C46-06 Severe Early-onset Emphysema in Heterozygous Alpha-1 Antitrypsin Deficiency: A Familial Investigation Into Genetic Modifiers

Abstract Background Alpha-1 antitrypsin deficiency (AATD) is a well-established cause of early-onset emphysema, typically in individuals with severe AATD caused by homozygosity for the SERPINA1 Z allele (ZZ genotype). Individuals heterozygous for the Z allele are generally considered at low risk of significant lung disease, particularly in the absence of smoking or environmental exposures. Case Presentation We report two siblings with severe, early-onset emphysema necessitating lung transplantation in early adulthood. Both are lifelong non-smokers and heterozygous (MZ genotype) for the SERPINA1 Z allele. The proband, a 27-year-old man, presented in 2005 with progressive dyspnea. Initial spirometry revealed an FEV1 of 0.89 L (23% predicted) and FEV1/FVC ratio of 0.35. CT imaging demonstrated advanced emphysema. He was diagnosed with MZ AATD and underwent a successful bilateral lung transplantation at age 35. Twelve years post-transplant, he remains oxygen-dependent with an FEV1 of 23%, despite no convincing evidence of graft dysfunction. Screening of family members revealed that a brother, also MZ, had similarly severe emphysema and died within one year of a successful lung transplant at age 39. Their mother, an MM genotype, demonstrated unexpected airflow limitation (FEV1 0.92 L, 56% predicted; FEV1/FVC 0.58; DLCO 48%) and radiologic evidence of emphysema and bronchiectasis, despite being a lifelong non-smoker with no known occupational exposures. Discussion The disease severity in both MZ siblings is striking and inconsistent with the expected clinical phenotype for Z heterozygotes without environmental risk factors. Preliminary investigations have excluded telomeropathy. Whole genome sequencing is underway to identify potential modifier genes or additional pathogenic variants. Comprehensive phenotyping of extended family members is ongoing. Conclusion This family study highlights a potentially novel genetic modifier(s) contributing to severe early-onset emphysema in moderate AATD. Further genomic and phenotypic analysis may advance understanding of emphysema pathogenesis, refine risk prediction for AATD individuals, and inform personalized surveillance and management strategies. This abstract is funded by: None