Primary ciliary dyskinesia (PCD) is a rare,

autosomal An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosomal (sex chromosome) pairs, which may have different structures. The DNA in autosom ...

recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

genetic

ciliopathy A ciliopathy is any genetic disorder that affects the cellular cilia or the cilia anchoring structures, the basal bodies, or ciliary function. Primary cilia are important in guiding the process of development, so abnormal ciliary function whi ...

, that causes defects in the action of cilia lining the upper and lower respiratory tract,

sinuses Paranasal sinuses are a group of four paired air-filled spaces that surround the nasal cavity. The maxillary sinuses are located under the eyes; the frontal sinuses are above the eyes; the ethmoidal sinuses are between the eyes and the sphenoid ...

, Eustachian tube,

middle ear The middle ear is the portion of the ear medial to the eardrum, and distal to the oval window of the cochlea (of the inner ear). The mammalian middle ear contains three ossicles, which transfer the vibrations of the eardrum into waves in the ...

, 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 Situs inversus (also called situs transversus or oppositus) is a congenital condition in which the major visceral organs are reversed or mirrored from their normal positions. The normal arrangement of internal organs is known as situs solitus. Al ...

the condition is known as Kartagener syndrome. Respiratory epithelial

motile cilia The cilium, plural cilia (), is a membrane-bound organelle found on most types of eukaryotic cell, and certain microorganisms known as ciliates. Cilia are absent in bacteria and archaea. The cilium has the shape of a slender threadlike projecti ...

, 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 Mucociliary clearance (MCC), mucociliary transport, or the mucociliary escalator, describes the self-clearing mechanism of the airways in the respiratory system. It is one of the two protective processes for the lungs in removing inhaled particl ...

, 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.

Signs and symptoms

The main consequence of impaired ciliary function is reduced or absent

mucus Mucus ( ) is a slippery aqueous secretion produced by, and covering, mucous membranes. It is typically produced from cells found in mucous glands, although it may also originate from mixed glands, which contain both serous and mucous cells. It ...

clearance from the lungs, and susceptibility to chronic recurrent respiratory infections, including

sinusitis Sinusitis, also known as rhinosinusitis, is inflammation of the mucous membranes that line the sinuses resulting in symptoms that may include thick nasal mucus, a plugged nose, and facial pain. Other signs and symptoms may include fever, head ...

bronchitis Bronchitis is inflammation of the bronchi (large and medium-sized airways) in the lungs that causes coughing. Bronchitis usually begins as an infection in the nose, ears, throat, or sinuses. The infection then makes its way down to the bronchi. ...

pneumonia Pneumonia is an inflammatory condition of the lung primarily affecting the small air sacs known as alveoli. Symptoms typically include some combination of productive or dry cough, chest pain, fever, and difficulty breathing. The severi ...

, and

otitis media Otitis media is a group of inflammatory diseases of the middle ear. One of the two main types is acute otitis media (AOM), an infection of rapid onset that usually presents with ear pain. In young children this may result in pulling at the ear, ...

. 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. In males, immotility of sperm can lead to infertility, although conception remains possible through the use of

in vitro fertilization In vitro fertilisation (IVF) is a process of fertilisation where an egg is combined with sperm in vitro ("in glass"). The process involves monitoring and stimulating an individual's ovulatory process, removing an ovum or ova (egg or eggs) f ...

, there also are reported cases where sperm were able to move. 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. Many affected individuals experience

hearing loss Hearing loss is a partial or total inability to hear. Hearing loss may be present at birth or acquired at any time afterwards. Hearing loss may occur in one or both ears. In children, hearing problems can affect the ability to acquire spoken ...

and show symptoms of otitis media which demonstrates variable responsiveness to the insertion of

myringotomy A myringotomy is a surgical procedure in which an incision is created in the eardrum (tympanic membrane) to relieve pressure caused by excessive buildup of fluid, or to drain pus from the middle ear. A tympanostomy tube may be inserted through th ...

tubes or

grommet Curtain grommets, used among others in shower curtains. A grommet is a ring or edge strip inserted into a hole through thin material, typically a sheet of textile fabric, sheet metal or composite of carbon fiber, wood or honeycomb. Grommets ar ...

s. Some patients have a poor sense of smell, which is believed to accompany high

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. Although the true incidence of the disease is unknown, it is estimated to be 1 in 32,000, although the actual incidence may be as high as 1 in 15,000.

Genetics

PCD is a genetically heterogeneous disorder affecting

motile Motility is the ability of an organism to move independently, using metabolic energy. Definitions Motility, the ability of an organism to move independently, using metabolic energy, can be contrasted with sessility, the state of organisms th ...

cilia which are made up of approximately 250 proteins. Around 90% 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% of these defects caused by mutations on two genes, DNAI1 and

DNAH5 Dynein axonemal heavy chain 5 is a protein that in humans is encoded by the ''DNAH5'' gene. ''DNAH5'' is a protein-coding gene.1 It provides the instructions for synthesizing a protein that belongs to a microtubule-associated protein complex made ...

