Cystic Fibrosis Overview Quiz

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Questions and Answers

What is a potential complication of advanced cystic fibrosis that can lead to pulmonary hypertension?

Type II Respiratory failure (correct)

Hypovolemic shock

Type I Respiratory failure

Chronic respiratory alkalosis

Which of the following symptoms may indicate liver disease in a patient with cystic fibrosis?

Chronic cough

Tachycardia

Weight gain

Abdominal pain and jaundice (correct)

What is a common manifestation of cystic fibrosis related to endocrine dysfunction?

Diabetic ketoacidosis

Hypoglycemia

Type 1 diabetes mellitus

Cystic fibrosis related diabetes (correct)

What physical examination finding is associated with cystic fibrosis?

Tachypnea and clubbing Signup and view all the answers

What genetic mutation is primarily responsible for dysfunctional CFTR protein in cystic fibrosis?

CFTR gene mutation Signup and view all the answers

How does CFTR protein function at the cellular level?

As a chloride ion channel Signup and view all the answers

What is the primary method used for newborn screening to detect cystic fibrosis?

Heel prick test Signup and view all the answers

What condition can result from the presence of obstructive azospermia in males with cystic fibrosis?

Infertility Signup and view all the answers

Which of the following CFTR classes is associated with no CFTR protein being produced?

Class I Signup and view all the answers

What is a primary method used for monitoring lung function in patients?

Regular spirometry (FEV1) Signup and view all the answers

Which of the following is classified as a dietary supplement for cystic fibrosis patients?

Fat-soluble vitamins Signup and view all the answers

What type of mutation is the F508del mutation categorized as?

Class II Signup and view all the answers

In Sanger Sequencing, what is the role of ddNTPs?

They terminate the synthesis of DNA fragments. Signup and view all the answers

Which of the following statements is true regarding CFTR mutations?

More than 2000 mutations have been identified. Signup and view all the answers

What is a common characteristic of Class III CFTR mutations?

Defective gating Signup and view all the answers

Which dietary supplement is specifically noted for pancreatic dysfunction in cystic fibrosis?

Pancreatic enzyme tablets Signup and view all the answers

What is the first step in the Next Generation Sequencing process?

Isolate DNA and divide into smaller fragments Signup and view all the answers

Which method is employed by Illumina's NGS platforms?

Reversible termination sequencing Signup and view all the answers

What is the primary advantage of NGS over Sanger sequencing?

Higher throughput for large-scale genomic sequencing Signup and view all the answers

In nanopore sequencing, how is the DNA moved through the protein pore?

By applying an electric current Signup and view all the answers

What is a key characteristic of third generation sequencing technologies?

They allow direct sequencing of single molecules Signup and view all the answers

During the sequencing by synthesis method, what happens once the correct base is incorporated?

The blocking group is removed to allow further extension Signup and view all the answers

Which of the following is NOT a step in the nanopore sequencing procedure?

Amplify DNA based on the flow cell Signup and view all the answers

What role does DNA polymerase play in the NGS process?

It synthesizes complementary strands by PCR Signup and view all the answers

What result from a sweat test definitively indicates cystic fibrosis (CF)?

<blockquote> 60 mmol/L </blockquote> Signup and view all the answers

Which of the following is a characteristic of nasal potential difference (NPD) testing?

Measures voltage across the nasal epithelium Signup and view all the answers

What is the main purpose of using hypertonic saline in CF management?

To hydrate and thin mucus Signup and view all the answers

Which of the following antibiotics is specifically indicated for treating Pseudomonas aeruginosa infections?

Tobramycin Signup and view all the answers

Which CFTR modulator is indicated for patients aged 6 and up with the G551D mutation?

Ivacaftor Signup and view all the answers

What treatment is commonly used for allergic bronchopulmonary aspergillosis in CF patients?

Oral Itraconazole Signup and view all the answers

What role does Mannitol (Bronchitol) play in the management of CF?

Thins and clears mucus from airways Signup and view all the answers

Which treatment option would NOT be used for chronic bacterial infections in CF?

Monthly oral prednisolone Signup and view all the answers

What is the primary genetic cause of cystic fibrosis?

Mutations in the CFTR gene Signup and view all the answers

Which of the following is a common respiratory symptom of cystic fibrosis exacerbation?

Productive cough with increased volume Signup and view all the answers

Which of these organisms is associated with increased susceptibility to lung infections in cystic fibrosis patients?

Pseudomonas aeruginosa Signup and view all the answers

What is a significant gastroenterological complication often seen in patients with cystic fibrosis?

Pancreatic insufficiency Signup and view all the answers

Which of the following symptoms indicates a failure to thrive in young children with cystic fibrosis?

Recurrent chest infections Signup and view all the answers

What type of diabetes is specifically related to cystic fibrosis?

CF-related diabetes Signup and view all the answers

Which respiratory condition may arise as a non-infectious complication of cystic fibrosis?

Pneumothorax Signup and view all the answers

What is a key characteristic of the F508del mutation related to cystic fibrosis?

