Abstract

Hereditary systemic amyloidosis is caused by deposition of genetically variant proteins as amyloid fibrils. The types that present with renal disease are usually associated with mutations in the genes for either apolipoprotein AI, apolipoprotein AII, lysozyme or fibrinogen A *-chain. These diseases are inherited in an autosomal dominant manner with variable penetrance, and can present clinically at any time from the teen years to old age, though usually in mid-adult life. Hereditary amyloidosis is uncommon, but its precise characterization has major implications for patient management and genetic counseling, and it has been an extremely valuable model for elucidating the pathogenesis of amyloid deposition generally. The amyloidogenic variant proteins associated with hereditary amyloidosis are less stable than their normal wild type counterparts and even under physiological conditions can populate partly unfolded states, involving loss of tertiary or higher order structure, which readily aggregate with retention of -sheet secondary structure into protofilaments and fibrils. The clinical phenotype of hereditary renal amyloid is non-specific and is readily misdiagnosed as acquired AL amyloidosis. Indeed, we have lately demonstrated that five percent of patients with apparent sporadic amyloid have hereditary fibrinogen A *-chain amyloidosis associated with the valine 526 variant. Penetrance of this particular mutation is extremely low in most families obscuring the genetic etiology, but the renal histology is very characteristic showing substantial accumulation of amyloid within enlarged glomeruli, but none in blood vessels or the interstitium. DNA analysis is now performed routinely in UK National Amyloidosis Centre in patients with systemic amyloidosis in whom AA or AL fibril type cannot be definitively verified.