, 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 Situs ambiguus is a rare congenital defect in which the major visceral organs are distributed abnormally within the chest and abdomen. Clinically heterotaxy spectrum generally refers to any defect of Left-right asymmetry and arrangement of the vi ...

syndromes and left-right asymmetry is also under investigation. At least 32 genes have been implicated in this condition.Zariwala MA, Knowles MR, Leigh MW (2015
Primary Ciliary Dyskinesia
In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993–2018 Another gene associated with this condition is

GAS2L2 Gas is one of the four fundamental states of matter (the others being solid, liquid, and plasma). A pure gas may be made up of individual atoms (e.g. a noble gas like neon), elemental molecules made from one type of atom (e.g. oxygen), or co ...

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 An axoneme, also called an axial filament is the microtubule-based cytoskeletal structure that forms the core of a cilium or flagellum. Cilia and flagella are found on many cells, organisms, and microorganisms, to provide motility. The axo ...

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 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 The primitive node (or primitive knot) is the organizer for gastrulation in most amniote embryos. In birds it is known as Hensen's node, and in amphibians it is known as the Spemann-Mangold organizer. It is induced by the Nieuwkoop center in am ...

at the anterior end of the primitive streak in the embryo, these are angled posteriorly such that they describe a D-shape rather than a circle. This has been shown to generate a net leftward flow in mouse and chick embryos, and sweeps the

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

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'') 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

, which can occur with or without

dextrocardia Dextrocardia (from Latin ''dextro'', meaning "right hand side," and Greek ''kardia'', meaning "heart") is a rare congenital condition in which the apex of the heart is located on the right side of the body, rather than the more typical placement t ...

, 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 Situs ambiguus is a rare congenital defect in which the major visceral organs are distributed abnormally within the chest and abdomen. Clinically heterotaxy spectrum generally refers to any defect of Left-right asymmetry and arrangement of the vi ...

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 Asplenia refers to the absence of normal spleen function and is associated with some serious infection risks. Hyposplenism is used to describe reduced ('hypo-') splenic functioning, but not as severely affected as with asplenism. ''Functional'' a ...

and complex congenital heart defects are more common in individuals with situs ambiguus and PCD, as they are in all individuals with situs ambiguus. 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.

Relation to other rare genetic disorders

Recent findings in genetic research have suggested that a large number of

genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...

s, both genetic syndromes and

genetic diseases A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...

, 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 In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...

-observed disorders. Thus, PCD is a

. Other known ciliopathies include

Bardet–Biedl syndrome Bardet–Biedl syndrome (BBS) is a ciliopathic human genetic disorder that produces many effects and affects many body systems. It is characterized by rod/cone dystrophy, polydactyly, central obesity, hypogonadism, and kidney dysfunction in so ...

, polycystic kidney and

liver disease Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common. Signs and symptoms Some of the si ...

, nephronophthisis,

Alström syndrome Alström syndrome (AS), also called Alström–Hallgren syndrome, is a very rare autosomal recessive genetic disorder characterised by childhood obesity and multiple organ dysfunction. Symptoms include early-onset type 2 diabetes, cone-rod dystr ...

, Meckel–Gruber syndrome and some forms of retinal degeneration.

Diagnosis

Several diagnostic tests for this condition have been proposed. 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.

Classification

When accompanied by the combination of

(reversal of the internal organs),

chronic sinusitis Sinusitis, also known as rhinosinusitis, is inflammation of the mucous membranes that line the sinuses resulting in symptoms that may include thick nasal mucus, a plugged nose, and facial pain. Other signs and symptoms may include fever, heada ...

, and bronchiectasis, it is known as Kartagener syndrome (only 50% of primary ciliary dyskinesia cases include situs inversus).

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. Severe fatal respiratory failure can develop; long-term treatment with macrolides such as

clarithromycin Clarithromycin, sold under the brand name Biaxin among others, is an antibiotic used to treat various bacterial infections. This includes strep throat, pneumonia, skin infections, '' H. pylori'' infection, and Lyme disease, among others. Clarith ...

, erythromycin and

azithromycin Azithromycin, sold under the brand names Zithromax (in oral form) and Azasite (as an eye drop), is an antibiotic medication used for the treatment of a number of bacterial infections. This includes middle ear infections, strep throat, pneumo ...

has been empirically applied for the treatment of primary ciliary dyskinesia in Japan, though controversial due to the effects of the medications.

Prognosis

There is no reliable estimate of life expectancy for people with PCD. The largest multi-center study of lung function in people with PCD across many European countries found strong evidence refuting a common assumption that it is a mild disease. This study found that lung function of people with PCD is comparable to those with cystic fibrosis in childhood but is better in young adulthood. Both diseases, however, are progressive and lung function declines with age relative to peer groups. Survey data indicate that respiratory symptoms increase progressively and continuously beginning in the mid-20s relative to the population norm.

Research

Research to further the understanding of cilia, with the future aims of functional restoration of motile cilia is advancing. However, charitable funding for medial 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. 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.

History

The classic symptom combination associated with PCD was first described in 1904 by A. K. Siewert, while Manes Kartagener published his first report on the subject in 1933. The disorder is often now referred to as Siewert's syndrome or Siewert-Kartagener syndrome.

References

External links

Genetic disorders of mucociliary clearance consortium
{{Other genetic disorders by mechanism Autosomal recessive disorders Respiratory diseases Cytoskeletal defects Ciliopathy Rare diseases Infertility Syndromes affecting the respiratory system