Primary Ciliary Dyskinesia
Introduction: Primary Ciliary Dyskinesia (PCD) is a recessive genetic disorder that affects the differentiation and motility functions of cilia in various organs and cells of the human body. The organ system that is primarily affected in this disease is the respiratory system where cilia beat continuously to remove mucus that traps inhaled pollutants and pathogens (Fig. 1).
Prevalence: Current estimate of the occurrence of PCD in the general population
is about 1: 10,000 to 1: 20,000, whereas in communities that practice
consanguinity the frequency can be much higher (1,2).
Figure 1. Diagram of motile cilia mediated mucus clearance in the airway of a healthy individual. Cilia are the hair-like projections on the multiciliated cells. The cilia beat continuously like a brush to move layers of mucus towards the throat and nose. In PCD patients, these cilia are dysfunctional due to genetic defects in cilia assembly and/or motility. Consequently, mucus clearance is affected, leading to recurrent respiratory infections and damage to the airway.
Cause: PCD arises
from mutations in genes that encode proteins required for the formation and
function of motile cilia (1). Motile cilia are hair like organelles that
project from the surface of specialized epithelial cells (3). Some cells
differentiate a single motile cilium, while others have hundreds of them.
Motile cilia are able to beat rhythmically, which is why they play important roles
in fluid clearance over epithelia or in cellular locomotion. In the human body,
motile cilia are present on cells lining the respiratory tract (where, as
discussed above, they function to clear mucus that traps inhaled pathogens and
pollutants), within the brain ventricles (for circulation of cerebrospinal
fluid [CSF]), within the oviducts of women and epididymis of men (where they
are required to transport the ova and sperm, respectively) and on the sperm
cells themselves (as long flagella, required for sperm propulsion). In
addition, during development, the human embryo is thought to have motile cilia
in a pit-like cavity called the ventral node. Nodal cilia movement creates an
asymmetric fluid flow that is required for initiating asymmetric development of
internal organs (like the heart positioned towards the left and the stomach
situated on the right) (4). In the absence of this directional flow due to
defects in nodal cilia motility, proper positioning of the internal organs can
be randomised. Sperm cells and node cells have single motile cilia (single
flagellum in case of sperm cells), while cells within the respiratory tract,
oviducts, epididymis and brain ventricles have so called multiciliated cells
with hundreds of motile cilia.
Reduced Generation of Multiple Motile Cilia: A more recently identified variant of PCD is reduced generation of multiple motile cilia (RGMC). In this disease, respiratory symptoms, hydrocephalus and infertility are the major issues because what is affected is the ability of multiciliated cells to form or for the multiciliated cells to generate sufficient numbers of motile cilia. Organ positioning within the body is not affected because the node cells have single motile cilia which are not affected by the disease. Only two genes have been associated with RGMC – one required for the muticiliated cells to form and the other for these cells to make sufficient numbers of motile cilia. The diagnosis and treatment options for RGMC largely remain the same as for conventional PCD.
Symptoms: PCD is
genetically heterogeneous and mutations in more than 30 ciliary genes have been
found be causative of this disorder (1). Patients with PCD have clinical
symptoms of disease manifest in all the tissues and cells that require motile
cilia for their proper functioning and development. Thus, they typically suffer
from chronic upper and lower respiratory tract infections due to ineffective
mucus clearance leading to bronchiectasis (and permanent lung damage if
untreated), chronic middle ear infections, infertility and sometimes
hydrocephalus or swelling of the brain ventricles due to improper csf
circulation. In addition, about half of PCD patients have developmental
anomalies of internal organs called situs
inversus (when the internal organs like heart, stomach, spleen etc are all
located on the opposite sides; for example, the heart tilted to the right and
the stomach on the left) or heterotaxy (when the internal organs are not
transposed in a mirror image inversion, but rather scrambled up). Heterotaxy
with cardiac abnormalities requires correction via surgical intervention.
Respiratory symptoms in PCD patients often present themselves at birth with
respiratory distress. Occurrence of respiratory symptoms along with organ
positioning defects is a strong indication of PCD. The presentation of
respiratory pathology like sinusitis and bronchiectasis along with situs inversus is often called
Kartagener syndrome.
