Primary ciliary dyskinesia and upper airway diseases

Kennedy, Marcus P.; Ostrowski, Lawrence E.

doi:10.1007/s11882-006-0030-7

Cited by 11 publications

(9 citation statements)

References 46 publications

(37 reference statements)

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“…Heterotaxy, defined as an abnormality where the internal thoracoabdominal organs demonstrate abnormal arrangement across the left–right axis of the body is described in approximately 6% of the cases (52). Patients with heterotaxy may also have complex cardiac defects such as double outlet right ventricle, atrioventricular canal defects, atrial and ventricular septal defects, L-transposition of the great arteries, and tetralogy of Fallot (52, 53). The respiratory phenotypes of the PCD patients with heterotaxy are not different than those without heterotaxy (28).…”

Section: Disease Manifestationsmentioning

confidence: 99%

Primary Ciliary Dyskinesia: An Update on Clinical Aspects, Genetics, Diagnosis, and Future Treatment Strategies

2017

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Primary ciliary dyskinesia (PCD) is an orphan disease (MIM 244400), autosomal recessive inherited, characterized by motile ciliary dysfunction. The estimated prevalence of PCD is 1:10,000 to 1:20,000 live-born children, but true prevalence could be even higher. PCD is characterized by chronic upper and lower respiratory tract disease, infertility/ectopic pregnancy, and situs anomalies, that occur in ≈50% of PCD patients (Kartagener syndrome), and these may be associated with congenital heart abnormalities. Most patients report a daily year-round wet cough or nose congestion starting in the first year of life. Daily wet cough, associated with recurrent infections exacerbations, results in the development of chronic suppurative lung disease, with localized-to-diffuse bronchiectasis. No diagnostic test is perfect for confirming PCD. Diagnosis can be challenging and relies on a combination of clinical data, nasal nitric oxide levels plus cilia ultrastructure and function analysis. Adjunctive tests include genetic analysis and repeated tests in ciliary culture specimens. There are currently 33 known genes associated with PCD and correlations between genotype and ultrastructural defects have been increasingly demonstrated. Comprehensive genetic testing may hopefully screen young infants before symptoms occur, thus improving survival. Recent surprising advances in PCD genetic designed a novel approach called “gene editing” to restore gene function and normalize ciliary motility, opening up new avenues for treating PCD. Currently, there are no data from randomized clinical trials to support any specific treatment, thus, management strategies are usually extrapolated from cystic fibrosis. The goal of treatment is to prevent exacerbations, slowing the progression of lung disease. The therapeutic mainstay includes airway clearance maneuvers mainly with nebulized hypertonic saline and chest physiotherapy, and prompt and aggressive administration of antibiotics. Standardized care at specialized centers using a multidisciplinary approach that imposes surveillance of lung function and of airway biofilm composition likely improves patients’ outcome. Pediatricians, neonatologists, pulmonologists, and ENT surgeons should maintain high awareness of PCD and refer patients to the specialized center before sustained irreversible lung damage develops. The recent creation of a network of PCD clinical centers, focusing on improving diagnosis and treatment, will hopefully help to improve care and knowledge of PCD patients.

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Section: Disease Manifestationsmentioning

confidence: 99%

Primary Ciliary Dyskinesia: An Update on Clinical Aspects, Genetics, Diagnosis, and Future Treatment Strategies

2017

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“…These diseases range from autosomal dominant polycystic kidney disease, caused by mutations in polycystin-1 or polycystin-2, that localize to the primary cilium of renal epithelial cells, to primary ciliary dyskinesia (PCD), in which defects in the motile cilia in the airways cause repeated pulmonary infections (Badano et al 2006; Fliegauf et al 2007; Ostrowski et al 2011). PCD is a genetically heterogeneous disease in which biallelic mutations cause a defect in one of the many proteins required for the assembly and function of cilia (Bush et al 2007; Kennedy and Ostrowski 2006; Leigh et al 2009a; Noone et al 2004; Zariwala et al 2011). This defect results in impaired or absent mucociliary clearance, and leads to sinusitis, otitis media, chronic airways infection, and bronchiectasis that in some cases is so severe a lung transplant is the only available treatment option.…”

