Characterization of the Mmalton carrier’s cohort within the EARCO (European Alpha- 1 Antitrypsin Research Collaboration) registry

Introduction: The PI*Mmalton variant is a rare form of alpha-1-antitrypsin (AAT) deficiency, caused by a mutation in the SERPINA1 gene and associated with reduced AAT levels. Its clinical significance remains uncertain due to the limited number of reported cases. Methods: This study characterizes PI*Mmalton carriers within the EARCO (European Alpha-1 Antitrypsin Research Collaboration) registry and compares them with PI*ZZ individuals. Patients were categorized into moderate PI*Mmalton (combined with PI*S or PI*I) and severe PI*Mmalton (combined with PI*Z, PI*Mmalton, PI*MProcida, or PI*MHerleen). Demographic data, lung function, respiratory symptoms, disease prevalence, and augmentation therapy use were analyzed. Results: Among 2074 individuals, 59 (2.8%) carried a PI*Mmalton allele. Severe PI*Mmalton patients exhibited lung function impairment comparable to PI*ZZ individuals, with a significantly lower FEV₁/FVC ratio (55.9% vs. 57.6%) and similar AAT levels (~ 25 mg/dL). Moderate PI*Mmalton patients had better lung function and higher AAT levels (median 54 mg/dL). Emphysema was more prevalent in severe PI*Mmalton (54.5%) and PI*ZZ (61.2%) than in moderate PI*Mmalton (34.6%). Augmentation therapy use was highest in severe PI*Mmalton (45.2%). Liver disease prevalence was comparable across groups. Conclusion: Severe PI*Mmalton patients exhibit clinical and functional similarities to PI*ZZ individuals, suggesting a comparable disease burden. Moderate PI*Mmalton patients, however, show milder impairment. These findings reinforce the need for genotype-specific management strategies and suggest that PI*Mmalton carriers, particularly those with severe variants, should be considered in future clinical trials.