Alpha1-antitrypsin Deficiency: Lessons Learned from the Bedside to the Gene and Back Again: First Cases of a XAT Deficiency

Alpha1-antitrypsin Deficiency: Lessons Learned from the Bedside to the Gene and Back Again: First Cases of a XAT DeficiencyHe presumably expected his chronic obstructive lung disease patients to have some abnormality in their immunoglobulins. They did not, but C-B. Laurell (who personally reviewed the paper electrophoretic strips) noted that some patients lacked a visible a 1-band. He first thought that bacterial contamination and neuraminidase activity in the samples was responsible for the observed phenomenon. Neuraminidase removes sialic acid residues from glycoproteins and thus retards their electrophoretic mobility towards the anode. But the samples were not contaminated. At that time, I was a resident at the Department of Medicine in Malmti, headed by Waldenstrttm. I had some experience in protein chemistry which was probably the reason why Laurell asked me to cooperate in the further evaluation of the missing otj-band. In a relatively short period of time, five such cases were found and formed the basis of the first report of a,AT deficiency. The paper electrophoretic pattern was quite typical (Fig 2). canadian-familypharmacy.com

The well-demarcated a,-band was missing, while the rest of the a, and all other zones seemed to be normal. With a variety of staining techniques it could be shown that other components of the o^-zone (ie, a-lipoprotein and orosomucoid) were present in normal amounts. We could deduce from data previously published by Jacobsson2 in 1955 on the partition of antitryptic activity in human serum after electrophoretic separation that the missing fraction corresponded to o^AT. This glycoprotein had been isolated in 1962 by investigators at Behring Werke in Marburg, Germany. The protein was homogenous after ultracentrifugation and free electrophoresis. It was a 3.5 S (Svedberg units) glycoprotein with the ability to inhibit trypsin activity and was therefore named antitrypsin. Consequently, we suggested the name antitrypsin deficiency for the deficiency state.

The protein, however, was not only subnormal in concentration. In our first paper we also demonstrated that axAT in deficient sera had a slightly decreased immunoelectrophoretic mobility consistent with a structural abnormality (Fig 3). We know today that this change of negative net charge is the result of the glutamic acid-lysine substitution in position 342 in the molecule (Fig 4). Clinical findings in the five patients included in this report were not clearcut but varied. Three had obstructive lung disease with chronic bronchitis, bronchiectasis and emphysema as main diagnoses. One young woman was completely healthy and one elderly woman had severe rheumatoid arthritis but no obvious signs of obstructive lung disease. We concluded that there was an association between degenerative pulmonary disease and axAT deficiency and suggested that the primary cause was an inborn error of metabolism.

Figure 2. Paper electrophoretic pattern of ot,AT deficient serum {above) and normal serum (below), Note lacking a,-band in deficiency

Figure 2. Paper electrophoretic pattern of ot,AT deficient serum {above) and normal serum (below), Note lacking a,-band in deficiency

Figure 3. Immunoelectrophoretic pattern of normal serum (above) compared with a,AT deficient serum {below). Note the retarded mobility of otjAT in the deficiency state. Anode to the left. (From Laurell and Eriksson).

Figure 3. Immunoelectrophoretic pattern of normal serum (above) compared with a,AT deficient serum (below). Note the retarded mobility of otjAT in the deficiency state. Anode to the left. (From Laurell and Eriksson).

Figure 4. Schematic structure of a,AT. In a,AT deficiency PiZ, there is a substitution of 342 Glu—*Lys.

Figure 4. Schematic structure of a,AT. In a,AT deficiency PiZ, there is a substitution of 342 Glu—*Lys.

Category: Health

Tags: emphysema, lung disease, trypsin inhibitory capacity