Alpha-1 antitrypsin (AAT) deficiency is an autosomal-codominant disorder, caused by mutations in the SERPINA1 gene on chromosome 14. Individuals affected by the most common mutations, SZ and ZZ, have serum AAT concentrations of 25% and 15% of normal levels, and present a higher risk of emphysema. Mutations causing total absence of serum AAT (Null mutations) were suggested to be associated with very early onset emphysema but their clinical phenotype is poorly known.

Absence of AAT in Null mutations results in more severe emphysema as compared to ZZ and SZ.

We genotyped all known Dutch subjects (n=12) with absent serum AAT, and compared their lung function values (FEV₁ and K_CO) with those of individuals with ZZ and SZ genotype, matched for age and smoking history.

All subjects with absent serum AAT presented homozygous Null mutations. In three subjects, a new mutation in exon 2 of the SERPINA1 gene was found. Subjects with Null mutations showed significantly lower lung function values than SZ and ZZ individuals (p=0.000 and 0.001 for FEV₁ and K_CO, respectively). In all groups, there was a positive correlation between serum AAT and lung function values (p=0.025 and 0.014 for FEV₁ and K_CO, respectively).

Serum levels of AAT are correlated with the severity of pulmonary phenotype. Subjects with Null mutations should be considered a subgroup at particularly high risk of emphysema within AAT deficiency (AATD). Early detection of carriers of this genotype would be important for preventive and therapeutic interventions.