Genetic Causes of Bronchiectasis: Primary Ciliary Dyskinesia

Abstract

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder reflecting abnormalities in the structure and function of motile cilia and flagella, causing impairment of mucociliary clearance, left-right body asymmetry, and sperm motility. Clinical manifestations include respiratory distress in term neonates, recurrent otosinopulmonary infections, bronchiectasis, situs inversus and/or heterotaxy, and male infertility. Genetic discoveries are emerging from family-based linkage studies and from testing candidate genes. Mutations in 2 genes, DNAI1 and DNAH5, frequently cause PCD as an autosomal recessive disorder. A clinical genetic test has been recently established for DNAI1 and DNAH5, which involves sequencing 9 exons that harbor the most common mutations. This approach will identify at least one mutation in these 2 genes in ∼25% of PCD patients. If biallelic mutations are identified, the test is diagnostic. If only one mutation is identified, the full gene may be sequenced to search for a trans-allelic mutation. As more disease-causing gene mutations are identified, broader genetic screening panels will further identify patients with PCD. Ongoing investigations are beginning to identify genetic mutations in novel clinical phenotypes for PCD, such as congenital heart disease and male infertility, and new associations are being established between ‘ciliary’ genetic mutations and clinical phenotypes.

Airway epithelial control of Pseudomonas aeruginosa infection in cystic fibrosis

“…But this abnormal physiology does not provide an explanation for why P. aeruginosa is so clearly the predominant pathogen in CF, as other pathogens could probably take advantage of this niche to cause lung infection. Indeed, in human genetic diseases such as immotile ciliary disorders, or the subset of these patients with Kartagener's syndrome, the loss of ciliary clearance of mucus clearly predisposes to frequent bronchiectasis, sinusitis and otitis but without the predominance of P. aeruginosa as an etiologic agent of infection, as is seen in CF [14]. In these patients, mucoid P. aeruginosa infection, where it occurs in ∼15% of affected individuals, primarily emerges after 30 years of age [14], whereas among CF patients, over 80% are infected with this organism by late adolescence.…”

“…Indeed, in human genetic diseases such as immotile ciliary disorders, or the subset of these patients with Kartagener's syndrome, the loss of ciliary clearance of mucus clearly predisposes to frequent bronchiectasis, sinusitis and otitis but without the predominance of P. aeruginosa as an etiologic agent of infection, as is seen in CF [14]. In these patients, mucoid P. aeruginosa infection, where it occurs in ∼15% of affected individuals, primarily emerges after 30 years of age [14], whereas among CF patients, over 80% are infected with this organism by late adolescence. Furthermore, in the disease diffuse panbronchiolitis, found commonly in Japanese patients with chronic obstructive pulmonary disease and thus impaired interactions of the airway epithelium with P. aeruginosa, mucoid P. aeruginosa infection is common, although CFTR function is intact [15].…”

Effectiveness of Balloon Exercise on Level of Dyspnoea among Patients with Lower Respiratory Tract Disorder

“…There was no association with most of the demographic variables like educational status, occupational status area of work, type of workers, co-morbid illness, tobacco chewing, alternative therapies, medication intake and life style practices with respiratory status which includes dyspnea scale. Whereas there was an association with age, gender, smoking habit and duration of illness with the level of dyspnea [4,12,13].…”

“…The report of "WORLD HEALTH STATISTICS 2011" Says that, 235 million people currently suffer from asthma, 90% of COPD deaths occur in low and middle income countries and > 3 million people died of COPD in 2005. The lower respiratory tract infection pneumonia remains that most common infection seen in the community and among hospitalized patient [3,4]. National Disease Statistics (2011) worldwide shows a high prevalence of respiratory morbidity among patients with respiratory disorders.…”

Biology of Cilia and Ciliopathies

“…This is useful for diagnosis since immunofluorescence can show if this mislocalization is present [102]. Genetic testing can also be done, but is not very reliable since the disease is very genetically heterogeneous, with the discovery of at least ten related genes from various loci on multiple chromosomes [103]. False positive diagnoses can occur during or after a respiratory infection or inflammation, since these conditions show impaired ciliary function.…”