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Neurology May 2023Hereditary transthyretin amyloidosis (hATTR) is a rare autosomal dominant systemic disease with variable penetrance and heterogeneous clinical presentation. Several...
BACKGROUND AND OBJECTIVES
Hereditary transthyretin amyloidosis (hATTR) is a rare autosomal dominant systemic disease with variable penetrance and heterogeneous clinical presentation. Several effective treatments can reduce mortality and disability, though diagnosis remains challenging, especially in the United States where disease is nonendemic. Our aim is to describe the neurologic and cardiac characteristics of common US ATTR variants V122I, L58H, and late-onset V30M at presentation.
METHODS
We conducted a retrospective case series of patients with a new diagnosis of ATTRv between January 2008 and January 2020 to characterize features of prominent US variants. The neurologic (examination, EMG, and skin biopsy), cardiac (echo), and laboratory assessments (pro b-type natriuretic peptide [proBNP] and reversible neuropathy screens) are described.
RESULTS
A total of 56 patients with treatment-naïve ATTRv with symptoms/signs of peripheral neuropathy (PN) or cardiomyopathy and confirmatory genetic testing presenting with Val122Ile (N = 31), late-onset Val30Met (N = 12), and Leu58His ATTRv (N = 13) were included. The age at onset and sex distributions were similar (V122I: 71.5 ± 8.0, V30M: 64.8 ± 2.6, and L58H: 62.4 ± 9.8 years; 26, 25, 31% female). Only 10% of patients with V122I and 17% of patients with V30M were aware of an ATTRv family history, while 69% of patients with L58H were aware. PN was present in all 3 variants at diagnosis (90%, 100%, and 100%), though neurologic impairment scores differed: V122I: 22 ± 16, V30M: 61 ± 31, and L58H: 57 ± 25. Most points (deficits) were attributed to loss of strength. Carpal tunnel syndrome (CTS) and a positive Romberg sign were common across all groups (V122I: 97%, 39%; V30M: 58%, 58%; and L58H: 77%, 77%). ProBNP levels and interventricular septum thickness were highest among patients with V122I (5,939 ± 962 pg/mL, 1.70 ± 0.29 cm), followed by V30M (796 ± 970 pg/mL, 1.42 ± 0.38 cm) and L58H (404 ± 677 pg/mL, 1.23 ± 0.36 cm). Atrial fibrillation was present among 39% of cases with V122I and only 8% of cases with V30M and L58H. Gastrointestinal symptoms were rare (6%) among patients with V122I and common in patients with V30M (42%) and L58H (54%).
DISCUSSION
Important clinical differences exist between ATTRv genotypes. While V122I is perceived to be a cardiac disease, PN is common and clinically relevant. Most patients with V30M and V122I were diagnosed de novo and therefore require clinical suspicion for diagnosis. A history of CTS and a positive Romberg sign are helpful diagnostic clues.
Topics: Female; Male; Humans; Retrospective Studies; Amyloid Neuropathies, Familial; Cardiomyopathies; Phenotype; Prealbumin
PubMed: 36941075
DOI: 10.1212/WNL.0000000000207158 -
European Journal of Heart Failure Feb 2021Amyloidoses are characterized by the tissue accumulation of misfolded proteins into insoluble fibrils. The two most common types of systemic amyloidosis result from the... (Review)
Review
Amyloidoses are characterized by the tissue accumulation of misfolded proteins into insoluble fibrils. The two most common types of systemic amyloidosis result from the deposition of immunoglobulin light chains (AL) and wild-type or variant transthyretin (ATTRwt/ATTRv). Cardiac involvement is the main determinant of outcome in both AL and ATTR, and cardiac amyloidosis (CA) is increasingly recognized as a cause of heart failure. In CA, circulating biomarkers are important diagnostic tools, allow to refine risk stratification at baseline and during follow-up, help to tailor the therapeutic strategy and monitor the response to treatment. Among amyloid precursors, free light chains are established biomarkers in AL amyloidosis, while the plasma transthyretin assay is currently being investigated as a tool for supporting the diagnosis of ATTRv amyloidosis, predicting outcome and monitor response to novel tetramer stabilizers or small interfering RNA drugs in ATTR CA. Natriuretic peptides (NPs) and troponins are consistently elevated in patients with AL and ATTR CA. Plasma NPs, troponins and free light chains hold prognostic significance in AL amyloidosis, and are evaluated for therapy decision-making and follow-up, while the value of NPs and troponins in ATTR is less well established. Biomarkers can be usefully integrated with clinical and imaging variables at all levels of the clinical algorithm of systemic amyloidosis, from screening to diagnosis and prognosis, and treatment tailoring.
