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South Carolina Society for
   Respiratory Care
           and
     Electromed, Inc.
Primary Ciliary Dyskinesia:

Missing a Beat: Primary Ciliary Dyskinesia
        Impaired Airway Clearance and
           Respiratory Disease

          Michele Manion, Executive Director
                   PCD Foundation
               www.pcdfoundation.org
Pcd presentation musc
What is Primary Ciliary
     Dyskinesia (PCD)?
 Umbrella term for genetic disorders affecting proteins
  responsible for the structure and/or function of motile
  (moving) cilia. Also called immotile cilia syndrome,
  Kartagener syndrome (PCD with situs inversus)

 One of three recognized genetic disorders of
  mucociliary clearance (along with cystic fibrosis and
  pseudohypoaldosteronism) currently being studied in a
  North American research consortium
PCD: The Historical Perspective
(or What’s With all the Names?)
•1904 AW Siewert makes first mention of a triad of
 bronchiectasis, dextrocardia and sinusitis/nasal polyps

•1933 Manes Kartagener (Swiss pediatrician) published a report
 of 4 children with bronchiectasis, sinusitis and situs inversus.
 The syndrome is named “Kartagener Syndrome.”

•1975 Afzelius (Swedish ultrastructuralist) and Pedersen
 (Denmark) independently hypothesize that “immotile cilia” may
 be the underlying cause and the syndrome is renamed
 “immotile cilia syndrome.” Both names (Kartagener & ICS
 persist).

•1981 Based on new understanding of cilia pathogenesis, Sleigh
 suggests a name change to “primary ciliary dyskinesia”
PCD Demographics

PCD Prevalence: Range from 1:4,100* to 1:15,000**



                               Estimated                     PCDF Database


           US:            20,773 – 74,880                           426
           SC                 312 – 1,411                               6




*Katsuhara K, Kawamoto S, Wakabayashi T, et al. Situs inversus totalis and
Kartagener’s syndrome in a Japanese population. Chest 1972; 61: 56–61.

**Afzelius BA, Stenram U. Prevalence and genetics of immotile-cilia syndrome and left-
handedness. Int J Dev Biol 2006; 50: 571–573 .
What are Cilia?
Three Types of Cilia in Human Cells:

Motile (respiratory epithelium, organs of
           reproduction, ependymal
           lining of ventricles of brain, etc.)
Nodal   (specialized organelle appearing once
            only on the embryonic node)
Primary (non-motile chemosensory monocilia)
What are Cilia?

Cilia and flagella are microtubule-based
organelles that extend from the surface of
almost all cell types in the human body




Ciliated Respiratory Epithelium              Nodal (Primary) Monocilia
               Courtesy Johnny Carson, PhD          Courtesy Fliegauf M, et al Nat Rev Mol Cell Biol. Nov 2007
What are Cilia?
                                                   Cross-section
                                                   of typical
                                                   “9+0” sensory
                                                   cilium




Ainesworth, C. NATURE Vol 448:9, August 2007
What are Cilia?
                                                   Cross-section
                                                   of typical
                                                   “9+2” motile
                                                   cilium




Ainesworth, C. NATURE, Vol 448:9 August 2007
What are Cilia?
                  700-750 genes
                  in the ciliary
                  structure
                  including the
                  basal body
What are Cilia?
   The Role of Non-Motile Cilia in Cells
     Once thought to be vestigial leftovers from
      evolution
     Importance only discovered in last decade
     Provide crucial sensory functions to the cells
     Now implicated in a number of human
      diseases, including PKD, spina bifida, bone &
      connective tissue disorders, retinal disorders
      and a host of pleiotropic diseases (Bardet-Biedl,
      Alstrom, Meckel’s, Joubert, Juene’s, etc.)
     Focus of intense research, due to connection
      between primary cilia and obesity.

Bush A, Hogg C. Primary ciliary dyskinesia: recent advances in epidemiology, diagnosis, management
and relationship with the expanding spectrum of ciliopathy. Expert Rev Respir Med. 2012 Dec;6(6):663-
82. doi: 10.1586/ers.12.60. PubMed PMID: 23234452.
What are Cilia?
Cilia vs. Flagella




Ciliated Respiratory Epithelium   Flagellated Chlamydomonas
                                  Courtesy David Howard: http://www.uwlax.edu/biology/faculty/Howard/Research.htm
What Are Cilia?
Where are Motile Cilia Found?
 Upper & lower respiratory tract
 Eustachian tube of middle ear
 Ependymal lining of the ventricles of the brain
 Fallopian tubes of the female reproductive
  system
 Sperm tails (technically flagella, but
  structurally similar to cilia)
What are Cilia?

 Cilia in the Respiratory Tract
•Ciliated cells account for approximately 80% of the cells lining surface
of the conducting airways.

•Ciliated cells in coordination with secretory cells represent a first line
of defense for the respiratory tract against potential pathogens/
particulate matter in the inspired air.

•Respiratory epithelial cells each have about 200-300 cilia that beat in a
coordinated “metachronal” wave.

•Effective ‘wave’ or beat facilitated by slippery glycoprotein coating on
individual cilium




Button B, et al A periciliary brush promotes the lung health by separating the mucus layer from airway
epithelia. Science. 2012 Aug 24;337(6097):937-41. doi: 10.1126/science.1223012. PubMed PMID: 2
How Do Motile Cilia Work?




                                                                  Microtubular pair

                                                               Outer dynein arms

                                                                  Microtubular pair



Cilia graphics courtesy Johnny Carson, PhD, UNC, Chapel Hill
How Do Motile Cilia Work?

ATP
How Do Motile Cilia Work?
How Do Motile Cilia Work?
                                How Important is ATP?




  Cilia from bovine trachea in                             Add a little ATP and… Voilà
  Petri dish

Cilia graphics courtesy Johnny Carson, PhD, UNC, Chapel Hill
How Do Motile Cilia Work?

                                                                               Normal
                                                                               Ciliary
                                                                               Activity
                                                                               (Real Time)




Courtesy of John C. Carson, PhD, University of North Carolina at Chapel Hill
How Do Motile Cilia Work?

                                                                            Normal
                                                                            Ciliary
                                                                            Activity
                                                                            (Real Time)




Courtesy John C. Carson, PhD, University of North Carolina at Chapel Hill
How Do Motile Cilia Work?
                                                                            Normal
                                                                            Ciliary
                                                                            Activity




Courtesy John C. Carson, PhD, University of North Carolina at Chapel Hill
How Do Motile Cilia Work?
    Metachronal, synchronized ‘wave’ of ciliated epithelium

                                                                               Normal
                                                                               Ciliary
                                                                               Activity




Courtesy of John C. Carson, PhD, University of North Carolina at Chapel Hill
How Do Motile Cilia Work?
                                                             Normal
                                                             Ciliary
                                                             Activity




Courtesy Robert E. Wood, MD, PhD, University of Cincinnati
What Happens in PCD?




