Sweat Test for Cystic Fibrosis Diagnosis

Questions and Answers

What is the primary function of the CFTR protein?

A hormone regulator in the endocrine system

A cation channel for Na+ and K+

An anion channel for Cl- and HCO3- (correct)

A protein involved in the breakdown of carbohydrates

What is the normal range of Cl- concentration in sweat?

Between 30-60 mM

Less than 30 mM

More than 60 mM

Less than 60 mM (correct)

What is the name of the gene that codes for the CFTR protein?

CFT1

CFTR (correct)

CFTR2

Cystic Fibrosis Gene

What is the purpose of the sweat test in diagnosing cystic fibrosis?

To measure Cl- and Na+ in sweat Signup and view all the answers

What is the name of the protein family that CFTR belongs to?

ABC transporter family Signup and view all the answers

What is required to activate the CFTR channel?

Phosphorylation Signup and view all the answers

What percentage of cystic fibrosis alleles carry the F508del variant?

50-70% Signup and view all the answers

What is the frequency of cystic fibrosis carriers in the general population?

1/25 Signup and view all the answers

Which of the following is a characteristic of classical cystic fibrosis?

Pancreatic insufficiency Signup and view all the answers

What is the effect of the 5T variant on CFTR function?

Decreased CFTR function Signup and view all the answers

What is the relationship between CFTR genotype and pulmonary disease?

Poor correlation Signup and view all the answers

What is the effect of mutant CFTR alleles on cholera toxin stimulation?

Decreased Cl- and water loss Signup and view all the answers

What is the characteristic of congenital bilateral absence of the vas deferens (CBAVD)?

Male infertility with mild CF features Signup and view all the answers

What is the proportion of cystic fibrosis patients carrying at least one F508del allele?

>80% Signup and view all the answers

What is the relationship between sweat chloride levels and CFTR function?

Direct correlation Signup and view all the answers

What is the role of modifier genes in cystic fibrosis?

Contribution to variable severity of clinical manifestations Signup and view all the answers

What is the function of Ivacaftor in the context of cystic fibrosis?

CFTR potentiator Signup and view all the answers

What is the purpose of amiloride in the Ussing chamber experiment?

To block Na currents Signup and view all the answers

Which of the following is used to activate CFTR in the Ussing chamber experiment?

Forskolin Signup and view all the answers

What type of epithelial cells are used in the Ussing chamber experiment?

Bronchial epithelial cells Signup and view all the answers

In which type of CFTR mutation is Ivacaftor more effective?

G551D/F508del CFTR Signup and view all the answers

In which journal was the study by Van Goor et al. published?

Proc Natl Acad Sci USA Signup and view all the answers

What is the name of the medication approved by the EMA in 2020 and marketed in Europe as?

Trikafta Signup and view all the answers

What is the predicted median survival for patients with CF initiating Trikafta treatment between the ages of 12 and 17 years?

82.5 years Signup and view all the answers

In what year was the Breakthrough Prize awarded to Sabine Hadida, Paul Negulescu, and Fredrick Van Goor for the development of Trikafta?

2024 Signup and view all the answers

Which of the following sources provides information on Cystic Fibrosis and Congenital Absence of the Vas Deferens?

Gene Reviews Signup and view all the answers

In what year was the article 'Cystic fibrosis' by Ratjen et al. published?

2015 Signup and view all the answers

Which of the following articles discusses the application of CFTR modulators in cystic fibrosis?

CFTR Modulators: Shedding Light on Precision Medicine for Cystic Fibrosis Signup and view all the answers

What is the outcome of treatment with lumacaftor in CF cell models?

Increase in F508del CFTR maturation and chloride secretion Signup and view all the answers

What is the method used to evaluate protein maturation in CF cell models?

Immunoblotting Signup and view all the answers

What is the effect of lumacaftor on non-CFTR misfolded proteins?

No effect on their maturation Signup and view all the answers

What is the outcome of combined treatment with lumacaftor and ivacaftor in CF patients?

Improvement in lung function Signup and view all the answers

What is the type of assay used to measure transepithelial chloride transport in CF cell models?

Ussing chambers Signup and view all the answers

What is the characteristic of lumacaftor compared to other CFTR correctors?

Selective correction of CFTR processing Signup and view all the answers

What is the duration of treatment with lumacaftor-ivacaftor in the clinical trial?

24 weeks Signup and view all the answers

What is the effect of lumacaftor on CFTR protein in CF cell models?

Increase in F508del CFTR maturation Signup and view all the answers

Study Notes

Cystic Fibrosis Diagnosis

Sweat test is used for clinical diagnosis of CF
- Measures Cl- and Na+ in sweat following stimulation with pilocarpine
- CF: [Cl-] > 60 mM
DNA test is used to confirm diagnosis
CFTR gene: located on 7q31.2, codes for CFTR protein
- Anion channel for Cl- and HCO3-
- Expressed on apical surface of epithelial cells in exocrine organs

CFTR Protein Structure

Member of ABC transporter family
- Consists of:
  - 2 membrane spanning domains (MSD1 and MSD2)
  - 2 intracellular nucleotide-binding domains (NBD 1 and NBD2)
  - 1 intracellular regulatory domain (R domain)

CFTR Variants

>2000 variants, of which ~380 are CF-causing
Most frequent variant: F508del (ΔF508)
- Deletion of Phe at aa 508
- Accounts for 50-70% of all CF alleles
- >80% of CF patients carry at least one copy

Global Distribution of CF

Prevalence: 1 in 2500 live births
Carrier frequency: 1/25
Heterozygote advantage: protection against infectious diseases (e.g. cholera and typhoid fever)

Classification of Pathogenic CFTR Variants

Classified into severe (minimal or no CFTR function) and mild (residual CFTR function)
Correlation between CFTR function and clinical phenotype:
- Pancreatic insufficiency: good correlation
- Pulmonary disease: poor correlation

Genotype-Phenotype Correlation

Pancreatic function: presence of 1 or 2 mild alleles → pancreatic sufficiency
Pulmonary disease: variability in severity and age of onset among individuals with same CFTR genotype

Genetic Factors Contributing to Phenotypic Variability

Combination of CFTR variants in trans or cis
Poly(T) tract variants in intron 8
- Affects splicing of exon 9
- 5T variant → loss of exon 9 → reduced quality of functional CFTR

Congenital bilateral absence of the vas deferens (CBAVD)
Recurrent idiopathic pancreatitis
Bronchiectasis

Correlation of CFTR Function with Sweat Chloride Levels and Clinical Phenotype

Sweat chloride levels: correlation with CFTR function and clinical phenotype
bronchiectasis: rare presentation in carriers, unclear correlation with CFTR genotype

CF Modifier Genes

Variants in modifier genes contribute to variable severity of clinical manifestations in patients with same CFTR genotype

CFTR Modulators

Ivacaftor (VX-770): acts as a CFTR potentiator to increase Cl- transport
Lumacaftor (VX-809): corrects F508del CFTR trafficking and function
Trikafta: combination of lumacaftor and ivacaftor
- Improves lung function in CF patients bearing homozygous F508del CFTR
- Approved by EMA and AIFA for prescription under the Italian public health service

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Description

This quiz assesses understanding of the sweat test used in diagnosing cystic fibrosis, including the measurement of chloride and sodium levels in sweat. It also covers the role of pilocarpine stimulation and the diagnostic criteria for CF.