Primary Ciliary Dyskinesia

From UBC Wiki
Click the animation to see cilia moving back and forth in a broom-like fashion to move mucus (yellow balls) towards the throat.

Primary Ciliary Dyskinesia (PCD) is a condition that can be passed on from parents to child[1]. Individuals with PCD have cilia that do not move the way they should. Cilia are very small structures that look like the hair on our head but instead are found inside our bodies within breathing airways, ears, and reproductive structures[1]. In turn, individuals with PCD face breathing problems, lung infections, ear infections, and in some cases, they are unable to have children (infertility)[2]. In about 50% of cases, individuals with PCD will also have their organs on opposite sides of where they normally should be [2].

Signs and symptoms of PCD can vary in type and severity and can show up as early as birth. However, children are often not diagnosed until later in life[3][4].

Around 1 in every 16,000 - 30,000 individuals have PCD[4][5][6].

The Role of Cilia Inside the Body

The major areas which make-up the breathing airway path. Cilia inside the nostrils, nasal cavity, sinuses (not shown), trachea, bronchi, and lungs trap potentially harmful material and move it towards the throat where it can be coughed up or swallowed for digestion.
The major areas which make-up the breathing airway path. Cilia inside the nostrils, nasal cavity, sinuses (not shown), trachea, bronchi, and lungs trap potentially harmful material and move it towards the throat where it can be coughed up or swallowed for digestion.
Cilia in the Lungs and Breathing Airways
  • The breathing airways are a pathway for air to go in and out of the body. Cilia line this pathway like a broom and work with a slimy material called mucus to trap dust, dirt, bacteria, viruses, and any other foreign object(s)[1][7]. Upon trapping, cilia from all areas move mucus towards the throat[1][7]. At the throat, mucus (and trapped material) can be coughed out or can be swallowed and digested by the stomach[7][8]. In either case, the cilia help keep the breathing airways clean and clear.
Cilia in the Ears
  • In the middle ear, cilia work with fluid and mucus to trap harmful material which is then drained down to the throat[1].
Cilia in Reproductive Structures
  • A special type of cilia on the female fallopian tube moves the egg down from the ovary into the uterus[1].
  • A special type of cilia, called flagella, move sperm cells to their destination, ‘the egg’[1].
Cilia During Development
  • When a baby is developing inside the womb, cilia help split the left and right sides of the body[1]. For example, in most individuals the stomach and heart are near the left side of the body while the liver is on the right.

Signs and Symptoms of PCD

A variety of areas (especially in the breathing airway path) are under stress in individuals with PCD.

The most common symptoms of PCD include ongoing airway (particularly lung) and ear infections, coughing, runny and/or stuffy nose[2][7][9][10]. Depending on a variety of factors (see genetics), individuals with PCD can have different symptoms with different severities[2][7][10].

Lungs
  • Mucus build-up blocks airway structures in the lungs (bronchi), leading to uncomfortable wet breathing and coughing[2][7][9].
  • The body’s natural instinct is to widen these bronchi to help air enter more smoothly into the lungs. In individual’s with PCD, this widened area only provides space for more mucus build-up and infectious bacteria, leading to the development of ongoing (usually year-round) infections such as pneumonia[2][7][9].
  • These infections, over time, can start to break down the lung walls and lead to a condition called bronchiectasis[2][7][9].
Ears
  • Bacteria from breathing airway infections can travel up to the middle ear where they can grow in fluid, leading to ongoing ear infections (chronic otitis media)[2][9].
  • Over time, these infections can lead to hearing loss as they begin to damage the internal structures of the ear [2][7].
Sinuses
  • Sinuses are small holes around the nose and forehead, lined with cilia.
  • Sinuses in individuals with PCD cannot clear out mucus well so individuals face ongoing sinus infections, stuffy nose, and runny nose[2].
Major Organs
  • About 50% of individuals with PCD have fully reversed organs (situs inversus)[7]. If an individual displays symptoms of PCD and has situs inversus, they are said to have Kartagener’s Syndrome [7].
  • About 12% of individuals with PCD have organs that did not form the right and left sides properly and/or have missing or additional organs, particularly the liver and spleen (situs ambiguus)[9]. Some individuals with PCD do not develop the left and right sides of the heart properly. These individuals will have heart problems present at birth[7][9].
Brain
  • In rare cases, individual's with PCD may also have fluid build-up in the brain[2][4][7].
Infertility (unable to have children)
  • Females with PCD may have trouble, or be unable to have children as movement of the egg is needed for healthy fertilization[1].
  • Males with PCD may not be able to have children because their sperm is unable to reach the egg for fertilization[1].  