ATP
What Happens in PCD?
What Happens in PCD?

                                                                            PCD
                                                                            Ciliary
                                                                            Activity
                                                                            (Real Time)




Courtesy John C. Carson, PhD, University of North Carolina at Chapel Hill
What Happens in PCD?

                                                                PCD Ciliary Activity
                                                                (Real Time)




Courtesy John C. Carson, PhD, University of North Carolina at Chapel Hill
What Happens in PCD?

                                                                            Ciliary
                                                                            Activity:
                                                                            Side by Side
                                                                            Comparison
                                                                            (Real Time)




Courtesy John C. Carson, PhD, University of North Carolina at Chapel Hill
PCD: Clinical Consequences

What are the Clinical Consequences of
                 PCD?

Consequences begin before birth
Specialized “nodal” cilia on the embryonic
 node are unique—9+0 cilia WITH dynein arms
Nodal cilia “twirl” rather than beat
PCD: Clinical Consequences

                              ‘9 + 0’ Nodal Cilium




Courtesy John C. Carson, PhD, University of North Carolina at Chapel Hill
PCD: Clinical Consequences

 Nodal cilia
 and left-right
 asymmetry




Hirokawa et al. Cell 125:33-45, 2006
PCD: Clinical Consequences
     Nodal cilia and left-right asymmetry
       The absence of nodal ciliary motion results in
       random organ placement, including laterality
       defects (also called heterotaxy):

       Situs solitus (typical organ placement)

       Situs inversus totalis (complete mirror-image
       organ placement)

       Situs ambiguus or ambiguous (any placement
       other than situs solitus or situs inversus)
Hirokawa et al. Cell 125:33-45, 2006
PCD: Clinical Consequences
   Ciliary Dysfunction and Laterality Defects




Fliegauf M, Benzing T, Omran H. Nat Rev Mol Cell Biol. 2007 Nov;8(11):880-93
PCD: Clinical Consequences
   Ciliary Dysfunction and Laterality Defects
   Without ciliary activity, organ placement (situs) is random
        Situs solitus (normal)                           Situs inversus totalis




                                                  L
                                                                     H
                            H


             L                                                   S
                                   S                                              L




       Monozygotic Twins with PCD
Noone et al., Am J Med Genet. 1999 Jan 15;82(2):155-60
PCD: Clinical Consequences
PCD: Clinical Consequences

                                      PCD Patients         Situs Status in PCD Patients
                                        n=337



   Situs Solitus                         Heterotaxy              Situs Inversus
   n=155 (46%)                          n=21 (6.3%)                  Totalis
                                                                 N=161 (47.7%)


                                 Complex Congenital               No cardiac or
    Vascular
                                   Heart Disease               vascular anomalies
   Anomalies
                                    n=8 (2.4%)                     n=9 (2.7%)
   n=4 (1.2%)

Kennedy, et al., Circulation. 2007 Jun 5;115(22):2814-21
PCD: Clinical Consequences
 PCD, Heterotaxy and CHD

     At least 13% (current data suggests 18-20) of patients with PCD had heterotaxy,
      which was usually associated with defective ODAs and more frequently
      mutations in DNAI1 and DNAH5
     Many PCD patients with heterotaxy had cardiac and/or vascular anomalies
      (12/21), and most (8/12) had complex CHD that required surgery
      The prevalence of CHD related to heterotaxy is 200-fold higher
       in PCD than in the general population (1:50 vs. 1:10,000)


                                         Conclusions
     1. Patients with PCD should have formal cardiac evaluation
     2. Genetic mutations that adversely affect respiratory and
        embryological nodal cilia cause heterotaxy and CHD, and patients
        with these conditions should be evaluated for cardiac defects


Kennedy, et al., Circulation. 2007 Jun 5;115(22):2814-21
PCD: Clinical Consequences
    PCD, Heterotaxy and CHD

         Pilot study at National Children’s Medical Center: Data From
         American Thoracic Society Symposium, May, 2009:
         Evaluated 26 children referred for CHD/heterotaxy surgical repairs
         Diagnostic workup included EM’s, nasal NO and compatible clinical
         history (chronic upper and lower respiratory infection)

          Results:
          50% of these children were determined to have probable PCD (7 with
          a confirmed phenotype and 6 with low nasal NO and ciliary
          dysmotility, but no observable beat defect).




N. Nakhleh; Data presented at ATS 2009
PCD: Clinical Consequences
PCD, Heterotaxy and CHD

  NHLBI Study on Dyskinesia, Heterotaxy and
  Congenital Heart Disease (NCT00608556)

  Currently recruiting
  325 Patients
  Ages 2 & above
  Patients with heterotaxy, situs inversus or CHD
  Patients with PCD
PCD: Clinical Consequences

PCD, Heterotaxy and CHD

“Patients with heterotaxy and congenital heart disease have high mortality and
morbidity (often related to respiratory complications). Recent studies have
revealed an association among heterotaxy, congenital heart disease, and
primary ciliary dyskinesia.”

•Retrospective chart review

•87 heterotaxy patients compared to 634 procedure matched non-heterotaxy
patients




 Swisher M, Jonas R, Tian X, Lee ES, Lo CW, Leatherbury L. Increased postoperative
 and respiratory complications in patients with congenital heart disease associated
 with heterotaxy. J Thorac Cardiovasc Surg. 2010 Sep 28.
PCD: Clinical Consequences

PCD, Heterotaxy and CHD
Findings: On all measures of post-surgical respiratory function, patients with
heterotaxy experienced significantly greater complications than procedure
matched non-heterotaxy patients. The authors suspect this is due to
undiagnosed ciliary dysfunction as a previously unrecognized surgical risk
factor in this group.

•Postoperative stay
•Mechanical ventilation
•Tracheostomies
•ECMO
•Death


 Swisher M, Jonas R, Tian X, Lee ES, Lo CW, Leatherbury L. Increased postoperative
 and respiratory complications in patients with congenital heart disease associated
 with heterotaxy. J Thorac Cardiovasc Surg. 2010 Sep 28.
PCD: Clues to Diagnosis
    Neonatal Respiratory Distress:
    A Very Important Diagnostic Indicator in PCD


      ~85-90% of PCD term neonates have respiratory
       distress thought to reflect the importance of ciliary
       activity when the neonatal lung switches from a
       liquid to a gas environment.

