Alpha-1 Antitrypsin Deficiency

A(z) condition ismertetése

An inherited condition caused by variants in the SERPINA1 gene, which lowers levels of a protein that protects the lungs. It can lead to early emphysema (especially in smokers) and to liver disease in children and adults.

Alpha-1 antitrypsin deficiency (AATD) is an autosomal codominant disorder caused by pathogenic variants in SERPINA1, the gene encoding alpha-1 antitrypsin (AAT), a serine protease inhibitor produced primarily in hepatocytes that protects lung parenchyma from neutrophil elastase-mediated destruction. AATD is estimated to affect 1 in 2,500 individuals of European ancestry and approximately 3.4 million people worldwide, making it one of the most common serious monogenic disorders, yet it remains chronically and severely underdiagnosed. Median time from first respiratory symptoms to diagnosis is 7-8 years, during which irreversible lung damage accumulates.

SERPINA1 alleles are designated by the Pi (protease inhibitor) nomenclature. The normal allele is Pi*M. The most clinically significant variants are Pi*Z (p.Glu342Lys; rs28929474) and Pi*S (p.Glu264Val; rs17580). Pi*ZZ homozygotes (the most severely affected genotype) have AAT serum levels approximately 15% of normal, due to both reduced secretion and intrahepatic polymerization of the misfolded Z protein. Pi*SZ compound heterozygotes have AAT levels approximately 40% of normal and face elevated but lower lung disease risk. The polymerizing Z protein accumulates in hepatocytes, causing progressive liver disease (cirrhosis, hepatocellular carcinoma) in a subset of Pi*ZZ individuals through a distinct toxic gain-of-function mechanism independent of the lung disease pathway.

Augmentation therapy with intravenous alpha-1 proteinase inhibitor (Prolastin, Zemaira, Aralast) slows emphysema progression in Pi*ZZ patients with established airflow obstruction, the only condition-specific approved treatment. Survival benefit is most pronounced when therapy begins before significant lung destruction. Smoking accelerates AATD lung disease dramatically; Pi*ZZ smokers lose lung function 3-4 times faster than non-smokers with AATD. Early diagnosis enables smoking cessation counseling before irreversible damage, avoidance of occupational dust and fume exposure, and initiation of augmentation therapy at the optimal stage of disease.

More than 120 SERPINA1 variants have been described. Rare alleles (Pi*I, Pi*F, Pi*P, Pi*Null) produce a spectrum of AAT deficiency phenotypes from intermediate deficiency to complete absence of secreted protein.

A vizsgált betegség

Miért a teljes genom szekvenálás

Standard AATD testing checks Z and S alleles in isolation. Complete SERPINA1 genotyping requires resolving the full allelic architecture, including rare alleles that determine whether a patient has AATD or simply carries one deficiency allele.

További respiratory conditions

• Alveolar Capillary Dysplasia with Misalignment of Pulmonary VeinsFOXF1
• Asthma
• Congenital Central Hypoventilation SyndromePHOX2B
• Congenital Diaphragmatic Hernia (Monogenic)ALDH1A2, PLS3, ZFPM2
• Cystic FibrosisCFTR
• Familial Pulmonary FibrosisNAF1, PARN, POT1, RPA1
• Primary Ciliary DyskinesiaCCDC39, CCDC40, CCNO, CENPF
• Pulmonary Alveolar MicrolithiasisSLC34A2
• Surfactant Metabolism DysfunctionABCA3, CSF2RA, CSF2RB, MARS1