A patient with the rare alpha-1-antitrypsin variant Zbristol in compound heterozygosity with the Z mutation

Abstract

Alpha-1-antitrypsin (AAT) is a protease inhibitor (PI), deficiency of which is associated with emphysema and liver disease. The most common deficiency alleles are the S (p.Glu288Val) and Z (p.Glu366Lys) alleles. The Z allele predisposes the AAT protein to polymerization with accumulation in hepatocytes leading to liver disease in PIZ individuals. Most AAT variants have a characteristic pattern of isoforms by isoelectric focusing (IEF). A novel AAT variant called PIZbristol (p.Thr109Met) with an unusual pattern on IEF was described in 1997. We report a patient with the PIZZbristol phenotype that has not been previously described. A 43-year-old man was referred by his GP to a respiratory clinic for breathlessness. His AAT concentration was 0.50 g/L (reference range 1.0–2.0 g/L). An unusual pattern on IEF was seen and sequencing revealed the presence of the rare variant Zbristol in combination with the Z mutation. This is the second reported case of Zbristol and the first in combination with the Z mutation. The patient maintained plasma AAT concentrations around 0.50–0.70 g/L which suggested that the Zbristol protein contributed to the low plasma concentration of AAT. The clinical symptoms associated with PIZ are usually attributed to the plasma deficiency, but his only respiratory complaint was that of breathlessness. This suggests that the PIZZbristol phenotype may confer an effect on respiratory function but is not involved in liver disease.