Alpha-1-Anti-Trypsin deficiency
From Iusmgenetics
Contents |
[edit] Alpha-1-Anti-Trypsin deficiency
[edit] General background information
- Important example of disease-environment interaction.
- Smokers are pretty much screwed.
[edit] Mode of inheritance
- Alpha-1-anti-trypsin deficiency is autosomal recessive
- Incidence of "ZZ" genotype is 1/2500 Caucasians
[edit] Single important gene
- AAT
- A serine protease inhibitor
- Major function is to inhibit elastase
- Elastase is made by neutrophils
- Elastase will eventually destroy lung tissue if not treated
- AAT is highly polymorphic
- There are two disease-causing alleles:
- "S" allele produces a protein with only 50-60% activity
- "Z" allele produces a protein with only 10-15% activity
- Null alleles produce no activity at all and the most severe disease form
- "M" allele is normal
[edit] Etiology
- Inability to inhibit elastase results in chronic destruction of the pulmonary and liver mesechymal ECM and thus fibrosis and cirrhosis.
[edit] Pathogenesis
- Pts with A1ATD are at a 20-fold higher risk of developing emphysema
- 80-90% eventually develop emphysema
[edit] Phenotypic information
- MM, MS, and SS genotypes manifest no disease
- SZ have an increased chance of developing emphysema
- ZZ have the full disease state
- Smokers develop disease earlier in life and with greater severity
- ZZ pts develop liver disease in addition to pulmonary fibrosis
- Liver disease develops from mutant protein aggregates
[edit] Diagnosis
[edit] Treatment
- Inhibitors (like AAT) injections
- Liver transplant for ZZ or null mutant pts
- Gene therapy one of these days?
