Primary ciliary dyskinesia
Primary ciliary dyskinesia | |
---|---|
Other names | Immotile ciliary syndrome or Kartagener syndrome |
runny nose.[1] | |
Complications | Chronic recurrent respiratory infections, including sinusitis, bronchitis, pneumonia, and otitis media.[2] |
Usual onset | Neonatal period.[1] |
Types | Kartagener syndrome.[3] |
Causes | Genetic mutations.[4] |
Diagnostic method | Nasal nitric oxide levels, light microscopy of biopsies for ciliary beat pattern and frequency, and electron microscopic examination of dynein arms.[5] |
Differential diagnosis | Neonatal respiratory distress, laterality defects, chronic cough, nasal congestion and sino-pulmonary disease, Cystic fibrosis, Asthma and Allergic rhinitis, Gastroesophageal reflux disease and aspiration, Immunodeficiency, and Interstitial lung disease.[6] |
Frequency | Rare. |
Primary ciliary dyskinesia (PCD) is a rare,
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.
Many affected individuals experience
Genetics
PCD is a genetically heterogeneous disorder affecting motile cilia[4] which are made up of approximately 250 proteins.[11] Around 90%[12] 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%[12] 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.[13]
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.
Type | OMIM
|
Gene | Locus |
---|---|---|---|
CILD1 | 244400 | DNAI1 | 9p21-p13 |
CILD2 | 606763 | ? | 19q13.3-qter |
CILD3 | 608644 | DNAH5 | 5p |
CILD4 | 608646 | ? | 15q13 |
CILD5 | 608647 | ? | 16p12 |
CILD6 | 610852 | TXNDC3
|
7p14-p13 |
CILD7 | 611884 | DNAH11 | 7p21 |
CILD8 | 612274 | ? | 15q24-q25 |
CILD9 | 612444 | DNAI2 | 17q25 |
CILD10 | 612518 | KTU
|
14q21.3 |
CILD11 | 612649 | RSPH4A | 6q22 |
CILD12 | 612650 | RSPH9 | 6p21 |
CILD13 | 613190 | LRRC50 | 16q24.1 |
Another gene associated with this condition is GAS2L2.[14]
Pathophysiology
This condition is genetically inherited. Structures that make up the cilia, including inner and/or outer
Specialised monocilia known as
However, in some individuals with PCD, mutations thought to be in the gene coding for the key structural protein left-right
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.[citation needed]
Diagnosis
Several diagnostic tests for this condition have been proposed.[5] 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.[6]
Classification
When accompanied by the combination of
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.[19]
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.[20]
Prognosis
There is no reliable estimate of life expectancy for people with PCD.[21] However, there is evidence that PCD, is a life altering[22] life shortening[23] multi-system condition, with some people progressing to lung transplant.[24][25][26][27]
Decline in lung function in people with PCD has been observed in most studies,[28][25][29][30][31] with FEV1 decline causing deterioration in health, impacting on, and reducing quality of life.[32] 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,[10][33][34][35][36][37][38] masked by those with milder phenotypes.[10][36]
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.[28][25][39][40][41] While prospective outcome data is limited due to the early-stage patient registries, there is a growing body of evidence[25][39][40][41][42] that dispels any "myth that PCD is a mild disease.[25][39][40][41][43][44][45]
The studies presented here demonstrate that children with PCD typically have worse lung function than those with cystic fibrosis.[28][31][29][46][30] While previously it was thought that with early diagnosis, lung function could largely be prevented in children with PCD,[47] it is key to note that poor lung function is repeatedly observed in children with PCD[46][28][31][29] 1,30,32,33,36–38 and some develop bronchiectasis during[48][33] 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.
History
The classic symptom combination associated with PCD was first described in 1904 by A. K. Siewert,[50] while Manes Kartagener published his first report on the subject in 1933.[51] The disorder is rarely referred to as Siewert's syndrome or Siewert-Kartagener syndrome.[52]
References
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- ^ a b c "DNAI1 - Dynein axonemal intermediate chain 1 - Homo sapiens (Human) - DNAI1 gene & protein". uniprot.org. Retrieved 7 May 2022.
- ^ PMID 15222957.
- ^ PMID 28790179.
- ^ PMC 3739704.
- ^ a b "PCDresearch.org". PCDresearch.org. Retrieved 2022-10-24.
- ^ "PCD Family Support Group : FAQs". Archived from the original on 2016-10-08. Retrieved 2012-03-04.[full citation needed]
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- ^ "FREQUENTLY ASKED QUESTIONS Everything you need to know about primary ciliary dyskinesia (PCD)!". PCD Foundation. Retrieved 16 September 2018.
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- ^ "Search of: primary ciliary dyskinesia — List Results — ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2022-10-24.
- ^ Siewert AK (8 February 1904). "Über einen Fall von Bronchiectasie bei einem Patienten mit situs inversus viscerum" [About a case of bronchiectasis in a patient avec situs inversus viscerum]. Berliner Klinische Wochenschrift (in German). 41 (6): 139–141.
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