Successful Hepatorenal Transplantation in Hereditary Amyloidosis Caused by a Frame-Shift Mutation in Fibrinogen Aa -Chain Gene

Abstract

Hereditary systemic amyloidosis comprises several autosomal dominant diseases caused by mutations in a number of plasma proteins, including the fibrinogen Aa -chain. Four mutations in the fibrinogen Aa -chain that are able to induce amyloidosis have been identified so far, the most common being the Glu526Val mutation. We have observed a family in which the father and his son reached end-stage renal failure because of renal amyloidosis induced by a frame-shift mutation in the fibrinogen Aa -chain gene producing a novel amyloid protein. Two kidney transplantations in the father and one in the son resulted in fast graft loss caused by recurrence of amyloid deposition. We then performed hepatorenal transplantation in the son. Three years later, liver and kidney functions are normal without recurrence of amyloid deposition. This case, together with three others with the Glu526Val mutation in the extensive literature, suggests that liver transplantation can cure hereditary fibrinogen amyloidosis, whatever the mutation may be.

Extracellular Chaperones and Proteostasis

“…In cases where the disease-relevant protein is primarily synthesized by the liver, organ transplantation is a drastic but effective means by which to control the disease. Currently, liver transplant is most common for the treatment of transthyretin (TTR) related familial amyloidosis (200), and has been successfully used to treat other forms of amyloidosis including those resulting from mutation in fibrinogen α-chain or lysozyme (201,202). Nevertheless, surgery of this kind carries serious risk and unless taken as a preemptive measure, damage to other organs may already be severe at the time of transplantation.…”

Nephrotic Syndrome Due to an Amyloidogenic Mutation in Fibrinogen A α Chain

“…Interestingly, the liver produces several of these proteins exclusively or predominantly; therefore, in these patients, liver transplantation has been tried as a form of treatment targeting the supply of abnormal protein. 6,7 A new class of anti-amyloid agents is also in clinical trials for AA and ATTR. 2,3 In view of the dramatic differences in treatment, the precise diagnosis of the amyloid type is critical.…”

“…4 -6,11 In AFib amyloidosis, there is a mutation in the fibrinogen A ␣ chain, and several variants have been reported. 5,7,8,10 The typical presentation is with nephrotic syndrome and hypertension, and the median age at presentation is 55 yr. Kidney involvement is associated with massive and exclusively glomerular amyloid with essentially no extraglomerular deposits. There is some phenotypic variability, depending on the Hereditary amyloidoses are underdiagnosed, although, with increased awareness, they are diagnosed more frequently.…”

“…3 Although some hereditary amyloidoses associate with polyneuropathy and others with polyneuropathy and cardiomyopathy, virtually all can involve the kidneys 4,5,7-11 (Table 1); however, the degree of renal involvement may vary, with some types affecting predominantly glomeruli, others with glomeruli and extraglomerular vasculature, and still others only in the interstitium with some limited to deep medulla. 4,5,[7][8][9][10][11] Moreover, within a given hereditary amyloidosis type, phenotypes may vary depending on the mutation 7,8,10 ( Table 1). There may also be a difference between homo-and heterozygotes.…”

Delayed diagnosis of fibrinogen Aα-chain amyloidosis after dual heart-kidney transplantation

“…Fibrinogen Aa-chain (AFib) amyloidosis involves the kidneys and causes proteinuria, hypertension, and progression to endstage renal disease (ESRD). Isolated renal transplantation has been proposed when ESRD is reached, but it is associated with risk of recurrence and premature graft loss [2,3]. Moreover, cardiac amyloidosis has been recently described among mutated patients [4] but its precise pathogenesis remains debated [2,5].…”