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Mechanisms of Fibril Formation and Cellular Response
Published in Martha Skinner, John L. Berk, Lawreen H. Connors, David C. Seldin, XIth International Symposium on Amyloidosis, 2007
Martha Skinner, John L. Berk, Lawreen H. Connors, David C. Seldin
A 71 year-old woman presented with epigastric discomfort and peripheral neuropathy, symptoms similar to her 76 year-old sister who had cardiac and gastrointestinal hereditary systemic amyloidosis caused by mutant transthyretin (ATTR). She was found to have both a genetic variant of transthyretin [TTR (T60A)] and a monoclonal gammopathy identified as Stage I multiple myeloma with free A light chains of 2700 mg/dl. Amyloid was readily evident in a Congo red-stained fat aspirate and was thought to represent ATTR based on immunohistochemistry. However, the patient subsequently developed macroglossia with teeth indentation and weight loss prompting concern for systemic AL amyloidosis. The amyloid deposits were further characterized by chemical typing and tandem mass spectrometry (MS/MS) to reveal no TTR-related molecules but rather the exclusive presence of A3 light chain-containing peptides (Figures 1 and 2), thus establishing a diagnosis of AL rather than ATTR amyloidosis.
Suppression of Transthyretin Synthesis by Antisense Oligonucleotides
Published in Gilles Grateau, Robert A. Kyle, Martha Skinner, Amyloid and Amyloidosis, 2004
M.D. Benson, B. Kluve-Beckerman, K.W. Sloop, D.M. Bodenmiller
The only specific therapy for transthyretin (TTR) amyloidosis is liver transplantation (1). Essentially all plasma transthyretin is synthesized by the liver and transplantation results in disappearance of the variant TTR from the circulation. This has proven to be an effective therapy for many individuals with TTR amyloidosis, especially those with the Val30Met mutation. A significant number of patients, however, have progression of systemic amyloidosis after liver transplantation, and it has been hypothesized that this is the result of deposition of amyloid fibrils which are a product of normal TTR (2). In particular, patients with TTR Thr60Ala, Leu58His, and Cys10Arg have been observed to have progression of cardiac amyloidosis after liver transplantation. The increased ratio of normal to variant transthyretin in cardiac tissues obtained at autopsy from these patients is in agreement with this hypothesis. As an alternative therapy we have explored the use of antisense oligonucleotides (ASO) to TTR, modified to target the liver to decrease expression of TTR. To test this therapeutic option we have created a transgenic mouse model carrying the Ile84Ser variant gene of human TTR. TTR specific ASOs were then administered to mice, and TTR expression was measured in plasma and TTR mRNA levels in hepatic tissues.
Extrahepatic Synthesis of Acute Phase Proteins
Published in Andrzej Mackiewicz, Irving Kushner, Heinz Baumann, Acute Phase Proteins, 2020
Gerhard Schreiber, Angela R. Aldred
Strong conservation of the structure of a protein, or parts thereof, is usually interpreted as an indication of the functional importance of the conserved molecule or regions thereof. In the bloodstream of larger mammals, transthyretin shares with albumin and thyroxinebinding globulin in the transport of thyroid hormones.131 However, transthyretin is the only thyroid hormone-binding protein which is strongly expressed in the brain. Analysis of the phylogeny of expression of transthyretin by the choroid plexus showed that this function is first found at the reptile stage (Figures 29 and 30). The importance of thyroid hormones for brain development may be the explanation for the strong conservation of the features of transthyretin involved in the binding of thyroxine. In the bloodstream, large amounts of transthyretin, synthesized and secreted by the liver, are first observed at the marsupial stage. This change in the tissue distribution of transthyretin gene expression changed the system for the transport of thyroid hormones in the blood. However, the system of thyroxine transport by transthyretin evolved much earlier in the brain, at the stage of the stem reptiles, about 350 million years ago. Thus, transthyretin evolved and existed for more than 200 million years as a protein synthesized exclusively outside the liver. It participated in maintaining homeostasis in the cerebral extracellular comparment. When transthyretin was expressed in the liver, it became a plasma protein, with a distribution of 22% in the intravascular and 78% in the extravascular compartment (calculated for rats from data in References 20 and 133). Expression of the transthyretin gene in the choroid plexus is not infuenced by trauma and inflammation. It is not known when, during evolution, transthyretin gene expression in the liver came under negative acute phase regulation.