Clinical Diagnosis

The average age of PCD diagnosis is between 5-5.5 years[2]. Diagnosis of PCD is often missed during early life because many of its symptoms, such as runny nose, coughing, and ear infections, are common in children[4][7][11][12]. A diagnosis may also be missed because individuals with PCD may develop symptoms later in life, have different symptom severities, or they may have a condition with symptoms similar to, but is not, PCD[7].

A picture of cilia under a very specialized microscope (electron microscope). Lab specialists are able to look at images like these and see if the cilia are working the way they should.

The specific combinations (e.g. ongoing lung and ear infections, cough, and organ reversal) and repetitive nature of symptoms help make the diagnostic process easier[11]. A mix of professionals are often involved in a child's care[11]. Some of the tools that are involved in diagnosis include:

Breathing Measurements

Breathing tests measure the amount and quality of air and substances found inside an individual's lungs and breathing airways[11][12]. They also give specialists an idea of whether the lungs are working the way they should [7].

Electron Microscopy

This test allows a sample of cilia from the nose to be looked at under a very specialized microscope. A lab specialist can see whether the cilia look and work the way that they should[3][11].

Genetic Testing

A blood test can allow specialists to look at a person's genes and see whether there are any changes causing the symptoms of PCD.

Genetics: Inheritance, Testing, and Counselling

Overview

The information our bodies use to determine what our cilia look like, how they move, and how healthy they are, are found on structures called “genes”. Individuals have two copies of each gene - one is passed on from mother and one from father.

The information on each gene is read by our body and turned into a product. For example, a gene may say “cilia move back and forth” in which case the person will have cilia which move back and forth. With a spelling mistake, this sentence now reads “cilia move back and froth”. In this case, the meaning is lost and may lead to a change in the way a person’s cilia work.

Carriers
  • PCD is passed on in an Autosomal Recessive Manner. When two parents are “carriers”, there is: * A 25% chance each parent passes on the working copy, in which case the child will not develop PCD. * A 25% chance each parent passes the non-working copy, in which case the child will develop PCD. * A 50% chance that one parent passes on a working copy and one parent passes on a non-working copy, in which case the child will be a carrier like their parents - likely not to show symptoms of PCD.
    Because individuals have two copies of each gene, sometimes a spelling mistake on one gene will not cause problems. This is because the individual has one copy which is still working and can make up for the gene which is not working. When an individual has one working copy and one non-working copy of a gene, they are said to be a “carrier”.
  • For an individual to develop PCD, they must have two non-working copies of a gene (e.g. they have two spelling mistakes). In this case, there is no gene to help take the place of the other since both copies are not working.
Passing PCD From Parents to Child: Autosomal Recessive
  • For an individual to have PCD, each of their parents must have one non-working copy (i.e. carriers) of a gene needed for cilia development[1] [13]. The chance of two parents who are carriers to have a child with PCD is 25%.
Passing PCD From Parents to Child: Other
  • There have been some cases where PCD is passed on in a sex (male/female) specific manner. However, these cases of PCD are usually part of a larger syndrome and with more features than PCD alone [14][15].
Genetic Changes and Testing
  • About 40 different genes have been associated with PCD; most of which are needed to help cilia work properly [10].
  • About 30% of individuals with PCD will have changes/spelling mistakes in the DNAI1 and DNAH5 genes [7]. These genes provide information to create the 'motor' which allows cilia to move back and forth[7]

If PCD is suspected, referral to a Geneticist and/or Genetic Counsellor may be beneficial. These professionals may offer genetic testing to confirm whether there are changes in the information that helps cilia work properly.

