A 35-year-old man is evaluated for symptoms of shortness of breath. He reports no other lung or heart disease. He smokes half pack a day for the past 10 years. On examination, his JVP is 2 cm, heart sounds normal, and lungs are clear. A CXR shows hyperinflation and increased lucency of the lung fields. A chest CT reveals bullae and emphysematous changes, while pulmonary function tests show an FEV1/FVC ratio of <70%. Evaluation of his family reveals other affected individuals. Which of the following is the most likely diagnosis?: (A) alpha1-antitrypsin deficiency, (B) beta-glycosidase deficiency, (C) glucose-6-phosphatase deficiency, (D) glucocerebrosides deficiency
Answer is A. Most people have two MM genes and a resultant alpha1-antitrypsin level in excess of 2.5 g/L. Homozygotes with ZZ or SS genotypes have severe alpha1-antitrypsin deficiency and develop severe pan acinar emphysema in the third or fourth decade of life. Smoking is an important cofactor in the development of disease. Heterozygotes (MZ or MS) have intermediate levels of alpha1-antitrypsin (i.e., genetic expression is that of an autosomal codominant allele). This heterozygous state is common (5-14% of general population), but it is unclear whether it is associated with lung function abnormalities.