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Digestive and Liver Disease : Official... Jun 2024Gastrointestinal manifestations are common across all hereditary transthyretin amyloidosis (ATTRv) genotypes. However, they are poorly specific, and their recognition as...
Gastrointestinal manifestations are common across all hereditary transthyretin amyloidosis (ATTRv) genotypes. However, they are poorly specific, and their recognition as part of ATTRv is difficult, resulting in misdiagnosis with more common conditions. Moreover, delays in diagnosis occur because of fragmented knowledge, a shortage of centers of excellence and specialists dedicated to ATTRv management, and the scarce involvement of gastroenterologists in multidisciplinary teams. A group of Italian gastroenterologists with experience in the management of ATTRv took part in a project aimed at assessing the awareness of ATTRv among the community of Italian gastroenterologists through an online survey and providing education about practical aspects of ATTRv management. Survey results reported low participation, and very few patients with ATTRv were cared for by gastroenterologists. This highlights the need for greater attention to rare diseases in gastroenterology and emphasizes increasing awareness of ATTRv and diagnostic suspicion. Based on the experts' recommendations, a diagnosis of ATTRv should be suspected when at least one of the 'red flags' is detected. Subsequently, it is suggested to promptly ask for genetic testing and exclude a serum and urinary monoclonal protein, even before the detection of amyloid in biopsy samples, particularly in non-endemic areas.
Topics: Humans; Amyloid Neuropathies, Familial; Italy; Gastrointestinal Diseases; Genetic Testing; Surveys and Questionnaires; Gastroenterology
PubMed: 38105149
DOI: 10.1016/j.dld.2023.11.025 -
Stem Cell Research Feb 2024Hereditary transthyretin amyloidosis with polyneuropathy (ATTR-PN) results from specific TTR gene mutations. In this study, we generated two induced pluripotent stem...
Hereditary transthyretin amyloidosis with polyneuropathy (ATTR-PN) results from specific TTR gene mutations. In this study, we generated two induced pluripotent stem cell (iPSC) lines derived from ATTR-PN patients with heterozygous TTR gene mutations (Ala97Ser and Phe64Leu). These iPSC lines exhibited normal morphology, karyotype, high pluripotency marker expression, and differentiation into cells representing all germ layers. The generation of these iPSC lines serve as a valuable tool for investigating the mechanisms of ATTR-PN across various cell types and facilitating patient-specific in vitro amyloidosis modeling.
Topics: Humans; Induced Pluripotent Stem Cells; Prealbumin; Amyloid Neuropathies, Familial; Polyneuropathies; Mutation
PubMed: 38100909
DOI: 10.1016/j.scr.2023.103265 -
Hellenic Journal of Nuclear Medicine 2023The purpose of this study was to evaluate the contribution of single photon emission computed tomography/computed tomography (SPECT/CT) standardized uptake value (SUV)...
OBJECTIVE
The purpose of this study was to evaluate the contribution of single photon emission computed tomography/computed tomography (SPECT/CT) standardized uptake value (SUV) metrics in classifying patients with suspected transthyretin cardiac amyloidosis (ATTR-CA) among the different Perugini grades.
SUBJECTS AND METHODS
One hundred four patients suspected of ATTR-CA underwent planar scintigraphy with bone seeking tracer (Tc pyrophosphate-PYP). Patients were classified according to the Perugini scale, the H/CL, H/Bone and H/Bkg ratios. A subset of 48 patients received additional SPECT/CT. Single photon emission computed tomography/CT SUV quantitative parameters, of the heart, myocardium, lungs, liver, soft tissues, bone, and SUV ratios (SUVmyo, SUVlungs, SUVliver, SUVbone and SUVsoft tissue ratios), were evaluated in order to investigate potential metrics that could more clearly differentiate Perugini grades.
RESULTS
A total of 33.7% of patients were considered grade 0, 34.6% grade 1 and 31.7% grade 2/3. A combination of H/CL >1.33 and H/Bone >0.85 showed the highest sensitivity 100%. Standardized uptake value-based metrics clearly differentiated grade 0 or 1 vs grades 2 or 3, whereas no significant difference was found between grades 0 and 1, or between grades 1 and 2. The combined cut-off values H/CL 1.33 and SUVmyo 2.88 yielded 100% sensitivity and 84.6% specificity in differentiating ATTR-CA positives vs negatives. The metric SUVmyo/SUVliver was the best metric to classify patients with grade 1 as negative (grade 0) or positive (grade 2 or 3).
CONCLUSION
Single photon emission computed tomography/CT SUV metrics could be complementary to planar scintigraphy in classifying patients among the different Perugini grades. The ratio SUVmyo/SUVliver was the only parameter with high affinity to differentiate patients with grade 1, as grade 0 or grade 2/3 for ATTR-CA.
Topics: Humans; Prealbumin; Amyloid Neuropathies, Familial; Single Photon Emission Computed Tomography Computed Tomography; Tomography, Emission-Computed, Single-Photon; Radionuclide Imaging
PubMed: 38085832
DOI: 10.1967/s002449912601 -
PNAS Nexus Dec 2023We previously presented a bioinformatic method for identifying diseases that arise from a mutation in a protein's low-complexity domain that drives the protein into...