Topics: Amyloidosis; Biomarkers; Cardiomyopathies; Heart Failure; Humans; Prealbumin
PubMed: 33527656
DOI: 10.1002/ejhf.2113 -
European Heart Journal Jul 2022Transthyretin amyloid cardiomyopathy (ATTR-CM) is increasingly diagnosed at an early stage of the disease natural history, defined as National Amyloidosis Centre (NAC)... (Observational Study)
Observational Study
AIMS
Transthyretin amyloid cardiomyopathy (ATTR-CM) is increasingly diagnosed at an early stage of the disease natural history, defined as National Amyloidosis Centre (NAC) ATTR Stage I. The natural history of early-stage ATTR-CM remains poorly characterized.
METHODS AND RESULTS
A retrospective multi-centre observational study of 879 patients with ATTR-CM, either wild-type TTR genotype or carrying the p.V142I TTR variant, and NAC ATTR Stage I biomarkers at the time of diagnosis who did not receive disease-modifying therapy for amyloidosis. Disease characteristics at diagnosis that were independently associated with mortality by Cox regression analysis were N-terminal pro-B-type natriuretic peptide (NT-proBNP), TTR genotype, and troponin T. Patients were categorized into NAC ATTR Stage Ia, defined as a furosemide equivalent diuretic requirement of <0.75 mg/kg and an NT-proBNP ≤500 ng/L or ≤1000 ng/L in the presence of atrial fibrillation, and NAC ATTR Stage Ib comprising all remaining Stage I patients. Median estimated survival among the 88% NAC ATTR Stage Ib patients was 75 (95% CI 57-93) months compared with >100 months in the 12% with Stage Ia disease [hazard ratio for death 5.06 (95% confidence interval 1.23-20.87); P = 0.025] despite significant cardiovascular morbidity at the time of diagnosis which increased during follow-up, including among patients diagnosed in NAC ATTR Stage Ia. Estimated survival among UK NAC ATTR Stage Ia patients was comparable to UK general population controls (P = 0.297).
CONCLUSION
Patients with NAC ATTR Stage I ATTR-CM can be further stratified according to NT-proBNP concentration and diuretic requirement at diagnosis. Patients with Stage Ia ATTR-CM have significant cardiovascular morbidity despite good short- and mid-term survival.
Topics: Amyloid Neuropathies, Familial; Cardiomyopathies; Cardiovascular Diseases; Disease Progression; Diuretics; Humans; Prealbumin
PubMed: 35608040
DOI: 10.1093/eurheartj/ehac259 -
General and Comparative Endocrinology May 2021In plasma, thyroid hormone (TH) is bound to several TH distributor proteins (THDPs), constituting a TH delivery/distribution network. Extensive studies of THDPs from... (Review)
Review
In plasma, thyroid hormone (TH) is bound to several TH distributor proteins (THDPs), constituting a TH delivery/distribution network. Extensive studies of THDPs from tetrapods has proposed an evolutionary scenario concerning structural and functional changes in THDPs, especially for transthyretin (TTR). When assessing, in an evolutionary context, the roles of THDPs as a component constituting part of the vertebrate thyroid system, the data from fish THDPs are critical. In this review the phylogenetic distributions, spatiotemporal expression patterns and binding properties of THDPs in fish are described, and the question of whether the evolutionary hypotheses proposed in tetrapod THDPs can be applied to fish THDPs is assessed. The phylogenetic distributions of THDPs are highly variable among fish groups. Analysis in this review reveals that the evolutionary hypotheses proposed in tetrapod THDPs cannot be applied to fish THDPs, and that the role of plasma lipoproteins as THDPs grows in importance in fish groups. In primitive fish, zinc is an import factor in TH binding to TTR, and high zinc content may facilitate the acquisition of high TH binding activity during the early evolution of TTR. Finally, the possible roles of THDPs in the vertebrate thyroid system are discussed.
