Background: Severe Alpha-1 Antitrypsin Deficiency (AATD) is an autosomal recessive condition underlying increased risk of lung and/or liver diseases. Since it is commonly thought that 95% of severe cases of AATD result from the homozygous Z allele, most of studies about AATD has been focused on Z variant. Nevertheless, over 500 Single Nucleotide Variations (SNV) in SERPINA1 gene have been identified.

Objectives: To obtain a comprehensive knowledge about the clinical presentation of subjects with severe AATD due to rare genotypes, we compared their clinical phenotypes to PI*ZZ and PI*SZ.

Methods: We enrolled patients of the Italian Registry for AATD (RIDA1) that respected the following inclusion criteria: diagnosis of severe AATD; age > 18years/old; consent to participate the study; complete clinical data at diagnosis and 3 years-follow up of respiratory function.

Results: A total of 281 patients were enrolled from the RIDA1 Registry and subdivided in 3 cohorts: PI*ZZ genotype (n=160), PI*SZ genotype (n=54), and rare genotypes PI*R (n=67).

We did not observed statistical differences among cohorts regarding gender, smoking habit and consumption, professional exposure and ages at diagnosis.

Median plasma concentration of AAT resulted 30.5, 62.0, and 26.0 mg/dL in PI*R, PI*SZ, and PI*ZZ cohorts, respectively. Distribution of lung clinical phenotype, lung function parameters and annual decline is very similar in PI*R and PI*ZZ vs PI*SZ.

Conclusions: Early and accurate diagnosis of PI*R subject is crucial. Patients with severe AATD due to rare genotypes have respiratory profiles similar to PI*ZZ subjects, and, therefore, they should benefit from the same preventive and therapeutic interventions.