Saturday, April 5, 2014

Article Review (2004) - Mutant fibrinogen A alpha-chain associated with hereditary renal amyloidosis and peripheral neuropathy

Before getting to today's article review I want to give a quick update on Mom. The previous update on Mom (March 7, 2014) described her reevaluation for getting back on the kidney transplant list. We were feeling good about her chances and expected to hear something in two to three weeks. Well, it seems like there has been very little progress with regard to the pre-transplant group gathering the information they need from Mom's various doctors. I sent an email to Mom's transplant coordinator who then called Mom a few days later, on March 31. She asked Mom several questions about recent doctor visits that Mom knows she answered when we were there at the end of February. Then someone else in the pre-transplant group called me on April 2 and said Mom needs to see her cardiologist so his office can provide a release letter. Gee, thanks for waiting a month before finding out about that.

Although Mom likely would not get a kidney for at least a year even if she were approved today, and her waiting time is still accruing while she is waiting to get back on the list, it is still frustrating to be in this situation after being told we would know something around the middle of March.

Today's article review is another repeat of a previous review that was done when I only had the abstract. This article was first reviewed on May 31, 2013, and it describes a case of fibrinogen amyloidosis that is unique for two reasons. It is the first reported case of fibrinogen amyloidosis from Portugal, and it is the first reported case of peripheral neuropathy in a patient with fibrinogen amyloidosis. The next few articles to be reviewed will also have a Portugal connection, which is why I waited until now to re-review this one.

Title: Mutant fibrinogen A alpha-chain associated with hereditary renal amyloidosis and peripheral neuropathy (1)

Authors: Mamede de Carvalho, Reinhold P Linke, Fernando Domingos, Teresinha Evangelista, José Luís Ducla-Soares, Walter BJ Nathrath, Conceição Azevedo-Coutinho, Raquel Lima and Maria João Saraiva (all from Portugal or Germany)

Journal: Amyloid (2004)


A middle age Portuguese woman was investigated for renal amyloidosis. She presented with progressive renal failure, proteinuria, hypertension, and sensory symptoms in the feet. Clinical and neurophysiological evaluation disclosed sensory-autonomic neuropathy. Cardiovascular tests and 123-MIBG investigation showed parasympathetic dysfunction and decrease of myocardial innervation, in accordance with small fiber neuropathy, as usually observed in amyloidosis. Immunohistochemical studies revealed AFib amyloidosis and genetic studies the amino acid exchange Glu526Val of the fibrinogen Aα-chain mutation, which was also present in one of her sons. The mutant gene in this patient was associated with the same haplotype as all other reported cases of Glu526Val mutations. This is the first reported AFib amyloidosis in Portugal, and the first case of AFib in which sensory and autonomic nerve fiber dysfunction is described, indicating that small nerve fiber lesion can occur in the fibrinogen A alpha chain mutation. This can be important for prognosis, in particular when liver transplantation is considered for treatment.

Here is a link to the article (not free) if you would like to follow along:

This article begins with a brief introduction to the proteins associated with hereditary renal amyloidosis (fibrinogen, lysozyme, and apolipoprotein AI and AII), then it gives some history of fibrinogen amyloidosis and the various mutations that had been discovered up to that point.

The patient in this case was a female who was referred to a nephrologist in 1988 at the age of 55 for proteinuria and moderate renal failure. She was diagnosed with hypertension at the age of 50. There was no history of renal failure in her family and all four of her sons were in good health. Her family originated from northern Portugal.

Her serum creatinine in 1988 was 1.4 mg/dl, and her 24-hour proteinuria was 2 grams. She was slightly anemic with hemoglobin of 10.8 g/dl. A kidney biopsy stained positive for amyloid deposits with Congo red. The amyloid deposits were concentrated in the glomeruli. Remember this was 1988, before the first fibrinogen mutation that caused amyloidosis was discovered.

Ten years later, in 1998, she developed mild neuropathy in her feet. Her serum creatinine was still 1.4 mg/dl but her 24-hour proteinuria had increased to 2.8 grams. An echocardiogram showed some signs of amyloid deposition.