     Neonatal respiratory distress in PCD can lead to infant
     mortality


GDMCC Study, unpublished data
PCD: Clues to Diagnosis
    Neonatal Respiratory Distress:
    Opportunity for Early Diagnosis?

     2011 HHS new recommendation for pulse oximetry
     screening of neonates 24 to 48 after birth.

     <95% repeat x 3
     <90% immediate echo and clinical eval




GDMCC Study, unpublished data
PCD: Clues to Diagnosis
    Neonatal Respiratory Distress: Opportunity for Early
    Diagnosis?


    150 Responses
    84.3% “Yes”




PCD Foundation Data, 2012
PCD: Clues to Diagnosis
    Neonatal Respiratory Distress: Opportunity for Early
    Diagnosis?


    55% Required
    NICU Admission




PCD Foundation Data, 2012
PCD: Clues to Diagnosis
    Neonatal Respiratory Distress: Opportunity for Early
    Diagnosis?




                    Average SPO2 in PCD
                    Term Neonates Was 82%



PCD Foundation Data, 2012
PCD: Clues to Diagnosis
Clinical Consequences of PCD:
Early Years
Majority of PCD infants have a history of neonatal respiratory
distress.
Most report repeated infections of the ears, sinuses and lungs
in the first year of life
“Noisy chest” or “juicy kid syndrome”
Often misdiagnosed as asthma or allergies
“Right middle lobe syndrome” common early dx
Hearing loss/speech delays
PCD: Clues to Diagnosis
        Clinical Consequences of PCD: Early Years
        Increased incidence of pectus deformities
        (10% vs. .3%) and scoliois/kyphoscoliosis (5-
        10%) 1




Manion, M. , personal adorable baby picture collection .
1, Kennedy, et al. 2007: Circulation. 115:2814-2821
Clues to Dx: ENT Findings in PCD




Otitis Media              Polyps
PCD: Clues to Diagnosis
                                                         Exhaled
                                                         Nasal Nitric
                                                         Oxide in PCD




Noone et al., Am J Med Genet. 1999 Jan 15;82(2):155-60
PCD: Clues to Diagnosis

     Respiratory Status in PCD: Early Years

         Common Bugs:                                  Less Common Bugs:
         S. aureus                                     P. aeruginosa (smooth)
         H. influenza                                  P. aeruginosa (mucoid)--rare
         S. pneumoniae                                 Nontuberculous mycobacterium


     Bronchiectasis develops early and 60% of PCD children between
     the ages of 5 and 18 have HRCT evidence of bronchiectasis in
     1 to 6 lobes


Leigh, et al. Pediatr Pulmonol. 2008 May;43(5):514-6
PCD: Clues to Diagnosis




Leigh, et al. Presentation at NACFC 2011
PCD: Clues to Diagnosis
     Extent of Bronchiectasis by Organisms in Sputum




Leigh, et al.
PCD: Clues to Diagnosis
  Extensive Bronchiectasis with Normal Spirometry


•10 year boy with PCD
•FEV1 90.1% predicted
•Chest CT:
    Bronchiectasis in both
    lower lobes, lingula and
    right middle lobe
    Atelectasis in right middle
    lobe and lingula




Leigh, et al.
PCD: Clues to Diagnosis
Clinical Consequences of PCD:
Adults
Neurogenic hearing loss may occur
Fertility issues are a concern
Bug profile gets nastier: NTM infections (20%), mucoid
 Pseudomonas and other gram-negatives more common.
Bronchiectasis is universal
Pulmonary functions are variable & don’t always correlate well
 to actual extent of lung disease and respiratory flora present
Many patients on disability by mid-30s to early 40s
Some opt for lung transplant
PCD: Clues to Diagnosis
   Clinical Consequences of PCD:
   Adults                 Age   Gender   Situs

                          0     M        SI
                          0     F        SA
                          0     F        SA

Average age at death:     0     M        SA
                          24    F        SA
44 (34.8 if infants are
                          24    M        SS
included)                 32    F        SS
                          39    F        SI
                          42    M        SS
                          45    F        SI
                          47    M        SS
                          50    F        SI
                          55    F        SS
                          64    M        SA
                          66    F        SS
Bottom Line: PCD IS A
PROGRESSIVE DISORDER THAT
   REQUIRES AGGRESSIVE
         TREATMENT
PCD: Making the Diagnosis

                           Assessing Ciliary Ultrastructure




Courtesy GDMCC Slide Set
PCD: Clues to Diagnosis
                                                        Assessing
                                                        ciliary
                                                        ultrastructure




Leigh, M., Semin Respir Crit Care Med. 2003 Dec;24(6)
PCD: Clues to Diagnosis

                                                        Assessing ciliary
                                                        ultrastructure




Leigh, M., Semin Respir Crit Care Med. 2003 Dec;24(6)
What are Cilia?




Harwell Mouse Genetics: http://www.har.mrc.ac.uk/research/functional-genomics-
section/cilia-development-and-disease/projects
PCD: Clues to Diagnosis

                                                        Assessing
                                                        ciliary beat




Leigh, M., Semin Respir Crit Care Med. 2003 Dec;24(6)
PCD: Clues to Diagnosis
                                                        CF vs. PCD
                                                        Comparison




Leigh, M., Semin Respir Crit Care Med. 2003 Dec;24(6)
PCD: Clues to Diagnosis

       PCD vs. CF




Courtesy Michael Knowles, MD, UNC, Chapel Hill
PCD: Clues to Diagnosis
       Characteristic of Both PCD and CF:
       Both are genetic disorders of mucociliary clearance
       Both are characterized by bronchiectatic lung
        disease and opportunistic pathogen infection
       Lung disease in PCD generally progresses slower
        than CF lung disease (preserved cough clearance?)

