RESUMEN
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.
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Estudios de Asociación Genética , Genotipo , Fenotipo , Humanos , Masculino , Femenino , Adulto , Niño , Adolescente , Adulto Joven , Persona de Mediana Edad , Europa (Continente) , Sistema de Registros , Dineínas Axonemales/genética , Volumen Espiratorio Forzado , Preescolar , Síndrome de Kartagener/genética , Síndrome de Kartagener/fisiopatología , Variación Genética , Mutación , Anciano , Lactante , Proteínas del Citoesqueleto , ProteínasRESUMEN
Though PCD usually presents after birth in term neonates, diagnosing PCD during the neonatal and infancy stages is uncommon, particularly in children who do not exhibit laterality defects. We report our recent experience with the diagnosis of PCD in the neonatal and early infantile period in a highly consanguine population. This was achieved by implementing a novel genetic-based diagnostic approach based on direct testing for recognized regional genetic variants. We conducted a retrospective analysis of children diagnosed with PCD at Soroka University Medical Center during the neonatal or early infantile period between 2020 and 2023. We included children under 3 months of age who had a genetic confirmation of PCD, as evidenced by the presence of two pathogenic variants in recognized genes. Genetic testing targeted regional genetic variants in previously identified PCD genes. Eight patients were included. The median age at diagnosis was 12.5 days. Three (38%) were born prematurely < 34 weeks gestational age. All patients were presented with respiratory distress and hypoxemia after birth. The median duration of oxygen support was 23 days, and upper lobe atelectasis was present in five patients (63%). Congenital cardiac malformation was present in four patients. Organ laterality defects were present in four patients. Genetic mutations identified were in the DNAAF5, DNAL1, DNAAF3, and DNAH1 genes. Conclusion: Neonatal diagnosis of PCD is uncommon, especially in atypical presentations such as children without laterality defects or preterms. Focusing on a genetic diagnosis of the local tribal pathogenic variants promotes a potential cost-efficient test leading to earlier diagnosis. There is a need for a standardized protocol for earlier diagnosis of PCD in high-consanguinity areas. What is Known: ⢠Primary ciliary dyskinesia (PCD) typically presents after birth in term neonates. ⢠Diagnosing PCD during neonatal and infancy stages is challenging, particularly in children without laterality defects. What is New: ⢠A novel genetic-based diagnostic approach was implemented on the neonatal population in a highly consanguine community, focusing on direct testing for regional genetic variants, leading to early and rapid diagnosis of PCD.
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Consanguinidad , Pruebas Genéticas , Humanos , Recién Nacido , Estudios Retrospectivos , Masculino , Femenino , Pruebas Genéticas/métodos , Lactante , Síndrome de Kartagener/diagnóstico , Síndrome de Kartagener/genética , Centros de Atención Terciaria , MutaciónRESUMEN
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.
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Trastornos de la Motilidad Ciliar , Humanos , Niño , Adolescente , Adulto Joven , Adulto , Estudios de Cohortes , Capacidad Vital , Volumen Espiratorio Forzado , PulmónRESUMEN
OBJECTIVE: To assess the feasibility of Fractional exhaled Nitric Oxide (FeNO) as a simple, non-invasive, cost-effective and portable biomarker and decision support tool for risk stratification of COVID-19 patients. METHODS: We conducted a single-center prospective cohort study of COVID-19 patients whose FeNO levels were measured upon ward admission by the Vivatmo-me handheld device. Demographics, COVID-19 symptoms, and relevant hospitalization details were retrieved from the hospital databases. The patients were divided into those discharged to recover at home and those who died during hospitalization or required admission to an intensive care unit, internal medicine ward, or dedicated facility (severe outcomes group). RESULTS: Fifty-six patients were enrolled. The only significant demographic difference between the severe outcomes patients (n = 14) and the home discharge patients (n = 42) was age (64.21 ± 13.97 vs. 53.98 ± 15.57 years, respectively, P = .04). The admission FeNO measurement was significantly lower in the former group compared with the latter group (15.86 ± 14.74 vs. 25.77 ± 13.79, parts per billion [PPB], respectively, P = .008). Time to severe outcome among patients with FeNO measurements ≤11.8 PPB was significantly shorter compared with patients whose FeNO measured >11.8 PPB (19.25 ± 2.96 vs. 24.41 ± 1.09 days, respectively, 95% confidence interval [CI] 1.06 to 4.25). An admission FeNO ≤11.8 PPB was a significant risk factor for severe outcomes (odds ratio = 12.8, 95% CI: 2.78 to 58.88, P = .001), with a receiver operating characteristics curve of 0.752. CONCLUSIONS: FeNO measurements by the Vivatmo-me handheld device can serve as a biomarker and COVID-19 support tool for medical teams. These easy-to-use, portable, and noninvasive devices may serve as valuable ED bedside tools during a pandemic.
