Primary ciliary dyskinesia

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• Kartagener-Syndrom
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Primary ciliary dyskinesia (PCD), also known as immotile ciliary syndrome or Kartagener Syndrome (KS), is a rare, ciliopathic, autosomal recessive genetic disorder which causes a defect in the action of the cilia lining the respiratory tract (lower and upper, sinuses, Eustachian tube, middle ear) and fallopian tube.

Cilia, which resemble microscopic hairs, are actually complex organelles that bear no biological or structural relationship to hair.^{[citation needed]}

PCD is a genetically heterogeneous disorder affecting motile cilia^[1] which are made up of approximately 250 proteins^[2]. Around 90%^[3] 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%^[3] 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.

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. The role of DNAH5 in heterotaxy syndromes and left-right asymmetry is also under investigation.

Classification

When accompanied by the combination of situs inversus (reversal of the internal organs), chronic sinusitis, and bronchiectasis, it is known as Kartagener syndrome. The phrase "immotile ciliary syndrome" is no longer favored, as sperm in affected men often retain some motility.

Axial CT image showing situs inversus with the liver and IVC on the left and the spleen and aorta on the right.

Axial CT image showing dextrocardia with the IVC and morphologic right ventricle on the left and the left ventricle on the right.

Axial CT image showing chronic sinusitis in a patient with Kartagener syndrome.

Signs and symptoms

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. Susceptibility to these infections can be drastically reduced by an early diagnosis, as treatment with various chest physiotherapy techniques during childhood helps prevent the lungs being damaged or colonised by infection during this vulnerable period. However, diagnosis is often missed early in life despite the characteristic signs and symptoms.^[4]

Many patients experience hearing loss and show symptoms of glue ear which demonstrate variable responsiveness to the insertion of myringotomy tubes or grommets. A poor sense of smell accompanies high mucus production in the sinuses. Infertility is common, due to defective ciliary action in the fallopian tube in affected females or diminished sperm motility in affected males, but IVF techniques have been successful for some parents with PCD. A subset of KS patients may experience chronic headaches and on rare occasion, hydrocephalus (spinal fluid buildup in the brain) due to impaired functioning of ventricular ependymal cilia.^{[citation needed]} Clinical progression of the disease is variable with lung transplantation required in severe cases. For most patients, aggressive measures to enhance clearance of mucus, prevent respiratory infections, and treat bacterial superinfections are recommended. Although the true incidence of the disease is unknown, it is estimated to be 1 in 32,000,^[5] although the actual incidence may be as high as 1 in 15,000.

Sagittal CT image showing "tree in bud" appearance of mucous impaction in distal small airways related to primary ciliary dyskinesia.

CT image showing dilated and thickened medium sized airways (bronchiectaisis)in a patient with Kartagener syndrome.

Oblique sagittal CT image showing lower lobe cylinidrical bronchiectasis in the same patient.

Pathophysiology

This disease 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.

Specialised monocilia 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 Hensen's node at the anterior end of the primitive streak in the embryo, these are angled posteriorly^[6][7] such that they prescribe a D-shape rather than a circle.^[7] This has been shown to generate a net leftward flow in mouse and chick embryos, and sweeps the Sonic Hedgehog (Shh) protein to the left, triggering normal asymmetrical development.

However, in some individuals with PCD, mutations thought to be in the gene coding for the key structural protein left-right dynein (lrd)^[1] 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, where the laterality of the internal organs is the mirror-image of normal. Affected patients therefore have Kartagener syndrome. This is not the case with all PCD-related genetic mutations: at least 6%^{[citation needed]} 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. 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 situs ambiguus patients.^[8]

The genetic forces linking failure of nodal monocilia and situs issues and the relationship of those forces to PCD are the subject of intense research interest. For now hypotheses abound--some, like the one above, are generally accepted. However, knowledge in this area is constantly evolving and it would be premature to assign an absolute cause/effect relationship to any hypothesis at this point.

Relation to other rare genetic disorders

Recent findings in genetic research have suggested that a large number of genetic disorders, both genetic syndromes and genetic diseases, that were not previously identified in the medical literature as related, may be, in fact, highly related in the genetypical root cause of the widely-varying, phenotypically-observed disorders. Thus, PCD is a ciliopathy. Other known ciliopathies include Bardet-Biedl syndrome, polycystic kidney and liver disease, nephronophthisis, Alstrom syndrome, Meckel-Gruber syndrome and some forms of retinal degeneration.^[9].

History

The classic symptom combination associated with PCD was first described by A. K. Zivert^[10] in 1904, while Kartagener published his first report on the subject in 1933.^[11].

References

See also

• Secondary ciliary dyskinesia

External links

• http://www.pcdfoundation.org
• http://www.pcdsupport.org.uk
• http://www.med.unc.edu/cystfib/PCD.htm
• http://www.cheo.on.ca/english/9301c.shtml
• http://www.pcdforum.com/
• Kartagener's syndrome on Who Named It

This article may contain some text from the public domain source "National Heart, Lung, and Blood Institute Rare Diseases Report FY 2001" available at http://www.nhlbi.nih.gov/resources/docs/raredisrpt01.htm