Monday, December 30, 2013

Article Review (2008) - Three German fibrinogen Alpha-chain amyloidosis patients with the p.Glu526Val mutation

We will wrap up the 2013 article reviews with one from 2008, which is the first report of fibrinogen amyloidosis from Germany. Or is it?

Title: Three German fibrinogen Alpha-chain amyloidosis patients with the p.Glu526Val mutation (1)

Authors: Magdalena Eriksson, Stefan Schonland, Raoul Bergner, Ute Hegenbart, Peter Lohse, Hartmut Schmidt, Christoph Rocken (Charite University Hospital, Berlin, Germany; University of Heidelberg, Heidelberg, Germany; Klinikum der Stadt Ludwigshafen, Ludwigshafen, Germany; University of Munich, Munich, Germany; University of Munster, Munster, Germany)

Journal: Virchows Archiv: The European Journal of Pathology (2008)

Plasma protein fibrinogen variants cause fibrinogen Aα-chain (AFib) amyloidosis, which presents with hypertension, proteinuria, and azotemia. Six AFib mutations have been reported thus far. We identified three patients who presented with marked proteinuria and serum creatinine elevations. Their kidney biopsies revealed destruction of the glomerular architecture by amyloid deposits with typical, apple-green birefringence in polarized light after Congo red staining. We found immunoreactivity against fibrinogen, which is typical for this type of amyloidosis. We sequenced the FGA exon 5 and demonstrated heterozygosity for the p.Glu526Val mutation in all three cases. This amino acid substitution is the most common fibrinogen Aα-chain variant causing AFib amyloidosis. The mutation has been reported in individuals of European and American descent but not yet in German patients. AFib amyloidosis should therefore be considered an important differential diagnosis in German patients with renal amyloidosis. In the cases described here, the use of antibodies directed against fibrinogen, followed by direct gene sequencing, revealed the underlying cause.
The introduction of this article has an overview of hereditary amyloidosis, which narrows to hereditary renal amyloidosis, which then narrows to what was known at the time about fibrinogen amyloidosis, such as the known mutations, typical symptoms, and treatment options. It then describes the three patients who were diagnosed with the Glu526Val mutation for fibrinogen amyloidosis.

Case 1: A 62-yer-old woman developed hypertension around the age of 52, and then at age 60 she was observed to have proteinuria and elevated creatinine clearance. A kidney biopsy showed amyloidosis of unknown type. No other organs were affected and a bone marrow biopsy was normal. She did show early signs of polyneuropathy in her fingers and feet. She had no family history of hereditary amyloidosis or kidney disease.

Case 2: A 49-year-old man with hypertension, hyperlipidemia (elevated lipid levels) and coronary artery disease was admitted to the hospital with severe nephrotic syndrome. Upon admission his proteinuria was 15 grams per day. A kidney biopsy showed amyloidosis, and no other organs were involved. The patient's mother had an unknown renal disease and died of a heart attack at the age of 61.

Case 3: A 64-year-old man with hypertension for 20 years and shortness of breath for four years developed progressive proteinuria and renal failure, eventually ending up on dialysis. A kidney biopsy showed amyloidosis.

All three of these patients were referred to the Amyloidosis Clinic at The University of Heidelberg in Germany. The article then describes the additional analysis done on the biopsy samples and the genetic testing on the individual patients. The biopsies of all three patients showed extensive amyloid deposits concentrated in the glomeruli. They performed immunohistochemistry on the biopsies, meaning they were stained with different antibodies that would react to the various precursor proteins known to cause amyloidosis. Some of the deposits did intensely stain in reaction to the fibrinogen antibody, which raised the suspicion of fibrinogen amyloidosis.

The genetic testing showed all three patients were heterozygous for the Glu526Val fibrinogen amyloidosis mutation. They also established that the three patients were not related (as far as the available geneaology records indicated.) Additional genetic testing on family members who consented showed the following:

Case 1: This patient has a son and a daughter. The daughter underwent genetic testing and she has the mutation but is asymptomatic.

Case 2: This patient has no siblings or children. His mother had an unknown kidney disease before she died, so her DNA was never tested for the mutation. But his mother's sister does have the mutation and is asymptomatic. She (the patient's aunt) has a daughter and two grandchildren who have not been tested.