       Characteristic of PCD, but not CF:
       •Neonatal respiratory distress                   •Chronic rhinorrhea
       •Situs anomalies                                 •Good nutritional status
       •Otitis media/hearing loss                       •Bronchiectasis
                                                         w/normal flora
Leigh, M., Semin Respir Crit Care Med. 2003 Dec;24(6)
PCD: Evidence-Based Treatments
Treatment for PCD

No therapeutic studies published in PCD

   •Small, geographically dispersed patient population

   •Seriously under and misdiagnosed (22-30%
    misdiagnosis) calling into question published “PCD
    data”

Most Centers Follow CF Treatment Guidelines:
   •Aggressive tx of infections
   •Aggressive airway clearance therapy
   •Routine PFTs, sputum culture surveillance
PCD DX & TX: The Future
GDMCC           (Genetic Disorders of Mucociliary
Clearance Consortium Study)
The PCDF is collaborating with UNC, Chapel Hill on a large
multi-center trial. This trial is sponsored by the Office of
Rare Diseases at the NIH. Aims of this first-ever effort to
collect data on a large cohort of PCD patients include:

•Identify patients and refine demographics
•Resolve diagnostic dilemmas
•Document natural history of the disease and identify
 possible targets for therapeutic intervention
http://rarediseasesnetwork.epi.usf.edu/
PCD DX & TX: The Future
The GDMC: Achievements So far:

Confirmed large cohort (400+ patients) to participate in clinical trials
Produced first diagnostic genetic test for PCD (picks up ~35% of all
cases of PCD and ~65% of PCD related to ODA defects)
Established connection between PCD, heterotaxy and CHD
Validated perceived problem with misdiagnosis
Identified previously unrecognized severity of lung disease in PCD
infants and young children
Identified areas of overlap between PCD and other ciliopathies
Discovered PCD outer dynein arm mutations (DNAH11) that has no
identifiable ultrastructural correlate and normal appearing beat

http://rarediseasesnetwork.epi.usf.edu/
PCD: Better Options for Dx
     Phenotype + nNO
               Four clinical features + nNO= 98% accuracy in one study


     Genetics
                 18 PCD genes confirmed and published
                 14 on commercially available tests
                  8 (at least) known to be in process of validation


     Potential for Neonatal Diagnosis with Newborn Screening for
     CCHD



Leigh, M., Semin Respir Crit Care Med. 2003 Dec;24(6)
PCD DX & TX: The Future
Eight PCD Research Network & “Centers of Excellence”
University of North Carolina, Chapel Hill, NC
(Michael Knowles, MD & Margaret Leigh, MD)
NIAID, NIH, Bethesda, MD (Ken Olivier, MD)
Washington University, St. Louis, MO (Thomas Ferkol, MD)
The Children’s Hospital, Denver, CO (Scott Sagel, MD)
Stanford University, Stanford, CA (Carlos Milla, MD)
University of Washington, Seattle, WA (Margaret Rosenfeld, MD)
The Hospital for Sick Children, Toronto (Sharon Dell, MD)
Indiana Children’s Hospital (Stephanie Davis, MD)



 http://rarediseasesnetwork.epi.usf.edu/
Path to Clinical Trials


      The Path to Clinical Trials (PTCT)

         Two mission critical building blocks:
         -Network of PCD Expert Centers
         -Patient Registry
Path to Clinical Trials

   Four PCD Clinical & Research Centers
   •Boston Children’s Hospital (Dr. Umakanth Khatwa)
   •University of Chicago (Dr. Pamela McShane)
   •Children’s Hospital of Philadelphia (Dr. Samuel Golfarb/Dr. Maureen Josephson
   •Rainbow Babies Hospital (Dr. Benjamin Gaston)
   Nine PCD Affiliate Center
   •University of South Carolina (Dr. Trey Brown)
   •University of Miami (Dr. Andrew Colin)
   •Children's Los Angeles (Dr. Sally Ward)
   •University of Tennessee (Dr. Dennis Stokes)
   •University of Tampa (Dr. Marisa Couluris)
   •University of Wisconsin (Dr. Diana Quintero)
   •Children’s Hospital of Eastern Ontario (Dr. Tom Kovesi)
   •McGill University Montreal, Quebec (Dr. Adam Shapiro)
   •Respiratory Associates Nova Scotia (Dr. Dimas Mateos-Corral



http://www.pcdfoundation.org/en/finding-a-cure/path-to-clinical-trials
Path to Clinical Trials

         Global Rare Diseases Registry




http://www.pcdfoundation.org/en/finding-a-cure/path-to-clinical-trials
PCD: Priorities for the Future



• Whole Exome/Genome Sequencing
 Pilot project in Seattle


• Small Molecule Compounds
 Success in laboratory setting
Making the Diagnosis of PCD:
        Why Does it Matter?


• Very few people have PCD, but we all have cilia

• The emerging field of ciliopathies demonstrates the
  importance of understanding ciliary genetics and
  disease function

• We are all only one conception away from discovering
  we carry a recessive trait like PCD.
PCD DX & TX: The Future


                                                           Classic PCD


                                              Atypical disease

                      Predisposition to disease




Courtesy Michael Knowles, MD, University of North Carolina, Chapel Hill
Thank you Sponsors, Electromed,
       PCD Research Group

Contact Information: Michele Manion
                     PCD Foundation
                     info@pcdfoundation.org
                     www.pcdfoundation.org
                     952-303-3155
The Faces of PCD

