APA (Old Order Amish; Eastern Pennsylvania)

Inheritance: autosomal recessive

Alpha-1-antitrypsin deficiency


Liver disease


Protease Inhibitor 1 Deficiency

Clinical Characteristics

General description (for patients): 

This is an enzymatic disorder that leads to chronic lung (emphysema) and liver disease, sometimes in young children but mostly in adults.  Its presence is a strong risk factor for emphysema.  Smoking becomes an especially serious risk in the presence of this enzyme deficiency.

Medical description: 

The association of emphysema and alpha-1-antitrypsin deficiency (known to be a protease inhibitor) has been recognized for a long time.  Many electrophoretic variants have been identified and virtually all are associated with the same phenotype, albeit with some variations.  The molecular mechanisms causing clinical disease results from the loss of anti-elastase activity and thus the lungs and liver especially are damaged by progressive proteolytic damage.  Smoking causes oxidation of the methionine residue in the alpha-1-antitrypsin molecule which limits its binding to serine protease and hence reduces its inactivation function even further.


A mutation on chromosome 14 in the SERPINA1 gene (14q32.1) is responsible for many variants of this disease which is inherited in an autosomal recessive pattern.  The gene product is alpha-1-antitrypsin, a protease inhibitor.  The defective product allows degradation of extracellular fibrils such as elastin with gradual loss of pulmonary function, for example.  One of the more common mutations, 1096G>A, causing a Glu342Lys change in the enzyme is listed as having been identified among plain people in Eastern Pennsylvania.


Intravenous concentrates of AAT combined with lifetime avoidance of smoking has been recommended but rigorous studies have not been done.


Dependent upon the severity of pulmonary and liver disease which can be highly variable.  Many patients succumb in the 5th decade.

Ancillary treatments and support:

Smoking cessation, avoidance of contaminated air.

Specialists and specialty centers: 

Pulmonologist, respiratory therapist, gastroenterologist.


Nukiwa, T., Satoh, K., Brantly, M.L., Ogushi, F., Fells, G.A., Courtney, M., and Crystal, R.G.:  Identification of a second mutation in the protein-coding sequence of the Z type alpha 1-antitrypsin gene.  261: 15989-15994, 1986.  PubMed ID: 3491072

Dahl, M., Tybjaerg-Hansen, A., Lange, P., Vestbo, J., and Nordestgaard, B.G.:  Change in lung function and morbidity from chronic obstructive pulmonary disease in alpha-1-trypsin MZ heterozygotes: a longitudinal study of the general population.  Ann. Intern. Med. 136: 270-279, 2002.  PubMed ID: 11848724


Alpha 1 Association

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