Complete Overview of Primary Ciliary Dyskinesia

What is CILIIA?

Cilia is a type of structure composed of microtubules and is present in various cells. It is present on the luminous surface. It performs multiple functions - the motile cilia acting in mucociliary clearance in the respiratory tract. The immotile cilia which act as sensory receptors to some of the cilia which appear transiently in embryonic time, deciding the right and left axis of the various organs. Cilia - a group of structures play a variety of functions. Cilia are microtubular structures, composed of microtubules.

Types of Cilia

Motile Cilia

9+2 arrangement (9 microtubules present at the periphery and 2 microtubules present at the center). Motile-planar motility or linear motility. Found in - nasopharynx, middle ear, paranasal sinuses, and upper major respiratory tract. Major function is mucociliary clearance. Kartagener syndrome, also known as Primary Ciliary Dyskinesia (PCD), is a disorder associated with motile cilia.

Primary Non Motile Cilia

It is also called sensory cilia. 9+0 structure PRESENT. Non-motile. Function:- Osmoreception, Mechanoreception, Thermoreception. Disorders associated with sensor cilia are polycystic kidney diseases and Joubert syndrome.

Nodal Cilia

They are also called embryonic cilia. 9+0 structure present, with some degree of motility. Rotational motility. Function:- guiding the movement of various cell lineages. Disorders associated with Situs inversus along with Heterotaxia Syndromes.

Ciliopathies Due to Abnormal Non-Motile / Sensory Cilia

• Polycystic kidney diseases due to abnormal nonmotile cilia.
• Nephronophthisis
• Bardet-Biedl Syndrome due to insensitive cilia.
• Meckel-Gruber Syndrome
• Joubert Syndrome
• Alstrom Syndrome
• Ellis van Creveld syndrome
• Jeune thoracic dystrophy
• Leber congenital amaurosis

Motile Cilia

• In Cross-section
  • A central apparatus with 2 microtubules is present.
  • 9 structures are present in the periphery: Two microtubules joined together
• Each microtubule at the periphery has multiple attachments:
  • That part attached to multiple things is called A structure.
  • One that does not have multiple attachments but is only attached to structure A is called the B structure.
• A-structure has two types of arms:
  • The outer arm is known as the outer Dynein arm.
  • The inner arm is known as the inner Dynein arm.
• Outer and inner dynein motors operate or beat and tend to move the Cilia.
  • The inner dynein arm - bending of each cilium,
  • The outer dynein arm - controls the rate, rhythm, and amplitude of the Cilia.
• A-structures are joined to the central proteins by a radial spoke.
• Radial Spokes do stabilization and integration.
• A network of proteins that joins all peripheral microtubules together to operate cohesively and in an integrated manner is known as the Nexin-Dynein regulatory complex.
• Different types of protein in motile cilia:
  • Core protein → Microtubules
  • Operating motors → Outer and inner dynein arms.
  • Nexin protein → Forms a nexus and connects all structures.
•  Abnormalities in different kinds of proteins are responsible for various varieties of primary ciliary dyskinesia. Lead to variation in the clinical presentation and the severity of various types of primary ciliary dyskinesia.

Non-Motile Cilia 

The non-motile Cilia are non-motile, due to two reasons:

• 9+0 structure
• The dynein arms are absent
• They tend to perform specialized functions related to sensory functions.

Primary Ciliary Dyskinesia

Also known as: Kartagener's syndrome, Immotile cilia syndrome. It is not a single condition but a combination of conditions. Inheritance - Autosomal Recessive. A wide variety of mutations can produce primary ciliary dyskinesia. CCNO gene mutation, MCIDAS gene mutations. No cilia on electron microscopy. RPGR gene mutation. Normal-looking cilia on electron microscopy.But many have X-linked variety of Retinitis Pigmentosa. Due apoptosis of the cells in retinal pigment epithelium. In RPGR gene mutation, the lung involvement is very mild or none. CCDC 39 and CCDC 40 gene. Associated with severe respiratory involvement.

