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HomePediatrics: General MedicinePrimary Ciliary Dyskinesia

Primary Ciliary Dyskinesia

Background

Immotile cilia syndrome (ICS) is an autosomal recessive disease with extensive genetic heterogeneity characterized by abnormal ciliary motion and impaired mucociliary clearance. Ultrastructural and functional defects of cilia result in the lack of effective ciliary motility, causing abnormal mucociliary clearance. This leads to recurrent or persistent respiratory infections, sinusitis, otitis media, and male infertility. In 50% of the patients, ICS is associated with situs inversus.

In 1933, Kartagener described a unique syndrome characterized by the triad of situs inversus, chronic sinusitis, and bronchiectasis, which was dubbed Kartagener syndrome.
Later, patients with this condition were noted to have defects in the ultrastructure of cilia. Afzelius coined the term immotile cilia.
Later studies showed that disorganized motion, rather than immotile cilia, resulted in the uncoordinated and ineffective ciliary beat, hence the term ciliary dyskinesia syndrome (CDS). Because transient ciliary dyskinesia may be acquired following epithelial injury from viral respiratory tract infections or exposure to pollutants,
the term primary ciliary dyskinesia (PCD) is used to describe the genetic defect and to differentiate it from acquired defects.

Dysfunction of the axonemal structure has been linked to the emerging class of disorders collectively known as ciliopathies, which includes PCD/Kartagener syndrome, Bardet-Biedl syndrome, hydrocephalus, polycystic kidney disease, polycystic liver disease, nephrolithiasis, Meckel-Gruber syndrome, and Joubert syndrome.
A report of 9 patients with PCD from an inbred Amish community reported genetic heterogeneity.

Review of normal and abnormal ciliary ultrastructure

The epithelial lining of the large airways and contiguous structures, including the paranasal sinuses, middle ears, and posterior nose, consists of ciliated pseudostratified columnar epithelium. Ciliated cells are also found in the ependymal lining of the brain and fallopian tubes. In addition, the spermatozoal flagella (tail of spermatozoa) has a core structure that is identical to cilia.

Each matured ciliated cell has up to 200 cilia. Each cilium has an array of longitudinal microtubules arranged as 9 doublets formed in an outer circle around a central pair (see image below). The main structural protein of these doublets is tubulin. The microtubules are anchored by a basal body in the apical cytoplasm of the cell. Radial spokes connect the outer microtubular doublets with a central sheath of protein around the central tubules.

Diagram showing the cross-section of normal cilia

Diagram showing the cross-section of normal cilia showing its ultrastructure. Important components are labeled.

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Cross-section of the cilia (see image below) reveals inner and outer dynein arms, which are attached to the A subunit of each microtubule doublet. The inner dynein arms are longer and form a hook, whereas the outer dynein arms are short and straight. Dynein, a type of ATPase, provides energy for microtubule sliding and the longitudinal displacement of adjacent microtubular doublets, resulting in ciliary bending. The protein nexin links the outer microtubular doublets, creating a circumferential network as straplike bands. Because nexin links maintain axonemal relationships while the basal bodies anchor the microtubules, the sliding of the outer microtubule results in bending of the cilium.

Ciliary ultrastructure, Left, Normal cilium from a

Ciliary ultrastructure, Left, Normal cilium from a healthy individual in which both inner and outer dynein arms can clearly identified. Right, the absence of outer and inner dynein arms in a patient with primary ciliary dyskinesia. Image courtesy of J. Carson, PhD, University of North Carolina.

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Ciliary movement involves 2 phases: an effective stroke phase that sweeps forward and a recovery phase during which the cilia bend backward and extend into the starting position for the stroke phase. The mucous lining present on the respiratory epithelium has an inner serous layer called the sol phase, in which the cilia recover from their active beat, and an outer, more viscous layer, the gel phase. The tips of the cilia contact the gel layer during the stroke phase to propel the secretions forward, but the cilia lose contact with the gel layer of the mucus during the recovery phase.

Normal ciliary beat frequency is 1000-1500 beats per minute. The frequency is slower in the peripheral airways (eg, bronchioles) compared to the larger airways (eg, trachea). The ciliary motility is maintained in the same plane along the length of airways and results in mucociliary transport rates up to 20-30 mm/min.

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