It is the most common mutation causing cystic fibrosis Signup and view all the answers

Study Notes

Cystic Fibrosis

Progressive, autosomal recessive genetic disorder
Primarily affects the lungs and pancreas
Caused by mutations in the CFTR gene leading to dysfunctional CFTR protein
F508del mutation is the most common cause of cystic fibrosis

Symptoms

Respiratory Issues:
- Chronic inflammation and bronchial wall thickening
- Air trapping leading to bronchiectasis
- Chronic cough, increased sputum production, shortness of breath, wheezing, and chest pain
- Chronic rhinosinusitis
- Respiratory failure is the main cause of death in CF patients
Gastrointestinal Issues:
- Pancreatic insufficiency: Difficulty maintaining weight, bowel issues, and fatty infiltration of the pancreas
- Large Bowel: Not mentioned in the text.
- Small Bowel: Not mentioned in the text.
- Upper GI: Not mentioned in the text
Increased susceptibility to lung infections:
- Pseudomonas aeruginosa
- Staphylococcus aureus
- Stenotrophomonas maltophilia
- Burkholderia cepacia complex
- Atypical mycobacteria
- Aspergillus
- Candida

Clinical Manifestations

Childhood Presentation:
- Failure to thrive
- Recurrent chest infections
- Meconium ileus
- Failure to reach growth milestones
Adult Symptoms:
- Respiratory: Pan-bronchiectasis, decreased mucociliary clearance, obstructive airway disease, respiratory failure
- Gastrointestinal: Pancreatic insufficiency, malabsorption, GORD, rectal prolapse, DIOS
- Other: CF-related diabetes, liver disease, osteoporosis, nasal polyps, infertility in males (CBAVD)

CF Exacerbation Symptoms

Increased productive cough
Increased sputum volume, purulence, and viscosity
Shortness of breath
Wheezing
Haemoptysis (blood in sputum)
Nasal and sinus symptoms
Duration of onset: few days to a couple of weeks
Fever not always present

CF Non-Infectious Respiratory Complications

Haemoptysis (blood in sputum)
Pneumothorax (pleuradiesis contraindicated)
Allergic bronchopulmonary aspergillosis: wheezing, unresponsive to antibiotics, thick mucus plugs, raised IgE
Atelectasis: due to mucus plugging; can lead to acute shortness of breath and hypoxia
Advanced disease: Type II Respiratory failure, Pulmonary hypertension with Cor Pulmonale

Other Manifestations

Liver Disease: Focal biliary cirrhosis, fatty infiltration, can lead to cirrhosis with splenomegaly, and varices; symptoms include jaundice, itch, abdominal pain, hematemesis
CF-related diabetes: Polyuria, polydipsia, lack of energy, failure to gain weight
Low bone mineral density/ osteoporosis: Usually asymptomatic, significance unknown, no increase in incidence of fractures
Growth retardation/ Delayed puberty:
Obstructive azospermia: Functional sterility in males (due to CAVBD)
CF Renal disease: Distinct entity, compounded by aminoglycoside use, and diabetes

Physical Examination Findings

General Inspection: Low BMI, delayed puberty, clubbing, cyanosis, oxygen dependence, tremor, tachypnea, accessory muscle use
Chest: Hyperinflation, portacath, crepitations, wheezing
Abdomen: Hepatosplenomegaly, PEG tube

CFTR Gene Mutations

CFTR gene mutations result in production of dysfunctional CFTR protein
Over 2000 mutations identified.
CFTR mutations are categorized into seven classes based on structural and functional consequences:
- Class I: No CFTR protein is produced.
- Class II: Defective protein processing.
- Class III: Defective gating.
- Class IV: Reduced ion conductance.
- Class V: Reduced protein synthesis.
- Class VI: Decreased CFTR stability at the membrane.
- Class VII: No mRNA production.

CFTR Protein

Member of the ATP-binding cassette (ABC) transporter superfamily
Located at the apical membrane of polarized epithelial cells
Cyclic AMP-regulated (phosphorylated by protein kinase A)
Acts as a chloride ion channel
Moves Cl- from inside the cell to outside the cell, attracting a layer of water
The water layer allows cilia on lung cells to move and sweep mucus out of the airways

CFTR Protein Mutations

Reduced chloride movement to the cell surface
Decreased volume and increased hyper-viscosity of mucosal secretions

Diagnosing Cystic Fibrosis

Newborn screening (NBS):
- Heel prick/Guthrie test
- IRT test measures immunoreactive trypsinogen levels in the blood; elevated levels indicate potential CF due to blocked pancreatic ducts.
- If IRT is raised, confirmation is done through genetic testing for common CF gene mutations: A diagnosis of CF is confirmed if two mutations are identified.
- Sweat test:
 - 60mmol/L indicates CF
 - 30-59mmol/L is inconclusive
 - <40 and >60 require a repeat test
- 60 mEq/L are considered abnormal.
- If genetic and sweat test are inconclusive:
 - Nasal potential difference (NPD): Assess CFTR protein function by evaluating ion movement (Cl-).
 - Intestinal current measurements (ICM): Assess chloride ion transport across rectal or colonic biopsies in vitro.

