Alpha-1 Antitrypsin Deficiency (AATD) is a genetic condition that can lead to serious health problems, particularly affecting the lungs and liver. This disorder arises from a defect within a specific gene, altering the body’s ability to produce a protective protein. Understanding the genetic basis of AATD helps clarify how it develops and impacts individuals.
Understanding Alpha-1 Antitrypsin
Alpha-1 antitrypsin (AAT) is a protein produced primarily by the liver. It protects the body’s tissues from damage caused by certain enzymes. Neutrophil elastase, an enzyme released by white blood cells (neutrophils) during inflammation or infection, helps break down harmful bacteria and damaged tissue.
AAT neutralizes neutrophil elastase, preventing it from damaging healthy tissues. This protective action is important in the lungs, where unchecked elastase activity can degrade the elastic fibers. Without sufficient functional AAT, these tissues become vulnerable to continuous breakdown.
How AAT Deficiency is Inherited
The SERPINA1 gene directs alpha-1 antitrypsin production. Individuals inherit two copies, one from each parent. Alpha-1 antitrypsin deficiency is inherited in an autosomal recessive manner. This means that for a person to develop the severe form of AATD, they must inherit two altered copies of the SERPINA1 gene, one from each parent.
Several variants of the SERPINA1 gene exist, but some are more common and cause deficiency. The PiM variant is considered normal and leads to typical AAT production. Variants like PiS and PiZ result in reduced or dysfunctional AAT. For example, the PiZ variant is associated with lower AAT levels because the protein misfolds and gets trapped within liver cells.
Individuals who inherit one normal copy (PiM) and one altered copy (e.g., PiS or PiZ) are considered carriers. These carriers (e.g., PiMZ or PiMS genotype) often produce enough AAT to prevent severe lung disease, though some may experience mild symptoms or an increased risk under certain conditions. Carriers can pass the altered gene copy to their children, meaning two carrier parents have a 25% chance with each pregnancy of having a child with two altered copies, leading to severe AATD.
Impact of Genetic Deficiency on Health
An altered SERPINA1 gene prevents the body from producing sufficient functional alpha-1 antitrypsin, leading to health consequences. The primary outcome is lung disease, particularly emphysema or chronic obstructive pulmonary disease (COPD). Without enough AAT to inhibit neutrophil elastase, this enzyme continuously breaks down the elastic tissue in the lungs, leading to loss of elasticity and impaired breathing over time. This damage often begins in the lower lobes of the lungs.
A common health concern is liver disease, affecting some individuals with AATD, especially those with the PiZZ genotype. In these cases, the altered AAT protein misfolds and accumulates within the liver cells rather than being released into the bloodstream. This buildup can damage liver cells, leading to inflammation, fibrosis, and eventually cirrhosis, a severe form of liver scarring. Less common manifestations include panniculitis, a skin condition involving inflammation of fatty tissue.
Genetic Screening and Family Considerations
Diagnosing alpha-1 antitrypsin deficiency involves blood tests to measure AAT protein levels. If levels are low, genetic testing is performed to identify variants of the SERPINA1 gene. This genetic analysis confirms the diagnosis and pinpoints the genotype (e.g., PiZZ or PiSZ), which helps predict the severity of the condition. Identifying the genotype is important for management and family counseling.
Since AATD is an inherited condition, individuals diagnosed with the deficiency are advised to have their family members screened. This includes parents, siblings, and children, as they may also be carriers or have the condition themselves. Genetic counseling plays an important role, providing families with information about inheritance patterns, health risks, and family planning options. Counselors help individuals understand their genetic status and implications for future generations.