What is AAT deficiency?

AAT deficiency, sometimes known simply as “alpha-1”, is a genetic disease primarily affecting the lungs and liver. It is characterised by a decrease in circulating levels of a protein called alpha₁ antitrypsin.¹

What is COPD and what can cause it?

Chronic obstructive pulmonary disease, or COPD is characterised by respiratory symptoms that are persistent with limitation of airflow due to airway or alveoli dysfunction.² 

Chronic airflow obstruction may be due to the destruction of parenchymal tissue (leading to emphysema) or small airways disease (leading to obstructive bronchitis). They may not occur together, or at the same rate, but are often caused by chronic inflammation.²
 

What are the main genetic risk factors for COPD?

AAT deficiency is the major known genetic risk factor for COPD, particularly emphysema with basilar predominance.³

What are the respiratory symptoms of AAT deficiency?

Respiratory symptoms of AAT deficiency, which are indistinguishable from smoking-induced COPD or asthma, chronic bronchitis and emphysema (usually in combination)^4,5 include:

• Wheezing^4,5
• Cough^4,5
• Excess sputum production^4,5
• Severe dyspnoea on exertion^4,5
   

AAT deficiency cannot be diagnosed on clinical presentation alone and should be confirmed with laboratory testing.^6-9

What are the risks associated with AAT deficiency?

• Chronic obstructive pulmonary disease (COPD)^1,8
• Reduced life expectancy^1,8
• Cirrhosis in infants, children and adults (with specific genetic variants)^1,8
• Necrotising panniculitis, a rare skin disease^1,8
• Wegener's disease (vasculitis)^1,8

The longer AAT deficiency remains undiagnosed, the greater the risk of irreparable lung damage.^9,10

What is alpha₁ antitrypsin (AAT)?

AAT is a protease inhibitor (Pi), an enzyme, a type of protein that is produced mainly in the liver. During an immune response in the lungs, resulting from infection or inhalation of environmental pollutants (or tobacco smoke), AAT travels there.¹¹

AAT helps to balance the immune response by inhibiting excess neutrophil elastase, another enzyme, that is released by neutrophils, a white blood cell, during infection. This counter-balance helps to protect lung tissue from destruction caused by excess neutrophil elastase.¹¹
 

What causes lung disease in AAT deficiency?

When there is a deficiency of the AAT protein, the balance between its actions and neutrophil elastase is disturbed. The resulting excess of neutrophil elastase slowly destroys the lung matrix components, alveolar structures and blood vessels which manifests as chronic obstructive bronchitis and emphysema. This is believed to be the main cause of lung disease in AAT deficiency.¹¹

What is a gene? What is an allele? What is a genotype? What is a phenotype?

A gene is commonly defined by the nucleic acid sequence that encodes the information necessary for the synthesis of a molecule, usually a protein.¹² Genes are physically located on the chromosomes at specific locations, or loci (plural; singular locus).¹³

An allele is one of many possible alternative forms of a gene.¹³

The genotype most often refers to an individual’s allele combination present at a particular locus.¹³

The phenotype refers to the physical manifestation of the genotype.¹³

In the example below, there are two individuals, one with the genotype PiZM and one with the genotype PiZZ.

How is AAT deficiency diagnosed?

According to guidelines from the European Respiratory Society (ERS), the quantitative level of AAT in the blood is usually the first step in identifying AAT deficiency. However, additional testing with a dried blood spot (DBS) is usually required for AAT genotyping.⁷

Because AAT is an acute-phase protein, the simultaneous quantification of C-reactive protein with AAT is necessary not to overestimate AAT levels.⁷

This problem is obviated using protein phenotyping or genotyping, which are both independent of the AAT level.⁷
 

What is the difference between screening and diagnosis?

Diagnosis, the first step in the clinical management of a patient, involves interpreting a patient’s history, clinical observations and laboratory testing – all tests that help determine the probability of a diagnosis.¹⁵ 

Screening is a systematic application of a test to identify individuals at sufficient risk of a specific disorder that may warrant further investigation (e.g. the type of testing that might lead to a diagnosis).¹⁵
 

What is the difference between genotyping and sequencing? When would I use one vs the other?

Genotyping refers to the detection of known AAT mutations, usually the S and Z variants. It can only detect known sequence variations because this process requires specific molecular tools called “primers” to detect known variants. It can detect “null” alleles.⁷

Whole gene sequencing can help identify novel and rare variants for which there are no primers.⁷