Differences in Symptom Severity

Predicting the types and severity of PCD as well as the exact age at which someone may develop PCD is difficult because:

  1.  More than one gene can have a change/spelling mistake[6].
  2. Specific changes/spelling mistakes can happen at different places on a gene. Depending on where the change happens it can have a different effect on how the cilia work[6]. For example, one type of change may not allow cilia to move at all, while another can allow them to move a little bit.
  3. Genes interact with other genes. When some genes have a spelling mistake, interactions with other genes (modifier genes) may make the symptoms even more severe[13].

Unfortunately, science has not yet determined every gene and every change involved in PCD.

Genetic Testing for Family Planning

Options for individuals concerned about their child having PCD may consider:

Carrier Testing

  • Testing both parents to see if they are carriers for a gene change associated with PCD.

Prenatal or Newborn Testing

  • If a healthcare professional deems necessary, genetic testing may be indicated in a fetus or newborn to see whether two changes in a gene associated with PCD are present.

Pre-implantation Genetic Diagnosis

  • If two parents are known to be carriers, they may consider using assisted reproductive technology to select for an embryo who will not develop PCD.

Management

Although there is no cure for PCD, treatments focus on minimizing the symptoms and reducing the amount of infections individuals face.

Breathing Airways[4]
  • Chest compression and exercise in order to loosen up mucus and to encourage coughing it out
  • Antibiotics to treat and prevent infection
  • Medications to increase the size of breathing airways
  • Lung Transplants (in very advanced cases)
Ears and Sinuses[4]
  • Medications to help with congestion and runny nose
  • Procedures to remove excess fluid from the ears
  • Hearing aids
Reproductive Organs
  • Individuals with PCD may consider assisted reproductive technologies as an option to have children

Living with PCD (Prognosis)

Depending on when the disorder is a diagnosed as well as the symptom severity, the prognosis can vary. In general, individuals have a normal life expectancy with proper treatment [16]. Each individual will have unique experiences, highlights and struggles that they face in living with PCD. Below are several resources where individuals living with PCD discuss their journeys and experiences.

Resources for Patients and Family Members

https://www.action.org.uk/blog/2013/07/15/kylies-story-its-not-been-easy-ride-primary-ciliary-dyskinesia-pcd

Whalley, Simon, and I. C. McManus. "Living with Primary Ciliary Dyskinesia: A Prospective Qualitative Study of Knowledge Sharing, Symptom Concealment, Embarrassment, Mistrust, and Stigma." BMC Pulmonary Medicine, vol. 6, no. 1, 2006, pp. 25-25. This article is available to the public. Just insert the title into the Google search bar!

https://pcdfoundation.org/

https://www.uncmedicalcenter.org/app/files/public/771/pdf-mclendon-labs-pcd-brochure.pdf

Frequently there are Facebook support groups for many different conditions, including PCD- use your search tool to see what is available!

