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PCD Blog
PCD Diagnosis: Understanding Research vs. Clinical Practice
Escrito por Michele Manion    Domingo 09 de Agosto de 2015 12:30    PDF Imprimir Correo electrónico

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It has been truly gratifying to see the growth of interest in PCD research over the past decade.  This interest holds the promise of exciting new technologies and therapies that will improve PCD diagnostics and quality of life. However, sometimes excitement over possibilities can lead to misinterpretation of what is actually useful in the clinical setting (i.e. at your physician’s office). There is a difference between technologies or therapies that are currently being evaluated for use (research) and those for which scientific evaluation has been done and they have been validated for use with actual patients (clinical practice).

Diagnosis of PCD is a challenging problem and one that has led to a number of advances in recent years. Many of these advances are still in the ‘being scientifically evaluated’ stage, which means they are in the research arena—not appropriate for,  or available in, the clinical setting yet, except as part of a clinical trial at specific participating centers.  To clarify the status of diagnostic tests in PCD, it is useful to divide the tests into those that have passed scientific ‘muster’ (been validated through research studies) and have been approved by regulatory authorities for use with patients vs. those still in the process of validation:

 

Validated and approved (FDA or other regulatory body) for PCD diagnosis:

1. Biopsy of cilia with electron microscopic assessment of ciliary ultrastructure (aka ‘biopsy’)

2. Genetic test showing known biallelic (one from each parent) PCD mutations on a confirmed PCD gene

 

Adjunct testing that may be useful, but cannot be used to make the diagnosis alone (diagnosis must be confirmed with one of the tests above):

3. Nasal nitric oxide measurement (validated standard operating procedures (SOPs) available; must be done at expert center)

4. Immunofluorescent assay test for ciliary proteins (validated assays available; must be done at expert center)

5.  High-speed videomicroscopy (no standard operating procedures yet established or validated; must be done at expert center)

 

As you can see, there are only two tests that are actually approved for making a clinical diagnosis of PCD—ciliary biopsy and genetics.  The other tests on the list can be helpful—sometimes extremely helpful—when trying to determine the likelihood of PCD or not PCD, but they cannot on their own establish the diagnosis. Most of them are also considered ‘research’ and not clinical tests. This means that they have not yet been validated for use in a clinical setting and can only be used under a research protocol. Their value in the clinical setting has yet to be firmly established or ‘validated.’

 

Every diagnostic option on this list has limitations. There is no single test that can pick up all cases of PCD and there are some forms of PCD for which no reliable test currently exists. In these cases, physicians may have to resort to diagnosing ‘likely’ or ‘probable’ PCD based on the evidence they are able to gather using available technology. This is frustrating for many families (and for many physicians), but relying on unvalidated tests that may or may not provide a reliable result will not reduce this frustration. It is more likely to compound it by introducing additional opportunities for misdiagnosis.  


Understanding the nature of PCD is important. It is not uncommon for us to hear families say ‘it must be PCD—I have/my child has all the symptoms.’ But while symptoms commonly seen in PCD may lead a doctor to suspect the disorder, PCD is not just a set of symptoms. It is a group of distinct genetic disorders. The diagnosis is made based on the presence of specific PCD genetic defects and not on PCD-like symptoms. This is similar to cystic fibrosis. Many children have repeated lung infections and fail to gain weight. However, no one would diagnose these children as having cystic fibrosis on the basis of symptoms alone without convincing evidence from validated tests (sweat test, CF genetic testing, nasal potential difference, etc.) done at a CF certified site proving that a CF mutation is responsible for symptoms.  Since we don’t know all the genes involved in PCD yet, other indications of PCD genetic defects—like specific ultrastructural changes on biopsy or very low nasal NO or distinctly impaired ciliary beat patterns—can provide evidence for a genetic defect.  But diagnoses made this way must be done very, very carefully, by people with a great deal of experience because it is very easy to misinterpret  these tests and mistake ‘acquired’ or ‘non-genetic’ changes for PCD changes.

 

Getting the diagnosis right is important for many reasons. First and foremost, PCD is a genetic disorder and the diagnosis carries implications for families. Second, a misdiagnosis of PCD will interfere with additional investigation to find the real reason for symptoms and possibly delay appropriate treatment. Finally, ‘un-diagnosis’ is a traumatic experience for families and one that can often be avoided by evaluation at an expert center.

 

In summary, PCD is a disorder of specific genetic mutations -- not just a set of symptoms-- that is currently difficult to diagnose. There are only two approved tests for confirming the diagnosis of PCD:  1.) Biopsy of cilia with transmission electron microscopic (TEM or EM) analysis of ultrastructure, or 2.) Genetic testing that demonstrates biallelic PCD mutations. Other PCD tests like video analysis of ciliary beat and nasal nitric oxide measurement are not diagnostic on their own and are often performed as part of a clinical trial to evaluate their reliability. Results from these research tests cannot establish the diagnosis of PCD and they must be confirmed by an approved, validated test.