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Pcd presentation musc

  • 1. Thank You South Carolina Society for Respiratory Care and Electromed, Inc.
  • 2. Primary Ciliary Dyskinesia: Missing a Beat: Primary Ciliary Dyskinesia Impaired Airway Clearance and Respiratory Disease Michele Manion, Executive Director PCD Foundation www.pcdfoundation.org
  • 4. What is Primary Ciliary Dyskinesia (PCD)?  Umbrella term for genetic disorders affecting proteins responsible for the structure and/or function of motile (moving) cilia. Also called immotile cilia syndrome, Kartagener syndrome (PCD with situs inversus)  One of three recognized genetic disorders of mucociliary clearance (along with cystic fibrosis and pseudohypoaldosteronism) currently being studied in a North American research consortium
  • 5. PCD: The Historical Perspective (or What’s With all the Names?) •1904 AW Siewert makes first mention of a triad of bronchiectasis, dextrocardia and sinusitis/nasal polyps •1933 Manes Kartagener (Swiss pediatrician) published a report of 4 children with bronchiectasis, sinusitis and situs inversus. The syndrome is named “Kartagener Syndrome.” •1975 Afzelius (Swedish ultrastructuralist) and Pedersen (Denmark) independently hypothesize that “immotile cilia” may be the underlying cause and the syndrome is renamed “immotile cilia syndrome.” Both names (Kartagener & ICS persist). •1981 Based on new understanding of cilia pathogenesis, Sleigh suggests a name change to “primary ciliary dyskinesia”
  • 6. PCD Demographics PCD Prevalence: Range from 1:4,100* to 1:15,000** Estimated PCDF Database US: 20,773 – 74,880 426 SC 312 – 1,411 6 *Katsuhara K, Kawamoto S, Wakabayashi T, et al. Situs inversus totalis and Kartagener’s syndrome in a Japanese population. Chest 1972; 61: 56–61. **Afzelius BA, Stenram U. Prevalence and genetics of immotile-cilia syndrome and left- handedness. Int J Dev Biol 2006; 50: 571–573 .
  • 7. What are Cilia? Three Types of Cilia in Human Cells: Motile (respiratory epithelium, organs of reproduction, ependymal lining of ventricles of brain, etc.) Nodal (specialized organelle appearing once only on the embryonic node) Primary (non-motile chemosensory monocilia)
  • 8. What are Cilia? Cilia and flagella are microtubule-based organelles that extend from the surface of almost all cell types in the human body Ciliated Respiratory Epithelium Nodal (Primary) Monocilia Courtesy Johnny Carson, PhD Courtesy Fliegauf M, et al Nat Rev Mol Cell Biol. Nov 2007
  • 9. What are Cilia? Cross-section of typical “9+0” sensory cilium Ainesworth, C. NATURE Vol 448:9, August 2007
  • 10. What are Cilia? Cross-section of typical “9+2” motile cilium Ainesworth, C. NATURE, Vol 448:9 August 2007
  • 11. What are Cilia? 700-750 genes in the ciliary structure including the basal body
  • 12. What are Cilia? The Role of Non-Motile Cilia in Cells  Once thought to be vestigial leftovers from evolution  Importance only discovered in last decade  Provide crucial sensory functions to the cells  Now implicated in a number of human diseases, including PKD, spina bifida, bone & connective tissue disorders, retinal disorders and a host of pleiotropic diseases (Bardet-Biedl, Alstrom, Meckel’s, Joubert, Juene’s, etc.)  Focus of intense research, due to connection between primary cilia and obesity. Bush A, Hogg C. Primary ciliary dyskinesia: recent advances in epidemiology, diagnosis, management and relationship with the expanding spectrum of ciliopathy. Expert Rev Respir Med. 2012 Dec;6(6):663- 82. doi: 10.1586/ers.12.60. PubMed PMID: 23234452.
  • 13. What are Cilia? Cilia vs. Flagella Ciliated Respiratory Epithelium Flagellated Chlamydomonas Courtesy David Howard: http://www.uwlax.edu/biology/faculty/Howard/Research.htm
  • 14. What Are Cilia? Where are Motile Cilia Found?  Upper & lower respiratory tract  Eustachian tube of middle ear  Ependymal lining of the ventricles of the brain  Fallopian tubes of the female reproductive system  Sperm tails (technically flagella, but structurally similar to cilia)
  • 15. What are Cilia? Cilia in the Respiratory Tract •Ciliated cells account for approximately 80% of the cells lining surface of the conducting airways. •Ciliated cells in coordination with secretory cells represent a first line of defense for the respiratory tract against potential pathogens/ particulate matter in the inspired air. •Respiratory epithelial cells each have about 200-300 cilia that beat in a coordinated “metachronal” wave. •Effective ‘wave’ or beat facilitated by slippery glycoprotein coating on individual cilium Button B, et al A periciliary brush promotes the lung health by separating the mucus layer from airway epithelia. Science. 2012 Aug 24;337(6097):937-41. doi: 10.1126/science.1223012. PubMed PMID: 2
  • 16. How Do Motile Cilia Work? Microtubular pair Outer dynein arms Microtubular pair Cilia graphics courtesy Johnny Carson, PhD, UNC, Chapel Hill
  • 17. How Do Motile Cilia Work? ATP
  • 18. How Do Motile Cilia Work?
  • 19. How Do Motile Cilia Work? How Important is ATP? Cilia from bovine trachea in Add a little ATP and… Voilà Petri dish Cilia graphics courtesy Johnny Carson, PhD, UNC, Chapel Hill
  • 20. How Do Motile Cilia Work? Normal Ciliary Activity (Real Time) Courtesy of John C. Carson, PhD, University of North Carolina at Chapel Hill
  • 21. How Do Motile Cilia Work? Normal Ciliary Activity (Real Time) Courtesy John C. Carson, PhD, University of North Carolina at Chapel Hill
  • 22. How Do Motile Cilia Work? Normal Ciliary Activity Courtesy John C. Carson, PhD, University of North Carolina at Chapel Hill
  • 23. How Do Motile Cilia Work? Metachronal, synchronized ‘wave’ of ciliated epithelium Normal Ciliary Activity Courtesy of John C. Carson, PhD, University of North Carolina at Chapel Hill
  • 24. How Do Motile Cilia Work? Normal Ciliary Activity Courtesy Robert E. Wood, MD, PhD, University of Cincinnati
  • 25. What Happens in PCD? ATP
  • 27. What Happens in PCD? PCD Ciliary Activity (Real Time) Courtesy John C. Carson, PhD, University of North Carolina at Chapel Hill
  • 28. What Happens in PCD? PCD Ciliary Activity (Real Time) Courtesy John C. Carson, PhD, University of North Carolina at Chapel Hill
  • 29. What Happens in PCD? Ciliary Activity: Side by Side Comparison (Real Time) Courtesy John C. Carson, PhD, University of North Carolina at Chapel Hill
  • 30. PCD: Clinical Consequences What are the Clinical Consequences of PCD? Consequences begin before birth Specialized “nodal” cilia on the embryonic node are unique—9+0 cilia WITH dynein arms Nodal cilia “twirl” rather than beat
  • 31. PCD: Clinical Consequences ‘9 + 0’ Nodal Cilium Courtesy John C. Carson, PhD, University of North Carolina at Chapel Hill
  • 32. PCD: Clinical Consequences Nodal cilia and left-right asymmetry Hirokawa et al. Cell 125:33-45, 2006