Diagnosis: Clinical
diagnosis of PCD is challenging (5). Although some symptoms are often apparent
at birth such as respiratory distress, definitive diagnosis usually occurs much
later in childhood or adulthood, by when the patient has developed significant
lung damage. The disease is often confused with cystic fibrosis, asthma and
other respiratory disorders. Historically, measurement of nasal nitric oxide
(NO) levels and evaluation of ciliary ultrastructure from ciliated cells
obtained by brushing of the nasal cavities (or brushing of the bronchi) by
electron microscopy have been used to diagnose PCD. While nasal NO levels are
typically low in PCD patients, measurement of NO levels is not a reliable
diagnostic test, especially in children. Transmission electron microscopy (TEM)
to examine defects in ciliary ultrastructure is a much more reliable method,
but is a demanding technique that is time-consuming and expensive to be used as
a routine diagnostic procedure. Moreover, not all ciliary defects are apparent
on TEM analysis. Yet, the importance of early diagnosis of the disease cannot
be emphasized enough as this allows for much better prognosis and maintenance
of healthy lung conditions in the patients into later life. Without early
diagnosis, atelectasis and bronchiectasis usually sets in by teenage and early
adult life, resulting in permanent lung damage that can only be rectified with
lung transplantation. Most clinics in Europe and America now use high-speed
videomicroscopy (HVM) of the nasal ciliated cells as an additional diagnostic
test for PCD. HVM is a simple and cost-effective technique that allows for
direct visualization of ciliary motility using a compound microscope and a
high-speed video camera. This technique not only helps to distinguish motile
from immotile cilia, but also differences in ciliary beat frequency as well as
ciliary beat pattern can be detected. Defects in both of these parameters can
also result in PCD. Once ciliary motility defects are identified, further
confirmatory tests are performed using immunofluorescence labelling with antibodies
to a variety of ciliary proteins, and then transmission electron microscopy TEM.
In addition, X-ray or ultrasound imaging of internal organs like the heart is
highly recommended, since as discussed above, the presence of respiratory
symptoms along with situs
abnormalities significantly raises the suspicion of PCD. Finally, whole exome
or whole genome sequencing as well as targeted sequencing of candidate gene/s leads
to the identification of the underlying mutation.
Treatment: Currently, there
is no cure for PCD. However, early diagnosis clearly helps to maintain a good
quality of life among affected individuals. Otherwise, the respiratory system
can get so badly damaged that lung transplantation will remain the only option.
The key is to maintain the health of the airways by aggressive antibiotic
treatments on infection, physiotherapy to regularly clear mucus, and timely
administration of appropriate health vaccines (6). Cardiac anomalies must be
corrected by appropriate surgical intervention. Infertility issues can be
effectively dealt with using in vitro
fertilization. It is expected that the various forms of genome editing
technologies that are rapidly evolving at the moment, may become useful for gene
therapy strategies in the future.
PCD in the regional context: Much of what we know about the genetics and pathology of PCD has
come from studies with patients from North America, Europe and West Eurasian
countries (and migrant Asian populations residing in these regions). More recently,
PCD reports are appearing from China and Japan. From India, there have been a
number of case reports of Kartagener syndrome patients. There is no clinic
currently available in the country equipped to make a formal diagnosis of PCD.
PCD historical information: The role of abnormal cilia in the pathogenesis of PCD was first
identified in the 1970s through TEM analysis of respiratory cilia obtained from
Kartagener syndrome patients (7,8). Mutations in DNAH5, the first gene responsible for PCD and encoding a major
dynein protein of cilia, were reported in 2002 (9). Since 2006, with
advancements in genomic technologies, there has been a rapid identification of mutations
is a large number of additional genes responsible for PCD.
References:
1. Primary
Ciliary Dyskinesia. Knowles MR, Zariwala M, Leigh M. Clin Chest Med. 2016; 37:449-61.
2. High
prevalence of primary ciliary dyskinesia in a British Asian population.
O'Callaghan C, Chetcuti P, Moya E. Arch Dis Child. 2010; 95:51-2.
3. SnapShot:
Motile Cilia. Zhou F, Roy S. Cell 2015; 162:224-224.
4. Left-right
asymmetry: cilia stir up new surprises in the node. Babu D, Roy S. Open Biol. 2013; 3:130052.
5. Diagnosis
of primary ciliary dyskinesia: potential options for resource-limited
countries. Rumman N, Jackson C, Collins S, Goggin P, Coles J, Lucas JS. Eur Respir Rev. 2017; 26(143).
6. Treatment
recommendations in Primary Ciliary Dyskinesia. Polineni D, Davis SD, Dell SD. Paediatr Respir Rev. 2016; 18:39-45.
7. A human
syndrome caused by immotile cilia. Afzelius BA. Science 1976; 193:317-9.
8. Absence of
axonemal arms in nasal mucosa cilia in Kartagener's syndrome. Pedersen H,
Mygind N. Nature 1976; 262:494-5.
9. Mutations
in DNAH5 cause primary ciliary
dyskinesia and randomization of left-right asymmetry. Olbrich H, Häffner K, Kispert
A, Völkel A, Volz A, Sasmaz G, Reinhardt R, Hennig S, Lehrach H, Konietzko N,
Zariwala M, Noone PG, Knowles M, Mitchison HM, Meeks M, Chung EM, Hildebrandt
F, Sudbrak R, Omran H. Nat Genet. 2002; 30:143-4.
Resources for patients and clinicians:
Sudipto Roy PhD
Senior Principal Investigator
Institute of Molecular and Cell Biology
Agency for Science, Technology and Research (A*STAR)
Proteos, 61 Biopolis Drive
Singapore, 138673
Reviewer:
Mohammad Khan MD, PhD
Children's Hospital of Philadelphia
University of Pennsylvania, Philadelphia, PA, USA
February 2017
Primary Ciliary Dyskinesia