Familial Amyloidotic Polyneuropathy Type I and Type II: Characterization of Two Distinct Genetic Defects and Identification of Carriers of Each Gene

Abstract

Familial amyloidotic polyneuropathy (FAP) Type I and FAP Type II have previously been classified on the basis of clinical presentation. Amyloid fibrils have been isolated from the tissues of patients with FAP Type I (Swedish) and FAP Tyep II (Indiana-Swiss) and the subunit protein of each type of amyloid structurally characterized as a variant of prealbumin. The FAP Type I prealbumin has a methionine for valine amino acid substitution at position 30 of the 127 residue molecule. FAP Tyep II subunit has a glycine for threonine substitution at position 49 as has been reported previously for amyloid from a Jewish patient in Israel. Carriers of the FAP Type I genetic defect have been identified by cleavage of their plasma prealbumin with cyanogen bromide. This generates two extra peptides because CNBr cleaves the variant prealbumin at both methionine residues. This difference from normal is readily seen by HPLC analysis of the cleaved prealbumins. Carriers of FAP Type II prealbumin have been shown to have significantly depressed plasma retinol binding protein concentrations. These two separate methods allow identification of carriers of the aberrant prealbumin genes before expression of the disease and may be useful in genetic counseling.