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

Tavares I, Lobato L, Matos C, Santos J, Moreira P, Saraiva MJ, Castro Henriques A - Case Rep Nephrol (2015)

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Nephrology, Centro Hospitalar de São João, 4200-319 Porto, Portugal ; Nephrology and Infectious Diseases Research and Development Group, INEB (I3S), University of Porto, 4150-180 Porto, Portugal.

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.

No MeSH data available.


Related in: MedlinePlus

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.
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fig1: 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.

Mentions: A 44-year-old Caucasian northern Portuguese woman who had suffered a single previous episode of upper gastrointestinal hemorrhage presented with hypertension, nephrotic syndrome, and renal failure in April 1989. Renal biopsy 1 year later revealed abundant glomerular amyloid deposition (Figure 1(a)); her serum creatinine was 4.0 mg/dL and proteinuria of 7.5 g/day was detected. In the absence of any underlying inflammatory disease and unawareness of family history, she was presumed to have immunoglobulin light chain (AL) amyloidosis. However, there was no evidence of cardiac amyloidosis, and neither a monoclonal immunoglobulin nor a plasma cell disorder was identified. She was treated with melphalan and corticosteroids but progressed rapidly to ESRF and started hemodialysis in December 1990. During hemodialysis, her functional status remained good.


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

Tavares I, Lobato L, Matos C, Santos J, Moreira P, Saraiva MJ, Castro Henriques A - Case Rep Nephrol (2015)

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.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4493303&req=5

fig1: 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.
Mentions: A 44-year-old Caucasian northern Portuguese woman who had suffered a single previous episode of upper gastrointestinal hemorrhage presented with hypertension, nephrotic syndrome, and renal failure in April 1989. Renal biopsy 1 year later revealed abundant glomerular amyloid deposition (Figure 1(a)); her serum creatinine was 4.0 mg/dL and proteinuria of 7.5 g/day was detected. In the absence of any underlying inflammatory disease and unawareness of family history, she was presumed to have immunoglobulin light chain (AL) amyloidosis. However, there was no evidence of cardiac amyloidosis, and neither a monoclonal immunoglobulin nor a plasma cell disorder was identified. She was treated with melphalan and corticosteroids but progressed rapidly to ESRF and started hemodialysis in December 1990. During hemodialysis, her functional status remained good.

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Nephrology, Centro Hospitalar de São João, 4200-319 Porto, Portugal ; Nephrology and Infectious Diseases Research and Development Group, INEB (I3S), University of Porto, 4150-180 Porto, Portugal.

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.

No MeSH data available.


Related in: MedlinePlus