Genetic disease and amyloid.

Amyloid results from the deposition, principally in connective tissue, of polymers that are for the most part incompletely digested precursor proteins. In man the resulting deposits are very resistant to resorption or digestion: their relentless accumulation often causes death by interfering with the function of vital organs such as the kidneys, heart, and gut. There are three definitive methods for recognising amyloid. (1) The dye congo red is bound more strongly by amyloid than by human albumin (Bennhold, 1922). It then exhibits a green birefringence in polarised light (Missmahl, 1957). (2) Electron microscopy reveals a characteristic fibrillar structure (Cohen and Calkins, 1959) that is nonbranching, of variable length, and 8-15 nm wide. (3) X-ray diffraction shows a pattern with an outer band of 4-75 A and an inner band of 9-8 A (Eanes and Glenner, 1968). These three properties result from an antiparallel f-pleated sheet conformation with the grooves of the pleats running along the length of the fibril. The bends of the pleating probably coincide with glycine or proline residues at about every 16 amino-acids. It is these amino-acids that seem to make amyloid fibrils very resistant to digestion. Only enzymes such as pronase can disrupt the fpleated sheet conformation, simultaneously destroying the three characteristic properties. The most sensitive method for detecting early amyloid deposition in tissues is electron microscopy. For preliminary screening, however, fluorescence microscopy after staining with thioflavine-T (Vassar and Culling, 1959), while not entirely specific, rarely fails to identify true amyloid (Hobbs, 1973). The genetic varieties of amyloidosis are rare in Britain. When all parts of the world are considered, however, some 2000 patients are now recorded. In most cases this relentless disease results from the overproduction of the amyloid precursor proteins. Symptoms appear between 25-45 years of age. The clinical disorder progresses to death within 10 years. An elegant description of most of the genetic varieties of amyloid has been written by Cohen (1972), and a simplified form of his clinical classification is used in this brief report. It is emphasised that many classifications of amyloid (Hobbs, 1973) have not yet benefited from the new knowledge gained about the precursor proteins; all classifications overlap. It is nevertheless reasonable to review the main genetic forms of amyloid in terms of the clinical character of their onset. I then consider how the excess of amyloid precursors occurs. Surely this must offer a key to the best hope for managing these diseases.