Over 70 transthyretin (TTR) mutations facilitate amyloidosis in tissues other than the central nervous system (CNS). In contrast, the D18G TTR mutation in individuals of Hungarian descent leads to CNS amyloidosis. D18G forms inclusion bodies in Escherichia coli, unlike the other disease-associated TTR variants overexpressed to date. Denaturation and reconstitution of D18G from inclusion bodies afford a folded monomer that is destabilized by 3.1 kcal/mol relative to an engineered monomeric version of WT TTR. Since TTR tetramer dissociation is typically rate limiting for amyloid formation, the monomeric nature of D18G renders its amyloid formation rate 1000-fold faster than WT. It is perplexing that D18G does not lead to severe early onset systemic amyloidosis, given that it is the most destabilized TTR variant characterized to date, more so than variants exhibiting onset in the second decade. Instead, CNS impairment is observed in the fifth decade as the sole pathological manifestation; however, benign systemic deposition is also observed. Analysis of heterozygote D18G patient's serum and cerebrospinal fluid (CSF) detects only WT TTR, indicating that D18G is either rapidly degraded postsecretion or degraded within the cell prior to secretion, consistent with its inability to form hybrid tetramers with WT TTR. The nondetectable levels of D18G TTR in human plasma explain the absence of an early onset systemic disease. CNS disease may result owing to the sensitivity of the CNS to lower levels of D18G aggregate. Alternatively, or in addition, we speculate that a fraction of D18G made by the choroid plexus can be transiently tetramerized by the locally high thyroxine (T(4)) concentration, chaperoning it out into the CSF where it undergoes dissociation and amyloidogenesis due to the low T(4) CSF concentration. Selected small molecule tetramer stabilizers can transform D18G from a monomeric aggregation-prone state to a nonamyloidogenic tetramer, which may prove to be a useful therapeutic strategy against TTR-associated CNS amyloidosis.

Background Treatment options in patients with amyloidotic transthyretin (ATTR) cardiomyopathy are limited. Epigallocatechin-3-gallate (EGCG), the most abundant catechin in green tea (GT), inhibits fibril formation from several amyloidogenic proteins in vitro. Thus, it might also halt progression of TTR amyloidosis. This is a singlecenter observational report on the effects of GT consumption in patients with ATTR cardiomopathy. Methods 19 patients with ATTR cardiomyopathy were evaluated by standard blood tests, echocardiography, and cardiac MRI (n = 9) before and after consumption of GT and/or green tea extracts (GTE) for 12 months.Results Five patients were not followed up for reasons of death (n = 2), discontinuation of GT/GTE consumption (n = 2), and heart transplantation (n = 1). After 12 months no increase of left ventricular (LV) wall thickness and LV myocardial mass was observed by echocardiography. In the subgroup of patients evaluated by cardiac MRI a mean decrease of LV myocardial mass (-12.5 %) was detected in all patients. This was accompanied by an increase of mean mitral annular systolic velocity of 9 % in all 14 patients. Total cholesterol (191.9 ± 8.9 vs. 172.7 ± 9.4 mg/dL; p \ 0.01) and LDL cholesterol (105.8 ± 7.6 vs. 89.5 ± 8.0 mg/dL; p \ 0.01) decreased significantly during the observational period. No serious adverse effects were reported by any of the participants. Conclusions Our observation suggests an inhibitory effect of GT and/or GTE on the progression of cardiac amyloidosis. We propose a randomized placebo-controlled investigation to confirm our observation. K. Altland, H. A. Katus contributed equally to this work.Electronic supplementary material The online version of this article (doi:10.1007/s00392-012-0463-z) contains supplementary material, which is available to authorized users.

Familial amyloidotic polyneuropathy (FAP) caused by amyloidogenic transthyretin (ATTR) mutations is the most common form of hereditary amyloidosis. We investigated the diagnostic value of the bone scanning agent technetium-99m 3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) in this disease. Eight patients (four males, four females; age 54.4+/-8.3 years, range 43-67 years) with ATTR-FAP proven by immunohistochemistry and molecular analysis and a control group comprising ten oncological out-patients (five males, five females; age 53.4+/-8.5 years, range 34-66 years) without evidence of bony metastases were studied using 99mTc-DPD. Whole body tracer retention was 80.1%+/-10.3% (range 65.1%-94.8%) in FAP patients and 55.7%+/-8.1% (range 40.2%-66.7%) in controls at 3 h p.i. (P<0.001), and cardiac uptake was 7.3%+/-2.2% (range 4.2%-10.1%) in FAP patients and 3.1%+/-0.5% (range 2.3%-4.0%) in controls (P<0.001). The heart/whole body uptake ratio was 8.9%+/-1.7% (range 6.5%-11.0%) in FAP patients and 5.6%+/-0.5% (range 5.1%-6.8%) in controls (P<0.001). The three FAP patients with the highest cardiac tracer uptake had cardiomyopathy or arrhythmia. 99mTc-DPD scintigraphy is proposed as a simple and valuable diagnostic aid to evaluate the severity of the disease and the risk of concomitant heart problems.

Familial amyloidotic polyneuropathy (FAP) and senile systemic amyloidosis (SSA) are characterized by systemic extracellular deposition of insoluble transthyretin (TTR) fibrils. While only normal TTR is found in fibrils from SSA patients who predominantly suffer from cardiomyopathy, autosomal dominant FAP preferentially affects peripheral nerves and heart and is associated with so-called amyloidogenic mutations of this protein, giving rise to TTR forms of decreased stability. Using isoelectric focusing in urea gradients we were able to demonstrate a stabilizing effect of sulfite on TTR monomers and tetramers, as well as an increase in the tetramer/monomer ratio. We demonstrate that this ratio, which is decreased in FAP patients, can be increased to beyond normal levels. We show that doses of sulfite which are tolerable in vivo produce a significant increase in the tetramer/monomer ratio and postulate that sulfite may be a potent drug for delaying the onset and progress of FAP and SSA.