Topics: Animals; Fishes; Phylogeny; Prealbumin; Thyroid Gland; Thyroid Hormones
PubMed: 33549607
DOI: 10.1016/j.ygcen.2021.113735 -
Current Problems in Cardiology Feb 2023Transthyretin cardiac amyloidosis is a restrictive cardiomyopathy caused by extracellular deposition in the heart of amyloid fibrils derived from plasma transthyretin... (Review)
Review
Transthyretin cardiac amyloidosis is a restrictive cardiomyopathy caused by extracellular deposition in the heart of amyloid fibrils derived from plasma transthyretin (ATTR), either in its hereditary (ATTRh) or acquired (ATTRwt) forms. Cardiac amyloidosis has a very poor prognosis if therapy is not started promptly. Therefore, it is very important to recognize cardiac amyloidosis early in order to immediately start a treatment capable of modifying the prognosis. Treatment of cardiac amyloidosis is not easy, often requiring a multidisciplinary team. New RNA-interfering drugs (such as patisiran) have been devised and are effective in the treatment of ATTRh amyloidosis. Tafamidis (a stabilizer of the native tetramer structure of TTR) is recommended to treat patients with genetic testing-proven hereditary hTTR-cardiomyopathy or wild-type TTR cardiomyopathy and NYHA Class I or II to reduce symptoms, CV hospitalization and mortality (Class I, level of evidence B). Patisiran should be considered in ATTRh cardiomyopathy with polyneuropathy. Thus, this review is intended to be a simple practical guide for the treatment of ATTR cardiac amyloidosis.
Topics: Humans; Amyloid Neuropathies, Familial; Prealbumin; Cardiomyopathies; Amyloid
PubMed: 36336119
DOI: 10.1016/j.cpcardiol.2022.101487 -
Cellular and Molecular Life Sciences :... Sep 2021Transthyretin (TTR) is an extracellular protein mainly produced in the liver and choroid plexus, with a well-stablished role in the transport of thyroxin and retinol... (Review)
Review
Transthyretin (TTR) is an extracellular protein mainly produced in the liver and choroid plexus, with a well-stablished role in the transport of thyroxin and retinol throughout the body and brain. TTR is prone to aggregation, as both wild-type and mutated forms of the protein can lead to the accumulation of amyloid deposits, resulting in a disease called TTR amyloidosis. Recently, novel activities for TTR in cell biology have emerged, ranging from neuronal health preservation in both central and peripheral nervous systems, to cellular fate determination, regulation of proliferation and metabolism. Here, we review the novel literature regarding TTR new cellular effects. We pinpoint TTR as major player on brain health and nerve biology, activities that might impact on nervous systems pathologies, and assign a new link between TTR and angiogenesis and cancer. We also explore the molecular mechanisms underlying TTR activities at the cellular level, and suggest that these might go beyond its most acknowledged carrier functions and include interaction with receptors and activation of intracellular signaling pathways.
Topics: Amyloidosis; Central Nervous System; Humans; Neurons; Prealbumin; Protein Aggregates; Reactive Oxygen Species; Thyroxine; Vitamin A
PubMed: 34297165
DOI: 10.1007/s00018-021-03899-3 -
Journal of Integrative Neuroscience Nov 2023Transthyretin (TTR) is secreted by hepatocytes, retinal pigment epithelial cells, pancreatic α and β cells, choroid plexus epithelium, and neurons under stress. The... (Review)
Review
Transthyretin (TTR) is secreted by hepatocytes, retinal pigment epithelial cells, pancreatic α and β cells, choroid plexus epithelium, and neurons under stress. The choroid plexus product is the main transporter of the thyroid hormone thyroxine (T4) to the brain during early development. TTR is one of three relatively abundant cerebrospinal fluid (CSF) proteins (Apolipoprotein J [ApoJ] (also known as clusterin), Apolipoprotein E [ApoE], and TTR) that interact with Aβ peptides , in some instances inhibiting their aggregation and toxicity. It is now clear that clusterin functions as an extracellular, and perhaps intracellular, chaperone for many misfolded proteins and that variation in its gene () is associated with susceptibility to sporadic Alzheimer's disease (AD). The function of ApoE in AD is not yet completely understood, although the allele has the strongest genetic association with the development of sporadic late onset AD. Despite and evidence of the interaction between TTR and Aβ, genomewide association studies including large numbers of sporadic Alzheimer's disease patients have failed to show significant association between variation in the gene and disease prevalence. Early clinical studies suggested an inverse relationship between CSF TTR levels and AD and the possibility of using the reduced CSF TTR concentration as a biomarker. Later, more extensive analyses indicated that CSF TTR concentrations may be increased in some patients with AD. While the observed changes in TTR may be pathogenetically or biologically interesting because of the inconsistency and lack of specificity, they offered no benefit diagnostically or prognostically either independently or when added to currently employed CSF biomarkers, i.e., decreased Aβ1-42 and increased Tau and phospho-Tau. While some clinical data suggest that increases in CSF TTR may occur early in the disease with a significant decrease late in the course, without additional, more granular data, CSF TTR changes are neither consistent nor specific enough to warrant their use as a specific AD biomarker.
