Imagine, You are in your 20s, active and healthy. Life is going fine but then you start noticing, you are losing weight and coughing a lot lately. You are very unsure of what's happening. You also start noticing your skin is becoming more dehydrated and despite of good diet and exercise, gaining weight seems impossible now. What's going on? you asked and rushed to your doctor.
After a few days and a series of tests, you are now diagnosed with a condition called Cystic Fibrosis(CF). Doctors explain to you that, it's a life-threatening disease. They also add that it's a genetic disease that starts in your lungs but later on affects other systems of the body too. But the catch is, it is caused by a single error in your DNA which leads to a cascade of problems.
In this article, we are diving deep into this Disorder and look at how a single gene mutation can create a cascade of problems. Let's begin.
The CFTR Mutation. Where it all begins.
As I said it is an inherited disease meaning passed from parents to children. But you need to be familiar with one more term "Autosomal Resseive disease". Here is a quick genetic refresher for you. Every cell in the human body has 46 chromosomes, 23 from the father and 23 from the mother. When both the father and mother are the "carriers" of the disease, then the mutated gene is passed down to the children and has only a 25% chance of being expressed. Here is a picture to describe it.
As you can see, Father and mother both carry a defective gene but remember they are only the carriers, they do not have the disease. Only one child out of 4 is affected, however, two of them are carriers now. This is what "Autosomal recessive" means, you got a disease because of your parent's defective recessive genes.
The culprit gene in this condition is the CFTR gene or Cystic fibrosis transmembrane conductance regulator gene. When this gene is normal, its function is to produce CFTR protein which embeds itself into the cell membrane and helps in the regulation of Chloride ions in and out of the cells. You have to know the basic law of biochemistry. Sodium ions always follow chloride ions and Water(H2O) always follows sodium ions. Therefore, this CFTR protein helps in maintaining the essential balance between salt and water in the body.
CFTR Protein in cell membrance. Credits: Wikipedia
When the CFTR is mutated, this protein won't be produced properly and most of it will be misfolded. This misfolding makes it difficult of to embed into the cell membrane. This malfunctioning leads to defective chloride ions regulation and in turn defective salt and water regulation in the cells. The real problem starts here.
How Cystic Fibrosis Affects the body?
Most people think that cystic fibrosis is only a lung disease, however, it's not the case. In fact, this affects multiple systems in the body. Let's see, how
Lungs : When this protein isn't working properly, the essential chloride ions regulation won't work correctly. This leads to salt and water retention in the lungs which will be seen as thick mucus. See, in healthy people, some degree of mucus is important to trap bacteria but in cystic fibrosis, this mucus is thick and excessive. The trapped bacteria starts growing inside this thick mucus over time and boom lung infections.
Over time, These persistent infections and thick mucus in the lungs make it difficult to breathe and produce scarring in the lungs. This heavily decreases lung functions and may need a lung transplant.Pancreas : The name "Cystic Fibrosis" comes due to the changes in this gland. Same as the lungs, thick mucus is also formed in the pancreatic ducts. These thick secretions block off the duct. The pancreatic juices are not able to go to the intestine and help in the abortion of fats. Repeated blockage in the pancreas leads to inflammation and may also lead to acute pancreatitis.
All, these processes form multiple cysts and multiple fibrosis in the pancreas. Hence the name "Cystic Fibrosis".
Symptoms. Credits: Wikipedia.
Digestion: When the pancreatic secretions are blocked off, digestion is severely affected. Pancreatic secretions are responsible for the absorption of fat and other nutrients. Without this, you will have a hard time gaining weight.
Liver: Thick mucus can also block the bile ducts. Which can eventually lead to severe liver cirrhosis and failure. Also, Fat absorption will be severely affected. This could also lead to decreased fertility in both men and women.
How Do we Diagnose it then?
In some countries, where Cystic Fibrosis is more prevalent, newborn screening is done, for early detection and treatment. how?
Sweat test: it's a simple test, when the CFTR gene in the skin is defective, Chloride ions can't go into the cell during sweating, hence there will be a high amount of chloride ions in the sweat, which indicates, the child might have CFTR gene mutation.
Pancreas Biopsy: The Biopsy shows, the pancreas is full of cysts and multiple fibrosis with layers of inflammations.
Genetic Testing: On genetic testing, Chromosome 7 is found to be defective. There is a missing Phe508 gene which codes for CFTR protein.
The road to managing cystic fibrosis.
As it is an inherited disease, so there is obviously no definitive cure now. But, there are options available to manage the symptoms and increase life expectancy.
These treatment options are inhaled medications for airway clearance, pancreatic supplements, and proper nutrition with insulin therapy.
Interestingly, in recent times, some advancements have been made though. Scientists have been working on CFTR modulators drugs that can directly modulate the defective CFTR protein itself. This helps in regulating the functions of the target protein which addresses the core problem. These drugs have been a game changer for many in recent years.
That's it for this article. See you in the next one.
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References:
https://www.uptodate.com/contents/cystic-fibrosis-treatment-with-cftr-modulators
https://www.uofmhealth.org/conditions-treatments/pulmonary/cystic-fibrosis