Clinical and genetic aspects of primary ciliary dyskinesia/Kartagener syndrome

Abstract

Primary ciliary dyskinesia is a genetically heterogeneous disorder of motile cilia. Most of the disease-causing mutations identified to date involve the heavy (dynein axonemal heavy chain 5) or intermediate(dynein axonemal intermediate chain 1) chain dynein genes in ciliary outer dynein arms, although a few mutations have been noted in other genes. Clinical molecular genetic testing for primary ciliary dyskinesia is available for the most common mutations. The respiratory manifestations of primary ciliary dyskinesia (chronic bronchitis leading to bronchiectasis, chronic rhino-sinusitis, and chronic otitis media)reflect impaired mucociliary clearance owing to defective axonemal structure. Ciliary ultrastructural analysis in most patients (>80%) reveals defective dynein arms, although defects in other axonemal components have also been observed. Approximately 50% of patients with primary ciliary dyskinesia have laterality defects (including situs inversus totalis and, less commonly, heterotaxy, and congenital heart disease),reflecting dysfunction of embryological nodal cilia. Male infertility is common and reflects defects in sperm tail axonemes. Most patients with primary ciliary dyskinesia have a history of neonatal respiratory distress, suggesting that motile cilia play a role in fluid clearance during the transition from a fetal to neonatal lung. Ciliopathies involving sensory cilia, including autosomal dominant or recessive polycystic kidney disease, Bardet-Biedl syndrome, and Alstrom syndrome, may have chronic respiratory symptoms and even bronchiectasis suggesting clinical overlap with primary ciliary dyskinesia.

Figure 1

Diversity of ciliary axoneme. Cross section of non motile (9+0 arrangement) and motile cilia (9+2 and 9+0 arrangement) are shown.^, Studies to date have not determined whether the 9+0 monocilium has radial spokes. The model showing synchronous motion of motile (9+2), rotatory motion of motile monocilium (9+0) and immotile monocilium (9+0) is also shown. * Solitary axoneme in the sperm mirrors the structure of the cilium ^§ Subcellular structure of the kinocilum is debatable. Some reports indicate 9+0 while others indicate 9+2 configuration. The function of the kinocilium is also not clear as it disappears during the mammalian early postnatal period.

Figure 2

Schematic diagram of the eukaryotic cilium. Cross-section illustrates the 9+2 configuration of nine peripheral microtubular doublets surrounding a central pair microtubule complex. The expanded view of a microtubular doublet schematically depicts cross-sections of the tubulin protofilaments including those shared by the A and B tubules. The dynein arms in the expanded view are rendered to schematically depict several light, intermediate, and heavy chains comprising each of these structures. While the outer arm exhibits a specific distribution of dyneins, being uniformly composed of three heavy, two intermediate and at least 8 light chains, the distribution of dyneins in the inner arm is thought to be more variable.

Figure 3

Electron micrographs of nasal cilia from patients with primary ciliary dyskinesia (PCD) illustrating dynein defects. Far left panel illustrates ultrastructure of a normal cilium from nasal epithelium of a healthy, clinically unaffected subject. The adjacent panels from three different PCD patients illustrates defects in both dynein arms, isolated defects of outer dynein arms only, and isolated defects of inner dynein arms only.