The hereditary form of amyloidosis, familial amyloidotic polyneuropathy (FAP) is an autosomal dominantly inherited condition associated with a mutant form of the protein transthyretin (TTR, also called pre-albumin). It is a rare late-onset genetic disease which results in rapid deterioration due to peripheral and autonomic neuropathy and cardiomyopathy in the third or fourth decade of life. It raises the question of how an abnormal gene which is present from birth produces disease a decade later. Biopsies have proven that amyloid deposition begins just prior to the time of first symptoms. Six variant forms of the amyloid precursor TTR had been identified. Each involves a single amino acid substitution in the normal 127 amino acid chain of TTR. In their population of patients from 28 families with FAP, the applicants have recently identified one new variant and have other families with variants of unknown type. They differ phenotypically and in ethnic origin from each other and do not have one of the known TTR variants. The applicants proposed to examine their DNA and/or plasma for TTR variations that have resulted in amyloid deposition and to determine techniques for the genetic testing of that mutation. One patient with a homozygous mutant pattern will provide the unique opportunity to examine its proteolysis and to develop an antibody only to the mutant protein. They plan to test the hypothesis that variations in clinical symptoms, age at onset, and disease progression may be explained by factors other than the single nucleotide mutation in the TTR gene. Their preliminary data suggest a radical change in the beta formation of the mutant TTR when digested with a proteolytic enzyme human neutrophil elastase. These studies will be extended to TTR proteins from individuals who have pre-symptomatic FAP and carried out on known proportions of normal and variant TTR in the isolated mixture. Understanding the pathogenetic mechanisms involved in the processing of the precursor TTR into amyloid fibrils, they anticipate, will aid in the ultimate goal of defining treatment intervention.
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