Tuesday Evening
The PCD and Diseases of the Cilium session was interesting. There were two talks on right-left laterality determination and how ciliary activity (of a specific kind of cilia called nodal cilia) most likely contributes to the proper development of “sidedness.” In the absence of this activity, left/right asymmetry is random. This appears to be true for both DNAH5 and DNAI1 defects. The evidence for how this works is pretty compelling for total situs inversus. It’s just not so clear for some of the other situs defects seen in PCD (in at least 6% of the population). These other defects, called situs ambiguous or heterotaxy syndromes are concerning because they are associated with a much greater risk (200 fold) of congenital heart defects and other problems. Most of these congenital problems are picked up right away after birth, so this is not to say you should suspect you or your child has a serious undiagnosed heart defect. It’s just something to be aware of in case symptoms should develop. This paper will be published soon and available to share with your personal physicians.
This Gordon conference is a little different in that the clinical session included PCD, cystic diseases of the kidney and diseases that result from genetic mutations in the basal body of the cilium rather than in the dynein arms or ciliary ultrastructure (like PCD). Basal body ciliary disorders are very serious and in some cases lethal in the neonatal period. One common factor in understanding all of these diseases of cilia is the concept of intraflagellar transport (IFT). IFT refers to the actual chemomechanical movement of proteins, lipids and enzymes from the surface of the ciliated tissue, into the basal body, and up the ciliary shaft (axoneme) to the appropriate place on the cilium. When these proteins don’t “localize” to their proper area, you get functional problems. In one known PCD genetic mutation, improper protein placement results in cilia that beat super fast at the tip, but have no functional stroke at all closer to the surface. This is an interesting discovery because these cilia appear to beat just fine under the microscope and biopsies taken from the functioning tip of the cilium will look ultrastructurally normal. It’s only by using high-speed video beat analysis that the defect can be detected.
There is some evidence of overlap between PCD and non-motile or basal body ciliary disorders. The development of cysts in the kidneys, liver and pancreas are one potential area of overlap, as is retinal dystrophy or degeneration syndromes. I’ve been working on a patient survey to get at how common these issues are in the patient group and in blood relatives of patients. Mike Knowles thought this would be a useful project for us as a patient group and referred to it as an “enabling” survey because it would enable them to follow families who appear to have overlap syndromes. I’ll be working with Johnny Carson and Joe Sisson on this project and we’ll provide updates on survey progress as they become available.
So far the only consistent clinical indicator of PCD, regardless of defect or gene, is low nasal NO. I’m looking forward to the discussion about this tomorrow.