Alpha-1 Antitrypsin Deficiency (AATD) is a co-dominant condition associated with an increased risk of lung and liver disease. Since it is commonly thought that 95% of severe cases of AATD have PI*ZZ genotype, most studies about AATD have been focused on the Z variant. Nevertheless, over 500 single nucleotide variations in the SERPINA1 gene have been identified. We investigated the clinical presentation of subjects with severe AAT deficiency due to rare genotypes of the SERPINA1 gene. We enrolled patients from the Italian Registry for AATD (RIDA1) with the following inclusion criteria: diagnosis of severe AATD; age >18 years; full clinical data available at diagnosis; three years of follow-up respiratory function data. A total of 281 patients were enrolled from the RIDA1 Registry and subdivided into 3 cohorts: PI*ZZ genotype (n = 160), PI*SZ genotype (n = 54), and rare genotypes PI*R (n = 67). We did not observe any statistical differences among the cohorts regarding sex, smoking habits, occupational exposure and age at diagnosis. Patients with severe AATD due to rare genotypes have clinical characteristics and respiratory profiles similar to PI*ZZ subjects, and differed from the PI*SZ patient group. Early and accurate diagnosis of PI*R subjects is therefore important for their appropriate clinical management.
Keywords: Alpha-1-antitrypsin; SERPINA1; lung function; orphan disease; rare mutations.