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COVID-19 , Espiración , Biomarcadores , Pruebas Respiratorias , COVID-19/diagnóstico , Prueba de Óxido Nítrico Exhalado Fraccionado , Humanos , Óxido Nítrico , Estudios Prospectivos , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: Long-term diuretic treatment in patients with bronchopulmonary dysplasia (BPD) is common despite lack of data that support its use. We aimed to characterize the commonly used diuretics weaning strategies for outpatient clinically stable preterm infants with BPD. STUDY DESIGN: We conducted a cross-sectional web-based survey among all pediatric pulmonologists and neonatologists in Israel. Questionnaire included data regarding practitioners' different diuretics-weaning practice in this population. RESULTS: The response rate for pulmonologists and neonatologists were 35/50 (70%) and 36/120 (30%), respectively. When both oxygen and diuretics are used, 59% wean oxygen first and 32% wean diuretics first. If patients are solely on diuretics, 27% discontinue instantly, 34% decrease the dosage gradually, and 34% outgrow the discharge dosage. Significantly more pulmonologists decrease the dosage gradually, while more neonatologists discontinue at once (p < 0.001). Most participants (94%) reported being unsatisfied with the existing data and guidelines regarding these issues. CONCLUSION: Our results showed a wide range of practice patterns in the weaning strategy of diuretics in outpatient preterm infants with BPD. Pulmonologists and neonatologists differ significantly in their weaning strategy. A prospective larger controlled study to explore the outcome of gradual tapering versus discontinuation without weaning is warranted. KEY POINTS: · Diuretic treatment in patients with BPD is common despite lack of data that support its use.. · We demonstrated a wide range of practice patterns in the weaning strategy of diuretics in outpatients' BPDs.. · Pulmonologists and neonatologists differ significantly in their weaning strategy.. · Most participants are unsatisfied with the existing data and guidelines regarding these issues..
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Displasia Broncopulmonar , Displasia Broncopulmonar/terapia , Niño , Estudios Transversales , Diuréticos/uso terapéutico , Humanos , Lactante , Recién Nacido , Recien Nacido Prematuro , Pacientes Ambulatorios , Oxígeno , Estudios Prospectivos , DesteteRESUMEN
Primary ciliary dyskinesia (PCD) is characterized by chronic airway disease, male infertility, and randomization of the left/right body axis as a result of defects of motile cilia and sperm flagella. We identified loss-of-function mutations in the open-reading frame C11orf70 in PCD individuals from five distinct families. Transmission electron microscopy analyses and high-resolution immunofluorescence microscopy demonstrate that loss-of-function mutations in C11orf70 cause immotility of respiratory cilia and sperm flagella, respectively, as a result of the loss of axonemal outer (ODAs) and inner dynein arms (IDAs), indicating that C11orf70 is involved in cytoplasmic assembly of dynein arms. Expression analyses of C11orf70 showed that C11orf70 is expressed in ciliated respiratory cells and that the expression of C11orf70 is upregulated during ciliogenesis, similar to other previously described cytoplasmic dynein-arm assembly factors. Furthermore, C11orf70 shows an interaction with cytoplasmic ODA/IDA assembly factor DNAAF2, supporting our hypothesis that C11orf70 is a preassembly factor involved in the pathogenesis of PCD. The identification of additional genetic defects that cause PCD and male infertility is of great importance for the clinic as well as for genetic counselling.
