Studies on plasma transthyretin (prealbumin) in familial amyloidotic polyneuropathy, Portuguese type.

Amyloid deposits in several heredofamilial forms of amyloidosis are known to be chemically related to transthyretin (TTR, the plasma protein usually referred to as prealbumin). A genetic mutation, leading to an abnormal TTR, may be involved. Studies were conducted to investigate whether or not Portuguese patients with familial amyloidotic polyneuropathy (FAP) have an abnormal species of TTR circulating in their plasma and, if so, whether this might have any impact on vitamin A transport and retinol-binding protein (RBP) metabolism in these patients. The initial studies examined the plasma concentrations of TTR, RBP, and retinol in patients with FAP. Significantly reduced (p less than 0.005) levels of TTR were found in patients with FAP. The TTR levels in 24 FAP patients were approximately two thirds of those of a group of 18 control subjects from the same geographic area. In contrast, RBP levels were not reduced, nor was there an abnormality in the ratio of retinol to RBP, in the patients with FAP. Thus there does not appear to be an abnormality in vitamin A transport in Portuguese patients with FAP. There does, however, appear to be an abnormality of TTR metabolism, accounting for the reduced plasma levels of TTR. TTR was isolated from pooled sera of the FAP patients and was characterized in detail. FAP-TTR was indistinguishable from normal TTR with regard to a variety of parameters, including (1) electrophoretic mobility, (2) chromatographic behavior, (3) molecular weight, (4) stability of the TTR tetramer, (5) immunoreactivity in TTR radioimmunoassays using antisera prepared against both normal and FAP-TTR, (6) ability to form a protein-protein complex with RBP and affinity for RBP as assessed by polarization of fluorescence, and (7) overall amino acid composition. The possible explanations are as follows: (1) an abnormal TTR molecule is not produced in this form of FAP; (2) the abnormal molecule is present in only trace amounts (not detectable in the present study) in FAP plasma; or (3) the abnormal TTR is structurally almost identical to normal TTR and does not differ from normal TTR with regard to the various physical and chemical properties investigated in this study. Preliminary observations suggest that FAP patients do produce an abnormal form of TTR that selectively deposits in tissues as amyloid protein.