Primary ciliary dyskinesia. Recent advances in diagnostics, genetics, and characterization of clinical disease

Abstract

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder of motile cilia that leads to oto-sino-pulmonary diseases and organ laterality defects in approximately 50% of cases. The estimated incidence of PCD is approximately 1 per 15,000 births, but the prevalence of PCD is difficult to determine, primarily because of limitations in diagnostic methods that focus on testing ciliary ultrastructure and function. Diagnostic capabilities have recently benefitted from (1) documentation of low nasal nitric oxide production in PCD and (2) discovery of biallelic mutations in multiple PCD-causing genes. The use of these complementary diagnostic approaches shows that at least 30% of patients with PCD have normal ciliary ultrastructure. More accurate identification of patients with PCD has also allowed definition of a strong clinical phenotype, which includes neonatal respiratory distress in >80% of cases, daily nasal congestion and wet cough starting soon after birth, and early development of recurrent/chronic middle-ear and sinus disease. Recent studies, using advanced imaging and pulmonary physiologic assessments, clearly demonstrate early onset of lung disease in PCD, with abnormal air flow mechanics by age 6-8 years that is similar to cystic fibrosis, and age-dependent onset of bronchiectasis. The treatment of PCD is not standardized, and there are no validated PCD-specific therapies. Most patients with PCD receive suboptimal management, which should include airway clearance, regular surveillance of pulmonary function and respiratory microbiology, and use of antibiotics targeted to pathogens. The PCD Foundation is developing a network of clinical centers, which should improve diagnosis and management of PCD.

Figure 1.

Normal motile cilia (9 + 2) configuration. Motile cilia are composed of highly complex microtubules of α- and β-monomers of tubulin, and associated accessory elements.

Figure 2.

Ciliary ultrastructure by electron micrographs (EMs) from (A) normal subject and (B–F) patients with primary ciliary dyskinesia (PCD). (A) The 9 + 2 axonemal structure is shown, with thick red arrows showing the outer dynein arm (ODA) and thin green arrow showing the inner dynein arm (IDA). (B) ODA defect denoted by thick red arrows (CCDC114 mutations). (C and D) Patient with PCD with CCDC40 mutations: (C) IDA defect denoted by thin green arrows, and (D) microtubular disorganization with one outer doublet translocating (disruption of 9 + 2 axonemal structure) into the central region in approximately 10% of cilia. (E) ODA + IDA defects noted by thick red arrow and thin green arrow. (F) Central apparatus defect; translocation of outer doublet into central region and loss of one of the central pair (seen in ∼5% of cilia with radial spokehead gene mutations).