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 Goggolidou, Paraskevi, and Taylor & Francis eBooks A-Z. Cilia: Development and Disease. CRC Press, Taylor & Francis Group, Boca Raton, 2018.
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 Knowles, M. R., MD, Zariwala, M., PhD, & Leigh, M., MD. (2016). Primary ciliary dyskinesia.Clinics in Chest Medicine, 37(3), 449-461. doi:10.1016/j.ccm.2016.04.008
  3. ↑ 3.0 3.1 M.E, Coren, et al. "Primary Ciliary Dyskinesia: Age at Diagnosis and Symptom History." Acta Paediatrica, vol. 91, no. 6, 2002, pp. 667-669.
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 Bush, Andrew, et al. "Primary Ciliary Dyskinesia: Current State of the Art." Archives of Disease in Childhood, vol. 92, no. 12, 2007, pp. 1136-1140.
  5. ↑ Bush A, Cole P, Hariri M, Mackay I, Phillips G, O'Callaghan C, Wilson R, Warner JO: Primary ciliary dyskinesia: diagnosis and standards of care. Eur Respir J. 1998, 12: 982-988. 10.1183/09031936.98.12040982
  6. ↑ 6.0 6.1 6.2 Blouin, J. L., et al. "Primary Ciliary Dyskinesia: A Genome-Wide Linkage Analysis Reveals Extensive Locus Heterogeneity." European Journal of Human Genetics : EJHG, vol. 8, no. 2, 2000, pp. 109-118.
  7. ↑ 7.00 7.01 7.02 7.03 7.04 7.05 7.06 7.07 7.08 7.09 7.10 7.11 7.12 7.13 7.14 7.15 7.16 7.17 Leigh, M. W., Pittman, J. E., Carson, J. L., Ferkol, T. W., Dell, S. D., Davis, S. D., . . . Zariwala, M. A. (2009). Clinical and genetic aspects of primary ciliary dyskinesia/Kartagener syndrome. Genetics in Medicine : Official Journal of the American College of Medical Genetics, 11(7), 473-487. doi:10.1097/GIM.0b013e3181a53562
  8. ↑ Sleigh MA, Blake JR, Liron N. The propulsion of mucus by cilia. Am Rev Respir Dis. 1988;137:726–741.
  9. ↑ 9.0 9.1 9.2 9.3 9.4 9.5 9.6 Shapiro, A. J., Davis, S. D., Ferkol, T., Dell, S. D., Rosenfeld, M., Olivier, K. N., . . . Genetic Disorders of Mucociliary Clearance Consortium. (2014). Laterality defects other than situs inversus totalis in primary ciliary dyskinesia: Insights into situs ambiguus and heterotaxy.Chest, 146(5), 1176.
  10. ↑ 10.0 10.1 10.2 Horani, Amjad, and Thomas W. Ferkol. "Advances in the Genetics of Primary Ciliary Dyskinesia: Clinical Implications." Chest, vol. 154, no. 3, 2018, pp. 645.
  11. ↑ 11.0 11.1 11.2 11.3 11.4 Lucas, Jane S., et al. "European Respiratory Society Guidelines for the Diagnosis of Primary Ciliary Dyskinesia." The European Respiratory Journal, vol. 49, no. 1, 2017, pp. 1601090-1601090.
  12. ↑ 12.0 12.1 Lucas, Jane S., and Woolf T. Walker. "NO Way! Nasal Nitric Oxide Measurement in Infants."The European Respiratory Journal, vol. 51, no. 6, 2018, pp. 1800958-1800958.
  13. ↑ 13.0 13.1 Berg, Jonathan S., et al. "Next Generation Massively Parallel Sequencing of Targeted Exomes to Identify Genetic Mutations in Primary Ciliary Dyskinesia: Implications for Application to Clinical Testing." Genetics in Medicine : Official Journal of the American College of Medical Genetics, vol. 13, no. 3, 2011, pp. 218-229.
  14. ↑ Budny B, Chen W, Omran H, et al. A novel X-linked recessive mental retardation syndrome comprising macrocephaly and ciliary dysfunction is allelic to oral-facial-digital type I syndrome. Hum Genet. 2006;120:171–178.
  15. ↑ Moore A, Escudier E, Roger G, et al. RPGR is mutated in patients with a complex X-linked phenotype combining primary ciliary dyskinesia and retinitis pigmentosa. J Med Genet. 2006;43:326–333.
  16. ↑ Whalley, Simon, and I. C. McManus. "Living with Primary Ciliary Dyskinesia: A Prospective Qualitative Study of Knowledge Sharing, Symptom Concealment, Embarrassment, Mistrust, and Stigma." BMC Pulmonary Medicine, vol. 6, no. 1, 2006, pp. 25-25.
Retrieved from "https://wiki.ubc.ca/index.php?title=Primary_Ciliary_Dyskinesia&oldid=777443"