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.
As stated in the abstract, this article reports on a Portuguese woman who was found to have fibrinogen amyloidosis (Glu526Val mutation). This was the first reported case of fibrinogen amyloidosis in Portugal, and as we will see in a future article it will not be the last.
The really interesting thing about this case is that in addition to the symptoms typically associated with fibrinogen amyloidosis (renal failure and proteinuria) this patient also presented with neuropathy in her feet. Since the lack of neuropathy was a distinguishing characteristic of hereditary renal amyloidosis that differentiated it from the other familial types of amyloidosis, the presence of neuropathy in this case is notable. At this point we do not know if this is an anomaly or if neuropathy will be reported as a symptom in a small percentage of cases.
Since this is such a short blog post I want to focus on one sentence in the abstract which uses a word I have seen in previous articles but have not investigated further until now: "The mutant gene in this patient was associated with the same haplotype as all other reported cases of Glu526Val mutations."
What the heck is a haplotype? To quote from an internet source, a haplotype is a set of DNA variations that tend to be inherited together. In the case of fibrinogen amyloidosis, the Glu526Val mutation is just one DNA variation. But when the researchers have examined the DNA of people with this mutation and looked at other DNA variations on the same chromosome (number 4), they see a number of variations that are common among all the patients (as of this article's publication in 2004). This set of DNA variations is a haplotype. If this same set of DNA variations is common to all patients with the fibrinogen Glu526Val mutation, that is a good indication that these patients all have a common ancestor. That common ancestor can be considered the "founder" of this mutation. We'll be on the lookout in future articles to see whether future cases of the Glu526Val mutation are associated with this same haplotype or with a different one.
Next up: Two articles that summarize what was known about hereditary renal amyloidosis in the mid-2000s.
(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.