Section: Introductionmentioning

confidence: 99%

Computer‐assisted image analysis of human cilia and Chlamydomonas flagella reveals both similarities and differences in axoneme structure

et al. 2012

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In the past decade, investigations from several different fields have revealed the critical role of cilia in human health and disease. Because of the highly conserved nature of the basic axonemal structure, many different model systems have proven useful for the study of ciliopathies, especially the unicellular, biflagellate green alga, Chlamydomonas reinhardtii. Although the basic axonemal structure of cilia and flagella is highly conserved, these organelles often perform specialized functions unique to the cell or tissue in which they are found. These differences in function are likely reflected in differences in structural organization. In this work, we directly compare the structure of isolated axonemes from human cilia and Chlamydomonas flagella to identify similarities and differences that potentially play key roles in determining their functionality. Using transmission electron microscopy and 2D image averaging techniques, our analysis has confirmed the overall structural similarity between these two species, but also revealed clear differences in the structure of the outer dynein arms, the central pair projections, and the radial spokes. We also show how the application of 2D image averaging can clarify the underlying structural defects associated primary ciliary dyskinesia (PCD). Overall, our results document the remarkable similarity between these two structures separated evolutionarily by over a billion years, while highlighting several significant differences, and demonstrate the potential of 2D image averaging to improve the diagnosis and understanding of PCD.

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“…Patients with genetic defects in MCC suffer from repeated episodes of airway infection and eventually develop bronchiectasis. Individuals afflicted with primary ciliary dyskinesia (PCD), an inherited disease caused by mutations that result in defective cilial function, exhibit chronic rhinosinusitis, otitis media, and bronchitis, frequently leading to bronchiectasis (3)(4)(5)(6). In cystic fibrosis (CF), mutations in the CF transmembrane conductance regulator (CFTR) protein result in a thick mucus layer that prevents effective MCC and results in the chronic lung disease that causes the majority of mortality associated with this disease (7,8).…”

mentioning

confidence: 99%

Conditional Deletion of Dnaic1 in a Murine Model of Primary Ciliary Dyskinesia Causes Chronic Rhinosinusitis

Ostrowski

Yin²,

Rogers³

et al. 2010

Am J Respir Cell Mol Biol

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109

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Studies of primary ciliary dyskinesia (PCD) have been hampered by the lack of a suitable animal model because disruption of essential ciliary genes in mice results in a high incidence of lethal hydrocephalus. To develop a viable mouse model for long-term studies of PCD, we have generated a transgenic mouse line in which two conserved exons of the mouse intermediate dynein chain gene, Dnaic1, are flanked by loxP sites (Dnaic1(flox/flox)). Dnaic1 is the murine homolog of human DNAI1, which is mutated in approximately 10% of human PCD cases. These mice have been crossed with mice expressing a tamoxifen-inducible Cre recombinase (CreER). Treatment of adult Dnaic1(flox/flox)/CreER(+/-) mice with tamoxifen results in an almost complete deletion of Dnaic1 with no evidence of hydrocephalus. Treated animals have reduced levels of full-length Dnaic1 mRNA, and electron micrographs of cilia demonstrate a loss of outer dynein arm structures. In treated Dnaic1(flox/flox)/CreER(+/-) animals, mucociliary clearance (MCC) was reduced over time. After approximately 3 months, no MCC was observed in the nasopharynx, whereas in the trachea, MCC was observed for up to 6 months, likely reflecting a difference in the turnover of ciliated cells in these tissues. All treated animals developed severe rhinosinusitis, demonstrating the importance of MCC to the health of the upper airways. However, no evidence of lung disease was observed up to 11 months after Dnaic1 deletion, suggesting that other mechanisms are able to compensate for the lack of MCC in the lower airways of mice. This model will be useful for the study of the pathogenesis and treatment of PCD.

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Primary ciliary dyskinesia and upper airway diseases

Cited by 11 publications

References 46 publications

Primary Ciliary Dyskinesia: An Update on Clinical Aspects, Genetics, Diagnosis, and Future Treatment Strategies

Primary Ciliary Dyskinesia: An Update on Clinical Aspects, Genetics, Diagnosis, and Future Treatment Strategies

Computer‐assisted image analysis of human cilia and Chlamydomonas flagella reveals both similarities and differences in axoneme structure

Conditional Deletion of Dnaic1 in a Murine Model of Primary Ciliary Dyskinesia Causes Chronic Rhinosinusitis

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