Management

Hydrators and Mucolytics:
- Hypertonic saline (3%-7%) 2-3x/day: Hydrate and thin mucus in the airways.
- Pulmozyme (Dornase Alpha): Recombinant human deoxyribonuclease I; breaks down DNA in mucus, reducing viscosity. Nebulized 1x/day.
- Mannitol (Bronchitol): Osmotic agent; draws water into airways, thinning and clearing mucus. 2x/day.
- Inhaled/ Nebulized bronchodilators: Salbutamol, Ipratropium
Anti-inflammatories: Not mentioned in the text.
Antibiotics for Chronic Bacterial Infections:
- IV antibiotics (2 weeks/2 agents):
  - H. influenza, S. aureus
  - P. aeruginosa: Tobramcyin + anti-pseudomonal semi-synthetic penicillin or 3rd generation cephalosporin or carbapenem.
  - Aspergillus: Allergic Bronchopulmonary Aspergillosis; Daily oral prednisolone or Monthly iv Methylprednisolone ± oral Itraconozole (12-18 months).
  - Stenotrophomonas: Sulfamethoxazole/Trimethoprim (Septrin)
  - MRSA: Vancomycin or Linezolid. If flucloxacillin is not effective, use vancomycin.
CFTR Modulators (Precision Medicine): Improve function at the cell membrane.
- Ivacaftor/Kalydeco: Patients aged 6 and up with one copy of the G551D mutation, a class III (gating) mutation.
- Help with protein folding and trafficking within the cell: Lumacaftor and Tezacaftor.
- Orkambi: Lumacaftor (corrector) + Ivacaftor (potentiator; for homozygous F508del)
- Symkevi: Tezacaftor (corrector) + Ivacaftor (potentiator; for homozygous F508del)
- Trikafta: Combination of two correctors (Elexacaftor, Tezacaftor) and a potentiator (Ivacaftor) for F508del mutation.
Physical Therapies: Airway clearance techniques, physiotherapy.
Dietary Supplements: Pancreatic enzymes, fat-soluble vitamins, high-fat diet.
- Pancreatic enzyme tablets: Creon
- Vitamin ADEK: Aquadek
- Proton pump inhibitors:
- Oral nutritional supplements:
- PEG feeds: Perative, Nutrison
Liver Disease: Ursofalk

Monitoring and Outpatient Care

Regular spirometry (FEV1), sputum culture, liver ultrasound, bone densitometry, chest X-ray, and annual measurements (OGTT, vitamin levels, liver function tests).

Outcomes

CF-related outcomes predicted by lung function (FEV1), BMI, exacerbation frequency, and infection control.
Transplantation may be considered in severe cases.

Common Mutations

Mutations in the CFTR gene lead to dysfunctional CFTR protein.
Over 2000 mutations identified.

Novel Genomics

Sanger Sequencing (First Generation): Uses chain-termination PCR; efficient for smaller sequences.
Next Generation Sequencing (NGS)/ Massively parallel sequencing/ Deep sequencing: More efficient than Sanger for large-scale genomic sequencing. Short-read sequencing with high accuracy but difficulty in covering repetitive genomic regions.
- Illumina (75-300bp): Uses a reversible termination sequencing method (sequencing by synthesis, reversible termination, optical detection).
Third Generation Sequencing: A subset of NGS technologies that directly sequence single molecules without amplification; focus on long-read sequencing for complex genomic regions like repetitive sequences.
- Nanopore and PacBio sequencing:

Nanopore Sequencing

Uses a protein pore and electrical disturbances to sequence DNA.
Individual nucleotides modify electrical current.
Can sequence both DNA and RNA.

5mC (5-Methylcytosine)

5mC is a form of DNA methylation in which a methyl group is attached to the 5th carbon atom of cytosine.
Procedure: 1. Extract DNA from a tissue sample. 2. End prep and nick repair. 3. Add sequencing adapters and motor proteins. 4. Load the library onto a flow cell.
Principle: Protein pore embedded in a membrane; DNA is negatively charged; apply a current to the space beneath the pore; as DNA passes through the pore, it creates an electrical disturbance.

5hmC (5-Hydroxymethylcytosine)

A modified form of cytosine that plays a significant role in epigenetic regulation and cellular signaling.
It is an intermediate in the demethylation pathway, where it is converted from 5-methylcytosine (5mC) to 5-formylcytosine (5fC) and then to cytosine.

5mA (5-Methylcytosine with N6-methyladenine)

A type of DNA methylation that is found in various organisms which plays a role in regulating gene expression and DNA replication.
The presence of 5mA is associated with repressive chromatin states and can influence DNA strand separation during replication - important for development- related functions.

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Description

Test your knowledge on cystic fibrosis, a progressive genetic disorder that affects the lungs and pancreas. This quiz covers the causes, symptoms, and complications associated with the condition. Challenge yourself and learn more about the F508del mutation and its impact on patients.