Transthyretin (TTR), which is one of the major amyloidogenic proteins in systemic amyloidosis, forms extracellular amyloid deposits in the systemic organs such as nerves, ligaments, heart, and ...arterioles, and causes two kinds of systemic amyloidosis, hereditary ATTR (ATTRv) amyloidosis induced by variant TTR and aging-related wild-type ATTR (ATTRwt) amyloidosis. More than 150 different mutations, most of which are amyloidogenic, have been reported in the TTR gene. Since most disease-associated mutations affect TTR tetramer dissociation rates, destabilization of TTR tetramers is widely believed to be a critical step in TTR amyloid formation. Recently, effective disease-modifying therapies such as TTR tetramer stabilizers and TTR gene silencing therapies have been developed for ATTR amyloidosis. This study reviews the clinical phenotypes of ATTR amyloidosis, TTR features, and recent progress in promising therapies for ATTR amyloidosis.
•TTR causes two different kinds of fatal diseases, ATTRv and ATTRwt amyloidosis.•ATTR amyloidosis is more common than previously thought.•New promising therapeutic strategies for ATTR amyloidosis have been developed.•TTR tetramer stabilizers and TTR gene silencing therapies are now clinically available for patients with ATTRv amyloidosis.
Hereditary transthyretin amyloidosis is caused by the deposition of misfolded transthyretin proteins in peripheral nerves and other tissues. This phase 3 trial tested patisiran, a small interfering ...RNA targeting transthyretin messenger RNA, to treat the disease.
Hereditary ATTR (ATTRm) amyloidosis (also called transthyretin-type familial amyloid polyneuropathy ATTR-FAP) is an autosomal-dominant, adult-onset, rare systemic disorder predominantly characterized ...by irreversible, progressive, and persistent peripheral nerve damage. TTR gene mutations (e.g. replacement of valine with methionine at position 30 Val30Met (p.Val50Met)) lead to destabilization and dissociation of TTR tetramers into variant TTR monomers, which form amyloid fibrils that deposit in peripheral nerves and various organs, giving rise to peripheral and autonomic neuropathy and several non-disease specific symptoms.Phenotypic and genetic variability and non-disease-specific symptoms often delay diagnosis and lead to misdiagnosis. Red-flag symptom clusters simplify diagnosis globally. However, in Japan, types of TTR variants, age of onset, penetrance, and clinical symptoms of Val30Met are more varied than in other countries. Hence, development of a Japan-specific red-flag symptom cluster is warranted. Presence of progressive peripheral sensory-motor polyneuropathy and ≥1 red-flag sign/symptom (e.g. family history, autonomic dysfunction, cardiac involvement, carpal tunnel syndrome, gastrointestinal disturbances, unexplained weight loss, and immunotherapy resistance) suggests ATTR-FAP. Outside of Japan, pharmacotherapeutic options are first-line therapy. However, because of positive outcomes (better life expectancy and higher survival rates) with living donor transplant in Japan, liver transplantation remains first-line treatment, necessitating a Japan-specific treatment algorithm.Herein, we present a consolidated review of the ATTR-FAP Val30Met landscape in Japan and summarize findings from a medical advisory board meeting held in Tokyo on 18th August 2016, at which a Japan-specific ATTR-FAP red-flag symptom cluster and treatment algorithm was developed. Beside liver transplantation, a TTR-stabilizing agent (e.g. tafamidis) is a treatment option. Early diagnosis and timely treatment using the Japan-specific red-flag symptom cluster and treatment algorithm might help guide clinicians regarding apt and judicious use of available treatment modalities.
•Transthyretin amyloid fibrils deposit predominantly in the t-tubules of cardiomyocytes at the early stage.•The structure of the t-tubules of cardiomyocytes with amyloid deposits is significantly ...deformed.•Voltage-dependent calcium channels are reduced in the cardiomyocytes with amyloid deposition.
