Understanding Cystic Fibrosis

Definition

Gene Mutation

CFTR Gene

Cystic Fibrosis (CF) is caused by a defect in a gene known as the cystic fibrosis transmembrane conductance regulator (CFTR) gene. This gene makes a protein that controls the movement of ions, such as chloride, and water, across cell membranes.^1,2

In people with CF, the CFTR gene does not work effectively. This results in thick, sticky mucus secretions – the underlying defect in CF.¹

Scientists identified the gene responsible for CF in 1989, leading to significant advances in the early detection and management of cystic fibrosis.³

Inheritance of Cystic Fibrosis

For a person to acquire CF, he or she must inherit two abnormal copies of the CFTR gene. That means that both of the person’s parents must carry at least one defective CFTR gene.⁴

If both parents carry an abnormal CFTR gene, their child has a one in four (25%) chance of inheriting two abnormal CFTR genes and having CF.
Children who inherit an abnormal CFTR gene from one parent and a normal CFTR gene from the other parent will not have CF; they will live a normal life as a carrier of CF.

CFTR Mutations

Classes of CFTR Mutations

More than 1000 mutations of the CFTR gene have been described, but only a few common mutations cause disease in most patients. These mutations can be grouped into six general classes based on the mechanism of dysfunction.^3,5

Class I to III mutations, sometimes referred to as classic or typical CF, are the most common.
Worldwide, class II mutations account for more than 70% of mutations in the white population of Britain and the United States.⁵
Class IV to VI mutations, the nonclassic or atypical forms, occur less frequently.⁵

Disease Severity

CFTR mutations are correlated with disease severity.³

Patients with class CF (class I to III mutations) generally experience more severe disease.⁶
Patients with nonclassic CF (class IV to VI) mutations develop some symptoms of CF. Nonclassic CF is often diagnosed later in life as patients have milder lung disease and often adequate pancreatic function.⁶

Lung function decline occurs in all patients with CF regardless of the mutation type. Patients with classic or nonclassic CF can have mild, moderate, or severe lung dysfunction.⁶

Source: Knowles MR, Durie PR. What is cystic fibrosis? N Engl J Med 2002 August 8;347(6):439-42.⁷

Lung dysfunction severity is based on the percentage of predicted FEV₁> as follows:⁸

Mild lung dysfunction is FEV₁ > 70% of predicted.
Moderate lung dysfunction is FEV₁40% to 69% of predicted.
Severe lung dysfunction is FEV₁<40% of predicted.

References:
1. Boucher RC. Cystic Fibrosis. In: Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL et al., editors. Harrison's Internal Medicine. 16th ed. New York: McGraw-Hill; 2005. p. 1-9.
2. Aitken M, Fiel SB, Stern RC. Cystic Fibrosis: Respiratory Manifestations. In: Taussig LM, Landau LI, editors. Pediatric Respiratory Medicine. 1st ed. St. Louis: Mosby, Inc.; 1999. p. 1-47.
3.  Welsh M. Cystic Fibrosis. In: Goldman L, Ausiello D, eds. Cecil Textbook of Medicine. 22nd ed. Philadelphia: WB Saunders; 2004. p. 1-22.
4. National Heart Lung and Blood Institute. What Is Cystic Fibrosis. US Department of Health and Human Services National institute of Health 2005;1.
5. Mason P. Cystic fibrosis-the disease. Hospital Pharmacist 2005;12:201-7.
6. Cystic Fibrosis Genotype-Phenotype Consortium. Correlation between genotype and phenotype in patients with cystic fibrosis. N Engl J Med 1993 October 28;329(18):1308-13.
7. Knowles MR, Durie PR. What is cystic fibrosis? N Engl J Med 2002 August 8;347(6):439-42.
8. Cystic Fibrosis Foundation. Patient Registry Annual Data Report. 2005