  • 33. PCD: Clinical Consequences Nodal cilia and left-right asymmetry The absence of nodal ciliary motion results in random organ placement, including laterality defects (also called heterotaxy): Situs solitus (typical organ placement) Situs inversus totalis (complete mirror-image organ placement) Situs ambiguus or ambiguous (any placement other than situs solitus or situs inversus) Hirokawa et al. Cell 125:33-45, 2006
  • 34. PCD: Clinical Consequences Ciliary Dysfunction and Laterality Defects Fliegauf M, Benzing T, Omran H. Nat Rev Mol Cell Biol. 2007 Nov;8(11):880-93
  • 35. PCD: Clinical Consequences Ciliary Dysfunction and Laterality Defects Without ciliary activity, organ placement (situs) is random Situs solitus (normal) Situs inversus totalis L H H L S S L Monozygotic Twins with PCD Noone et al., Am J Med Genet. 1999 Jan 15;82(2):155-60
  • 37. PCD: Clinical Consequences PCD Patients Situs Status in PCD Patients n=337 Situs Solitus Heterotaxy Situs Inversus n=155 (46%) n=21 (6.3%) Totalis N=161 (47.7%) Complex Congenital No cardiac or Vascular Heart Disease vascular anomalies Anomalies n=8 (2.4%) n=9 (2.7%) n=4 (1.2%) Kennedy, et al., Circulation. 2007 Jun 5;115(22):2814-21
  • 38. PCD: Clinical Consequences PCD, Heterotaxy and CHD  At least 13% (current data suggests 18-20) of patients with PCD had heterotaxy, which was usually associated with defective ODAs and more frequently mutations in DNAI1 and DNAH5  Many PCD patients with heterotaxy had cardiac and/or vascular anomalies (12/21), and most (8/12) had complex CHD that required surgery  The prevalence of CHD related to heterotaxy is 200-fold higher in PCD than in the general population (1:50 vs. 1:10,000) Conclusions 1. Patients with PCD should have formal cardiac evaluation 2. Genetic mutations that adversely affect respiratory and embryological nodal cilia cause heterotaxy and CHD, and patients with these conditions should be evaluated for cardiac defects Kennedy, et al., Circulation. 2007 Jun 5;115(22):2814-21
  • 39. PCD: Clinical Consequences PCD, Heterotaxy and CHD Pilot study at National Children’s Medical Center: Data From American Thoracic Society Symposium, May, 2009: Evaluated 26 children referred for CHD/heterotaxy surgical repairs Diagnostic workup included EM’s, nasal NO and compatible clinical history (chronic upper and lower respiratory infection) Results: 50% of these children were determined to have probable PCD (7 with a confirmed phenotype and 6 with low nasal NO and ciliary dysmotility, but no observable beat defect). N. Nakhleh; Data presented at ATS 2009
  • 40. PCD: Clinical Consequences PCD, Heterotaxy and CHD NHLBI Study on Dyskinesia, Heterotaxy and Congenital Heart Disease (NCT00608556) Currently recruiting 325 Patients Ages 2 & above Patients with heterotaxy, situs inversus or CHD Patients with PCD
  • 41. PCD: Clinical Consequences PCD, Heterotaxy and CHD “Patients with heterotaxy and congenital heart disease have high mortality and morbidity (often related to respiratory complications). Recent studies have revealed an association among heterotaxy, congenital heart disease, and primary ciliary dyskinesia.” •Retrospective chart review •87 heterotaxy patients compared to 634 procedure matched non-heterotaxy patients Swisher M, Jonas R, Tian X, Lee ES, Lo CW, Leatherbury L. Increased postoperative and respiratory complications in patients with congenital heart disease associated with heterotaxy. J Thorac Cardiovasc Surg. 2010 Sep 28.
  • 42. PCD: Clinical Consequences PCD, Heterotaxy and CHD Findings: On all measures of post-surgical respiratory function, patients with heterotaxy experienced significantly greater complications than procedure matched non-heterotaxy patients. The authors suspect this is due to undiagnosed ciliary dysfunction as a previously unrecognized surgical risk factor in this group. •Postoperative stay •Mechanical ventilation •Tracheostomies •ECMO •Death Swisher M, Jonas R, Tian X, Lee ES, Lo CW, Leatherbury L. Increased postoperative and respiratory complications in patients with congenital heart disease associated with heterotaxy. J Thorac Cardiovasc Surg. 2010 Sep 28.
  • 43. PCD: Clues to Diagnosis Neonatal Respiratory Distress: A Very Important Diagnostic Indicator in PCD ~85-90% of PCD term neonates have respiratory distress thought to reflect the importance of ciliary activity when the neonatal lung switches from a liquid to a gas environment. Neonatal respiratory distress in PCD can lead to infant mortality GDMCC Study, unpublished data
  • 44. PCD: Clues to Diagnosis Neonatal Respiratory Distress: Opportunity for Early Diagnosis? 2011 HHS new recommendation for pulse oximetry screening of neonates 24 to 48 after birth. <95% repeat x 3 <90% immediate echo and clinical eval GDMCC Study, unpublished data
  • 45. PCD: Clues to Diagnosis Neonatal Respiratory Distress: Opportunity for Early Diagnosis? 150 Responses 84.3% “Yes” PCD Foundation Data, 2012
  • 46. PCD: Clues to Diagnosis Neonatal Respiratory Distress: Opportunity for Early Diagnosis? 55% Required NICU Admission PCD Foundation Data, 2012
  • 47. PCD: Clues to Diagnosis Neonatal Respiratory Distress: Opportunity for Early Diagnosis? Average SPO2 in PCD Term Neonates Was 82% PCD Foundation Data, 2012
  • 48. PCD: Clues to Diagnosis Clinical Consequences of PCD: Early Years Majority of PCD infants have a history of neonatal respiratory distress. Most report repeated infections of the ears, sinuses and lungs in the first year of life “Noisy chest” or “juicy kid syndrome” Often misdiagnosed as asthma or allergies “Right middle lobe syndrome” common early dx Hearing loss/speech delays
  • 49. PCD: Clues to Diagnosis Clinical Consequences of PCD: Early Years Increased incidence of pectus deformities (10% vs. .3%) and scoliois/kyphoscoliosis (5- 10%) 1 Manion, M. , personal adorable baby picture collection . 1, Kennedy, et al. 2007: Circulation. 115:2814-2821
  • 50. Clues to Dx: ENT Findings in PCD Otitis Media Polyps
  • 51. PCD: Clues to Diagnosis Exhaled Nasal Nitric Oxide in PCD Noone et al., Am J Med Genet. 1999 Jan 15;82(2):155-60
  • 52. PCD: Clues to Diagnosis Respiratory Status in PCD: Early Years Common Bugs: Less Common Bugs: S. aureus P. aeruginosa (smooth) H. influenza P. aeruginosa (mucoid)--rare S. pneumoniae Nontuberculous mycobacterium Bronchiectasis develops early and 60% of PCD children between the ages of 5 and 18 have HRCT evidence of bronchiectasis in 1 to 6 lobes Leigh, et al. Pediatr Pulmonol. 2008 May;43(5):514-6
  • 53. PCD: Clues to Diagnosis Leigh, et al. Presentation at NACFC 2011
  • 54. PCD: Clues to Diagnosis Extent of Bronchiectasis by Organisms in Sputum Leigh, et al.
