Sunday, April 13, 2014

Article Reviews (2005 and 2008) - AFib in Portugal

Today's blog post will actually cover two more abstracts, both of which describe fibrinogen amyloidosis patients in Portugal

Title: Fibrinogen A-alpha Chain Amyloidosis: Homozygosity for the Glu526Val Mutation

Authors: Carlos M. Matos, Isabel Tavares, Paul Moreira, Elísio Carvalho, Maria J. Saraiva, Luisa Lobato. (Nephrology, Hospital Geral de Santo António, Porto, Portugal; Nephrology, Hospital de São João, Porto, Portugal; Molecular Neurobiology, Instituto de Biologia Molecular e Celular, Porto, Portugal.)

Here is a link to this abstract if you would like to follow along:

This paper is an abstract presented at the XLII ERA-EDTA Congress in June of 2005. ERA-EDTA is the European Renal Association - European Dialysis and Transplant Association.

The previously reviewed article (in the April 5, 2014 blog post) described the first case of fibrinogen amyloidosis in Portugal. The current abstract, from 2005, presents another case from Portugal with an interesting twist we have not seen before. The patient in this case was a Portuguese woman who presented with hypertension and renal failure (among other things) at the age of 44. A kidney biopsy showed extensive amyloid deposits in the glomeruli. She started hemodialysis at the age of 45 and received a kidney transplant six years later. Nothing unusual about this case so far . . .

Her original kidney biopsy was re-evaluated by immunohistochemistry and found to be positive for fibrinogen. DNA analysis showed she had the Glu526Val mutation, but instead of being heterozygous (one gene is normal, one is mutated) she was homozygous for the mutation. That means she inherited the mutation from her mother and from her father. Both of her parents died in their 80s without any known kidney issues. The only family history of kidney disease she was aware of was an aunt on her father's side who developed end-stage renal disease late in life.

At the time this abstract was written, it was 8 years after her kidney transplant and she had stable kidney function with no proteinuria and a serum creatinine level of 1 mg/dL.


We cannot reach any firm conclusions about the effects of being homozygous vs. heterozygous for the Glu526Val mutation from this one case. It does mean 100% of her fibrinogen was variant instead of 50% for heterozygous patients. On the one hand, she required dialysis at the age of 45, which is toward the low end of the range (36 to 82) presented in the 2009 article by Gillmore, et al. On the other hand, her kidney transplant was showing no clinical sign of amyloid after 8 years. They did find that her fibrinogen levels were low but her blood clotting times were normal.

The fact that this patient inherited the Glu526Val mutation from both parents means the mutation was present in two different family trees that happened to join together when her parents married and had offspring. So the chances are good that some more cases from Portugal will be reported. Sure enough, three years later, at this same conference, another abstract is presented that reports on fibrinogen amyloidosis patients in Portugal.

Title: Fibrinogen Amyloidosis: Report of the Portuguese Cluster

Authors: Isabel Tavares, Luciana Moreira, Joaquim Pinheiro, M. João Rocha, Elíseo Carvalho, Paulo P. Costa, Luísa Lobato. (Unit of Inv. and Research in Nephrology (FCT-725), Portugal, Fac. of Medicine, Porto, Portugal; Centro Estudos Paramiloidose, INSA, Porto, Portugal; Depart. Nephrology, Hospital Militar, D. Pedro, Porto, Portugal; Depart. Nephrology, Hospital Geral Santo António, Porto, Portugal)

Here is a link to this abstract if you would like to follow along:

This paper is an abstract presented at the XLV ERA-EDTA Congress in May of 2008. It states that Portuguese patients with amyloidosis, proteinuria or renal failure since 1985 were evaluated for this study. Biopsies were tested by immunohistochemistry, and if AL, AA, or ATTR amyloidosis could not be identified, then DNA analysis was done to identify mutations in apolipoprotein A1 and A2, fibrinogen and lysozyme. They did not identify any patients with apolipoprotein A1 or A2, or lysozyme, but they did identify 12 patients with the fibrinogen Glu526Val mutation, including the homozygous patient described in the 2005 abstract. (That does explain why her kidney biopsy was re-evaluated, as mentioned in the previous abstract.)

Since all of these patients were from Portugal, a country with a population of about 10 million, that alone seems like a high concentration of fibrinogen amyloidosis patients. But now consider the fact that all of these patients are from the Braga district in northern Portugal, which has a population between 800 and 900 thousand, and it is clear that the word "cluster" to describe this group of AFib patients is appropriate. These kindreds had no known relation to each other, but it is quite likely they have a common ancestor, given the geographical distribution of the families.

The abstract gives some more clinical data on these patients, and it does state that organ involvement in addition to kidneys was frequent with them. I am not going to discuss those details at this point because it is repeated in the next article up for review, which was published three years later in 2011. But I will let you know that the homozygous patient described in the 2005 abstract still had no sign of recurring amyloidosis when this 2008 abstract was written, 11 years after her kidney transplant.

The next article to be reviewed will have more information on these Portuguese patients, plus it will have the benefit of three more years of follow-up. We will take a closer look at the symptoms among this group, and we will also find out about the homozygous patient and her kidney transplant. Stay tuned . . .

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