Cardiac involvement is one of the most frequent and fatal manifestations of hereditary transthyretin (ATTRv) amyloidosis. This study sought to clarify the pathogenesis of ATTRv amyloidosis, specifically, how transthyretin (TTR) amyloid begins to deposit in cardiomyocytes and how this deposition progresses in these cells.
We analyzed autopsy cardiac tissues from five patients with ATTRv amyloidosis by using confocal microscopy with thioflavin S staining and immunofluorescence and electron microscopy to demonstrate the pattern of TTR amyloid deposition in cardiomyocytes.
We demonstrated predominant amyloid deposition in the transverse tubules (t-tubules) of cardiomyocytes at the early stage of TTR amyloid deposition. Also, a pattern of the progression of amyloid deposition from deeply invaginated extracellular matrix, that is, t-tubules, to cell surface extracellular matrix, that is, basement membrane, was noted. Three-dimensional confocal microscopic images revealed the abnormal architecture of the t-tubules with nodular swelling, branching, and confluence in the cardiomyocytes with amyloid deposition. Double immunofluorescence staining with anti-TTR antibody and CACNA1C antibody demonstrated reduced voltage-dependent calcium channels around amyloid deposition.
Our pathological study demonstrated that t-tubule involvement is an early event in cardiomyocytes in the pathogenesis of ATTRv amyloidosis. This finding may indicate that disruption of t-tubules in cardiomyocytes may contribute to the pathogenesis of cardiac events including heart failure and arrhythmia.
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•Metformin reduced cerebral Aβ in APP23-ob/ob mice and mixed model CAA-T2DM mice..•Metformin reduced hippocampal and cortical soluble and insoluble Aβ42 and Aβ40.•Metformin increased ...levels of hippocampal IDE.•Metformin attenuated CAA severity by enhancing Aβ-cleaving IDE expression.•Metformin may be a new therapeutic strategy in CAA, especially for T2DM patients.
Sporadic cerebral amyloid angiopathy (CAA), which is characterized by cerebrovascular amyloid β (Aβ) deposits, causes cerebral hemorrhages and dementia in elderly people. Metformin has been used to treat patients with type 2 diabetes mellitus (T2DM), and animal and clinical studies have reported therapeutic effects of metformin in Alzheimer’s disease (AD). However, the therapeutic effects of metformin in CAA are unclear. Here, we used a mixed mouse model of CAA and T2DM (APP23-ob/ob) to investigate whether metformin has therapeutic effects on cerebrovascular Aβ deposits. We dissolved metformin hydrochloride in water and administered it orally at 350 mg/kg/day. Treatments started when mice were 6 weeks old and continued until they were 15 months old. After we treated APP23-ob/ob mice with metformin, we counted the numbers of vessels with Aβ and measured levels of Aβ40 and Aβ42 (soluble and insoluble), amyloid precursor protein (APP), APP-processing enzymes (α-, β-, and γ-secretases), and Aβ-degrading enzymes (insulin-degrading enzyme IDE, neprilysin). Metformin significantly reduced cerebrovascular Aβ deposits in APP23-ob/ob mice (p < .05). Compared with controls, metformin-treated APP23-ob/ob mice had significantly reduced Aβ levels in the cerebral cortex (p < .05) and hippocampus (p < .05) and increased levels of IDE in the hippocampus (p < .01). Our results indicate that metformin attenuates the severity of CAA by enhancing Aβ-cleaving IDE expression. The clinical application of metformin may lead to a novel therapeutic strategy in CAA treatment, especially in patients with T2DM.
