Primary Ciliary Dyskinesia

Question 1

Describe the inheritence pattern of Primary Ciliary Dyskinesia

Answer 1

Autosomal recessive

Affects 1:20,000 Britons, but X-linked PCD occurs as result of RPGR gene mutations

Question 2

Describe the role of cilia in the airways (2) and identify where they are found (5).

Answer 2

Host defence and mucus clearance

Found in respiratory tract, cerebral cilia, eustacian tubes, reproductive system (fallopian tubes, sperm), embyronic node

Question 3

Describe the two main symptoms and one sign experienced in PCD

Answer 3

Wet/productive cough

Recurrent chest infections

Bronchiectasis

Question 4

Describe four associated conditions of PCD

Answer 4

Chronic URT and LRT infections (rhinitis and sinusitis) (100%)

situs anomalies - Situs Inversus (55%)

Recurrent Otitis Media (95%)

Infertility/Ectopic pregnancy

73% have neonatal respiratory symptoms. Other abnormalities include hydrocephalus, retinal abnormalities (RPGR PCD). Associations with congenital heart disease

Question 5

How is a clinical diagnosis made for PCD? (4)

Answer 5

Clinical history

Genetic testing

High-speed video microscopy* - Nasal brushings

Nasal NO (↓NO in PCD)

Transmission electron microscopy diagnostic tool - however, not gold standard as PCD may be present where no detectable ultrastructural abnormality can be found.

Question 6

Structure of the cilia: Cilia have _______ peripheral microtublue doublets and _______ single microtubles found in the ________. Each microtubule doublet on the perihpery have an ___ and ___ subunit. Each microtubule is linked by a ________ link. They also have an outer and inner ___________ arm. Each peripheral doublet has a _________ ___________ which plays a role in mechanical movement of the cilia.

Answer 6

Cilia have nine peripheral microtublue doublets and two single microtubles found in the centre. Each microtubule doublet on the perihpery have an A and B subunit. Each microtubule is linked by a nexin link. They also have an outer and inner dynein arm. Each peripheral doublet has a radial spoke which links it to the central doublet - they play a role in mechanical movement of the cilia.

Question 7

Name the first two PCD-associated genes and describe the defect observed and the effect on the cilia

Answer 7

DNAI1 and DNAH5 -> outer dynein arm defect -> immotile or hypokinetic cilia

Question 8

PCD is a genetic disease characterised by motile ciliary dysfunction. There is much heterogeneity in this condition. TEM can usually identify what 3 defects. Which 3 defects can it not identify (30%)

Answer 8

Identifies:

• Complete or partial absence of ODA
• Combined ODA and IDA defect
• Microtubule disorganisation

Does not identify:

• Nexin link defects
• Central pair defects
• DNAH11 mutations

Question 9

Other gene mutations identified in PCD include:

__________: DNAL1, DNAH5, _______

Outer arm docking complex: CCDC151, CCDC114

Dynein-regulatory complex (________): CCDC39, ________

Central apparatus: ________, RSPH1, _______

Answer 9

Other gene mutations identified in PCD include:

ODA proteins: DNAL1, DNAH5, DNAH11

Outer arm docking complex: CCDC151, CCDC114

Dynein-regulatory complex (nexin link): CCDC39, CCDC40

Central apparatus: HYDIN, RSPH1, RSPH9

DNAL/H = Dynein Axonemal Light/Heavy Chain; CCDC = Coiled-Coil Domain Containing proteins; RSPH = Radial Spoke Head x Homlog

Question 10

Mutations of genes encoding central apparatus (HYDIN, RSPH4A, RSPH9) have a unique phenotype which manifests as:

a. Immotile cilia
b. Hypokinetic cilia
c. Rotational waveform
d. Irregular, non-controlled

Answer 10

Rotational waveform

This mutation is less likely to be associated with situs anomalies as nodal cilia normally lack the central pair.

Question 11

Respiratory ciliated cells have an average 200 cilia per cell. There have been reports of patients with a marked reduction in number of motile cilia experiencing PCD symptoms. This is referred to as Reduced Generation of Multiple Motile Cilia (RGMC). Name two gene mutations which cause RGMC

Answer 11

Cyclin O (CCNO):

Required for centriole production which leads to ↓basal bodies and mislocalisation of basal bodies and defective migration to cell membrane

Multiciliate Differentiation and DNA Synthesis Associated Cell Cycle Protein (MCIDAS):

Controls centriole repilcation required for normal ciliated cell formation

Question 12

Name the 3 most common gene mutations found in PCD

Answer 12

DNAI1, DNAH5, DNAH11

DNAI1 = Dynein Axonemal Intermediate Chain 1

Question 13

Which zone of the lungs is most affected by mucus plugging in PCD. How does this differ to other respiratory disease.

Answer 13

PCD: lower zone mucus plugging

Bronchiectasis: upper zone mucus plugging

Question 14

Describe the difference in findings of a bronchoscopy of patient with PCD and CF with regards to inflammation and mucus.

Answer 14

PCD: non-inflammed, mucus

CF: inflammed, mucus

Question 15

Describe some situs or cardiac anomalies (6)

Answer 15

Situs solitus (normal)

Situs inversus totalis

Left isoemrism (two left hearts and lungs) and polysplenia

Right isomerism and asplenia

Situs inversus thoracalis

Situs inversus abdominalis

Question 16

Name a scoring system used for PCD.

Answer 16

PICADAR: a 7-question survey which is used in patients that have a daily wet cough that started in early childhood. It predicts the likelihood of PCD

5 points (out of 14) has 0.9 sensitivity and 0.75 specificity

Question 17

Screening test used for PCD

Answer 17

nNO (<5)

Nasal NO