ALPHA 1 ANTITRYPSIN DEFICIENCY

Mutation of an enzyme inhibitorAutosomal recessive disease.It is excessive in hepatocytes, consequently it is

decreased in blood and lungs.Causes emphysema, COPD (chronic obstructive

pulmonary disease), and liver cirrhosis.Alpha 1 antitrypsin is a protein that inhibits

enzyme activity of elastase, which breaks down neutrophil elastin(elasticity) in the lungs.

Present in white populations, 1 in 5000 people are affected and 2% are carriers.

Genetics:Alpha 1 antitrypsin belongs to protease

inhibitors or serpins.Serpina 1 is a gene that translates the

alpha 1 antitrypsin on chromosome 14q32.

Normal allele is “M”.A missense mutation in exon 5 produces

the mutant allele “Z” (glu342lys)

In heterozygotes, blood levels of alpha 1 antitrypsin are reduced between 40% and 60%, which is sufficient to protect the lungs in people who don’t smoke.

In homozygotes, alpha 1 antitrypsin levels are less than 15% of normal and patients are likely to develop emphysema at a young age, 50% of these will develop liver cirrhosis, because it is accumulated in the liver and not secreted well.

17% of homozygotes present with neonatal jaundice and 20% of this group develop liver cirrhosis.

Liver disease is caused by a novel property mutation.Mutation in “Z” allele causes alpha one antitrypsin polymers to aggregate in hepatocytes in a form of long bead like shaped necklaces, which cannot be released into the plasma anymore, consequently it accumulates in the liver and cause liver cirrhosis.Note: it is a conformational disease, because its shape or size will change and become disposed in one place.

Two mechanisms contribute to the imbalance between elastase and alpha 1 antitrypsin:1. Only 15% of normal plasma

concentration of alpha 1 antitrypsin is present.

2. Its activity is decreased, alpha 1 antitrypsin has only about 20% of the ability of the normal alpha 1 antitrypsin to inhibit elastase.

It is an ecogenic disorder:It is greatly affected by smoking, survival of 60% in non smokers and 10% survival in smokers.This is caused by oxidation of the active site methionine 358 by cigarrete smoke and inflammatory cells, thus reducing its affinity for elastase 2000 fold.

Treatment:Augmentation therapy (intravenous

infusions-replacement strategies).Liver or lung transplantationNo smoking

VKC ( vernal keratoconjunctivitis) is a severe allergic disorder that causes inflammation of the conjunctiva .It was discovered that there is a rise in blood concentration of alpha 1 antitrypsin when someone has VKC.Conclusion: inc. and dec. of alpha 1 antitrypsin concentration in the blood, can be used as a prognosis for VKC.

Bibliography:-Ahsan A1, Salman KA2, Alam S1, et al, Alpha-1 antitrypsin, a diagnostic and prognostic marker of vernal keratoconjunctivitis, 8(5):CC08-10. doi: 10.7860/JCDR/2014/6342.4362, 2014 May, J Clin Diagn Res. PubMed.-By Robert L. Nussbaum, Roderick R. McInnes, and Huntington F. Willard, alpha 1 antitrypsin deficiency: mutations of an enzyme inhibitor, 358-359, AUG 2007, Thompson and Thompson GENETICS IN MEDICINE.