pcd presentation musc

Thank You

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 DirectorPCD Foundation

www.pcdfoundation.org

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 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.

PCD Demographics

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)

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

What are Cilia?

Ciliated Respiratory Epithelium Courtesy Johnny Carson, PhD

Nodal (Primary) Monocilia 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

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.

The Role of Non-Motile Cilia in Cells

What are Cilia?

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.

Cilia vs. FlagellaCilia vs. Flagella

What are Cilia?

Ciliated Respiratory Epithelium

Flagellated Chlamydomonas Courtesy David Howard: http://www.uwlax.edu/biology/faculty/Howard/Research.htm

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)

Where are Motile Cilia Found?

What Are Cilia?

What are Cilia?

•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

Cilia in the Respiratory Tract

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

Microtubular pair

Outer dynein arms

Cilia graphics courtesy Johnny Carson, PhD, UNC, Chapel Hill

ATP



Cilia graphics courtesy Johnny Carson, PhD, UNC, Chapel Hill

How Important is ATP?

Cilia from bovine trachea in Petri dish

Add a little ATP and… Voilà


Courtesy of John C. Carson, PhD, University of North Carolina at Chapel Hill

Normal Ciliary Activity(Real Time)

Normal Ciliary Activity

(Real Time)

Courtesy John C. Carson, PhD, University of North Carolina at Chapel Hill



Metachronal, synchronized ‘wave’ of ciliated epithelium

Courtesy of John C. Carson, PhD, University of North Carolina at Chapel Hill



Courtesy Robert E. Wood, MD, PhD, University of Cincinnati


What Happens in PCD?

ATP

PCD Ciliary Activity

(Real Time)



Ciliary Activity: Side by Side Comparison

(Real Time)



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



Hirokawa et al. Cell 125:33-45, 2006

Nodal cilia and left-right asymmetry


Hirokawa et al. Cell 125:33-45, 2006

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)


Fliegauf M, Benzing T, Omran H. Nat Rev Mol Cell Biol. 2007 Nov;8(11):880-93

Ciliary Dysfunction and Laterality Defects


Ciliary Dysfunction and Laterality DefectsWithout ciliary activity, organ placement (situs) is random

S

L

L

H H

LS

Situs solitus (normal) Situs inversus totalis

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


No cardiac orvascular anomalies

n=9 (2.7%)

Situs Status in PCD PatientsPCD Patientsn=337

Situs Solitusn=155 (46%)

Heterotaxyn=21 (6.3%)

Situs InversusTotalis

N=161 (47.7%)

VascularAnomaliesn=4 (1.2%)

Complex CongenitalHeart Disease

n=8 (2.4%)

Kennedy, et al., Circulation. 2007 Jun 5;115(22):2814-21


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



N. Nakhleh; Data presented at ATS 2009

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).



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


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.


“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.


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


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 Foundation Data, 2012


150 Responses84.3% “Yes”




55% Required NICU Admission




Average SPO2 in PCD Term Neonates Was 82%

Clinical Consequences of PCD: Early YearsMajority 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


Clinical Consequences of PCD: Early Years

Manion, M. , personal adorable baby picture collection.1, Kennedy, et al. 2007: Circulation. 115:2814-2821


Increased incidence of pectus deformities (10% vs. .3%) and scoliois/kyphoscoliosis (5-10%) 1

Clues to Dx: ENT Findings in PCD

Otitis Media Polyps

Exhaled Nasal Nitric Oxide in PCD

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


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


Leigh, et al. Presentation at NACFC 2011


Leigh, et al.


Extent of Bronchiectasis by Organisms in Sputum

Leigh, et al.


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

Clinical Consequences of PCD: AdultsNeurogenic 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


Clinical Consequences of PCD: Adults


Average age at death: 44 (34.8 if infants are included)

Age Gender Situs

0 M SI

0 F SA

0 F SA

0 M SA

24 F SA

24 M SS

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

Assessing Ciliary Ultrastructure

Courtesy GDMCC Slide Set

PCD: Making the Diagnosis


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

Assessing ciliary ultrastructure

What are Cilia?

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



Assessing ciliary beat



CF vs. PCD Comparison

PCD vs. CF

Courtesy Michael Knowles, MD, UNC, Chapel Hill



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


PCD: Evidence-Based TreatmentsPCD: 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

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


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


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)


Eight PCD Research Network & “Centers of Excellence”


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


Global Rare Diseases Registry

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

PCD: Priorities for the FuturePCD: Priorities for the Future

• Whole Exome/Genome Sequencing Pilot project in Seattle

• Small Molecule CompoundsSuccess in laboratory setting

Making the Diagnosis of PCD: Making the Diagnosis of PCD: Why Does it Matter?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.

Atypical disease

Predisposition to disease

Classic PCD

Courtesy Michael Knowles, MD, University of North Carolina, Chapel Hill


Thank you Sponsors, Electromed, PCD Research Group

Contact Information: Michele Manion PCD Foundation [email protected] www.pcdfoundation.org 952-303-3155

The Faces of PCD

pcd presentation musc

Documents

types of cilia

motile cilia work

immotile cilia syndrome

role of nonmotile cilia

motile respiratory epithelium

motile ciliumainesworth

respiratory epithelial

kartagener syndrome