Familial amyloid polyneuropathy patients with the Val30Met mutation differ in clinical symptoms, gene variants, and age of disease onset between endemic (where the disease is common) and non-endemic areas of Japan, a study reveals.
In the study, “Origin of sporadic late-onset hereditary ATTR Val30Met amyloidosis in Japan,” published in the journal Amyloid, the researchers also compared the data with that of patients from Portugal and Sweden.
Val30Met — which changes valine to methionine at amino acid 30 in the transthyretin (TTR) gene — is the most common mutation in FAP patients worldwide. Patients with this mutation vary in age of disease onset, depending on geographic location: Those in Sweden typically show a later onset — older than 50 years — than patients in Portugal and endemic areas of Japan, who often develop the disease between the ages of 30 and 40.
Like patients in Portugal, those in the endemic Kumamoto and Nagano districts of Japan usually experience small fiber polyneuropathy (nerve damage) and severe autonomic disturbances as initial symptoms, with cardiac and renal failure, gastrointestinal disturbances, and ocular symptoms happening later.
Sporadic cases of late-onset FAP have been reported in non-endemic areas, mostly affecting men, in contrast to an almost equal number of male and female patients in the endemic areas. It is also characterized by milder clinical symptoms.
Data from the team at Kumamoto University in Japan showed that 11 of 104 FAP patients (10%) had the Val30Met mutation in endemic areas, most of which were early-onset. This is in contrast to 53 patients (51%) with this mutation in non-endemic regions, who had a mean age of onset of 67 years. The results also showed that 82% of the patients in endemic regions had family history of FAP, compared with 33% of those in non-endemic areas.
The team’s 2004 study in patients in Europe and Japan showed that patients from Kumamoto had a 40% frequency of a major haplotype — a set of polymorphisms, or gene variants, that tend to be inherited together. However, this haplotype was very rare in a control group of Japanese individuals. When they compared the data with Portuguese FAP patients with the Val30Met mutation, the scientists found that most regions of the TTR gene were common between these patients and those in endemic areas in Japan.
The haplotypes of patients in non-endemic areas were different from both endemic areas and from each other. The data from Japan is in contrast to that from Sweden, where all patients are thought to have originated from one founder mutation, subsequently passed down through generations.
FAP onset is earlier when the mutation is inherited from the mother. Analyses of mitochondrial DNA (mtDNA) — the unique DNA in the mitochondria, which provide energy to cells, also only inherited from the mother — revealed that mitochondrial haplogroups — groups of similar haplotypes that share a common ancestor — correlated with age of disease onset in Swedish and French patients. The mtDNA copy number also showed a significant association with age of disease onset in Portuguese patients.
As for why the Val30Met mutation is the most frequent worldwide in FAP patients, the team said that 57 of the 127 amino acids of the TTR monomer (the protein’s building block) are arranged in a type of conformation called beta-strands that lead to amyloid formation. In addition, the first guanine nucleotide — one of the four possible nucleotides in genes — of valine at position 30 is part of a well-known hotspot for mutations.
Because the haplotypes are similar among Portuguese, Brazilian, Spanish, and Japanese patients with FAP caused by the Val30Met mutation and the highest incidence of this type of FAP is in Portugal, the researchers hypothesize that mutated genes may have been passed down during the Age of Discovery, in the 16th century, when Europeans embarked on more overseas exploration.
An analysis in Swedish patients revealed two forms of amyloid deposits — A and B — with different size, arrangement, and proportion of full-length TTR. Patients with the shorter type A form had later disease onset. Fragments of TTR in amyloid deposits were related to age of FAP onset in Japanese patients, and frequently occurred in non-endemic areas. This suggests that genetic factors may be involved in the fragmentation of TTR, the investigators said.
Although a significant amount of data has been generated from genetic and biochemical studies, “further investigation is needed to answer the following challenging questions: Why is only the Val30Met mutation distributed worldwide? Why do the onset and penetrance ages of the same [FAP] Val30Met amyloidosis patients highly vary between different countries and regions?” the scientists wrote.