C46-03 A Rare Null Variant in Alpha-1 Antitrypsin Deficiency: A Case Study in a Small Private Practice

Abstract Introduction Alpha-1 Antitrypsin Deficiency (AATD) is a single-gene disorder first discovered in 19631. Knowledge gained since this time has not translated into clinical practice. Screening for AATD is overlooked by primary care providers (PCPs) and specialists, even among symptomatic patients, delaying diagnosis on average 7 yrs2. Prevalence rates in the U.S. remain 10% of expected. This case highlights the missed opportunities to identify a common genetic disorder in a complex presentation. Case JK, a 62 yo never-smoker consulted by pulmonary medicine for post-COVID dyspnea. In the months prior, he had 3 emergency room (ER) visits, frequently missed work and required O2 supplementation. PMH includes myxofibrosarcoma s/p surgical resection with adjuvant anthracycline-based chemotherapy. He developed chemotherapy-induced cardiomyopathy which improved with medical management. Other history included DM2, Obesity, AFIB, sleep apnea and heart failure. PFT data showed an FEV1 48%, FVC 65% and TLC 110%. Chest CTs failed to show evidence of bronchiectasis, emphysema, or other lung pathology. Dyspnea was routinely documented dating back to 2013, even after resolution of the cardiomyopathy. He was screened for Alpha-1 which showed PiM/Q0bellingham with a subtherapeutic level of 64mg/dl. After one year of enzyme replacement, his FEV1 improved to 71% and he had zero acute exacerbations or ER visits. Discussion AATD results from uninhibited protease enzymes leading to multisystemic disease. PiM is designated as the wild-type with roughly 120 known deficient allele combinations3 with widely variable penetrance even among homogeneous groups. The null alleles (Q0bellingham) are associated with a total absence of Alpha-1 production among homozygotes or severe reduction in heterozygotes. Studies show that null variants often cause more severe lung reduction than those SZ or even ZZ individuals4. Despite the knowledge gained since its discovery, AATD continues to elude timely diagnosis. Multiple reasons are cited to include knowledge/confidence in discussing genetics, time constraints and lack of understanding of testing or interpreting result5. Managing patients with multi-morbidities increases the risk of diagnosis bias in patients with overlapping phenotypes. JK initially reported dyspnea in 2013 which was attributed to chemotherapy-induced cardiomyopathy, masking suspicion of underlying pulmonary disease. With a plausible cause for his symptoms, no additional investigation was considered. Several methods to improve screening have been reported with success; EHR alerts using software rules6 and ICD-10 codes, patient-driven approaches using educational material, and support staff training have been shown to improve screening rates. For Alpha-1, early detection favors better outcomes. This abstract is funded by: None