We previously presented a bioinformatic method for identifying diseases that arise from a mutation in a protein's low-complexity domain that drives the protein into pathogenic amyloid fibrils. One protein so identified was the tropomyosin-receptor kinase-fused gene protein (TRK-fused gene protein or TFG). Mutations in TFG are associated with degenerative neurological conditions. Here, we present experimental evidence that confirms our prediction that these conditions are amyloid-related. We find that the low-complexity domain of TFG containing the disease-related mutations G269V or P285L forms amyloid fibrils, and we determine their structures using cryo-electron microscopy (cryo-EM). These structures are unmistakably amyloid in nature and confirm the propensity of the mutant TFG low-complexity domain to form amyloid fibrils. Also, despite resulting from a pathogenic mutation, the fibril structures bear some similarities to other amyloid structures that are thought to be nonpathogenic and even functional, but there are other factors that support these structures' relevance to disease, including an increased propensity to form amyloid compared with the wild-type sequence, structure-stabilizing influence from the mutant residues themselves, and double-protofilament amyloid cores. Our findings elucidate two potentially disease-relevant structures of a previously unknown amyloid and also show how the structural features of pathogenic amyloid fibrils may not conform to the features commonly associated with pathogenicity.
PubMed: 38077690
DOI: 10.1093/pnasnexus/pgad402 -
Journal of Cardiac Failure Jun 2024Wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM), an increasingly recognized cause of heart failure (HF), often remains undiagnosed until later stages of the...
BACKGROUND
Wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM), an increasingly recognized cause of heart failure (HF), often remains undiagnosed until later stages of the disease.
METHODS AND RESULTS
A previously developed machine learning algorithm was simplified to create a random forest model based on 11 selected phenotypes predictive of ATTRwt-CM to estimate ATTRwt-CM risk in hypothetical patient scenarios. Using U.S. medical claims datasets (IQVIA), International Classification of Diseases codes were extracted to identify a training cohort of patients with ATTRwt-CM (cases) or nonamyloid HF (controls). After assessment in a 20% test sample of the training cohort, model performance was validated in cohorts of patients with International Classification of Diseases codes for ATTRwt-CM or cardiac amyloidosis vs nonamyloid HF derived from medical claims (IQVIA) or electronic health records (Optum). The simplified model performed well in identifying patients with ATTRwt-CM vs nonamyloid HF in the test sample, with an accuracy of 74%, sensitivity of 77%, specificity of 72%, and area under the curve of 0.82; robust performance was also observed in the validation cohorts.
CONCLUSIONS
This simplified machine learning model accurately estimated the empirical probability of ATTRwt-CM in administrative datasets, suggesting it may serve as an easily implementable tool for clinical assessment of patient risk for ATTRwt-CM in the clinical setting.
BRIEF LAY SUMMARY
Wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM for short) is a frequently overlooked cause of heart failure. Finding ATTRwt-CM early is important because the disease can worsen rapidly without treatment. Researchers developed a computer program that predicts the risk of ATTRwt-CM in patients with heart failure. In this study, the program was used to check for 11 medical conditions linked to ATTRwt-CM in the medical claims records of patients with heart failure. The program was 74% accurate in identifying ATTRwt-CM in patients with heart failure and was then used to develop an educational online tool for doctors (the wtATTR-CM estimATTR).
Topics: Humans; Machine Learning; Male; Female; Cardiomyopathies; Amyloid Neuropathies, Familial; Aged; Middle Aged; Risk Assessment; Heart Failure; Prealbumin; Predictive Value of Tests
PubMed: 38065306
DOI: 10.1016/j.cardfail.2023.11.017 -
Advanced Science (Weinheim,... Feb 2024The application of lipid-based nanoparticles for COVID-19 vaccines and transthyretin-mediated amyloidosis treatment have highlighted their potential for translation to... (Review)
Review
The application of lipid-based nanoparticles for COVID-19 vaccines and transthyretin-mediated amyloidosis treatment have highlighted their potential for translation to cancer therapy. However, their use in delivering drugs to solid tumors is limited by ineffective targeting, heterogeneous organ distribution, systemic inflammatory responses, and insufficient drug accumulation at the tumor. Instead, the use of lipid-based nanoparticles to remotely activate immune system responses is an emerging effective strategy. Despite this approach showing potential for treating hematological cancers, its application to treat solid tumors is hampered by the selection of eligible targets, tumor heterogeneity, and ineffective penetration of activated T cells within the tumor. Notwithstanding, the use of lipid-based nanoparticles for immunotherapy is projected to revolutionize cancer therapy, with the ultimate goal of rendering cancer a chronic disease. However, the translational success is likely to depend on the use of predictive tumor models in preclinical studies, simulating the complexity of the tumor microenvironment (e.g., the fibrotic extracellular matrix that impairs therapeutic outcomes) and stimulating tumor progression. This review compiles recent advances in the field of antitumor lipid-based nanoparticles and highlights emerging therapeutic approaches (e.g., mechanotherapy) to modulate tumor stiffness and improve T cell infiltration, and the use of organoids to better guide therapeutic outcomes.