Topics: Humans; Alzheimer Disease; Clusterin; Prealbumin; Apolipoproteins E; Biomarkers; Amyloid beta-Peptides
PubMed: 38176942
DOI: 10.31083/j.jin2206158 -
European Heart Journal Jun 2023
Topics: Humans; Prealbumin; Amyloid Neuropathies, Familial; Cardiomyopathies; Radionuclide Imaging
PubMed: 37282599
DOI: 10.1093/eurheartj/ehad281 -
Computers in Biology and Medicine Mar 2023Non-covalent intramolecular interactions play a key role in the protein folding process. Aminoacidic mutations or changes in physiological conditions such as pH and/or...
Non-covalent intramolecular interactions play a key role in the protein folding process. Aminoacidic mutations or changes in physiological conditions such as pH and/or temperature variations can compromise intramolecular stability generating misfolding or unfolding proteins with consequent impairment of functionality and the triggering of pathological states. The intramolecular HINT scoring function recently implemented and validated, is proposed as a rapid and sensitive method for the evaluation of different conformational states characterizing destabilization processes. In this work, the stability of Transthyretin, whose denaturation is related to amyloid fibril formation, is evaluated by generating multiple structural mutated models under different pH conditions in comparison with experimental data. These results suggest that the HINT scoring function can be used for an accurate and rapid evaluation and computational prediction of the effects of structural changes on any protein system.
Topics: Prealbumin; Amyloid; Comprehension; Protein Denaturation; Protein Folding
PubMed: 36805224
DOI: 10.1016/j.compbiomed.2023.106667 -
Amyloid : the International Journal of... Dec 2023In ATTR amyloidosis, transthyretin (TTR) protein is secreted from the liver and deposited as toxic aggregates at downstream target tissues. Despite recent advancements...
BACKGROUND
In ATTR amyloidosis, transthyretin (TTR) protein is secreted from the liver and deposited as toxic aggregates at downstream target tissues. Despite recent advancements in treatments for ATTR amyloidosis, the mechanisms underlying misfolded TTR-mediated cellular damage remain elusive.
METHODS
In an effort to define early events of TTR-associated stress, we exposed neuronal (SH-SY5Y) and cardiac (AC16) cells to wild-type and destabilized TTR variants (TTR (p.V142I) and TTR (p.L70P)) and performed transcriptional (RNAseq) and epigenetic (ATACseq) profiling. We subsequently compared TTR-responsive signatures to cells exposed to destabilized antibody light chain protein associated with AL amyloidosis as well as ER stressors (thapsigargin, heat shock).
RESULTS
In doing so, we observed overlapping, yet distinct cell type- and amyloidogenic protein-specific signatures, suggesting unique responses to each amyloidogenic variant. Moreover, we identified chromatin level changes in AC16 cells exposed to mutant TTR that resolved upon pre-incubation with kinetic stabilizer tafamidis.
CONCLUSIONS
Collectively, these data provide insight into the mechanisms underlying destabilized protein-mediated cellular damage and provide a robust resource representing cellular responses to aggregation-prone proteins and ER stress.
Topics: Humans; Amyloid Neuropathies, Familial; Amyloidogenic Proteins; Amyloidosis; Neuroblastoma; Neurons; Prealbumin
PubMed: 37439769
DOI: 10.1080/13506129.2023.2224494