Primary ciliary dyskinesia
Template:Infobox medical condition (new) Primary ciliary dyskinesia (PCD) is a rare, autosomal recessive genetic ciliopathy, that causes defects in the action of cilia lining the upper and lower respiratory tract, sinuses, Eustachian tube, middle ear, fallopian tube, and flagella of sperm cells. The alternative name of "immotile ciliary syndrome" is no longer favored as the cilia do have movement, but are merely inefficient or unsynchronized. When accompanied by situs inversus the condition is known as Kartagener syndrome.<ref name="uniprot"/>
Respiratory epithelial motile cilia, which resemble microscopic "hairs" (although structurally and biologically unrelated to hair), are complex organelles that beat synchronously in the respiratory tract, moving mucus toward the throat. Normally, cilia beat 7 to 22 times per second, and any impairment can result in poor mucociliary clearance, with subsequent upper and lower respiratory infection. Cilia also are involved in other biological processes (such as nitric oxide production), currently the subject of dozens of research efforts.<ref name="PCDresearch.org">Template:Cite web</ref>
Signs and symptoms
Around 80% of people with primary ciliary dyskinesia experience respiratory problems beginning within a day of birth. Many have a collapsed lobe of the lung and blood oxygen low enough to require treatment with supplemental oxygen.<ref name=Lucas2020/> Within the first few months of life, most develop a chronic mucus-producing cough and runny nose.<ref name=Lucas2020>Template:Cite journal</ref> The main consequence of impaired ciliary function is reduced or absent mucus clearance from the lungs, and susceptibility to chronic recurrent respiratory infections, including sinusitis, bronchitis, pneumonia, and otitis media. Progressive damage to the respiratory system is common, including progressive bronchiectasis beginning in early childhood, and sinus disease (sometimes becoming severe in adults). However, diagnosis is often missed early in life despite the characteristic signs and symptoms.<ref name=pmid12162599>Template:Cite journal</ref> In males, immotility of sperm can lead to infertility, although conception remains possible through the use of in vitro fertilization, there also are reported cases where sperm were able to move.<ref>Template:Cite webTemplate:Full citation needed</ref> Trials have also shown that there is a marked reduction in fertility in females with Kartagener's syndrome due to dysfunction of the oviductal cilia.<ref name=pmid3488922>Template:Cite journal</ref>
Many affected individuals experience hearing loss and show symptoms of otitis media which demonstrates variable responsiveness to the insertion of myringotomy tubes or grommets. Some patients have a poor sense of smell, which is believed to accompany high mucus production in the sinuses (although others report normal – or even acute – sensitivity to smell and taste). Clinical progression of the disease is variable, with lung transplantation required in severe cases. Susceptibility to infections can be drastically reduced by an early diagnosis. Treatment with various chest physiotherapy techniques has been observed to reduce the incidence of lung infection and to slow the progression of bronchiectasis dramatically. Aggressive treatment of sinus disease beginning at an early age is believed to slow long-term sinus damage (although this has not yet been adequately documented). Aggressive measures to enhance clearance of mucus, prevent respiratory infections, and treat bacterial superinfections have been observed to slow lung-disease progression. The predicted incidence is 1 in approximately 7500.<ref name="Zariwala2015" />
Genetics
PCD is a genetically heterogeneous disorder affecting motile cilia<ref name=pmid15222957>Template:Cite journal</ref> which are made up of approximately 250 proteins.<ref name="gene reviews"/> Around 90%<ref name=pmid17059358>Template:Cite journal</ref> of individuals with PCD have ultrastructural defects affecting protein(s) in the outer and/or inner dynein arms, which give cilia their motility, with roughly 38%<ref name=pmid17059358/> of these defects caused by mutations on two genes, DNAI1 and DNAH5, both of which code for proteins found in the ciliary outer dynein arm.<ref name="Zariwala Omran Ferkol 2011 pp. 430–433">Template:Cite journal</ref>
