Homozygosity for the E526V Mutation in Fibrinogen A Alpha-Chain Amyloidosis: The First Report

Abstract

Systemic hereditary amyloidoses are autosomal dominant diseases associated with mutations in genes encoding ten different proteins. The clinical phenotype has implications on therapeutic approach, but it is commonly variable and largely dependent on the type of mutation. Except for rare cases involving gelsolin or transthyretin, patients are heterozygous for the amyloidogenic variants. Here we describe the first patient identified worldwide as homozygous for a nephropathic amyloidosis, involving the fibrinogen variant associated with the fibrinogen alpha-chain E526V (p.Glu545Val) mutation. In 1989, a 44-year-old woman presented with hypertension, hepatosplenomegaly, nephrotic syndrome, and renal failure. She started hemodialysis in 1990 and 6 years later underwent isolated kidney transplantation from a deceased donor. Graft function and clinical status were unremarkable for 16 years, despite progressively increased left ventricular mass on echocardiography. In 2012, 4 months before death, she deteriorated rapidly with severe heart failure, precipitated by Clostridium difficile colitis and urosepsis. Affected family members developed nephropathy, on average, nearly three decades later, which may be explained by the gene dosage effects on the phenotype of E526V (p.Glu545Val) fibrinogen A alpha-chain amyloidosis.

Figure 1

Homozygous E526V (p.Glu545Val) mutation in the fibrinogen alpha-chain gene (FGA) associated with fibrinogen A alpha-chain amyloidosis in a Portuguese patient. (a) shows abundant glomerular amyloid deposition with typical apple-green birefringence (Congo red staining under polarized light, ×200, left). Immunohistochemical staining was positive with polyclonal anti-fibrinogen antibodies, (×200, right). (b) shows a partial sequence chromatogram of FGA. The mutation identified in the proband, which alters codon 545 (position 526 of the mature protein) from GAG (glutamic acid) to GTG (valine), is depicted in a circle. (c) shows the pedigree of the affected kindred. The homozygous patient (proband) is indicated by the arrow. The FGA p.Glu545Val mutation was identified heterozygously in family members III7, III8, III10, IV3, IV4, IV5, and IV6 (indicated by half-solid symbols). Obligatory heterozygotes IV2 and IV7 (indicated by question marks) did not perform genotyping because the former was abroad and the latter died at young age. Those with chronic renal failure who have not undergone histologic or genetic testing are indicated by a black column inside the symbol. Familiars whose genetic tests were negative are indicated by an N inside the symbol. Blank symbols indicate that tests have not been conducted and/or information is unavailable for these individuals. Slashes denote deceased members.