Clinical Features of Primary Ciliary Dyskinesia

The clinical features broadly can be categorized into three parts.

Respiratory Manifestation

• Begin in the neonatal period.
• Neonatal Respiratory Distress (NRD)
  • Common manifestation in term neonates.
  • Tachypnoea, retractions, and some response to oxygen.
  • Chest X-ray shows upper lobe or middle lobe Atelectasis.
• Chronic productive cough, beginning from infancy.
• Bronchiectasis.
  • Bacteria responsible for worsening:
    • Haemophilus Influenzae (non-typable forms)
    • Staphylococcus Aureus
    • Streptococcus pneumoniae
    • Pseudomonas aeruginosa
  • Repeated chronic otitis media and persistent middle ear effusion.
  • Chronic, non-seasonal rhinosinusitis and nasal polyps.
  • Atypical, refractory Asthma
  • Digital clubbing (adolescents)
  • Recurrent pneumonia

Left-Right Laterality Defects

• 25-50% have problems with the nodal cilia,
  • The ability of the cell lineages is affected.
    • Situs inversus totalis
    • Heterotaxy with or without complex congenital heart diseases

Miscellaneous including Infertility

• Male infertility with immotile sperm
• Subfertility in females, Fertility is reduced due to dysfunctional or absent cilia in the fallopian tube. (Decreased motility)
• Ectopic pregnancy
• Neonatal hydrocephalus(rare)

Investigation and Work Up

Radiological Imaging

• X-Ray of the paranasal sinuses (PNS)
• Chest X-ray
  • Peribronchial cuffing
  • Atelectasis
  • Lobur bronchiectasis
• HRCT chest (preferred) - bronchiectasis seen

Transmission Electron Microscopy

• Gold standard to access ciliary structure defects.
• Specimen - Curettage from nasal epithelium or endobronchial brushing.
• Limitation - PCD can exist even in the absence of visible EM abnormalities.

Nasal Nitric Oxide (NO) Measurements

• Useful for screening tests for patients above 5 years of age.
• Normally, small amounts of NO are produced by pseudostratified columnar epithelium (ciliated)

Mutational Analysis

• Investigation of choice
• Biallelic or two alleles are affected by a particular gene mutation.

Diagnostic Criteria for PCD

Neonates

• Situs Inversus Totalis and
• Neonatal Respiratory Distress in term babies
• Plus any 1 of the following:
  • Diagnostic ciliary ultrastructure on electron micrographs or
  • Two mutations in PCD-associated genes.

Children Aged From 1 Month To 5 Years of Age

• > 2 major PCD clinical criteria
  • NRD
  • Chronic Productive Cough
  • Persistent Nasal Congestion
  • Laterality defects
• PLUS any 1 of the following:
  • Diagnostic ciliary ultrastructure on electron micrographs or
  • Two mutations in PCD associated gene or
  • Abnormal, persistent ciliary waveform on high-speed video microscopy on multiple occasions.

Children Aged From 5 To 18 Years of Age and Adults

• > 2 major PCD clinical criteria
  • NRD
  • Chronic Productive Cough
  • Persistent Nasal Congestion
  • Laterality defects
• PLUS, any 1 of the following:
  • Diagnostic ciliary ultrastructure electron micrographs or
  • Two mutations in PCD associated gene or
  • Abnormal, persistent ciliary waveform on high-speed video microscopy on multiple occasions or
  • Nasal Nitric Oxide during the plateau phase, if it is < 77 nanolitres/minute on two occasions and >2 months apart (with CF excluded).

Treatment 

• Enhance Mucociliary Clearance
  • Postural drainage
  • Chest physiotherapy
  • PEP devices
  • Percussion vests.
  • No role for mucolytic agents; avoid cough suppressants.
• Avoid Cigarette Smoking and Pollutants.
• Antibiotics should be given when exacerbation is suspected.

Prognosis 

• Progress to end-stage lung diseases
• Become candidates for lung transplants.
• Progression is slow; thus, the prognosis is better than cystic fibrosis.

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