Bench To Bedside: New Findings in Primary Ciliary Dyskinesia

By Joseph H. Sisson, MD; and Johnny L. Carson, PhD

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PCD: A Historical Perspective

The disparate symptoms comprising Kartagener’s triad—bronchiectasis, chronic sinusitis, and situs inversus—have been known for almost a century.^14,15 However, it was not until the advent of routine biological electron microscopy that Afzelius¹⁶ and others¹⁷ provided the first descriptions of abnormal ciliary ultrastructure associated with the syndrome and brought the term “immotile cilia syndrome” into common use. Subsequently, other investigators identified additional ultrastructural anomalies of PCD cilia^18,19 and characterized the “heterogeneity” of ciliary morphology associated with the syndrome.²⁰ A growing awareness that ciliary dyskinesia, rather than complete ciliary immotility, represented the functional characteristic of cilia from many affected individuals, as well as the observation that situs inversus appeared only in a segment of the patient population, led to the proposal that the term primary ciliary dyskinesia be used to describe the syndrome deriving from congenital ciliary abnormalities of which Kartagener’s triad is a subset (Fig 3).²¹

More recently, reports of ciliary abnormalities relating to PCD represent variations on the theme of earlier reports, although Rutland and deIongh²² have proposed that ultrastructural analysis of ciliary beat orientation is sufficient to confer a diagnosis of PCD. In contrast to normal ciliated epithelium, in which the central microtubular pair of adjacent cilia are aligned within 30 degrees of their neighbors, the cilia in this type of PCD are anchored on the epithelium in a haphazard orientation. This causes adjacent cilia to beat in random directions so that, while the cilia are not immotile, metachronal waves are not produced and therefore mucus is not cleared. This means that both individual cilium anatomy and the relative orientation of multiple cilia on the epithelium must be assessed as part of the electron microscopy evaluation. Because acquired ciliary defects occur commonly, the electron microscopic evaluation must examine a large number of cilia and take into account the types of defects that may represent acquired anomalies, such as compound cilia, megacilia, or random microtubular defects. Importantly, because acquired anomalies can also be seen in samples from patients with PCD, ciliary defects must be uniform to implicate PCD.

Subsequent to these clinical observations documenting dynein and radial-spoke defects in PCD, basic studies of Chlamydomonas reinhardtii revealed flagellar mutants that expressed patterns of axonemal defects structurally similar to those seen in PCD.^23-25 These observations combined with the rapid development and application of molecular genetic techniques in the late 20th century have led to a number of studies aimed at achieving a better understanding of the molecular basis of PCD.

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