Alpha One Antitrypsin Deficiency: From Gene to Treatment

Abstract

α1-antitrypsin deficiency is a genetic disorder which contributes to the development of chronic obstructive pulmonary disease, bronchiectasis, liver cirrhosis and panniculitis. The discovery of α1-antitrypsin and its function as an antiprotease led to the protease-antiprotease hypothesis, which goes some way to explaining the pathogenesis of emphysema. This article will review the clinical features of α1-antitrypsin deficiency, the genetic mutations known to cause it, and how they do so at a molecular level. Specific treatments for the disorder based on this knowledge will be reviewed, including α1-antitrypsin replacement, gene therapy and possible future therapies, such as those based on stem cells.

Chronic Obstructive Pulmonary Disease: Official diagnosis and treatment guidelines of the Czech Pneumological and Phthisiological Society; a novel phenotypic approach to COPD with patient-oriented care

“…AAT-deficient patients with FEV 1 between 30-60% of the predicted value, who are not active smokers, having a severe form of deficit (serum concentration <0.5 g/L) caused by a homozygous mutation in the protease inhibitor (Pi) gene encoding AAT, PiZZ (common deficiency allele encoding a G342K mutation) or Pinull (nil detectable), should be treated with a regular application of AAT augmentation therapy (once per 1-2 weeks intravenously) (ref. 85,86 ). Treatment of emphysematic patients with the presence of large bullae consists of resection of the bullae -so called bullectomy (especially if it occupies at least 1/3 of 87,88 ).…”

Genetics of ?1 Anti-Trypsin (AAT) Deficiency

“…SERPINA1 gene has been fully sequenced and cloned [7]; it shows a co-dominant pattern of inheritance as each allele contributes by 50% of the total circulating enzyme inhibitor [8]. It is a highly polymorphic gene with approximately 125 single nucleotide polymorphisms (SNPs) reported in public databases [9], a proportion of which have an effect on AAT level or function (Table 1 shows selected allelic variants with normal and abnormal gene functions). Traditionally, each variant is identified by its speed of migration on polyacrylamide gel electrophoresis called isoelectric focusing (IEF) in a pH 4-5, the most common forms being F (fast), M (medium), S (slow) and Z (very slow).…”

Similarities in the Computed Tomography Appearance in α1-Antitrypsin Deficiency and Smoking-Related Chronic Obstructive Pulmonary Disease in a Smoking Collective

“…α1-antitrypsin deficiency (AATD) is an autosomal recessive disorder in which homozygosis for the so-called PiZZ mutation genetic defect of Alpha-1 Antitrypsin (A1AT) causes accumulation of α1-protease in liver cells resulting in inflammation and cirrhosis [1][2][3] and predisposition to the early-onset development of emphysema. Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by chronic obstruction of airflow that interferes with normal breathing.…”