A challenging diagnosis of alpha-1-antitrypsin deficiency: identification of a patient with a novel F/Null phenotype

Alpha-1 Antitrypsin (A1AT) is a serine protease inhibitor that is encoded by the SERPINA 1 gene located on chromosome 14 [1,2]. It is a highly effective inhibitor of neutrophil elastase, and serves a protective function to prevent excessive proteolysis of matrix components in the airways and other organs [1,2]. A wide variety of mutations in the SERPINA1 gene are possible, and these can result in low/absent levels or non-functional protein [1-3]. A1AT deficiency results in early onset emphysema, and may induce liver disease, necrotizing panniculitis, or a C-ANCA positive vasculitis [1,2].A1AT deficiency is most often seen in a population of European origin, but can affect all races [3]. It is estimated that in the United States there is 1 case per 3000-5000 persons, though the carrier frequency of mutant alleles has been reported to be 2-3% of the American population, suggesting that the prevalence may be higher than this [1-3]. It is also estimated that only about 10% of the patients with this condition are currently identified, due in part to low recognition of the disease, genetic heterogeneity, and complexities of diagnosis [1-3].The normal A1AT gene product is designated Pi*M, and there more than 100 known variants [1]. The most common mutant alleles are Pi*Z and Pi*S, and inheritance of these as homozygous alleles (i.e. Pi*ZZ, Pi*SS) or compound heterozygotes (Pi*SZ) results in a deficiency state [1-3]. These mutations are characterized by low levels and dysfunction of A1AT. Rare null mutations result in completely absent protein, and others, such as F, confer dysfunctional protein with normal levels [4-6]. Available diagnostic tests include measurement of protein levels, genotyping for common mutations, or phenotypic analysis of variants by isoelectric focusing (IEF) [7]. However, given the wide spectrum of mutations, diagnosis can be challenging and use of any of these tests alone can be misleading.We present an A1AT-deficient patient with a novel and previo