SERPINA1 gene
OMIM#613490 https://omim.org/entry/613490
1. The disease
A rare hereditary, metabolic disease characterized by serum levels of alpha-1-antitrypsin (AAT) that are well below the normal range. In the most severe form, the disease can clinically manifest with chronic liver disorders (cirrhosis, fibrosis), respiratory disorders (emphysema, bronchiectasis), and rarely panniculitis or vasculitis.
2. The symptoms
The severe form, caused by homozygous Z variant in the gene SERPINA1, is the most clinically relevant and referred to here as Z-AATD. Lack of early signs or symptoms does not exclude the diagnosis.
- Z-AATD has an extraordinary heterogeneous disease course. Some individuals remain healthy, while others develop a severe lung or liver disease, rarely both.
- The age of onset is variable in Z-AATD, liver disease presents typically in newborn/early childhood age or later in adult life (typically at ≥ 40 years of age).
- Z-AATD can lead to neonatal cholestasis in about 10 % of the affected infants and about 30-50% of these will develop chronic progressive liver disease. About 10% of adults develop liver cirrhosis.
- Onset of lung disease is generally between 20 and 50 years of age. The main pulmonary manifestations include early onset panacinar emphysema, bronchiectasis, bronchial asthma or vasculitis presenting with persistent, dyspnea, cough, wheezing, and production of sputum.
- Smoking is a major factor affecting the course of the pulmonary manifestations and is associated with earlier onset. Other features include weight loss, recurrent respiratory infections, and fatigue. A strongly increased risk of developing liver cirrhosis and hepatocellular carcinoma has been reported. The course may be severe in the absence of appropriate treatment and continued tobacco smoking.
- Panniculitis of variable severity and developing at any age is a rare disease manifestation.
3. Actions to take in case of early diagnosis
- Infants with a positive genetic test (having 2 pathogenic variants or 2 copies of a single pathogenic variant in the SERPINA1 gene) should continue breastfeeding.
- Biochemical correlation with low serum concentration of alpha-1 antitrypsin (AAT) can also help to establish the diagnosis.
- AATD is a lifelong condition that requires lifetime management and regular follow-up with a multidisciplinary approach to care, including pediatrics, gastroenterology, pulmonology, genetics, and nutrition.
- Liver transplantation is the definitive treatment for severe disease (will restore AAT levels).
- Augmentation therapy with periodic intravenous infusion of pooled human serum alpha-1 antitrypsin (AAT) is used in individuals who have established emphysema. Lung transplantation may be an appropriate option for individuals with end-stage lung disease.
- Dapsone or doxycycline therapy is used for panniculitis; if refractory to this, high-dose intravenous AAT augmentation therapy is indicated.
- Genetic counseling is highly recommended for family planning and evaluation of at-risk family members such as siblings.