Gelsolin-related familial amyloidosis, Finnish type (FAF), and its variants found worldwide.
Gelsolin-related familial amyloidosis, Finnish type, occurs worldwide, most likely as a result of sporadic low-frequency mutations. Two mutations at nucleotide 654 in the gelsolin gene have been demonstrated, which result in a characteristic triad of ophthalmologic, neurologic and dermatologic manifestations distinct from other amyloidoses. Some phenotypic variation, particularly in the age of onset and severity of manifestations, occurs but in general the disease is clinically rather homogeneous. Systemic deposition of amyloid is found in most tissues, predominantly in blood vessel walls and associated with basement membranes. The mutations result in amino acid substitutions with a charge change in the gelsolin molecule, postulated to alter the susceptibility for proteases thereby rendering the molecule amyloidogenic. Gelsolin fragments constitute the amyloid fibrils, but abnormal fragments also occur in patients' plasma and CSF providing evidence for the role of aberrant proteolysis in the disease pathomechanism. This is further strengthened by in vitro expression analyses showing both disease-related mutations to result in secretion of an abnormal gelsolin fragment, the likely precursor protein of gelsolin amyloid. Of the two forms of gelsolin, secretory and cytoplasmic, the secretory plasma form is the likely source of amyloid. The origin of the systemic amyloid deposits is not known but, beside a circulatory origin, local synthesis and deposition is an attractive pathomechanical alternative. The final goal of preventing or curing this disease has come closer, but still awaits further comprehensive pathological, functional and experimental studies in order to dissect all pathogenetically important events.
Kiuru
S
S
Department of Neurology, University of Helsinki, Finland.
D000682:Amyloid / Q000737:chemistry / Q000235:genetics*; D017772:Amyloid Neuropathies / Q000453:epidemiology / Q000209:etiology / Q000503:physiopathology; D005260:Female; D005799:Genes, Dominant / Q000235:genetics; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics*
D000682:Amyloid; D010446:Peptide Fragments; C103598:amyloid AGel protein, human