Alpha-1 Antitrypsin Deficiency

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Alpha-1 Antitrypsin Deficiency

Genetics of Alpha-1 Antitrypsin Deficiency

The gene that makes alpha-1 antitrypsin (AAT) is called the SERPINA1 gene.  There are two common changes, or mutations, in this gene.  These mutations cause the gene to make less AAT.  Low levels of AAT increase the chances for symptoms of Alpha-1 to develop.

The mutations are named with letters. PI*M is the normal form of the gene.  PI*S and PI*Z are the two common mutations.  Ninety-five percent of people with Alpha-1 have two copies of PI*Z (also called PI ZZ).

Other types of mutations have been seen in the SERPINA1 gene.  These mutations are very rare and are not picked up by the usual genetic testing for Alpha-1. They can only be picked up by gene sequencing.

Recessive Inheritance

Everyone has two copies of each gene. We inherit one copy from our mother and one copy from our father. Alpha-1 is a recessive condition. This means that people must inherit two AAT gene mutations — one from their mother and one from their father — in order to develop symptoms from Alpha-1.

People who have one normal AAT gene and one gene with a mutation are called carriers. About 1 in 10 to 1 in 33 people in the U.S. are Alpha-1 carriers, but most do not know it. Having one working gene is usually enough to prevent symptoms.

Carriers may have a higher chance for lung or liver disease in some cases, especially when they have environmental risk factors.  Avoiding smoking and other exposures can be important even for carriers.

Autosomal Recessive Inheritance

Carriers can pass the AAT mutation to their children. If both parents are carriers, there is a 1 in 4 (or 25%) chance with each pregnancy that the child will inherit both parents' mutations. Having two mutations significantly increases the chance of developing signs and symptoms of Alpha-1.

Gene Combinations

It matters whether you have one or two gene mutations and how they are combined with each other.  The table below shows how different gene pairs work in Alpha-1, and how they combine with environmental factors like smoking to cause disease. "M" is the normal gene, "S" is a mild mutation, and "Z" is a more severe mutation.

Test ResultHealth Effects
PI MM
  • Normal
PI MS
  • Normal
PI SS
  • Generally normal
PI MZ
  • Non-smokers may show mild differences in lung function but rarely have clinical symptoms
  • Smokers have impaired lung function; some may have clinical symptoms
  • Low risk for adult-onset liver disease
  • No increased risk for childhood liver disease
PI SZ
  • Risk of lung disease is low in non-smokers
  • Lung disease in smokers can be as severe as in PI ZZ
  • Low risk for adult-onset liver disease
  • No increased risk for childhood liver disease
PI ZZ
  • Adult-onset lung disease, more severe in smokers
  • Higher risk for adult-onset liver disease (15% to 19% chance for those over the age of 50)
  • Risk for severe childhood liver disease is about 2%

Next: Who Should Test for Alpha-1 Antitrypsin Deficiency?

Why are you considering genetic testing?

I think I might have Alpha-1, but I haven't seen a doctor yet.

I probably have Alpha-1 but have not yet had genetic testing.

I have a family member with definite or possible Alpha-1.

My partner has Alpha-1 or is a known carrier, and we want to know the risks for our children.

The symptoms you may feel from Alpha-1 Antitrypsin Deficiency are very similar to symptoms caused by many different breathing conditions. People with symptoms of breathing or liver problems may need lab tests, imaging, breathing tests, and other tests to help a doctor find the likely cause of those symptoms.

Genetic testing shouldn't be considered until all of the other common causes have been ruled out.

When testing finds two mutations, the results confirm that you have Alpha-1 antitrypsin deficiency. Knowing information about your Alpha-1 mutations can provide you with information to treat your condition and prevent complications. Your results give you information to:

  • Make informed choices about health care, lifestyle, career, and family planning
  • Take steps to slow the progression of Alpha-1
  • Avoid harmful behaviors such as smoking and alcohol consumption
  • Modify your exposure to environmental factors such as dust, pollution, and certain chemicals
  • Start appropriate treatments
  • Identify relatives who may also be at-risk for having Alpha-1
    • Your brothers and sisters would have the highest chance to also have the disease. There is a chance for other relatives as well because of how common carriers are

When testing doesn't find a mutation, the results don't completely rule out that you have Alpha-1 antitrypsin deficiency. Genetic testing cannot find all of the gene mutations that cause Alpha-1 Antitrypsin Deficiency. Additional testing, such as protein testing or gene sequencing, may be helpful if your doctor thinks the chances are very high that you have Alpha-1 even when your test results are normal.

If you have a family member with Alpha-1, your chances to have it are higher. The chance is highest if your brother or sister has Alpha-1. The first person in the family to have genetic testing should be someone most likely to have Alpha-1. If your relative(s) that might have Alpha-1 aren't available or willing to have genetic testing, you can have testing but the meaning of your results may be less clear.

  • When testing finds two mutations, you can be certain that you have inherited Alpha-1. The symptoms of Alpha-1 can be different between people in the same family. Some people have the mutations but never get symptoms at all. So, your results don't necessarily predict your future but they do mean that you need may need screening tests to check your lungs and liver. Your results give you information to:
    • Make informed choices about health care, lifestyle, career, and family planning
    • Take steps to slow the progression of Alpha-1
    • Avoid harmful behaviors such as smoking and alcohol consumption
    • Modify your exposure to environmental factors such as dust, pollution, and certain chemicals
    • Start appropriate treatments
    • Identify other relatives who may also be at-risk for having Alpha-1
  • When testing finds one mutation, you are a carrier of Alpha-1. The chance for you to develop lung or liver problems is low, especially if you don't smoke. However, you have a higher chance to have a child with Alpha-1. You may wish to consider carrier testing for your partner. If both parents are carriers, there is a 1 in 4 (25%) chance with each pregnancy to have a child with Alpha-1.
  • When testing doesn't find a mutation, there are two possible explanations – you may not have inherited either of the mutations that cause Alpha-1 in your family or the mutation that causes Alpha-1 in your family can't be found with the test that was done. In this situation, a normal result doesn't rule out the chance that you are an Alpha-1 carrier. However, it is very unlikely that you have Alpha-1 or are a carrier. Genetic testing finds about 95% of the mutations that cause Alpha-1.

If you don't have a family history of Alpha-1, the chance for you to be a carrier is between 1 in 10 and 1 in 33. The chances may be lower if your ancestors are not from Europe.

  • When testing finds a mutation, then you are a carrier of Alpha-1.
    • If your partner has Alpha-1, the chance for you to have a child with Alpha-1 is 1 in 2 (50%) with each pregnancy.
    • If your partner is a carrier of Alpha-1, the chance for you to have a child with Alpha-1 is 1 in 4 (25%) with each pregnancy.
    • Prenatal diagnosis is possible for Alpha-1. However, this testing is not useful for telling how mild or severe the disease might be, or when a child might begin to have symptoms. The chance for health problems in childhood is low.
  • When testing doesn't find a mutation, then the chance for you to be a carrier is very low. Testing detects about 95% of the mutations that cause Alpha-1. You are at a very low risk to have a child affected by Alpha-1.