Genetic Aspects of Amyloidosis

Abstract

The amyloidoses are diseases characterized by the extracellular accumulation of insoluble protein fibrils. From the initial pathologic description by Virchow in the mid-19th century until the early 1970s, the idea of a single amyloid substance was dominant, and the systemic amyloid syndromes were classified on clinical grounds, i.e., the anatomic distribution of amyloid deposition and the associated clinical findings. The most widely accepted nosology acknowledged only three basic types of systemic amyloidosis, “secondary,” “familial,” and “primary” (in addition to rare forms of amyloidosis localized to a single organ). Thus, deposits of amyloid material in the kidney, liver, and spleen in association with chronic inflammatory processes such as tuberculosis and rheumatoid arthritis were termed “secondary amyloidosis.” Familial amyloidosis was recognized by its distinctive clinical manifestations and the positive family history. All other types of amyloidosis, except that associated with the neoplasm multiple myeloma, were termed “primary,” in the sense of “idiopathic”; this category included unrecognized inherited forms, “secondary” amyloidosis without an identified cause, and localized amyloidoses. The failure of many instances of amyloid deposition to fit neatly into the prescribed clinical and histologic categories should have suggested that the notion of a unique amyloid substance was conceptually inadequate.