What causes Alpha-1 Antitrypsin (A1AT) deficiency?

From the Guidelines

Alpha 1 antitrypsin deficiency is caused by mutations in the SERPINA1 gene, which provides instructions for making the alpha-1 antitrypsin protein, and is inherited in an autosomal codominant pattern. This genetic disorder is defined as an insufficient amount of serum alpha-1 antitrypsin, a plasma protein with antiproteolytic activity, and predisposes to chronic obstructive airway disease, chronic liver disease, and rarely to skin and vasculitic disorders 1. The most common harmful mutation is called the Z allele, while the normal version is called the M allele. People with two Z alleles (ZZ) have severe deficiency, while those with one Z and one M allele (MZ) have mild to moderate deficiency.

Key Points

• The mutated gene leads to abnormal alpha-1 antitrypsin protein that cannot be properly released from the liver into the bloodstream, resulting in low levels of the protein in the blood and lungs.
• Without sufficient alpha-1 antitrypsin, enzymes called neutrophil elastases can damage lung tissue, leading to emphysema.
• Additionally, the abnormal protein can accumulate in liver cells, potentially causing liver damage.
• The condition affects approximately 1 in 2,500 to 5,000 individuals of European descent but can occur in any ethnic group.

Diagnosis and Management

The American Thoracic Society and European Respiratory Society have developed recommendations for genetic testing and management of individuals with alpha-1 antitrypsin deficiency 1. Laboratory testing, including alpha-1 antitrypsin serum level, and lung function testing, such as FEV1, are used to diagnose and monitor the condition. Augmentation therapy, which involves monthly infusion of alpha-1 antitrypsin, may be indicated for individuals with obstructive lung disease, regardless of phenotype.

From the FDA Drug Label

Alpha1-PI deficiency is an autosomal, co-dominant, hereditary disorder characterized by low serum and lung levels of Alpha1-PI. The molecular basis of alpha-1-antitrypsin deficiency is related to mutations in the alpha1-antitrypsin gene, which can lead to low levels of the protein in the blood and lungs 2. The alpha1-antitrypsin gene and its mutations have clinical consequences, including the development of emphysema, and strategies for therapy have been discussed in the literature 2.

The cause of alpha 1 antitrypsin deficiency is a genetic mutation in the alpha1-antitrypsin gene, leading to low levels of Alpha1-PI in the blood and lungs. This is an autosomal, co-dominant, hereditary disorder. Key points include:

• Genetic mutation: The molecular basis of the deficiency is related to mutations in the alpha1-antitrypsin gene.
• Low Alpha1-PI levels: The deficiency is characterized by low serum and lung levels of Alpha1-PI.
• Hereditary disorder: The disorder is autosomal, co-dominant, and hereditary.
• Clinical consequences: The deficiency can lead to the development of emphysema and other clinical consequences 2, 2.

From the Research

Causes of Alpha 1 Antitrypsin Deficiency

• Alpha-1 antitrypsin deficiency (AATD) is caused by mutations in the SERPINA1 gene, which encodes the alpha-1 antitrypsin (AAT) protein 3, 4.
• These mutations can result in quantitative and/or qualitative changes in AAT, leading to AATD-associated lung and liver disease 3.
• The types of pathogenic mutations are varied, often resulting in misfolding or truncating of the AAT amino acid sequence 3.
• Over 200 SERPINA1 variants have been identified, many of which cause the quantitative and/or qualitative changes in AAT responsible for AATD-associated lung and liver disease 3.
• The characteristic Pi*Z mutation results in hepatic Z-AAT accumulation, leading to diminished serum AAT levels and predisposing to chronic obstructive pulmonary disease and lung emphysema 5.

Genetic Basis

• AATD is an autosomal inherited disorder, meaning that genetic testing should be offered not only to patients at increased AATD risk but also to relatives of those with an abnormal result 3.
• Genetic counseling may help patients and family members understand the possible outcomes of testing and the implications for the family 3.
• The loss-of-function lung disease is treated by weekly intravenous administration of purified AAT, while recombinant modified AAT and oral protease inhibitors are currently in clinical trials 5.

Pathogenesis

• AATD is characterized by reduced serum levels of alpha-1-antitrypsin (AAT) and associated with increased risks of pulmonary emphysema and liver disease in both children and adults 4.
• Pathogenic variants can be subdivided into either loss- or gain-of-function according to their pathophysiological effects 4.
• The loss-of-function is correlated with an uncontrolled activity of elastase by its natural inhibitor, the AAT, while the gain-of-function is connected with the formation of AAT polymers and their switching on of cellular stress and inflammatory responses 4.