Alpha-1-Antitrypsin Deficiency

Alpha-1 antitrypsin (AAT) deficiency is an inherited disorder that may cause lung and/or liver disease. First signs and symptoms of lung disease usually develop between the ages of 30 and 40 in smokers. The first signs of symptoms in non smokers usually develop between 40 and 55. These symptoms include shortness of breath following mild activity, reduced ability to exercise, and wheezing. Affected individuals often develop a lung disease called emphysema, making it difficult to breathe and produces a hacking cough. The appearance of emphysema and damage to the lungs is accelerated by smoking or exposure to tobacco smoke. Life expectancy may be normal for non-smokers. About 10 percent of infants with AAT deficiency develop liver disease, and about 15 percent of adults develop liver damage. Signs of liver disease or damage include a swollen abdomen, swollen feet or legs, and jaundice (yellowing of the skin and whites of the eyes). The risk of liver cancer is increased in all individuals with alpha-1 antitrypsin deficiency. AAT deficiency is caused by pathogenic variants in the SERPINA1 gene.

This condition is inherited in an autosomal codominant pattern. Codominance is a relationship between two versions of an allele. An allele is one of two or more versions of a gene. Codominance inheritance means that two different versions of the gene may be active (expressed), and both versions contribute to the genetic trait. The most common allele of the SERPINA1 gene is M allele, which can produce normal amount of alpha-1 antitrypsin. The S allele produces moderately low levels of this protein, and the Z allele produces very little alpha-1 antitrypsin. Individuals with two copies of the Z allele (ZZ) in each cell are likely to have alpha-1 antitrypsin deficiency. Those with the SZ combination have an increased risk of developing lung diseases (such as emphysema), particularly if they smoke.

Individuals with one normal (M) allele or two SS alleles usually produce enough alpha-1 antitrypsin to protect the lungs. However, the Z allele is more severe. Individuals with one Z allele may have an increased risk for lung disease, especially if they smoke. Individuals with one copy of the Z allele also have a slightly increased risk of liver dysfunction. Individuals with two copies of the Z allele are at high risk for both liver and lung disease. A reproductive risk will be present if an individual has an S allele and their partner has a Z allele or if an individual has a Z allele and their partner has either an S or Z allele. Testing of reproductive partners is therefore recommended for carriers of alpha-1 antitrypsin deficiency.

AATdeficiency occurs worldwide, but varies by population. This disorder affects about 1 in 1,500 to 3,500 individuals of European ancestry. It is uncommon in people of Asian and African descent. Many individuals with alpha-1 antitrypsin deficiency are likely undiagnosed. Some patients with chronic obstructive pulmonary disease (COPD) are thought to have AAT deficiency.

Genetics Home Reference: Alpha-1 antitrypsin deficiency (http://ghr.nlm.nih.gov/)

OMIM [Alpha-1-antitrypsin deficiency: 613490] (http://www.ncbi.nlm.nih.gov/omim)
Gene Reviews: Alpha-1-antitrypsin deficiency (http://www.ncbi.nlm.nih.gov/books/NBK1116/)

• Full gene sequencing