Primary ciliary dyskinesia: critical evaluation of clinical symptoms and diagnosis in patients with normal and abnormal ultrastructure

Abstract

BackgroundPrimary ciliary dyskinesia (PCD) is a rare disorder with variable disease progression. To date, mutations in more than 20 different genes have been found. At present, PCD subtypes are described according to the ultrastructural defect on transmission electron microscopy (TEM) of the motile cilia. PCD with normal ultrastructure (NU) is rarely reported because it requires additional testing. Biallelic mutations in DNAH11 have been described as one cause of PCD with NU.The aim of our study was to describe the clinical characteristics of a large population of patients with PCD, in relation to the ultrastructural defect. Additionally, we aimed to demonstrate the need for biopsy and cell culture to reliably diagnose PCD, especially the NU subtype.MethodsWe retrospectively analyzed data from 206 patients with PCD. We compared the clinical characteristics, lung function, microbiology and imaging results of 68 patients with PCD and NU to those of 90 patients with dynein deficiencies and 41 patients with central pair abnormalities. In addition, we aimed to demonstrate the robustness of the diagnosis of the NU subtype in cell culture by data from genetic analysis.ResultsPCD with NU comprised 33% (68/206) of all patients with PCD. Compared to other subtypes, patients with PCD and NU had a similar frequency of upper and lower respiratory tract problems, as well as similar lung function and imaging. With the currently widely applied approach, without cell culture, the diagnosis would have been missed in 16% (11/68) of patients with NU. Genetic analysis was performed in 29/68 patients with PCD and NU, and biallelic mutations were found in 79% (23/29) of tested patients.ConclusionsWe reported on the clinical characteristics of a large population of patients with PCD and NU. We have shown that systematic performance of biopsy and cell culture increases sensitivity to detect PCD, especially the subtype with NU.PCD with NU has similar clinical characteristics as other PCD types and requires biopsy plus ciliogenesis in culture for optimal diagnostic yield.

Accuracy of Immunofluorescence in the Diagnosis of Primary Ciliary Dyskinesia

“…There are two recently published approaches to define specific criteria for a clinical phenotype that have significant predictive power for a subject having PCD, which could be used in future studies (18,19), although both also have imperfect sensitivity and specificity. (2) The lack of ciliary electron microscopy defects in approximately 30% of patients with PCD (9), and many of these cannot be diagnosed by immunofluorescence. (3) The limitations of high-speed videomicroscopy.…”

Diagnosis of primary ciliary dyskinesia: searching for a gold standard

“…Repeat testing or reanalysis following culture at the air-liquid interface (ALI) [18] or under submerged conditions [19] has, therefore, been recommended [4] to confirm primary rather than secondary defects. Most defects of ciliary ultrastructure defined in adequate numbers of cilia with good preparation and sampling of images have 100% specificity; however, analysis of cilia by TEM will miss the 30% of patients who do not have ''hallmark'' ultrastructural defects [20]. Some ultrastructural defects (e.g.…”

Clinical Features and Associated Likelihood of Primary Ciliary Dyskinesia in Children and Adolescents

“…Therefore, the actual incidence may be higher than these estimates. While the clinical spectrum of PCD has been described for decades, recent literature continues to redefine the phenotype (3)(4)(5)(6)(7)(8)(9)(10).…”