Absence of alpha-1-antitrypsin (Pi Null Bellingham) and the early onset of emphysema

Alpha-1-antitrypsin is the body's major inhibitor of human neutrophil elastase, a powerful proteolytic enzyme capable of degrading the common tissue components. There are over 70 genetic variants of alpha-1-antitrypsin, with the Z allele being of greatest clinical relevance. Individuals homozygous for this allele (approximately one in 2500 in Caucasians) have low serum alpha-1-antitrypsin levels (10-20% of normal) and are predisposed to emphysema, especially if they smoke. Much rarer are mutations which result in the complete or almost complete absence of alpha-1-antitrypsin in the serum.

To determine the cause of complete absence of alpha-1-antitrypsin in a patient who at age 27 years had both emphysema and idiopathic cardiomyopathy.

Molecular biology techniques were used to sequence the alpha-1-antitrypsin gene. Allele specific amplification was used to show the presence of the mutations in other family members.

Investigation showed 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 additional rare variant P Lowell, Asp 256 (GAT) to Val (GTT), a variant that also results in alpha-1-antitrypsin deficiency.

Patients with complete absence of alpha-1-antitrypsin develop premature emphysema not having smoked or after only minimal exposure, and much earlier than the more common Pi Z individuals who have the usual form of alpha-1-antitrypsin deficiency.