Alpha1-antitrypsin Deficiency: Lessons Learned from the Bedside to the Gene and Back Again: First Family with oixAT Deficiency

The First Family with oixAT Deficiency
Early during the clinical evaluation of a!AT deficiency, I had the good fortune to come across a family with three siblings suffering a severe form of obstructive lung disease. This family was the basis of an article in Acta Medica Scandinavica in 1964. One brother had died of lung disease and we lacked a blood sample. A sister and another brother were still alive. All three siblings had a severe form of emphysema (Fig 5). X-ray results were typical, with flat diaphragms and lack of basal vascular markings. They had a very advanced obstructive ventilatory impairment which was irreversible after attempts at bronchodilatation. At this time, we had started to use agar gel to separate the plasma proteins. After separation in such gels, the fractions were cut out, eluted and each fractions ability to inactivate added trypsin was evaluated. As a trypsin substrate we used benzoyl-d-L-arginine-p-nitroanilide (BAPNA). Figure 6 illustrates the partition of antitryptic activity in a normal individual as compared to an ajAT deficient family member. The findings confirmed earlier observations that the main trypsin inhibitory capacity of serum was associated with the electrophoretic oix-fraction and the remaining 10 percent with the a2-fraction. so
Total trypsin inhibitory capacity (TIC) in the deficient patients was reduced to approximately 10 to 20 percent of normal. Analysis of TIC in family members very clearly demonstrated the hereditary nature of o^AT deficiency (Fig 5). The family members belonged to one of three TIC levels: namely, normal, 60, and 10 percent of normal. The intermediate level represented a heterozygous state, and the lowest level a homozygous state of an inherited defect transmitted by an autosomal gene. The occurrence of emphysema in three homozygous siblings lent strong support to the hypothesis that genetic factors might be of importance in the pathogenesis of emphysema. At that time, the true biologic significance of a!AT was unknown, so any attempt to explain the causal mechanism of emphysema in the patients with deficiency remained speculative.

Figure 5. The first family with a,AT deficiency (reprinted from Eriksson, by permission).

Figure 5. The first family with a,AT deficiency (reprinted from Eriksson, by permission).

Figure 6. Partition of trypsin inhibitory capacity in a normal serum (below) and an a,AT deficient serum (above). (Reprinted from Eriksson by permission.)

Figure 6. Partition of trypsin inhibitory capacity in a normal serum (below) and an a,AT deficient serum (above). (Reprinted from Eriksson by permission.)

Category: Health

Tags: emphysema, lung disease, trypsin inhibitory capacity