C46-11 Beyond Pi*zz: A Turkish Case Series of Severe Alpha-1 Antitrypsin Deficiency With Rare Genotypes, Diagnostic Delays - Real World Experience

Abstract Introduction Alpha-1 Antitrypsin Deficiency (AATD) is a rare hereditary disorder that predisposes individuals to early-onset Chronic Obstructive Pulmonary Disease (COPD). Even though genetic testing and specific augmentation therapy exist, diagnosis is often delayed, resulting in patients presenting with advanced disease. We report a single-center case series from Turkey describing the genetic spectrum, clinical and functional characteristics, treatment patterns, and outcomes in AATD. Description of Case Series A retrospective review of records from 2018 to 2025 was conducted for a cohort of seven patients (four male, three female; median age ≈ 58 years) with genetically confirmed AATD. The genotype distribution comprised PIZZ (n = 2, who are brothers), PIMMalton (n = 3), PIMZ (n = 1), and PIM/M Procida (n = 1). Diagnostic delay was observed, with a median of six years (range 2-13). The available FEV1 measures demonstrated severe airflow limitation (median ≈ 26% predicted), and in four patients, documented absolute declines of 0.14-0.40 L over 1-3 years. In Türkiye, augmentation therapy is indicated for patients with the PIZZ genotype and FEV1 30% predicted; for non-ZZ genotypes, applications may be made only if serum AAT levels are below 80 mg/dL. Among the five patients who received intravenous augmentation therapy, three with PIMMalton genotypes were treated based on documented severe AAT deficiency. Two newly diagnosed patients are eligible and awaiting initiation. The overall mortality rate was 28.5%. The demise of both subjects was attributed to respiratory failure resulting from COPD exacerbation. One was an active heavy smoker who passed away before the commencement of therapy, and the other was a never-smoker with the lowest recorded AAT level (9.0 mg/dL), and both had no family support (Table 1). Written informed consent for the utilisation of clinical data was obtained from all subjects. Discussion This case series shows that diagnostic delay remains a major barrier to effective AATD management, with a consistent multi-year gap between obstructive lung disease onset and genetic confirmation highlighting the need for greater clinician awareness and wider testing. AATD in this setting was characterised by severe functional impairment and rapid decline, confirming its aggressive nature even under augmentation therapy. Rare genotypes such as PI*MMalton and PI*M/M Procida produced disease severity comparable to the classic PI*ZZ form, consistent with recent Turkish data showing broad genotype diversity. Both fatal cases—despite contrasting risk profiles—illustrate that psychosocial factors critically influence outcomes, underscoring the need for comprehensive, multidisciplinary care in AATD management. This abstract is funded by: Genetic analysis was provided free of charge by Dem Ilac and Grifols