Topics: Humans; COVID-19 Vaccines; Immunotherapy; Neoplasms; Amyloid Neuropathies, Familial; Lipids; Tumor Microenvironment
PubMed: 38054651
DOI: 10.1002/advs.202305769 -
Therapeutics and Clinical Risk... 2023Variant transthyretin amyloidosis (ATTRv) is an autosomal dominant inherited genetic disorder that affects 5000-10,000 people worldwide. It is caused by mutations in... (Review)
Review
Variant transthyretin amyloidosis (ATTRv) is an autosomal dominant inherited genetic disorder that affects 5000-10,000 people worldwide. It is caused by mutations in the transthyretin (TTR) gene and results in amyloid deposition in a variety of organs due to abnormal accumulation of TTR protein fibrils. Although this is a multisystem disorder, the heart and peripheral nerves are the preferentially affected organs. Over 150 TTR gene mutations have been associated with this disease and the clinical phenotype can vary significantly. Severe forms of the disorder can be fatal. Fortunately, the oligonucleotide-based therapy era has resulted in the development of several novel treatment options. Patisiran is a small interfering RNA (siRNA) encapsulated in a lipid nanoparticle that targets both mutant and wild-type TTR and results in significant reductions of the TTR protein in the serum and in tissue deposits. Patisiran has been approved for treatment of adults with polyneuropathy due to hereditary TTR-mediated amyloidosis in both the United States (US) and European Union (EU). In this review, we will discuss the development of patisiran, the clinical trials that lead to treatment approval, and provide guideline parameters for use in clinical practice. .
PubMed: 38047038
DOI: 10.2147/TCRM.S361706 -
The Journal of Physical Chemistry... Dec 2023Transthyretin (TTR) is a small tetrameric protein that aggregates, forming highly toxic oligomers and fibrils. In the blood and cerebrospinal fluid, TTR can interact...
Transthyretin (TTR) is a small tetrameric protein that aggregates, forming highly toxic oligomers and fibrils. In the blood and cerebrospinal fluid, TTR can interact with various biomolecules, phospho- and sphingolipids, and cholesterol on the red blood cell plasma membrane. However, the role of these molecules in TTR aggregation remains unclear. In this study, we investigated the extent to which phosphatidylcholine (PC), sphingomyelin (SM), and cholesterol (Cho), important components of plasma membranes, could alter the rate of TTR aggregation. We found that PC and SM inhibited TTR aggregation whereas Cho strongly accelerated it. The presence of these lipids during the stage of protein aggregation uniquely altered the morphology and secondary structure of the TTR fibrils, which changed the toxicity of these protein aggregates. These results suggest that interactions of TTR with red blood cells, whose membranes are rich with these lipids, can trigger irreversible aggregation of TTR and cause transthyretin amyloidosis.
Topics: Humans; Amyloid; Sphingomyelins; Prealbumin; Amyloid Neuropathies, Familial; Protein Aggregates; Cholesterol
PubMed: 38033106
DOI: 10.1021/acs.jpclett.3c02613 -
Vaccines Nov 2023Alzheimer disease (AD) is one of the most common and disabling neuropathies in the ever-growing aged population around the world, that especially affects Western...
Alzheimer disease (AD) is one of the most common and disabling neuropathies in the ever-growing aged population around the world, that especially affects Western countries. We are in urgent need of finding an effective therapy but also a valid prophylactic means of preventing AD. There is a growing attention currently paid to DNA vaccination, a technology particularly used during the COVID-19 era, which can be used also to potentially prevent or modify the course of neurological diseases, including AD. This paper aims to discuss the main features and hurdles encountered in the immunization and therapy against AD using DNA vaccine technology. Ultimately, this work aims to effectively promote the efforts in research for the development of safe and effective DNA and RNA vaccines for AD.
PubMed: 38006038
DOI: 10.3390/vaccines11111706 -
Common transthyretin-derived amyloid fibril structures in patients with hereditary ATTR amyloidosis.Nature Communications Nov 2023Systemic ATTR amyloidosis is an increasingly important protein misfolding disease that is provoked by the formation of amyloid fibrils from transthyretin protein. The...
Systemic ATTR amyloidosis is an increasingly important protein misfolding disease that is provoked by the formation of amyloid fibrils from transthyretin protein. The pathological and clinical disease manifestations and the number of pathogenic mutational changes in transthyretin are highly diverse, raising the question whether the different mutations may lead to different fibril morphologies. Using cryo-electron microscopy, however, we show here that the fibril structure is remarkably similar in patients that are affected by different mutations. Our data suggest that the circumstances under which these fibrils are formed and deposited inside the body - and not only the fibril morphology - are crucial for defining the phenotypic variability in many patients.
Topics: Humans; Amyloid; Amyloid Neuropathies, Familial; Cryoelectron Microscopy; Prealbumin; Proteostasis Deficiencies
PubMed: 37993462
DOI: 10.1038/s41467-023-43301-3