Characterization of three new SERPINA1 variants PiQ0Heidelberg II, PiQ0Heidelberg III and PiQ0Heidelberg IV in patients with severe alpha-1 antitrypsin deficiency

Abstract

Background: The clinical and molecular characteristics of three patients with previously unreported SERPINA1 mutations associated with severe alpha-1 antitrypsin deficiency (AATD) are described. The pathophysiology of the chronic obstructive pulmonary disease (COPD) present in these patients was characterized through clinical, biochemical, and genetic examinations.

Case presentations: Case 1: A 73-year-old male with bilateral centri-to panlobular emphysema and multiple increasing ventrobasal bullae and incomplete fissures, COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade III B), progressive dyspnea on exertion (DOE), AAT level of 0.1-0.2 g/L. Genetic testing revealed a unique SERPINA1 mutation: Pi*Z/c.1072C > T. This allele was designated PiQ0_{Heidelberg II}. Case 2: A 47-year-old male with severely heterogenous centri-to panlobular emphysema concentrated in the lower lobes, COPD GOLD IV D with progressive DOE, AAT <0.1 g/L. He also had a unique Pi*Z/c.10del mutation in SERPINA1. This allele was named PiQ0_{Heidelberg III}. Case 3: A 58-year-old female with basally accentuated panlobular emphysema, GOLD II B COPD, progressive DOE. AAT 0.1 g/L. Genetic analysis revealed Pi*Z/c.-5+1G > A and c.-472G > A mutations in SERPINA1. This variant allele was named PiQ0_{Heidelberg IV}.

Conclusions: Each of these patients had a unique and previously unreported SERPINA1 mutation. In two cases, AATD and a history of smoking led to severe lung disease. In the third case, timely diagnosis, and institution of AAT replacement stabilized lung function. Wider screening of COPD patients for AATD could lead to faster diagnosis and earlier treatment of AATD patients with AATD which could slow or prevent progression of their disease.

Keywords: Alpha-1 antitrypsin deficiency; Chronic obstructive pulmonary disease; Emphysema; SERPINA1.

Fig. 1

CT scans and YACTA analysis of Case 1 - PiQ0_{Heidelberg II.}A. A transverse view of the patient's lungs showing ventrally focused panlobular emphysema and deformed bronchopathy. B. A sagittal CT of the patient's lung again showing ventrally focused panlobular emphysema. C. YACTA analysis of the patient's sagittal CT scan showing panlobular emphysema (yellow) with an overall emphysema index of the lung of approximately 38%. Courtesy: Oliver Weinheimer, University Hospital Heidelberg. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2

CT scans and YACTA analysis of Case 2 - PiQ0_{Heidelberg III.}A. A transverse view of the patient's lungs showing panlobular emphysema with deforming bronchopathy. Valves have been inserted in the right lower lobe with downstream dystelectic bundling. B. A coronal CT of the patient's lung showing severe panlobular emphysema especially in the right lower lobe. C. YACTA analysis of the patient's coronal CT scan showing severe panlobular emphysema (yellow) with an overall emphysema index of the lung of approximately 57%. Courtesy: Oliver Weinheimer, University Hospital Heidelberg. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 3

CT scan and YACTA analysis of Case 3 - PiQ0_{Heidelberg IV.}A. A coronal view of the patient's lungs showing basal-focused panlobular emphysema and deforming bronchopathy with squamous atelectasis. B. YACTA analysis of the patient's coronal CT scan showing severe panlobular emphysema (yellow) with an overall emphysema index of the lung of approximately 19%. Courtesy: Oliver Weinheimer, University Hospital Heidelberg. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)