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Tipificación del Cuerpo , Dineínas/genética , Síndrome de Kartagener/genética , Mutación/genética , Proteínas Nucleares/genética , Cilios/metabolismo , Cilios/ultraestructura , Dineínas/ultraestructura , Femenino , Genes Recesivos , Humanos , Mutación con Pérdida de Función/genética , Masculino , Cola del Espermatozoide/metabolismoRESUMEN
The clinical spectrum of ciliopathies affecting motile cilia spans impaired mucociliary clearance in the respiratory system, laterality defects including heart malformations, infertility and hydrocephalus. Using linkage analysis and whole exome sequencing, we identified two recessive loss-of-function MNS1 mutations in five individuals from four consanguineous families: 1) a homozygous nonsense mutation p.Arg242* in four males with laterality defects and infertility and 2) a homozygous nonsense mutation p.Gln203* in one female with laterality defects and recurrent respiratory infections additionally carrying homozygous mutations in DNAH5. Consistent with the laterality defects observed in these individuals, we found Mns1 to be expressed in mouse embryonic ventral node. Immunofluorescence analysis further revealed that MNS1 localizes to the axonemes of respiratory cilia as well as sperm flagella in human. In-depth ultrastructural analyses confirmed a subtle outer dynein arm (ODA) defect in the axonemes of respiratory epithelial cells resembling findings reported in Mns1-deficient mice. Ultrastructural analyses in the female carrying combined mutations in MNS1 and DNAH5 indicated a role for MNS1 in the process of ODA docking (ODA-DC) in the distal respiratory axonemes. Furthermore, co-immunoprecipitation and yeast two hybrid analyses demonstrated that MNS1 dimerizes and interacts with the ODA docking complex component CCDC114. Overall, we demonstrate that MNS1 deficiency in humans causes laterality defects (situs inversus) and likely male infertility and that MNS1 plays a role in the ODA-DC assembly.
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Codón sin Sentido , Lateralidad Funcional/genética , Homocigoto , Infertilidad Masculina/genética , Proteínas Nucleares/metabolismo , Adolescente , Adulto , Animales , Dineínas Axonemales/genética , Dineínas Axonemales/metabolismo , Axonema/metabolismo , Proteínas de Ciclo Celular , Niño , Preescolar , Cilios/ultraestructura , Femenino , Regulación de la Expresión Génica , Ligamiento Genético , Humanos , Lactante , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Proteínas Nucleares/deficiencia , Proteínas Nucleares/genética , Linaje , Polimorfismo de Nucleótido Simple , Cola del Espermatozoide , Secuenciación del Exoma , Adulto JovenRESUMEN
Primary ciliary dyskinesia (PCD) is a genetically heterogeneous chronic destructive airway disease. PCD is traditionally diagnosed by nasal nitric oxide measurement, analysis of ciliary beating, transmission electron microscopy (TEM), and/or genetic testing. In most genetic PCD variants, laterality defects can occur. However, it is difficult to establish a diagnosis in individuals with PCD and central pair (CP) defects, and alternative strategies are required because of very subtle ciliary beating abnormalities, a normal ciliary ultrastructure, and normal situs composition. Mutations in HYDIN are known to cause CP defects, but the genetic analysis of HYDIN variants is confounded by the pseudogene HYDIN2, which is almost identical in terms of intron/exon structure. We have previously shown that several types of PCD can be diagnosed via immunofluorescence (IF) microscopy analyses. Here, using IF microscopy, we demonstrated that in individuals with PCD and CP defects, the CP-associated protein SPEF2 is absent in HYDIN-mutant cells, revealing its dependence on functional HYDIN. Next, we performed IF analyses of SPEF2 in respiratory cells from 189 individuals with suspected PCD and situs solitus. Forty-one of the 189 individuals had undetectable SPEF2 and were subjected to a genetic analysis, which revealed one novel loss-of-function mutation in SPEF2 and three reported and 13 novel HYDIN mutations in 15 individuals. The remaining 25 individuals are good candidates for new, as-yet uncharacterized PCD variants that affect the CP apparatus. SPEF2 mutations have been associated with male infertility but have not previously been identified to cause PCD. We identified a mutation of SPEF2 that is causative for PCD with a CP defect. We conclude that SPEF2 IF analyses can facilitate the detection of CP defects and evaluation of the pathogenicity of HYDIN variants, thus aiding the molecular diagnosis of CP defects.
