ABSENCE OF ALPHA-1-ANTITRYPSIN (PI-NULL-BELLINGHAM) AND THE EARLY-ONSET OF EMPHYSEMA

Background: Alpha-1-antitrypsin is the body's major inhibitor of human neutrophil elastase, a powerful proteolytic enzyme capable of degradi ng the common tissue components. There are over 70 genetic variants of alpha-1-antitrypsin, with the Z allele being of greatest clinical rel evance. Individuals homozygous for this allele (approximately one in 2 500 in Caucasians) have low serum alpha-1-antitrypsin levels (10-20% o f normal) and are predisposed to emphysema, especially if they smoke. Much rarer are mutations which result in the complete or almost comple te absence of alpha-1-antitrypsin in the serum. Aim: To determine the cause of complete absence of alpha-1-antitrypsin in a patient who at a ge 27 years had both emphysema and idiopathic cardiomyopathy. Methods: Molecular biology techniques were used to sequence the alpha-1-antitr ypsin gene. Allele specific amplification was used to show the presenc e of the mutations in other family members. Results: Investigation sho wed that the proband was homozygous for the Pi Null Bellingham variant of alpha-1-antitrypsin due to the mutation Lys 217 (AAG) to Stop (TAG ). His grandmother was heterozygous for Pi Null Bellingham and the add itional rare variant P Lowell, Asp 256 (GAT) to Val (GTT), a variant t hat also results in alpha-1-antitrypsin deficiency. Conclusion: Patien ts with complete absence of alpha-1-antitrypsin develop premature emph ysema not having smoked or after only minimal exposure, and much earli er than the more common Pi Z individuals who have the usual form of al pha-1-antitrypsin deficiency.