Objective To clarify the underlying diseases, clinical manifestations, and treatment strategies for Amyloid A (AA) amyloidosis (AAA) in Japanese patients. Methods We conducted a survey on Japanese ...patients with AAA treated between January 1, 2012, and December 31, 2014. Results A total of 199 patients with AAA were included in the present study. The underlying diseases of AAA were rheumatoid arthritis (60.3%), uncharacterized inflammatory disorders (11.1%), neoplasms (7.0%), other rheumatic diseases (6.5%), inflammatory bowel diseases (4.5%), chronic infection (4.5%), Castleman's disease (4.0%), and autoinflammatory diseases (2.0%). The clinical manifestations at the diagnosis of AAA were moderate to severe renal dysfunction (46.2%), moderate to severe proteinuria (30.7%), intractable diarrhea (32.2%), melena (4.5%), paralytic ileus (3.5%), heart failure (11.6%), cardiac conduction disturbances (10.1%), arrhythmia (5.5%), and hypothyroidism (11.6%). Diagnostic biopsies were performed most frequently in the gastrointestinal tract (66.3%), followed by the kidneys (22.1%), heart (5.5%), abdominal fat (4.0%), and others (3.0%). Biologics were used to treat 97 patients with AAA (48.7%). Tocilizumab (TCZ) was administered to 66 patients, with 95.5% showing good responses. Anti-TNF agents were administered to 27 patients, with 74.1% showing good responses. The treatment effects of TCZ were significantly superior to those of anti-TNF agents (p<0.007). Conclusion The most common underlying diseases of AAA were rheumatic diseases. Uncharacterized inflammatory disorders and neoplasms were also frequently observed in patients with AAA. Renal and gastrointestinal manifestations were common and important for the diagnosis of AAA, with cardiac manifestations also being of significance. Biologics, particularly TCZ, were effective therapeutic modalities.
Cerebral amyloid angiopathy (CAA) is characterized by accumulation of amyloid β (Aβ) in walls of leptomeningeal vessels and cortical capillaries in the brain. The loss of integrity of these vessels ...caused by cerebrovascular Aβ deposits results in fragile vessels and lobar intracerebral hemorrhages. CAA also manifests with progressive cognitive impairment or transient focal neurological symptoms. Although development of therapeutics for CAA is urgently needed, the pathogenesis of CAA remains to be fully elucidated. In this review, we summarize the epidemiology, pathology, clinical and radiological features, and perspectives for future research directions in CAA therapeutics. Recent advances in mass spectrometric methodology combined with vascular isolation techniques have aided understanding of the cerebrovascular proteome. In this paper, we describe several potential key CAA-associated molecules that have been identified by proteomic analyses (apolipoprotein E, clusterin, SRPX1 (sushi repeat-containing protein X-linked 1), TIMP3 (tissue inhibitor of metalloproteinases 3), and HTRA1 (HtrA serine peptidase 1)), and their pivotal roles in Aβ cytotoxicity, Aβ fibril formation, and vessel wall remodeling. Understanding the interactions between cerebrovascular Aβ deposits and molecules that accumulate with Aβ may lead to discovery of effective CAA therapeutics and to the identification of biomarkers for early diagnosis.
After BNT162b2 messenger ribonucleic acid (mRNA) coronavirus disease 2019 (COVID-19) vaccination, a 30-year-old man developed bilateral lateral gaze palsy, diplopia, absent tendon reflexes, and ...ataxic gait. Serum anti-GQ1b and anti-GT1a immunoglobulin G (IgG) antibodies were strongly positive. Based on those findings, he was diagnosed with Miller Fisher syndrome (MFS). Intravenous immunoglobulin therapy was administered, and his symptoms fully recovered within approximately 3 months. To the best of our knowledge, this is the first report to describe the development of MFS after COVID-19 mRNA vaccination.
Autoimmune polyglandular syndrome (APS) causes autoimmune diseases of multiple organs and can also present with neurological symptoms. We here report a 58-year-old man who presented with progressive ...gait disturbance that had started 7 years ago. He had spasticity, reduced deep sensations, and truncal cerebellar ataxia. Laboratory examinations revealed autoantibody-related cobalamin deficiency and the presence of anti-thyroid antibodies and anti-glutamic acid decarboxylase antibodies. His gait worsened after cobalamin replenishment, but additional steroid therapy was effective. APS can cause refractory gait disturbance that requires not only cobalamin replenishment but also immunotherapy.
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