Primary Ciliary Dyskinesia - Pathophysiology

Pathophysiology

This disease is genetically inherited. Structures that make up the cilia including inner and/or outer dynein arms, central apparatus, radial spokes, etc. are missing or dysfunctional and thus the axoneme structure lacks the ability to move. Axonemes are the elongated structures that make up cilia and flagella. Additionally, there may be chemical defects that interfere with ciliary function in the presence of adequate structure. Whatever the underlying cause, dysfunction of the cilia begins during and impacts the embryologic phase of development.

Specialised monocilia are at the heart of this problem. They lack the central-pair microtubules of ordinary motile cilia and so rotate clockwise rather than beat; in Hensen's node at the anterior end of the primitive streak in the embryo, these are angled posteriorly such that they prescribe a D-shape rather than a circle. This has been shown to generate a net leftward flow in mouse and chick embryos, and sweeps the Sonic Hedgehog (Shh) protein to the left, triggering normal asymmetrical development.

However, in some individuals with PCD, mutations thought to be in the gene coding for the key structural protein left-right dynein (lrd) result in monocilia which do not rotate. There is therefore no flow generated in the node, Shh moves at random within it, and 50% of those affected develop situs inversus which can occur with or without dextrocardia, where the laterality of the internal organs is the mirror-image of normal. Affected individuals therefore have Kartagener syndrome. This is not the case with some PCD-related genetic mutations: at least 6% of the PCD population have a condition called situs ambiguus or heterotaxy where organ placement or development is neither typical (situs solitus) nor totally reversed (situs inversus totalis) but is a hybrid of the two. Splenic abnormalities such as polysplenia, asplenia and complex congenital heart defects are more common in individuals with situs ambiguus and PCD, as they are in all individuals with situs ambiguus.

The genetic forces linking failure of nodal monocilia and situs issues and the relationship of those forces to PCD are the subject of intense research interest. For now hypotheses abound—some, like the one above, are generally accepted. However, knowledge in this area is constantly advancing.