Case 3: This patient's father and aunt developed kidney disease but were never genetically tested for the mutation. The patient has three healthy children who have not been tested.

The final section of the article gives some technical information about the fibrinogen molecule itself, and the molecular impact of the various mutations known to cause fibrinogen amyloidosis. It then discusses the importance of immunohistochemistry in the analysis of these biopsy samples, and recommends that fibrinogen amyloidosis be included in the differential diagnosis of any German patient presenting with renal amyloidosis.


This article describes three patients with the typical symptoms of fibrinogen amyloidosis, whose kidney biopsies showed the usual pattern of amyloid deposits concentrated in the glomeruli. Fortunately they were not misdiagnosed with AL amyloidosis, but were instead referred to an amyloidosis clinic and were correctly diagnosed. We also have one of these patients having no family history of kidney disease, which is not unusual.

One thing that got my attention regarding these cases was how many years two of these patients had hypertension before developing any of the other usual symptoms of fibrinogen amyloidosis, such as proteinuria or elevated serum creatinine levels. I do not recall such long time periods in previous articles. Perhaps hypertension could be a very early warning sign of the kidneys being affected by fibrinogen amyloidosis in patients who are known to have the mutation. Hypertension alone would certainly not lead a doctor to suspect any type of amyloidosis, given all the other possible causes of hypertension. But hypertension in a patient with a known genetic mutation for fibrinogen amyloidosis should cause a doctor (and a knowledgeable patient) to suspect amyloidosis.

One other item of note, which I was not aware of until I recently read this article again, is that these patients were not the first reported German patients with fibrinogen amyloidosis. They were the first reported with the Glu526Val mutation, but there was a previous German patient with a different mutation reported in an abstract presented at the Xth International Symposium on Amyloid and Amyloidosis in April of 2004. That abstract can be found in the book Amyloid and Amyloidosis, published in November of 2004, edited by Gilles Grateau, Robert Kyle and Martha Skinner. I have not gotten my hands on a copy of that book yet, but I did find this complete one-page abstract online at the publisher's web site at this link: This particular mutation is discussed a bit more in a 2009 article, but I want to go ahead and review the abstract from the 2004 symposium in this blog post.

Title: Hereditary Renal Amyloidosis In A German Family Associated With Fibrinogen A Alpha Chain Glu540Val (2)

Authors: A. Bybee, M. Hollenbeck, E. R. Debusmann, D. Gopau, J. A. Gilbertson, H. J. Lachmann, M. B. Pepys, P. N. Hawkins (Nephrologische Klinik, Knappschaftskrankenhaus, Bottrop, Germany; National Amyloidosis Centre, London, UK)

Book: Amyloid and Amyloidosis (2004)

A German woman presented with proteinuria and haematuria (blood in the urine) at the age of 49. A kidney biopsy showed amyloid deposits in the glomeruli, which suggested fibrinogen amyloidosis. DNA analysis determined she was heterozygous for a newly discovered mutation, Glu540Val. (This is the exact same substitution that occurs in the Glu526Val mutation, but it occurs just 14 amino acids later in the sequence.)

This patient's father had died of renal failure at the age of 47. The patient's sister was found to also have the Glu540Val mutation, and her only symptom is proteinuria. She had a kidney biopsy that was similar to her sister's. Two of her three children also have the mutation and are currently asymptomatic.

There was no evidence of amyloid involvement in any other organs, although SAP scintigraphy on both sisters showed some amyloid desposits in the spleen. Based on these two patients, the Glu540Val mutation is indistinguishable from the Glu526Val mutation.

The next articles up for review will also come from Europe, this time from France. We have already had fibrinogen amyloidosis reported in France, but this next report includes something we have not seen before.



(1) Eriksson M, Schönland S, Bergner R, et al. Three German fibrinogen Aalpha-chain amyloidosis patients with the p.Glu526Val mutation. Virchows Arch. 2008;453(1):25-31.

(2) Grateau G, Kyle RA, Skinner M. Amyloid and Amyloidosis: Taylor & Francis; 2004.

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