Knowledge on rare diseases and orphan drugs

Prevalence of the genetic condition at birth is estimated between 1/1,600-5,000 in Western Europe and in the USA.

The severe form, caused by homozygous Z variant in the gene SERPINA1, is the most clinically relevant and referred to here as Z-AATD. 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 on 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. Panniculitis of variable severity and developing at any age is a rare disease manifestation. 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.

The disease is due to variants in SERPINA1 (14q32.13). Major gene sequencing efforts carried out in disease populations disclosed more than 100 rare SERPINA1 variants which may cause the absence of circulating AAT (null alleles), poor AAT secretion from hepatocytes (deficiency alleles) or even form a modified enzyme inhibitory activity (dysfunctional alleles). The low levels of the serine protease inhibitor alpha-1-antitrypsin, involved in regulation of neutrophil elastase and proteinase 3, leads to alveolar damage. The pathophysiology of lung alveolar damage is based on the protease-antiprotease balance hypothesis.

Manifestations are non-specific and therefore may lead to delayed diagnosis. Liver and lung diseases are investigated with imaging and biopsies. The diagnosis is based on detection of low serum concentrations of AAT and molecular genetic testing.

The main differential diagnoses include asthma in younger patients and chronic obstructive pulmonary disease (COPD) in older individuals. Chronic viral hepatitis, hemochromatosis, Wilson disease, non-alcoholic/alcoholic fatty liver and primary biliary cirrhosis should be considered as alternative causes of liver disease.

When mutations have been identified in an affected family, prenatal diagnosis is possible.

Inheritance is autosomal recessive and genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.

There is currently no curative treatment. Treatment is similar to that used for COPD and emphysema and aims at reducing symptoms and slowing progression. Long-acting bronchodilators, antibiotics, corticosteroid inhalations, and long-acting beta-agonists are the mainstay of treatment. Another treatment option in severe cases involves augmentation therapy with administration of purified human AAT to reach normal physiological levels. Smoking and exposure to tobacco smoke should be avoided. Vaccines for common respiratory disorders may be beneficial. Lung transplantation may be required for end-stage lung disease. Likewise, liver transplantation can be considered for advanced liver disease. Panniculitis usually responds to treatment with intravenous augmentation of AAT. Several treatments for lung and liver disease are currently in clinical trials.

The prognosis is generally very good in non-smokers. Smoking is known to exacerbate the disease and leads to poorer outcomes. Obesity, diabetes, alcohol misuse, metabolic syndrome and male sex are risk factors for liver disease.

Last update: April 2021 - Expert reviewer(s): Dr J. [Jan] STOLK | ERN-LUNG* - Pr Pavel STRNAD | RARE-LIVER*

* European Reference Network