Diagnosis of alpha-1 antitrypsin deficiency: Modalities, indications and diagnosis strategy

Alpha-1 antitrypsin (alpha(1)-AT) deficiency is an autosomal recessive genetic disorder, which predisposes affected patients to development of pulmonary emphysema or liver cirrhosis. Despite the guidelines from the American Thoracic Society and the European Respiratory Society about alpha(1)-AT deficiency screening, it remains significantly under recognized. So, it seems necessary to propose an efficient and suitable biological approach to improve diagnosis and management of alpha(1)-AT deficiency. alpha(1)-AT is a 52 kDa glycoprotein predominantly produced in the liver and its physiological serum concentration for adults ranges from 0.9 to 2.0 g/L (17-39 mu mol/L). It is encoded by the SERPINA1 gene, which is highly pleomorphic, and to date, more than 100 alleles have been identified. alpha(1)-AT testing would initially involve quantification of serum alpha(1)-AT concentration with possible complementary measurement of the elastase inhibitory capacity of serum. If the serum alpha(1)-AT concentration is reduced below the reference value, two strategies for laboratory testing can be used: (i) serum alpha(1)-AT phenotyping by isoelectric focusing which allows identification of the most common variant designated as the PI M variant but also of various deficient variants besides the predominant PI S and PI Z ones; (ii) genotyping by allele-specific PCR methods which allows only identification of the deficient PI S and PI Z alleles. Identification of the null alleles or of other rare deficient alleles can be performed by direct sequencing of the whole SERPINA1 gene as a reflex test. (C) 2014 SPLF. Published by Elsevier Masson SAS. All rights reserved.