Alpha1-antitrypsin deficiency with M-like phenotype

Area of Science:

• Pulmonology
• Clinical Genetics
• Biochemistry

Background:

• Alpha1-antitrypsin deficiency (AATD) is a genetic disorder that increases the risk of lung and liver disease.
• The most common deficiency allele is Z, but other rare alleles exist.
• Phenotypic analysis of alpha1-antitrypsin (AAT) is crucial for diagnosing AATD.

Observation:

• A patient presented with severe airways obstruction and emphysema, despite an M-like AAT phenotype, and had low serum AAT concentrations (0-1 g/l).
• Her parents and siblings exhibited the PIM phenotype, with approximately half-normal AAT levels in all but the father.
• The M-like variant was indistinguishable from M-AAT in heterozygotes.

Findings:

• The M-like variant, when co-inherited with the M allele, results in low serum AAT levels and severe pulmonary disease in the proposita.
• Family members with the PIM phenotype and reduced AAT levels showed varying degrees of lung disease or remained asymptomatic.
• This case suggests that certain M-like variants can cause AATD and associated lung pathology.

Implications:

• Accurate identification of AAT variants is critical for predicting disease risk and guiding genetic counseling.
• The study underscores the need for comprehensive AAT phenotyping and genotyping, especially in patients with unexplained obstructive lung disease.
• Further research into rare AAT variants is necessary to fully understand their clinical significance and associated disease spectrum.