There is an international effort to identify genes that code for inner dynein arm proteins or proteins from other ciliary structures (radial spokes, central apparatus, etc.) associated with PCD.<ref name="Leigh Pittman Carson Ferkol 2009 pp. 473–487"/> The role of DNAH5 in heterotaxy syndromes and left-right asymmetry is also under investigation. At least 50 genes have been implicated in this condition.<ref name="Zariwala2015">Template:Cite journal</ref>
| Type | OMIM | Gene | Locus |
|---|---|---|---|
| CILD1 | Template:OMIM | DNAI1 | 9p21-p13 |
| CILD2 | Template:OMIM | DNAAF3 | 19q13.3-qter |
| CILD3 | Template:OMIM | DNAH5 | 5p |
| CILD4 | Template:OMIM | ? | 15q13 |
| CILD5 | Template:OMIM | HYDIN | 16p12 |
| CILD6 | Template:OMIM | TXNDC3 | 7p14-p13 |
| CILD7 | Template:OMIM | DNAH11 | 7p21 |
| CILD8 | Template:OMIM | ? | 15q24-q25 |
| CILD9 | Template:OMIM | DNAI2 | 17q25 |
| CILD10 | Template:OMIM | KTU | 14q21.3 |
| CILD11 | Template:OMIM | RSPH4A | 6q22 |
| CILD12 | Template:OMIM | RSPH9 | 6p21 |
| CILD13 | Template:OMIM | LRRC50 | 16q24.1 |
Another gene associated with this condition is GAS2L2.<ref name=Bustamante-Marin2019>Template:Cite journal</ref>
Pathophysiology
This condition is genetically inherited. Structures that make up the cilia, including inner and/or outer dynein arms, central apparatus, radial spokes, etc. are missing or dysfunctional and thus the axoneme structure lacks the ability to move. Axonemes are the elongated structures that make up cilia and flagella. Additionally, there may be chemical defects that interfere with ciliary function in the presence of adequate structure. Whatever the underlying cause, dysfunction of the cilia begins during and impacts the embryologic phase of development.<ref name="Leigh Pittman Carson Ferkol 2009 pp. 473–487"/>
Specialised monocilia known as nodal cilia are at the heart of this problem. They lack the central-pair microtubules of ordinary motile cilia and so rotate clockwise rather than beat; in the primitive node at the anterior end of the primitive streak in the embryo, these are angled posteriorly<ref name=pmid15118088>Template:Cite journal</ref><ref name=pmid16035921>Template:Cite journal</ref> such that they describe a D-shape rather than a circle.<ref name=pmid16035921/> This has been shown to generate a net leftward flow in mouse and chick embryos, and sweeps the protein to the left, triggering normal asymmetrical development.<ref name="Dykes 2014 pp. 52–72">Template:Cite journal</ref>
However, in some individuals with PCD, mutations thought to be in the gene coding for the key structural protein left-right dynein (lrd)<ref name=pmid15222957/> result in monocilia which do not rotate. There is therefore no flow generated in the node, Shh moves at random within it, and 50% of those affected develop situs inversus, which can occur with or without dextrocardia, where the laterality of the internal organs is the mirror-image of normal. Affected individuals therefore have Kartagener syndrome. This is not the case with some PCD-related genetic mutations: at least 6% of the PCD population have a condition called situs ambiguus or heterotaxy, where organ placement or development is neither typical (situs solitus) nor totally reversed (situs inversus totalis) but is a hybrid of the two.<ref name="Leigh Pittman Carson Ferkol 2009 pp. 473–487">Template:Cite journal</ref> Splenic abnormalities such as polysplenia, asplenia and complex congenital heart defects are more common in individuals with situs ambiguus and PCD, as they are in all individuals with situs ambiguus.<ref name=pmid17515466>Template:Cite journal</ref>
The genetic forces linking failure of nodal cilia and situs issues and the relationship of those forces to PCD are the subject of intense research interest. However, knowledge in this area is constantly advancing.Template:Citation needed
Diagnosis
Several diagnostic tests for this condition have been proposed.<ref name=pmid28790179>Template:Cite journal</ref> These include nasal nitric oxide levels as a screening test, light microscopy of biopsies for ciliary beat pattern and frequency and electron microscopic examination of dynein arms, as the definite diagnosis method. Genetic testing has also been proposed but this is difficult given that there are multiple genes involved.<ref name="Leigh Pittman Carson Ferkol 2009 pp. 473–487"/>
Classification
When accompanied by the combination of situs inversus (reversal of the internal organs), chronic sinusitis, and bronchiectasis, it is known as Kartagener syndrome<ref name="uniprot">Template:Cite web</ref> (only 50% of primary ciliary dyskinesia cases include situs inversus).<ref name="gene reviews">Template:Cite web</ref>