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Proteínas de Ciclo Celular/deficiencia , Cilios/química , Trastornos de la Motilidad Ciliar/genética , Proteínas de Microfilamentos/genética , Axonema/química , Axonema/ultraestructura , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/fisiología , Trastornos de la Motilidad Ciliar/diagnóstico , Trastornos de la Motilidad Ciliar/patología , Codón sin Sentido , Estudios de Cohortes , Análisis Mutacional de ADN , Células Epiteliales/citología , Células Epiteliales/metabolismo , Femenino , Heterogeneidad Genética , Homocigoto , Humanos , Mutación con Pérdida de Función , Masculino , Proteínas de Microfilamentos/fisiología , Microscopía Electrónica de Transmisión , Microscopía Fluorescente , Depuración Mucociliar/genética , Mutación , Mutación Missense , Linaje , Cultivo Primario de Células , Situs Inversus/diagnóstico , Situs Inversus/genética , Situs Inversus/patologíaRESUMEN
BACKGROUND: Lung resection is a controversial and understudied therapeutic modality in Primary Ciliary Dyskinesia (PCD). We assessed the prevalence of lung resection in PCD across countries and compared disease course in lobectomised and non-lobectomised patients. METHODS: In the international iPCD cohort, we identified lobectomised and non-lobectomised age and sex-matched PCD patients and compared their characteristics, lung function and BMI cross-sectionally and longitudinally. RESULTS: Among 2896 patients in the iPCD cohort, 163 from 20 centers (15 countries) underwent lung resection (5.6%). Among adult patients, prevalence of lung resection was 8.9%, demonstrating wide variation among countries. Compared to the rest of the iPCD cohort, lobectomised patients were more often females, older at diagnosis, and more often had situs solitus. In about half of the cases (45.6%) lung resection was performed before presentation to specialized PCD centers for diagnostic work-up. Compared to controls (n = 197), lobectomised patients had lower FVC z-scores (- 2.41 vs - 1.35, p = 0.0001) and FEV1 z-scores (- 2.79 vs - 1.99, p = 0.003) at their first post-lung resection assessment. After surgery, lung function continued to decline at a faster rate in lobectomised patients compared to controls (FVC z-score slope: - 0.037/year Vs - 0.009/year, p = 0.047 and FEV1 z-score slope: - 0.052/year Vs - 0.033/year, p = 0.235), although difference did not reach statistical significance for FEV1. Within cases, females and patients with multiple lobe resections had lower lung function. CONCLUSIONS: Prevalence of lung resection in PCD varies widely between countries, is often performed before PCD diagnosis and overall is more frequent in patients with delayed diagnosis. After lung resection, compared to controls most lobectomised patients have poorer and continuing decline of lung function despite lung resection. Further studies benefiting from prospective data collection are needed to confirm these findings.
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Trastornos de la Motilidad Ciliar/cirugía , Pulmón/cirugía , Adolescente , Adulto , Índice de Masa Corporal , Estudios de Casos y Controles , Niño , Preescolar , Estudios de Cohortes , Estudios Transversales , Femenino , Volumen Espiratorio Forzado , Humanos , Estudios Longitudinales , Masculino , Prevalencia , Estudios Prospectivos , Pruebas de Función Respiratoria , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: Children with asthma-like symptoms may not clinically wheeze. The objectives of this study were to evaluate if children, without physician-documented wheeze, wheeze during bronchial-challenge-testing (BCT), and if measurements of O2Sat and respiratory rate during BCT improve the BCT sensitivity? METHODS: Seven hundred and twenty-four children, who were referred for suspicion of asthma, performed a BCT. Positive BCT was determined by the provocation concentration (PC) which resulted in a 20% decrease in FEV1 (PC20), (in those who were able to perform spirometry, group B), or (in those unable to perform spirometry, group A) a 50% increase in respiratory rate (PCRR), or a 5% decrease in oxygen-saturation (PCO2-Sat) or appearance of wheezing (PCwheeze). RESULTS: Five hundred and seven BCTs were positive: group A n = 89 age, median (IQR), 3 (2.5-3.7) years (17.6%), were unable to perform spirometry, and group B n = 418 age 10.7 (6.8-15.6) years (82.4%), were able to perform spirometry. Children, without physician-documented wheeze in the total population (groups A plus B), were more likely (65.5%) to have a positive BCT without wheeze compared with those with physician-documented wheeze (41.0%, P < 0.001). In group A, adding PCRR and PCO2-Sat increased BCT sensitivity by 23.6%. CONCLUSIONS: Many children in both groups did not wheeze despite reaching BCT endpoints. Children without physician-documented wheeze tended not to wheeze at BCT. This may result in clinical under-diagnosis of asthma if depending on the presence of wheeze. In young children, adding PCRR and PCO2-Sat substantially increases BCT sensitivity and may improve asthma diagnosis.
