PCD Foundation Blog

I spoke with Johnny C last night about putting a patient survey together looking for clues to other cilia-related phenomenen in PCD–particularly cystic lesions in the liver, pancreas and kidneys, splenic abnormalities, congenital heart defects and eye problems.  There is increasing evidence of the importance of ciliary function in skeletal development, as well.  The problem is that some of these issues in patients are “sub-clinical” and may not rise to the level of being diagnosed, even though they may be compounding the respiratory problems faced in PCD.  Coming up with a survey that is easy enough for patients to participate in, yet provides enough valid information may be difficult.  Asplenia is of particular concern because it does happen with PCD (very rarely, however) and if it is missed, can lead to sudden overwhelming infection and even death.  I think there is valid reason to do thoracic  and abdominal evaluations on all people who carry a diagnosis of PCD, but doubt that will become standard for many years.
Back to the survey–there are also privacy concerns.  We would want to make the information available to researchers, but won’t have individual details to match a survey to a particular person.  Not sure how we will get around these issues, but it is information that really needs to be collected somewhere and we could at least make a good start.  More on this as we get closer to having a completed survey.

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.

The official PCD session is due to start in about an hour.  I just got back from the poster session where I had the opportunity to speak with several of the researchers.  The Gordon Conference has strict rules about sharing unpublished material–they want to protect the work of the scientists, so I will have to limit my posts to things that are published or that I have received permission to share.  Mostly I was stunned, again, by the complexity of the cilium and the processes that go into producing functional cilia,whether motile or non-motile.  There are so many steps along the way and one mistake shoots the whole deal!

Networking is another benefit to attending these conferences.  I spoke with Scott Randell, the UNC person who handles tissue sample collection.  He has communicated with several members of the group regarding tissue donation post-transplant or in the case of death and he very much wants to set up an easy process for PCD patients to be able to make tissue donations.  The key is to have the pieces in place prior to the event, and he suggested getting consents signed and pathologist contact information as soon as a PCD patient is on the “Go” list for transplant.  We are going to try to make the necessary forms, from his end, available on our website.  Other institutions may require additional forms.  I was very glad that he tracked me down about this, though, because it seemed that the PCD community was willing to do whatever was needed–we just needed information from the other end.

I also had the chance to speak with Mike Knowles about a new bronchiectasis registry project we’ve been invited to participate in.  It is a joint effort with the NIH (specifically the MAC study) and the COPD Foundation.  It sounds like an excellent opportunity for PCD patients because the goal is to identify therapeutic targets for non-CF bronchiectasis–and we certainly fit right in to that category.  It’s tricky right now because the NHLBI is not willing (or able) to set aside research dollars for bronchiectasis, so individual groups and researchers are trying to step in to the breach.  Because pretty much 100% of our patient population develops bronchiectasis at some point in their life, this seems like a very good place for us to focus therapeutic research dollars (if we ever have them!).  The COPD Foundation is closely associated with the Alpha-1 Foundation and they do a terrific job managing resources so I look forward to working with them on this project.
There is a Gordon Conference on nitric oxide (NO) just down the road.  We have barely scratched the surface regarding the “why” for low NO in PCD, but there is compelling evidence that very low NO, in a patient who has been positively ruled out for CF, is diagnostic for PCD.  Under rare circumstances NO can be very low in bad sinusitis, but PCD and CF are the only other conditions that show low NO (and PCD is usually lower than CF), so if you are absolutely sure a patient with low NO doesn’t have CF, it leaves PCD as the likely culprit.  NO analyzers are becoming more common in large clinical facilities, so this may help us with earlier diagnosis.  We will meet with the NO group on Wednesday and I’ll let you know what comes of it.
I have to run, but I just need to say that intraflagellar transport (IFT) is really cool.  I’ll post about it later.

So I’m in the hotel cafe having my pre-breakfast coffee.  There are about 200 people at the conference and we have all meals together, but since I’m pretty useless until my first cup of caffeine, I try to fit one in prior to meeting with everyone.

I estimate that the attendance is almost half and half, American and international.  It is amazing to see the collaborative spirit in the cilia research community.  Many projects are jointly sponsored by labs all over the world.  Last night, the speakers focused on the extreme complexity of the structure of cilia and flagella.  This has been recognized for years, but there is seemingly new information coming out all the time.  Dynein arms themselves are very complex structures and the goal is to use what is being learned in Chlamydamonas (a single-celled algae) flagella because this information translates into the human genome quite nicely.

Again the researchers pointed out that not only do the structures in the cilium look different (outer dynein arms vs. inner dynein arms vs. central pair), but they are biochemically distinct which is why it is so difficult to find all the potential areas of dysfunction.  I’ve seen these models and heard the talks for years now, but when you see the complexity of ciliary ultrastructure, it actually is amazing that cilia EVER work they way they’re supposed to!

The UNC group was pretty much dragging last night–all day in planes or on shuttles and a three hour time difference to boot, so we’ll have more time to talk today.

That’s it for now–need to get back to my IV caffeine infusion–

It is Sunday evening and I’m sitting in the lobby of the Ventura Beach Marriott.  I’ve been told there is an actual beach nearby, but I’ve yet to find it!  The first session of the Gordon conference begins in about an hour, but already I’m very glad I came.  At registration, we received a schedule that includes all poster presentations and there are about 20 scientific posters related to motile cilia function.  In some ways, the posters are even more important than the formal talks because they represent the “cutting edge”–material that has not even been published yet.  It’s a great opportunity to see what’s coming up in the future for research.

Saw Johnny Carson (ultrastructure guy), Maimoona Zariwala (geneticist) and Milan Hazucha (NO guy) from UNC already.  Dr. Hazucha is in Ventura for a Gordon Conference on NO which just happens to be taking place about 2 miles from the Gordon Conference on Cilia.  We will be having a joint meeting with the NO people Wednesday afternoon.

Tonight’s session is called “Generation and Control of Ciliary Movement.”  There will be six speakers covering topics including how the structural anatomy of a cilium contributes to ciliary motility and how the actual cilium is built.  I’ll try to post after the session, if I am still awake.

The Gordon Conference on Cilia, Mucus and Mucociliary Interaction begins today.  Michele Manion is attending as a representative of the PCD Foundation.  Look for her informative updates in this blog.