In 1999 her blood pressure became more difficult to control and edema appeared in her legs. Her serum creatinine was still stable but her proteinuria had increased to 3.3 grams/day. A second kidney biopsy was done, and in addition to Congo Red staining, this biopsy also underwent immunohistochemical analysis. (More on that later.)

In 2001 her renal failure progressed to the point that she started hemodialysis, with a serum creatinine was 5.3 mg/dl. Her peripheral neuropathy remained stable compared to her evaluation in 1998.

The Methods section of this article goes into detail on the methods of performing the immunohistochemistry on various tissue samples, the DNA analysis, another type of genetic analysis, and autonomic and cardiovascular evaluations. Most of that is beyond my understanding so we will move to the Results section.

The Results section begins by discussing the immunohistochemistry findings. There was a moderate (not strong) reaction for fibrinogen, with all other types showing a weak or negative reaction. DNA analysis showed she had the fibrinogen Glu526Val mutation. The article says three of her siblings did not have the mutation, then it says the one with the mutation had normal renal function. I am confused by that because at the beginning of the article it says she had three sisters and one brother, but the brother died before the age of two. The abstract says one of her sons had the mutation, so perhaps "the one with the mutation" should be "the one offspring with the mutation."

The results of the haplotype studies are then discussed. A "haplotype," in case you do not remember from the previous review of this article, is a set of DNA variations that tend to be inherited together. This patient's mutation was part of the same haplotype as found in all patients previously described in the medical literature with the Glu526Val mutation, which is a strong indication that all of these patients have a common ancestor with the mutation.

The Discussion section begins by summarizing the case and stating it is the first Portuguese family described with the fibrinogen Glu526Val mutation. The article states that fibrinogen amyloidosis is associated with kidney, liver and spleen involvement, and this case is the first one described with polyneuropathy. Although no amyloid deposits were found on this patient's sural nerve biopsy, this is not unusual and is often the case in ATTR patients because the amyloid does not deposit in a uniform manner along the length of the nerve. There is some additional discussion of this patient's neuropathy that I am unfamiliar with, so I won't try to explain that.


Although this case is the first description of neuropathy in a fibrinogen amyloidosis patient, I find this case very interesting due to the length of time it took the disease to progress from mild renal failure to end stage renal failure. In 1988 this patient had hypertension, proteinuria, and biopsy-proven amyloidosis, yet she did not need dialysis until 2001, 13 years later. In the study of 71 patients published in 2009 (reviewed in the January 12, 2014 blog post),  the median time from presentation with proteinuria to end stage renal disease was 4.6 years, with the longest time at 10.2 years. So this patient from Portugal experienced a much slower progression of the disease than most people do. Her serum creatinine remained stable for at least 11 years (1988 through 1999), so maybe serum creatinine is a better indicator of disease progression then proteinuria.

Next up for review: More patients from Portugal.

==Monthly Blog Status Update===== 

As of March 31, 2014:

Total posts: 132 (4 in March)

Total pageviews: 13,400 (~1200 in February)

Email subscribers: 10 (gained 2 in March)

Total number of countries that have viewed the blog: 88

3 new countries viewed the blog in March:

Puerto Rico


(1) de Carvalho M, Linke RP, Domingos F, Evangelista T, Ducla-Soares JL, Nathrath WB, Azevedo-Coutinho C, Lima R, Saraiva MJ. Mutant fibrinogen A-alpha-chain associated with hereditary renal amyloidosis and peripheral neuropathy. Amyloid 2004;11:200–207.


  1. The long slow progression of creatinine levels seemed to end in a quick rise of from about 1.4 mg/dl in 1999 to 5.3 mg/dl in 2001, showing progression of kidney failure that was not linear. We saw similar decline rates in kidney function in Cathy before her liver transplant. I will share that data with you sometime.

    1. Thanks Lon. I have some of Cathy's numbers on the Patient Timelines page that I picked up from her blog and some earlier correspondence she and I had, so anything else you can provide to fill in the gaps would be appreciated.