos
Síndrome de Kartagener , Cílios/fisiologia , Humanos , Síndrome de Kartagener/diagnóstico , Síndrome de Kartagener/genética , Síndrome de Kartagener/terapiaRESUMO
BACKGROUND: Asthma and airway hyper-responsiveness are reportedly more common in children with sickle cell disease (SCD). AIM: To determine airway responsiveness, airway inflammation and clinical features of asthma in SCD. METHODS: A prospective, single-centre study of 50 SCD children without overt pulmonary vascular disease and 50 controls. Exhaled nitric oxide (FeNO) and total serum IgE were measured and spirometry and methacholine challenge were performed. The methacholine dose-response slope (DRS) was calculated. RESULTS: Doctor diagnosis of asthma was made in 7 (14%) SCD versus 12 (24%) control subjects (p=0.203). FeNO levels were similar in SCD and controls (p=0.250), and were higher in those with atopy and an asthma diagnosis (OR 4.33, 95% CI 1.7 to 11.1; p<0.05). zFEV1 (p=0.002) and zFEV1/FVC (p=0.003) but not zFVC (p=0.098) were lower in SCD versus controls. DRS was higher in those with asthma (p=0.006) but not in SCD versus controls (p=0.403). DRS correlated with FeNO and blood eosinophil count in controls but not SCD. In SCD, DRS was higher in those admitted to hospital with respiratory symptoms (n=27) versus those never admitted (n=23) (p=0.046). DRS was similar in those with at least one acute chest syndrome episode (n=12) versus those with none (n=35) (p=0.247). CONCLUSIONS: SCD children have airflow obstruction despite having minimal evidence of pulmonary vascular disease. Airflow obstruction is not associated with increased methacholine sensitivity or eosinophilic inflammation, at least as judged by FeNO. Airflow obstruction in SCD does not appear to be related to childhood eosinophilic asthma, but its pathophysiology remains ill understood.
Assuntos
Anemia Falciforme/fisiopatologia , Asma/fisiopatologia , Fluxo Expiratório Forçado/fisiologia , Imunoglobulina E/sangue , Cloreto de Metacolina , Óxido Nítrico/análise , Adolescente , Obstrução das Vias Respiratórias/metabolismo , Obstrução das Vias Respiratórias/fisiopatologia , Anemia Falciforme/metabolismo , Asma/diagnóstico , Asma/metabolismo , Testes Respiratórios , Estudos de Casos e Controles , Criança , Eosinófilos , Feminino , Humanos , Hipersensibilidade/metabolismo , Hipersensibilidade/fisiopatologia , Contagem de Leucócitos , Pulmão/irrigação sanguínea , Masculino , Óxido Nítrico/metabolismo , Espirometria , Estatísticas não ParamétricasAssuntos
Transtornos da Motilidade Ciliar/diagnóstico , Microscopia Eletrônica/tendências , Microscopia de Vídeo/tendências , Cavidade Nasal/química , Óxido Nítrico/análise , Criança , Pré-Escolar , Transtornos da Motilidade Ciliar/patologia , Europa (Continente) , Feminino , Fidelidade a Diretrizes , Humanos , Masculino , Guias de Prática Clínica como AssuntoRESUMO
Introduction: Nearly all patients with primary ciliary dyskinesia (PCD) report ear-nose-throat (ENT) symptoms. However, scarce evidence exists about how ENT symptoms relate to pulmonary disease in PCD. We explored possible associations between upper and lower respiratory disease among patients with PCD in a multicentre study. Methods: We included patients from the ENT Prospective International Cohort (EPIC-PCD). We studied associations of several reported ENT symptoms and chronic rhinosinusitis (defined using patient-reported information and examination findings) with reported sputum production and shortness of breath, using ordinal logistic regression. In a subgroup with available lung function results, we used linear regression to study associations of chronic rhinosinusitis and forced expiratory volume in 1â s (FEV1) accounting for relevant factors. Results: We included 457 patients (median age 15 years, interquartile range 10-24 years; 54% males). Shortness of breath associated with reported nasal symptoms and ear pain of any frequency, often or daily hearing problems, headache when bending down (OR 2.1, 95% CI 1.29-3.54) and chronic rhinosinusitis (OR 2.3, 95% CI 1.57-3.38) regardless of polyp presence. Sputum production associated with daily reported nasal (OR 2.2, 95% CI 1.20-4.09) and hearing (OR 2.0, 95% CI 1.10-3.64) problems and chronic rhinosinusitis (OR 2.1, 95% CI 1.48-3.07). We did not find any association between chronic rhinosinusitis and FEV1. Conclusion: Reported upper airway symptoms and signs of chronic rhinosinusitis associated with reported pulmonary symptoms, but not with lung function. Our results emphasise the assessment and management of upper and lower respiratory disease as a common, interdependent entity among patients with PCD.
RESUMO
Tubulin, one of the most abundant cytoskeletal building blocks, has numerous isotypes in metazoans encoded by different conserved genes. Whether these distinct isotypes form cell type- and context-specific microtubule structures is poorly understood. Based on a cohort of 12 patients with primary ciliary dyskinesia as well as mouse mutants, we identified and characterized variants in the TUBB4B isotype that specifically perturbed centriole and cilium biogenesis. Distinct TUBB4B variants differentially affected microtubule dynamics and cilia formation in a dominant-negative manner. Structure-function studies revealed that different TUBB4B variants disrupted distinct tubulin interfaces, thereby enabling stratification of patients into three classes of ciliopathic diseases. These findings show that specific tubulin isotypes have distinct and nonredundant subcellular functions and establish a link between tubulinopathies and ciliopathies.