Treatment
There are no standardized effective treatment strategies for the condition. Current therapies for PCD are extrapolated from Cystic Fibrosis and patients with non-CF bronchiectasis and lack validation for PCD-specific use.<ref>Template:Cite journal</ref>
Severe fatal respiratory failure can develop; long-term treatment with macrolides such as clarithromycin, erythromycin and azithromycin has been empirically applied for the treatment of primary ciliary dyskinesia in Japan, though controversial due to the effects of the medications.<ref name="pmid22576394">Template:Cite journal</ref>
Prognosis
There is no reliable estimate of life expectancy for people with PCD.<ref>Template:Cite web</ref> However, there is evidence that PCD, is a life altering<ref name="Wilkins PA302">Template:Cite journal</ref> life shortening<ref>Template:Cite journal</ref> multi-system condition, with some people progressing to lung transplant.<ref>Template:Cite journal</ref><ref name=":0">Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>
Decline in lung function in people with PCD has been observed in most studies,<ref name=":8">Template:Cite journal</ref><ref name=":0" /><ref name=":2">Template:Cite journal</ref><ref name="Marthin 1262–1268">Template:Cite journal</ref><ref name=":3">Template:Cite journal</ref> with FEV1 decline causing deterioration in health, impacting on, and reducing quality of life.<ref>Template:Cite journal</ref> With such a genetically and phenotypically heterogenous group, observation of median/mean decline in lung function risks regression to the mean, missing those groups with significantly worse lung function,<ref name="Zariwala2015" /><ref name="Davis 316–324">Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name=":4">Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> masked by those with milder phenotypes.<ref name="Zariwala2015" /><ref name=":4" />
The recent body of published data from respected clinicians in (the United Kingdom, Europe, North America, Canada and Israel) indicate that PCD morbidity and mortality appear to have been under-estimated by the medical community.<ref name=":8"/><ref name=":0" /><ref name=":5">Template:Cite journal</ref><ref name=":6">Template:Cite journal</ref><ref name=":7">Template:Cite journal</ref> While prospective outcome data is limited due to the early-stage patient registries, there is a growing body of evidence<ref name=":0" /><ref name=":5" /><ref name=":6" /><ref name=":7" /><ref>Template:Cite journal</ref> that dispels any "myth that PCD is a mild disease.<ref name=":0" /><ref name=":5" /><ref name=":6" /><ref name=":7" /><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>
The studies presented here demonstrate that children with PCD typically have worse lung function than those with cystic fibrosis.<ref name=":8"/><ref name=":3" /><ref name=":2"/><ref name=":9">Template:Cite journal</ref><ref name="Marthin 1262–1268"/> While previously it was thought that with early diagnosis, deterioration of lung function could largely be prevented in children with PCD,<ref>Template:Cite journal</ref> poor lung function is repeatedly observed in children with PCD<ref name=":9" /><ref name=":8" /><ref name=":3" /><ref name=":2" /> 1,30,32,33,36–38 and some develop bronchiectasis during<ref>Template:Cite journal</ref><ref name="Davis 316–324"/> childhood.
Research
Research to further the understanding of cilia, with the future aims of functional restoration of motile cilia is advancing. However, charitable funding for medical research, particularly for rare disease is vital and in the UK contributes to more than 50% of grants. The UK registered charity PCD Research supports research into PCD worldwide, with the ultimate aim of funding potentially curative research.<ref name="PCDresearch.org"/> Future promising avenues for functional replacement of cilia involve antisense, gene editing via CRISPR-Cas9 and mRNA therapies. At present there have only been a handful of interventional trials in PCD.<ref>Template:Cite web</ref>
History
The classic symptom combination associated with PCD was first described in 1904 by A. K. Siewert,<ref>Template:Cite journal</ref> while Manes Kartagener published his first report on the subject in 1933.<ref>Template:Cite journal</ref> The disorder is rarely referred to as Siewert's syndrome or Siewert-Kartagener syndrome.<ref>Template:Cite journal</ref>