Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis
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Serum transthyretin (TTR) levels are reduced in familial amyloidotic polyneuropathy (FAP). A single study of patients with senile systemic amyloidosis (SSA) in Sweden found that those individuals also had a significantly lower mean serum TTR concentration than age- and gender-matched controls. To determine if the same phenomenon prevailed in an ethnically more heterogeneous population, we compared the serum TTR levels, as determined by ELISA, in 45 documented SSA patients with congestive heart failure, 20 AL patients with congestive heart failure and population controls. ⋯ We also compared TTR concentrations in 12 African-Americans carrying the TTR V122I allele with those in 826 African-Americans who were homozygous wild type at the TTR locus. The TTR V122I carriers had significantly lower serum TTR concentrations than appropriate controls even though the majority of such individuals had not reached the age of clinical or anatomic risk, i.e. over 60. Thus, as in carriers of other TTR mutations the serum TTR level is lower than normal, despite having a much later appearance of clinical disease.
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Transthyretin (TTR) familial amyloid polyneuropathies (FAP) are autosomal dominant devastating afflictions. They were first described in Portugal, later in Japan and Sweden and are now recognized worldwide. The TTR Val30Met mutation is the most common, and depending on the geographic origin, a wide variation in age at onset of the disease is observed. ⋯ Differences between Piteå and Skellefteå regions were observed. Moreover, penetrance was significantly higher when the mutation was inherited from the mother than from the father. The low penetrance observed in TTR FAP kindreds and its variations is important information for the genetic counseling and treatment of Swedish FAP patients and their families.
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Mounting evidence points to soluble peptide oligomers as the primary agents in various amyloid and prion diseases. Multiple mechanisms appear to contribute to the cytotoxic effects of these oligomers. Here, an additional, general mechanism is proposed - that soluble amyloid peptide oligomers serve as "all-purpose"beta strands that can interact with transiently unfolded or nascent proteins where interior beta-sheet edges are exposed. ⋯ If the bound amyloid oligomer dissociates at some point after the misfolded protein is committed to the UPS pathway, the oligomer could then repeat the process, adding a catalytic aspect to the misfolding mechanism. Direct proof of this proposed mechanism requires detection of amyloid oligomer-beta-sheet protein complexes, and a co-immunoprecipitation experiment is proposed. This hypothesis supports therapies that increase amyloid oligomer degradation or sequestration, as well as therapies that upregulate chaperone activity, for combating amyloid-related diseases.
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We report three patients with AL amyloidosis manifesting as systemic lymphadenopathy, mainly in the cervical and supraclavicular regions. Histopathology of lymph nodes showed massive deposition of AL amyloid with no abnormal findings suggestive of lymphoproliferative disorders. ⋯ The remaining patient showed no obvious change in the size of lymph nodes or detectable M-protein in serum. The prognosis of AL amyloidosis manifesting as lymphadenopathy is usually good as long as there are no hematological malignancies or rapid increases in the size of lymph nodes, but in cases of the systemic type, intensive chemotherapy, such as high-dose melphalan with auto-PBSCT, should be actively considered in order to avoid possible involvement of visceral organs.
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Familial transthyretin amyloidosis (ATTR), caused by mutant transthyretin deposition, is mainly characterized by peripheral neuropathy, autonomic dysfunction, and cardiomyopathy. There are few reports among the Chinese population. We previously described the TTR mutation (Val30Ala) in the first Hong Kong Chinese family with ATTR. ⋯ We performed DNA analysis in 46 subjects and detected a total of 21 patients, including the four probands, affected with ATTR, 15 of whom were still at a symptom-free stage at the time of writing. We conclude that ATTR remains largely underdiagnosed in the Chinese population. A high clinical suspicion is crucial for a timely diagnosis and can thus lead to a significant decrease in morbidity and mortality.