  • 55. PCD: Clues to Diagnosis Extensive Bronchiectasis with Normal Spirometry •10 year boy with PCD •FEV1 90.1% predicted •Chest CT: Bronchiectasis in both lower lobes, lingula and right middle lobe Atelectasis in right middle lobe and lingula Leigh, et al.
  • 56. PCD: Clues to Diagnosis Clinical Consequences of PCD: Adults Neurogenic hearing loss may occur Fertility issues are a concern Bug profile gets nastier: NTM infections (20%), mucoid Pseudomonas and other gram-negatives more common. Bronchiectasis is universal Pulmonary functions are variable & don’t always correlate well to actual extent of lung disease and respiratory flora present Many patients on disability by mid-30s to early 40s Some opt for lung transplant
  • 57. PCD: Clues to Diagnosis Clinical Consequences of PCD: Adults Age Gender Situs 0 M SI 0 F SA 0 F SA Average age at death: 0 M SA 24 F SA 44 (34.8 if infants are 24 M SS included) 32 F SS 39 F SI 42 M SS 45 F SI 47 M SS 50 F SI 55 F SS 64 M SA 66 F SS
  • 58. Bottom Line: PCD IS A PROGRESSIVE DISORDER THAT REQUIRES AGGRESSIVE TREATMENT
  • 59. PCD: Making the Diagnosis Assessing Ciliary Ultrastructure Courtesy GDMCC Slide Set
  • 60. PCD: Clues to Diagnosis Assessing ciliary ultrastructure Leigh, M., Semin Respir Crit Care Med. 2003 Dec;24(6)
  • 61. PCD: Clues to Diagnosis Assessing ciliary ultrastructure Leigh, M., Semin Respir Crit Care Med. 2003 Dec;24(6)
  • 62. What are Cilia? Harwell Mouse Genetics: http://www.har.mrc.ac.uk/research/functional-genomics- section/cilia-development-and-disease/projects
  • 63. PCD: Clues to Diagnosis Assessing ciliary beat Leigh, M., Semin Respir Crit Care Med. 2003 Dec;24(6)
  • 64. PCD: Clues to Diagnosis CF vs. PCD Comparison Leigh, M., Semin Respir Crit Care Med. 2003 Dec;24(6)
  • 65. PCD: Clues to Diagnosis PCD vs. CF Courtesy Michael Knowles, MD, UNC, Chapel Hill
  • 66. PCD: Clues to Diagnosis Characteristic of Both PCD and CF: Both are genetic disorders of mucociliary clearance Both are characterized by bronchiectatic lung disease and opportunistic pathogen infection Lung disease in PCD generally progresses slower than CF lung disease (preserved cough clearance?) Characteristic of PCD, but not CF: •Neonatal respiratory distress •Chronic rhinorrhea •Situs anomalies •Good nutritional status •Otitis media/hearing loss •Bronchiectasis w/normal flora Leigh, M., Semin Respir Crit Care Med. 2003 Dec;24(6)
  • 68. Treatment for PCD No therapeutic studies published in PCD •Small, geographically dispersed patient population •Seriously under and misdiagnosed (22-30% misdiagnosis) calling into question published “PCD data” Most Centers Follow CF Treatment Guidelines: •Aggressive tx of infections •Aggressive airway clearance therapy •Routine PFTs, sputum culture surveillance
  • 69. PCD DX & TX: The Future GDMCC (Genetic Disorders of Mucociliary Clearance Consortium Study) The PCDF is collaborating with UNC, Chapel Hill on a large multi-center trial. This trial is sponsored by the Office of Rare Diseases at the NIH. Aims of this first-ever effort to collect data on a large cohort of PCD patients include: •Identify patients and refine demographics •Resolve diagnostic dilemmas •Document natural history of the disease and identify possible targets for therapeutic intervention http://rarediseasesnetwork.epi.usf.edu/
  • 70. PCD DX & TX: The Future The GDMC: Achievements So far: Confirmed large cohort (400+ patients) to participate in clinical trials Produced first diagnostic genetic test for PCD (picks up ~35% of all cases of PCD and ~65% of PCD related to ODA defects) Established connection between PCD, heterotaxy and CHD Validated perceived problem with misdiagnosis Identified previously unrecognized severity of lung disease in PCD infants and young children Identified areas of overlap between PCD and other ciliopathies Discovered PCD outer dynein arm mutations (DNAH11) that has no identifiable ultrastructural correlate and normal appearing beat http://rarediseasesnetwork.epi.usf.edu/
  • 71. PCD: Better Options for Dx Phenotype + nNO Four clinical features + nNO= 98% accuracy in one study Genetics 18 PCD genes confirmed and published 14 on commercially available tests 8 (at least) known to be in process of validation Potential for Neonatal Diagnosis with Newborn Screening for CCHD Leigh, M., Semin Respir Crit Care Med. 2003 Dec;24(6)
  • 72. PCD DX & TX: The Future Eight PCD Research Network & “Centers of Excellence” University of North Carolina, Chapel Hill, NC (Michael Knowles, MD & Margaret Leigh, MD) NIAID, NIH, Bethesda, MD (Ken Olivier, MD) Washington University, St. Louis, MO (Thomas Ferkol, MD) The Children’s Hospital, Denver, CO (Scott Sagel, MD) Stanford University, Stanford, CA (Carlos Milla, MD) University of Washington, Seattle, WA (Margaret Rosenfeld, MD) The Hospital for Sick Children, Toronto (Sharon Dell, MD) Indiana Children’s Hospital (Stephanie Davis, MD) http://rarediseasesnetwork.epi.usf.edu/
  • 73. Path to Clinical Trials The Path to Clinical Trials (PTCT) Two mission critical building blocks: -Network of PCD Expert Centers -Patient Registry
  • 74. Path to Clinical Trials Four PCD Clinical & Research Centers •Boston Children’s Hospital (Dr. Umakanth Khatwa) •University of Chicago (Dr. Pamela McShane) •Children’s Hospital of Philadelphia (Dr. Samuel Golfarb/Dr. Maureen Josephson •Rainbow Babies Hospital (Dr. Benjamin Gaston) Nine PCD Affiliate Center •University of South Carolina (Dr. Trey Brown) •University of Miami (Dr. Andrew Colin) •Children's Los Angeles (Dr. Sally Ward) •University of Tennessee (Dr. Dennis Stokes) •University of Tampa (Dr. Marisa Couluris) •University of Wisconsin (Dr. Diana Quintero) •Children’s Hospital of Eastern Ontario (Dr. Tom Kovesi) •McGill University Montreal, Quebec (Dr. Adam Shapiro) •Respiratory Associates Nova Scotia (Dr. Dimas Mateos-Corral http://www.pcdfoundation.org/en/finding-a-cure/path-to-clinical-trials
  • 75. Path to Clinical Trials Global Rare Diseases Registry http://www.pcdfoundation.org/en/finding-a-cure/path-to-clinical-trials
  • 76. PCD: Priorities for the Future • Whole Exome/Genome Sequencing Pilot project in Seattle • Small Molecule Compounds Success in laboratory setting
  • 77. Making the Diagnosis of PCD: Why Does it Matter? • Very few people have PCD, but we all have cilia • The emerging field of ciliopathies demonstrates the importance of understanding ciliary genetics and disease function • We are all only one conception away from discovering we carry a recessive trait like PCD.
  • 78. PCD DX & TX: The Future Classic PCD Atypical disease Predisposition to disease Courtesy Michael Knowles, MD, University of North Carolina, Chapel Hill
  • 79. Thank you Sponsors, Electromed, PCD Research Group Contact Information: Michele Manion PCD Foundation info@pcdfoundation.org www.pcdfoundation.org 952-303-3155

