Alpha-1 antitrypsin deficiency

Alpha-1 antitrypsin (AAT) deficiency is a genetic disorder with an autosomal inheritance pattern and codominant expression of alleles.

Allele mutations cause ineffective activity of AAT, the enzyme responsible for neutralizing neutrophil elastase.

Pulmonary and hepatic manifestations include emphysema, COPD, bronchiectasis, and cirrhosis.

Granulomatosis with polyangiitis (formerly known as Wegener granulomatosis) and necrotizing panniculitis are infrequent complications but can prompt diagnosis.

Plasma AAT levels, protein phenotyping (called PI-typing), and genotyping may be necessary for diagnosis. Rare alleles may require gene sequencing.

Intravenous AAT augmentation therapy benefits some patients.

Alpha-1 antitrypsin (AAT) deficiency is an autosomal codominant genetic disorder (i.e., one allele is inherited from each parent and each allele is expressed equally). It results from allele mutations in the SERPINA1 gene at the protease inhibitor (PI) locus.[1]European Association for the Study of the Liver. EASL Clinical Practice Guidelines on genetic cholestatic liver diseases. J Hepatol. 2024 Aug;81(2):303-25. https://www.journal-of-hepatology.eu/article/S0168-8278(24)00274-5/fulltext http://www.ncbi.nlm.nih.gov/pubmed/38851996?tool=bestpractice.com

The PI locus is highly polymorphic. Different protein variants have different charges because of amino acid alterations. The charge affects the speed of protein migration on serum electrophoresis.[2]Fagerhol MK, Laurell CB. The polymorphism of "prealbumins" and alpha-1-antitrypsin in human sera. Clin Chim Acta. 1967 May;16(2):199-203. http://www.ncbi.nlm.nih.gov/pubmed/4166396?tool=bestpractice.com Alleles are assigned a letter from A to Z depending on their relative speed of migration, with A being the fastest and Z the slowest. The allele most widely associated with clinical AAT deficiency is allele Z. The pattern of protein migration observed on serum electrophoresis is called the PI phenotype, which is written in form PI*[allele A][allele B].[3]DeMeo DL, Silverman EK. Alpha 1-antitrypsin deficiency. 2: genetic aspects of alpha 1-antitrypsin deficiency: phenotypes and genetic modifiers of emphysema risk. Thorax. 2004;59:259-64. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1746953 http://www.ncbi.nlm.nih.gov/pubmed/14985567?tool=bestpractice.com

PI* allele mutations cause ineffective activity of the specific protease inhibitor AAT, the enzyme responsible for neutralizing neutrophil elastase and preventing inflammatory tissue damage in the lungs.[4]Laurell CB, Eriksson S. The electrophoretic alpha 1-globulin pattern of serum in alpha 1-antitrypsin deficiency. Scand J Clin Lab Invest. 1963;15:132-140.[5]Brantly M, Nukiwa T, Crystal RG. Molecular basis of alpha 1-antitrypsin deficiency. Am J Med. 1988;84:13-31. http://www.ncbi.nlm.nih.gov/pubmed/3289385?tool=bestpractice.com Variants of the enzyme may also polymerize and accumulate in the liver, resulting in hepatic failure in some patients.

AAT is also known as alpha-1 proteinase inhibitor.