 

This article was medically reviewed by a member of the PCDF Medical and Scientific Advisory Board prior to publication

 
Community Volunteer Spotlight
Escrito por Lynn Ehrne    Miércoles 04 de Marzo de 2015 16:26    PDF Imprimir Correo electrónico

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Last fall, the PCDF launched the "Move 4 a Cure" campaign designed to get folks moving while raising awareness and much needed funds for PCDF programs. As part of this campaign, the PCD community set a goal of $25,000 for our annual October Awareness month. Thanks to the dedicated efforts of our awesome PCD community, the group not only met, but surpassed that goal, collectively raising $26,000 for PCDF!

In total, fundraisers were held in 13 states from Alaska to Mississippi. Events included walks, runs, spinning competitions, basketball free throws, various home parties, crowd- funded online fundraisers and T-shirt sales. People of all ages participated in events. Three families sold over 500 PCD tee-shirts- that is 500 people wearing PCD conversation starters!

We were overwhelmed by the support and hard work of the PCD community and very grateful for an incerdibly supportive community.  Big or small- every event counts, every cent counts, every conversation counts. You made a difference!  Together will we continue to 'Move" towards a cure.

 

On behalf of the PCD Foundation Board,

Thank you for all of your hard work & efforts!

Lynn Ehrne

 

 

 
North American PCD Registry Now Accepting Entries
Escrito por Michele Manion    Jueves 01 de Mayo de 2014 20:44    PDF Imprimir Correo electrónico

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Here is Your Link to the PCD Community! 

The North American PCD Registry (NAPCDR) is now open for entries! Click here to add your voice to growing community of PCD patients, caregivers and experts working to make a difference for people with PCD.


We encourage electronic entry, but if you require a hard copy of the registry form, please contact the PCD Foundation at: 

NAPCDR
C/O PCD Foundation
10137 Portland Avenue South
Minneapolis, Minnesota 55420

And remember, ALL COMPLETED ENTRIES RECEIVED BY MAY 10, 2014 WILL AUTOMATICALLY BE ELIGIBLE FOR A DRAWING TO WIN AN APPLE iPAD OR ONE OF FIVE RED BOX MOVIE GIFT CARDS.

We are very excited about this milestone for the PCD community and look forward to the participation of our expanding PCD family!





 
Dr. Knowles Interviewed about Rare Diseases
Escrito por Michele Manion    Martes 07 de Mayo de 2013 07:14    PDF Imprimir Correo electrónico

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This is a very nice overview of history of accelerated interested in rare disease research.  Dr. Michael Knowles from UNC is quoted in reference to his role with the Genetic Disorders of Mucociliary Clearance Consortium (GDMCC, aka 'PCD study'):

 

 
Ciliary Ultrastructure: What Your Doctor Sees
Escrito por Michele Manion    Miércoles 03 de Abril de 2013 10:36    PDF Imprimir Correo electrónico

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Here are examples of ciliary ultrastructure analyzed from the biopsy samples taken to diagnose PCD.  To get these views, the cilia (which are microscopic) need to be sliced for cross-section. Cilia are long and thin (think blade of grass). The cross-section view would be like looking down at the inside of the grass blade after it's been cut.  

 

To enable cross-section slicing, the sample is preserved in a wax-like substance that hardens and tiny slices are prepared for analysis under the electron microscope. This microscope is orders of magnitude more sensitive than a regular microscope, but can still only magnify items that are 'electron dense.' We now know that certain defects (for instance, DNAH11 outer dynein arm defects) appear not to be electron dense, so they don't show up on biopsy.  We don't know how many other PCD genetic mutations may fall into this category, though, which is why the biopsy alone is not sufficient for ruling PCD out. Having a 'normal' biopsy does not necessarily mean you don't have PCD--just that you don't have PCD caused by a defect that shows up on biopsy. 

To give you an idea of the challenges faced by pathologists and doctors trying to analyze these biopsies, here is a slide showing normal ultrastructure (bottom left) and PCD with absence of dynein arms (bottom right). These slides represent the 'perfect world' of biopsy samples. They are clear, the defect is obvious and, if the defect was seen in many cilia, it would not be hard to make the call for PCD caused by absence of dynein arms. You will need to click on the link, as I could not figure out how to get the picture uploaded directly to this site:

 

Ciliary Ultrastructure: Normal and PCD

 

And here are four examples of what pathologists see in the 'real world.' 

 

Ciliary Ultrastructure: Abnormal

 

As you can see, what pathologists normally get to work with is far from ideal. The images are blurry and while these are  very defective looking cilia, the defects tend to be inconsistent within the same sample. The important point is that these ciliary samples all came from people without PCD. They represent a small sample of the temporary ciliary defects that can occur from having a respiratory infection or from exposure to an environment toxin. You can see why diagnosis of PCD via biopsy tends to be as much art as science at times. 

 

 

 


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