Notas do Editor

  1. Kartagener ultimately reviewed hundreds of cases—all pediatric—so he never made the connection with infertility, which is what triggered Afzelius’s eventual “light bulb” that cilia might be the common factor explaining both Siewert and Kartagener’s findings. There was a flurry of interest and many publications between 1975 and 1980. Further investigation demonstrated that the cilia were not truly immotile, but had dsykinetic motility. Iren 1981, Sleigh recommended renaming the syndrome “primary ciliary dyskinesia” to reflect both the genetic nature of the disorder and more accurately reflect the reality of the motility disorder.
  2. Estimates vary wildly. ‘Classic’ PCD is likely to affect 1:12-15,000. One contributing factor to the difficulty in diagnosing people with PCD is nomenclature. There is no known gender or race bias in PCD although small communities where inter-marriage is practiced tend to have a higher rate (Amish, East Indian, Native American, Ashkenazic Jews).
  3. There are three main types of cilia, distinguished by their ultrastructure. ed on motility and the presence or absence of a central pair of microtubules. Sensory cilia (also called primary or monocilia) are almost always 9+0 meaning they have no central pair of microtubules and no dynein arms.
  4. Basically divided by cilia that move (motile) and cilia that do not (primary or sensory).
  5. 3 dimensional view of 9 + 2 cilium, showing the plasma membrane that anchors the cilium to the epithelial layer and the basal body where the cilium is produced.
  6. Cross-sectional schematic of a typical 9+2 “motile” cilium. The 9 refers to the 9 pairs of microtubule doublets inside the cell membrane. The 2 refers to the presence of a central pair of microtubules. Other important structures include the dynein arms, which are the functional units that make the cilium move.
  7. 3 dimensional view of 9 + 2 cilium, showing the plasma membrane that anchors the cilium to the epithelial layer and the basal body where the cilium is produced. In all there are more than 700 genes that code for proteins that make up the ciliary structure, including more than 200 in the axonemal shaft structures.
  8. For our purposes, we will focus on “motile’ cilia and flagella. Structurally, they are nearly identical with flagella being slightly longer. Cilia, however, like to clump together and work collaboratively. They are anchored to the cell surface and their motility affects the environment around them. Flagella are usually found as singles, but may be doubles (bi-flagellates) or appear in groups. However, they are not anchored, tend to work independently and function by moving an organism through an environment.
  9. Formerly considered the “janitors” of the respiratory system, motile cilia are now known to also have sensory functions.
  10. Slides courtesy of Johnny Carson, PhD at UNC. We talked about dynein arms in an earlier slide. Dynein arms, in concert with a fuel source, in this case the nucleotide adenosine phosphate or ATP, are molecular motors.
  11. Slides courtesy of Johnny Carson, PhD at UNC. We talked about dynein arms in an earlier slide. Dynein arms, in concert with a fuel source, in this case the nucleotide adenosine phosphate or ATP, are molecular motors.
  12. Ciliary activity is very important beginning in the embryonic period
  13. An interesting “hybrid” cilium found on the cells of the embyronic node combine 9+0 “sensory” activity with unusual motility. Rather than beating, these cilia “twirl” creating a leftward vortex in the fluid surrounding the node. This leftward nodal flow triggers a cascade of asymmetrical signaling that eventually results in the left-oriented “D” looping of the heart tube which sets the stage for eventual visceral asymmetry in normal development. In the absence of this trigger, organ placement and even development can be random.
  14. An interesting “hybrid” cilium found on the cells of the embyronic node combine 9+0 “sensory” activity with unusual motility. Rather than beating, these cilia “twirl” creating a leftward vortex in the fluid surrounding the node. This leftward nodal flow triggers a cascade of asymmetrical signaling that eventually results in the left-oriented “D” looping of the heart tube which sets the stage for eventual visceral asymmetry in normal development. In the absence of this trigger, organ placement and even development can be random.
  15. People with PCD have an equal chance of having situs solitus or situs inversus totalis
  16. Somewhere between the ages of 4 and 5, it is possible to measure nasal NO as a screening tool for PCD
  17. Lobectomy still popular in PCD. Very few children actually diagnosed before age 5. Some not until adulthood.
  18. Lobectomy still popular in PCD. Very few children actually diagnosed before age 5. Some not until adulthood.
  19. Lobectomy still popular in PCD. Very few children actually diagnosed before age 5. Some not until adulthood.
  20. Lobectomy still popular in PCD. Very few children actually diagnosed before age 5. Some not until adulthood.
  21. “ Classic” PCD
  22. “ Classic” PCD
  23. Because of similarities in the respiratory consequences of the two disorders, most PCD patients are followed in CF Clinics and the PCDF encourages that.
  24. Because of similarities in the respiratory consequences of the two disorders, most PCD patients are followed in CF Clinics and the PCDF encourages that.
  25. Kinesin molecular motors anterograde (on the way up); cytoplasmic dynein on the way down. IFT particles carry axomenal subunits to tip of the axoneme and also deposit protein cargoes along the microtubule.
  26. Because of similarities in the respiratory consequences of the two disorders, most PCD patients are followed in CF Clinics and the PCDF encourages that.
  27. Seven known genes—been looking since late 80’s PTC 124
  28. Links to connective tissue diseases like Marfan syndrome. Possible PCD carrier/COPD connection.