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Asma/diagnóstico , Asma/fisiopatología , Ruidos Respiratorios/fisiopatología , Adolescente , Enfermedades Asintomáticas , Pruebas de Provocación Bronquial , Niño , Preescolar , Femenino , Humanos , Masculino , Cloruro de Metacolina/farmacología , Oxígeno/sangre , Pruebas de Función Respiratoria , EspirometríaRESUMEN
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.
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Trastornos de la Motilidad Ciliar/fisiopatología , Pulmón/fisiopatología , Adolescente , Adulto , Factores de Edad , Índice de Masa Corporal , Niño , Preescolar , Fibrosis Quística/fisiopatología , Femenino , Volumen Espiratorio Forzado , Humanos , Lactante , Recién Nacido , Internacionalidad , Modelos Lineales , Masculino , Persona de Mediana Edad , Valores de Referencia , Estudios Retrospectivos , Factores Sexuales , Espirometría , Capacidad Vital , Adulto JovenRESUMEN
Primary ciliary dyskinesia (PCD) is a genetic condition of impaired ciliary beating, characterized by chronic infections of the upper and lower airways and progressive lung failure. Defects of the outer dynein arms are the most common cause of PCD. In about half of the affected individuals, PCD occurs with situs inversus (Kartagener syndrome). A minor PCD subgroup including defects of the radial spokes (RS) and central pair (CP) is hallmarked by the absence of laterality defects, subtle beating abnormalities, and unequivocally apparent ultrastructural defects of the ciliary axoneme, making their diagnosis challenging. We identified homozygous loss-of-function mutations in STK36 in one PCD-affected individual with situs solitus. Transmission electron microscopy analysis demonstrates that STK36 is required for cilia orientation in human respiratory epithelial cells, with a probable localization of STK36 between the RS and CP. STK36 screening can now be included for this rare and difficult to diagnose PCD subgroup.
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Trastornos de la Motilidad Ciliar/genética , Mutación/genética , Proteínas Serina-Treonina Quinasas/genética , Axonema/metabolismo , Línea Celular , Dineínas/genética , Células Epiteliales/metabolismo , Femenino , Humanos , Masculino , Fenotipo , Mucosa Respiratoria/metabolismoRESUMEN
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.
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Estatura , Índice de Masa Corporal , Trastornos de la Motilidad Ciliar/fisiopatología , Estado Nutricional , Adolescente , Adulto , Distribución por Edad , Niño , Preescolar , Progresión de la Enfermedad , Femenino , Humanos , Lactante , Recién Nacido , Modelos Lineales , Masculino , Persona de Mediana Edad , Valores de Referencia , Pruebas de Función Respiratoria , Estudios Retrospectivos , Adulto JovenRESUMEN
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.
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Síndrome de Kartagener/diagnóstico , Síndrome de Kartagener/fisiopatología , Adolescente , Adulto , Niño , Preescolar , Europa (Continente) , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Metaanálisis como Asunto , Persona de Mediana Edad , Fenotipo , Pronóstico , Estudios Retrospectivos , Literatura de Revisión como Asunto , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
Reduced generation of multiple motile cilia (RGMC) is a novel chronic destructive airway disease within the group of mucociliary clearance disorders with only few cases reported. Mutations in two genes, CCNO and MCIDAS, have been identified as a cause of this disease, both leading to a greatly reduced number of cilia and causing impaired mucociliary clearance. This study was designed to identify the prevalence of CCNO mutations in Israel and further delineate the clinical characteristics of RGMC. We analyzed 170 families with mucociliary clearance disorders originating from Israel for mutations in CCNO and identified two novel mutations (c.165delC, p.Gly56Alafs*38; c.638T>C, p.Leu213Pro) and two known mutations in 15 individuals from 10 families (6% prevalence). Pathogenicity of the missense mutation (c.638T>C, p.Leu213Pro) was demonstrated by functional analyses in Xenopus. Combining these 15 patients with the previously reported CCNO case reports revealed rapid deterioration in lung function, an increased prevalence of hydrocephalus (10%) as well as increased female infertility (22%). Consistent with these findings, we demonstrate that CCNO expression is present in murine ependyma and fallopian tubes. CCNO is mutated more frequently than expected from the rare previous clinical case reports, leads to severe clinical manifestations, and should therefore be considered an important differential diagnosis of mucociliary clearance disorders.
