Cilia diagnostics in primary ciliary dyskinesia

Prof. Heymut Omran (Munster University Hospital, Germany) demonstrated that diagnosing primary ciliary dyskinesia (PCD) requires a combined approach utilising characteristic phenotypes and complementary methods for detection of defects of ciliary function and ultrastructure, measurement of nasal nitric oxide, and genetic testing [1].

Prof. Omran and colleagues observed that, currently, biallelic mutations in 73 different genes have been linked to PCD, allowing a genetic diagnosis in approximately 60% of cases, and that management includes surveillance of pulmonary function, imaging, and microbiology of upper and lower airways, in addition to daily airway clearance and prompt antibiotic treatment of infections.

PCD is caused by impaired mucociliary clearance attributed to poor ciliary motility. Clinically, PCD is characterised by chronic airway infections and randomisation of the left/right body asymmetry. Dynein heavy chains are motor proteins of the outer dynein arms (ODAs) essential for ciliary motility. Human respiratory cilia contain different types of ODAs. ODAs type 1 contain the dynein heavy chains DNAH5 and DNAH11 and are located in the proximal axonemal compartment. ODAs type 2 contain DNAH5 and DNAH9 and are located in the distal axonemal compartment.

The investigators also emphasised that early referral to specialised centres using a multidisciplinary approach is likely to improve outcomes, but that, currently, evidence-based knowledge on PCD care —let alone management guidelines— is missing. Research and clinical investigators, supported by European and North American patient support groups, have joined forces under the name of BESTCILIA, a European Commission-funded consortium dedicated to improve PCD care and knowledge. Core network programmes include the establishment of the international PCD registry, the generation of PCD quality of life questionnaires, and the first randomised controlled trial in PCD. The main goal of BESTCILIA is to characterise the clinical course and improve the diagnosis and treatment of PCD patients, and the organisation points to marked discrepancies among European countries in the availability of PCD diagnostic services. Prof. Omran further described how different gene mutations in motile cilia affect specific phenotypes including mucus clearing and heterotaxy/situs inversus, but also occasionally atypical phenotypes.

For example, Prof. Omran and colleagues recently identified loss-of-function mutations in DNAH9 in 5 independent families that cause situs abnormalities and heart defects and are associated with subtle respiratory ciliary dysfunction. Consistent with the observed subtle respiratory phenotype, high-speed video microscopy demonstrated distally impaired ciliary bending in DNAH9-mutant respiratory cilia, reflecting a subtle defect in clearance. Absence of DNAH9 results in absence of other ODA components such as DNAH5, DNAI1, and DNAI2 from the distal axonemal compartment. Although DNAH9-mutant respiratory cilia show a distal deficiency of ODA complexes, mucociliary clearance is not disturbed in these individuals. In contrast, absence of DNAH11, affecting the proximally located ODA type 1, results in disturbed mucociliary clearance and PCD. In vitro ciliogenesis cell culture experiments demonstrate that DNAH11 is first recruited to the ciliary axoneme during early ciliogenesis, while DNAH9 appears in later stages of ciliogenesis in the distal ciliary compartment.

While significant advances have been made with regard to understanding the aetiology of this disease, Prof. Omran concluded that multi-disciplinary collaboration is necessary to best diagnose these patients. Genetics and NO measurements are the most reliable means since nasal scrapings and high-speed videography quality differ between hospitals and are less robust.

Figure: Left to right: electron scanning microscopy of primary cilia in renal tubule tissue; confocal image of basal body (yellow) ciliary axoneme (red), and ciliary tip (green); histology staining of cilia in renal tubules; cilia in retina (yellow-green); multiciliated respiratory epithelial cell; ciliated neurons (green) in the nematode C. elegans. Photos on file.

1. 
   
   1. Omran H, et al. A7385, ATS 2019, 17-22 May, Dallas, USA.

Posted on 23 July 20195 August 2021