Predictors of cognitive dysfunction in hereditary transthyretin amyloidosis with liver transplant
Published in Amyloid, 2023
Sara Cavaco, Ana Martins da Silva, Joana Fernandes, Ana Paula Sousa, Cristina Alves, Márcio Cardoso, Armando Teixeira-Pinto, Teresa Coelho
The transthyretin (TTR)-related amyloidoses are a group of clinically heterogeneous diseases. One of the main predominant phenotypes is a sensorimotor and autonomic neuropathy, hereditary ATTR (ATTRv) amyloidosis, frequently referred to as familial amyloid polyneuropathy (FAP). The two non-neuropathic forms are the cardiac amyloidoses (hereditary amyloid cardiomyopathy and wild-type cardiac ATTR amyloidosis) and the leptomeningeal amyloidosis [1]. These phenotypes are associated with specific TTR pathogenic variants, though there is considerable overlap [2]. ATTRv amyloidosis was first recognized by Corino de Andrade, in Portugal [3]. TTRVal30Met is the most common mutation associated with ATTRv amyloidosis. It typically presents as a progressive, axonal length dependent, sensorimotor and autonomic neuropathy with mixed involvement of other organs such as the eyes, the heart, the kidneys and/or the central nervous system (CNS) [4]. However, clinical manifestations of ATTRv amyloidosis may vary with age at disease onset and geographic origin [5].
Clinical and apparative investigation of large and small nerve fiber impairment in mixed cohort of ATTR-amyloidosis: impact on patient management and new insights in wild-type
Published in Amyloid, 2022
Aikaterini Papagianni, Sandra Ihne, Daniel Zeller, Caroline Morbach, Nurcan Üçeyler, Claudia Sommer
Early diagnosis of transthyretin amyloidosis (ATTR), a rare multiorgan protein deposition disease, remains challenging, since presenting signs and symptoms may be unspecific and may resemble more common diseases affecting both the heart and the nervous system. Two types of ATTR amyloidosis are defined, the hereditary type (ATTRv/variant) caused by one of about 130 different gene mutations in the transthyretin (TTR) gene (http//www.amyloidosismutations.com) and the wild-type (ATTRwt) form, in which amyloid deposits are composed of non-mutated TTR [1]. The estimated global prevalence of ATTRv amyloidosis ranges between 10,000 to 40,000 people [2], whereas the global prevalence of ATTRwt is unknown; a recently published Japanese cardiomyopathy register data reported a prevalence of 170 patients per million [3].
A special case of hypertrophic cardiomyopathy with a differential diagnosis of isolated cardiac amyloidosis or junctophilin type 2 associated cardiomyopathy
Published in Acta Clinica Belgica, 2021
Sévérine De Bruijn, Xavier Galloo, Gilles De Keulenaer, Edgard A. Prihadi, Christiane Brands, Mark Helbert
In ATTR, the hepatic transport protein TTR, previously called prealbumin, is misfolded into an amyloid protein. TTR-related CA accounts for 18% of all cases of CA and is characterised by a progressive infiltrative cardiomyopathy that mimics hypertensive hypertrophic heart disease [7]. Transthyretin amyloidosis encompasses two subtypes. The hereditary/familial type (mATTR) – also called mutant type – arises from misfolding a mutated TTR precursor protein. It is characterized by autosomal dominant inheritance with variable penetrance. In sporadic or wild type (wtATTR), formally also known as senile systemic amyloidosis (SSA), amyloid arises from genetically unaltered TTR [9]. In contrast to AL amyloidosis, mATTR and wtATTR are typically associated with milder clinical manifestations, slower progression, and hence also better prognosis. Since the very slow progression (an 86-your-old patient) and mild clinical presentation (general fatigue with only mild decreased systolic function and no overt clinical heart decompensation) the differential diagnosis of an AL amyloidosis is very improbable based on anamnesis and physical exam. Further work-up confirmed normal immunoglobulin light chains. Arguments in favour of an ATTR are elderly patient, male, slow progression and mild clinical symptoms. As the patient described above only presents cardiac manifestations without altered kidney or liver function, the preferred differential diagnosis of wtATTR is withheld over mATTR.