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Trastornos de la Motilidad Ciliar/diagnóstico , Trastornos de la Motilidad Ciliar/genética , ADN Glicosilasas/genética , Variación Genética , Animales , ADN Glicosilasas/metabolismo , Análisis Mutacional de ADN , Diagnóstico Diferencial , Femenino , Mutación del Sistema de Lectura , Estudios de Asociación Genética , Sitios Genéticos , Pruebas Genéticas , Humanos , Masculino , Ratones , Mutación , Mutación Missense , Fenotipo , Transporte de Proteínas , Radiografía Torácica , Pruebas de Función Respiratoria , Tomografía Computarizada por Rayos X , Xenopus laevisRESUMEN
Primary ciliary dyskinesia (PCD) is a recessively inherited disease that leads to chronic respiratory disorders owing to impaired mucociliary clearance. Conventional transmission electron microscopy (TEM) is a diagnostic standard to identify ultrastructural defects in respiratory cilia but is not useful in approximately 30% of PCD cases, which have normal ciliary ultrastructure. DNAH11 mutations are a common cause of PCD with normal ciliary ultrastructure and hyperkinetic ciliary beating, but its pathophysiology remains poorly understood. We therefore characterized DNAH11 in human respiratory cilia by immunofluorescence microscopy (IFM) in the context of PCD. We used whole-exome and targeted next-generation sequence analysis as well as Sanger sequencing to identify and confirm eight novel loss-of-function DNAH11 mutations. We designed and validated a monoclonal antibody specific to DNAH11 and performed high-resolution IFM of both control and PCD-affected human respiratory cells, as well as samples from green fluorescent protein (GFP)-left-right dynein mice, to determine the ciliary localization of DNAH11. IFM analysis demonstrated native DNAH11 localization in only the proximal region of wild-type human respiratory cilia and loss of DNAH11 in individuals with PCD with certain loss-of-function DNAH11 mutations. GFP-left-right dynein mice confirmed proximal DNAH11 localization in tracheal cilia. DNAH11 retained proximal localization in respiratory cilia of individuals with PCD with distinct ultrastructural defects, such as the absence of outer dynein arms (ODAs). TEM tomography detected a partial reduction of ODAs in DNAH11-deficient cilia. DNAH11 mutations result in a subtle ODA defect in only the proximal region of respiratory cilia, which is detectable by IFM and TEM tomography.
Asunto(s)
Dineínas Axonemales/metabolismo , Cilios/metabolismo , Dineínas/metabolismo , Pulmón/metabolismo , Secuencia de Bases , Cilios/ultraestructura , Dineínas/ultraestructura , Homocigoto , Humanos , Síndrome de Kartagener/genética , Mutación/genética , Transporte de ProteínasRESUMEN
Defects of motile cilia cause primary ciliary dyskinesia (PCD), characterized by recurrent respiratory infections and male infertility. Using whole-exome resequencing and high-throughput mutation analysis, we identified recessive biallelic mutations in ZMYND10 in 14 families and mutations in the recently identified LRRC6 in 13 families. We show that ZMYND10 and LRRC6 interact and that certain ZMYND10 and LRRC6 mutations abrogate the interaction between the LRRC6 CS domain and the ZMYND10 C-terminal domain. Additionally, ZMYND10 and LRRC6 colocalize with the centriole markers SAS6 and PCM1. Mutations in ZMYND10 result in the absence of the axonemal protein components DNAH5 and DNALI1 from respiratory cilia. Animal models support the association between ZMYND10 and human PCD, given that zmynd10 knockdown in zebrafish caused ciliary paralysis leading to cystic kidneys and otolith defects and that knockdown in Xenopus interfered with ciliogenesis. Our findings suggest that a cytoplasmic protein complex containing ZMYND10 and LRRC6 is necessary for motile ciliary function.