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

Date Published: November 13, 2011

Publisher: BioMed Central

Author(s): Michael R Ringenbach, Erin Banta, Melissa R Snyder, Timothy J Craig, Faoud T Ishmael.


Alpha-1-antitrypsin (A1AT) deficiency is a genetic disease characterized by low levels and/or function of A1AT protein. A1AT deficiency can result in the development of COPD, liver disease, and certain skin conditions. The disease can be diagnosed by demonstrating a low level of A1AT protein and genotype screening for S and Z mutations, which are the most common. However, there are many genetic variants in A1AT deficiency, and this screening may miss rarer cases, such as those caused by dysfunctional protein. We identified a patient with a previously unreported F/null phenotype that was missed by routine screening. This case highlights the wide variation in possible mutations, limitations in diagnostics, and the importance of combining clinical suspicion with measurement of protein levels, phenotypic analysis, and in appropriate cases expanded genetic analysis.

Partial Text

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].

The patient is a 64 year old male who was seen with a chief complaint of dyspnea and recurrent skin rash. His dyspnea had been persistent and worsening in nature since he was diagnosed with COPD at age 49. Treatment with fluticasone 220 mcg 2 puffs twice a day via a HFA inhaler did not provide benefit, and he required use of albuterol as a rescue inhaler multiple times per week. He had a 10 pack-year history of cigarette-smoking, but stopped 7 years ago. His rash was described as diffuse, pruritic, erythematous, and raised, consistent with urticaria. It started approximately eight months ago and presented multiple times per week. Treatment with antihistamines (cetirizine 10 mg daily, hydroxyzine 50 mg every 6 hours as needed) and prednisone 40 mg daily were both ineffective. There were no known triggers and no implicated drugs or foods. His past medical history was otherwise significant only for chronic rhinitis. He had no history of liver disease or vasculitis. Review of systems was unremarkable. There was no family history of lung disease, liver disease, or autoimmunity.

We present a patient with A1AT whose diagnosis was delayed secondary to the presence of a rare mutation and A1AT level just below normal limits. The case emphasizes the importance of maintaining a high level of suspicion for disease in patients with COPD, and reinforces the utility of A1AT screening in these patients as this disease is under-diagnosed. This case supports an algorithm of screening that includes measuring an A1AT level, followed by genotyping and phenotypic assays. The limitations of each should be considered, and in some cases more extensive gene sequencing may be necessary to confirm the genotype.

Written informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

A1AT: alpha-1-antitrypsin; IEF: isoelectric focusing; SNP: single nucleotide polymorphism.

The authors declare that they have no competing interests. TC has a research grant with CSL-Behring.

MR performed molecular genetics studies and drafted the manuscript, EB assisted with molecular genetics studies and aided in drafting the manuscript, MS performed the isoelectric focusing experiment and aided in drafting the manuscript, TC participated in the design of the study and aided in drafting the manuscript, FI conceived of the study, and participated in its design and coordination and helped to draft the manuscript. All authors have seen the final draft of the manuscript.




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