Monday, November 25, 2013

Article Review (2006) - Familial Amyloid Nephropathy of Fibrinogen A Alpha (E526V) Origin. Report of the First Case from Austria

Today's article review is the first of three papers I will be reviewing that were presented at the eleventh annual International Symposium on Amyloidosis, which was held in Woods Hole, Massachusetts in November of 2006. The papers presented at this symposium can be found in the book XIth International Symposium on Amyloidosis, edited by Drs. Skinner, Berk, Connors and Seldin, all of the Amyloidosis Center at Boston University. The book was published in July of 2007 and is currently available for only $219.95 at ($154.54 for Amazon Prime members.) If you would like to look at the book without spending that much money, Muriel Finkel will loan out her copy. (But try not to keep it for four months like I did.)

In our first paper from the 2006 Symposium, fibrinogen amyloidosis continues its global spread, this time into Austria.

Title: Familial Amyloid Nephropathy of Fibrinogen A Alpha (E526V) Origin. Report of the First Case from Austria (1)

Authors: S. Hargassner, G. Biesenbach, G. Syre, K. Altland, and R. P. Linke (General Hospital Linz, Austria; Institute of Human Genetics, Giessen, Germany; and Max-Planck-Institute of Biochemistry, Marinsried, Germany)

BookXIth International Symposium on Amyloidosis (2007)

Abstract: None

The patient in this article is a 63-year-old woman who initially presented with elevated serum creatinine. She was suspected of having lupus nephritis (kidney inflammation due to lupus) and was treated for that. Three months later she was admitted to the hospital with hypertension, serum creatinine of 3.18 mg/dl, proteinuria (3.5 grams per 24 hours), GFR of 16, and microhematuria (very small amount of blood in the urine). Her leading symptom was dyspnea (difficulty breathing), so she was initially treated for that, and then underwent further investigation.

A kidney biopsy was done, and Congo red staining showed significant amyloid deposits in the glomeruli. The biopsy was further analyzed immunohistochemically (staining against specific proteins), which showed the presence of fibrinogen. Genetic testing showed the patient had the Glu526Val mutation. She also had another fibrinogen mutation that, if I understand correctly, is a benign mutation that is randomly found in a small percentage of the population. She began hemodialysis a year later and was listed for a kidney transplant, although she was told a combined liver and kidney transplant might be curative.

There was no known history of kidney failure in her family. Both of her sons tested positive for the Glu526Val mutation, and her sister tested negative. The article then states that a de novo point mutation seems to be a possibility. (More on that later.)

The conclusion of the paper states some of the facts about fibrinogen amyloidosis that were known at the time, specifically:

  • Inheritance is autosomal dominant
  • Fibrinogen is produced in the liver
  • Family history is usually negative (for kidney issues)
  • Penetrance is incomplete
  • Most patients suffer renal failure alone
  • Combined liver and kidney transplantation appears to be curative

This paper describes another case where the patient presents with the classic symptoms of fibrinogen amyloidosis, which are hypertension, elevated serum creatinine and proteinuria. A kidney biopsy showed the characteristic sign of fibrinogen amyloidosis, which is amyloid deposits in the glomeruli. An additional symptom noted with this patient that I do not recall seeing before is microhematuria, which is a very small amount of blood in the urine (not enough to cause discoloration.) As Dr. Benson stated at the recent familial amyloidosis meeting in Chicago, over time you see a pattern of symptoms develop in patients and there is a typical progression of the disease, but occasionally there will be a patient who has not read the book and has something outside of the norm.

Regarding the possibility that this was a de novo mutation, I suppose that is always a theoretical possibility until genetic testing is done on both parents of a patient. But this case does fit the pattern of the propositus (first person diagnosed) being the first person in the family known to have any kidney issues, so I don't really know why the authors of this paper bothered to include the sentence about the possibility of this being a do novo mutation.

In the next article review from the 2006 symposium, we have our first paper that could be considered a study of a large number of fibrinogen amyloidosis patients (20), instead of patients from only one or two families.


(1) Skinner M, Berk JL, Connors LH, Seldin DC. XIth International Symposium on Amyloidosis: Taylor & Francis; 2010.

[Edited December 23, 2013. Minor change to first sentence.]

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