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Amyloidosis AND (Hattr OR Hereditary OR Familial)

Susan J Keam
Ionis Pharmaceuticals and Akcea Therapeutics have developed inotersen (Tegsedi™), an antisense oligonucleotide inhibitor of mutant and wild-type human transthyretin (TTR), for the treatment of hereditary transthyretin amyloidosis (hATTR). Mutation of the TTR gene results in accumulation of TTR protein fragments as amyloid deposits throughout the organs in patients with hATTR, including the peripheral nervous system and the heart. Treatment with inotersen, which selectively binds to TTR mRNA, prevents the synthesis of TTR protein in the liver, thus reducing further amyloid deposition throughout the body...
August 17, 2018: Drugs
Meera Sridharan, W Edward Highsmith, Paul J Kurtin, Michael T Zimmermann, Jason D Theis, Surendra Dasari, David Dingli
Hereditary amyloidosis represents a group of diseases in which mutant proteins are deposited in various organs leading to their dysfunction. Correct identification of the amyloid-causing protein is critical because this will determine the optimal therapy for the patient. The most common type of hereditary amyloidosis is due to mutant transthyretin (ATTRm) deposition and often presents with heart failure or peripheral neuropathy. We report the first known case of a patient who had amyloidosis both due to a mutant transthyretin (p...
August 7, 2018: Mayo Clinic Proceedings
J Vollmar, J Ch Schmid, M Hoppe-Lotichius, A P Barreiros, M Azizi, T Emrich, C Geber, A Schad, V Weyer, G Otto, M Heise, J Mittler, F Birklein, H Lang, P R Galle, T Zimmermann
BACKGROUND: Liver transplantation (LT) is the first-line therapy in patients with transthyretin (TTR) amyloidosis and progressive familial amyloid polyneuropathy (FAP). Explanted organs from these patients can be used for domino liver transplantation (DLT). After DLT, de novo amyloidosis may develop in domino recipients (DR). METHODS: Data were collected prospectively in a transplant database. Electroneurography by nerve conduction velocity (NCV), quantitative sensory testing, heart rate variability (HRV), sympathetic skin response, orthostatic reaction (tilt table test), transthoracic echocardiography, cardiac MRI and organ biopsy results were evaluated...
August 8, 2018: Transplant International: Official Journal of the European Society for Organ Transplantation
Ageliki Laina, Aikaterini Gatsiou, Georgios Georgiopoulos, Kimon Stamatelopoulos, Konstantinos Stellos
Since our knowledge on structure and function of messenger RNA (mRNA) has expanded from merely being an intermediate molecule between DNA and proteins to the notion that RNA is a dynamic gene regulator that can be modified and edited, RNA has become a focus of interest into developing novel therapeutic schemes. Therapeutic modulation of RNA molecules by DNA- and RNA-based therapies has broadened the scope of therapeutic targets in infectious diseases, cancer, neurodegenerative diseases and most recently in cardiovascular diseases as well...
2018: Frontiers in Physiology
Hafize Emine Sönmez, Pelin Esmeray, Ezgi Deniz Batu, Zehra Serap Arıcı, Selcan Demir, Erdal Sağ, Seza Özen, Yelda Bilginer
Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease in the world. The disease characteristics may vary in different age groups. In this study, we aimed to compare disease characteristics and treatment compliance according to the age of pediatric FMF patients. This is a single-center, cross-sectional study. Between August and October 2016, patients who were diagnosed with FMF, participated to the study. 378 pediatric FMF patients were enrolled in the study. Among those, age at symptom onset was ≤ 5 years in 69%, 6-11 years in 26% and ≥ 12 years in 5%...
August 7, 2018: Rheumatology International
Di Wu, Min Shen, Xiaofeng Zeng
Objectives: FMF is the most frequent monogenic auto-inflammatory disease worldwide. There have been hardly any cases reported in the Chinese population. We aimed to describe the first cohort of adult FMF patients in China. Methods: We evaluated all the adult patients suffering from FMF referred to our centre from April 2015 through March 2017. Patients were diagnosed clinically according to the Tel Hashomer criteria. Whole exome sequencing was performed in each patient...
August 2, 2018: Rheumatology
Michelle Stewart, Shannon Shaffer, Brian Murphy, Jane Loftus, Jose Alvir, Michael Cicchetti, William R Lenderking
INTRODUCTION: Transthyretin amyloidosis (ATTR amyloidosis), whether manifesting as familial amyloid polyneuropathy (ATTR-PN) or cardiomyopathy (ATTR-CM), is a progressive, debilitating, and often fatal, rare disease requiring significant caregiver support. This study aims to better characterize the burden of disease for ATTR amyloidosis patients and caregivers. METHODS: Patients and caregivers in the USA and Spain were recruited through patient advocacy groups to complete a cross-sectional survey...
August 2, 2018: Neurology and Therapy
Sedat Yılmaz, Emre Tekgöz, Muhammet Çınar
There is no established treatment protocol for amyloid-A (AA) amyloidosis secondary to Familial Mediterranean Fever (FMF). Recently, we reported the efficacy of tocilizumab in 11 amyloidosis cases associated with FMF. In 2 patients of 11, we discontinued the tocilizumab administeration owing to the normalization of amyloidosis-related symptoms, but proteinuria re-occurred eventually. Fortunately, the patients responded to tocilizumab re-treatment. This led us to conclude that physicians should not stop the treatment, even in patients with normalized proteinuria levels...
July 20, 2018: European Journal of Rheumatology
Yasufumi Sakakibara, Michiko Sekiya, Takashi Saito, Takaomi C Saido, Koichi M Iijima
BACKGROUND: Alzheimer's disease (AD), the most common cause of dementia, is characterized by the progressive deposition of amyloid-β (Aβ) peptides and neurofibrillary tangles. Mouse models of Aβ amyloidosis generated by knock-in (KI) of a humanized Aβ sequence provide distinct advantages over traditional transgenic models that rely on overexpression of amyloid precursor protein (APP). In App-KI mice, three familial AD-associated mutations were introduced into the endogenous mouse App locus to recapitulate Aβ pathology observed in AD: the Swedish (NL) mutation, which elevates total Aβ production; the Beyreuther/Iberian (F) mutation, which increases the Aβ42/Aβ40 ratio; and the Arctic (G) mutation, which promotes Aβ aggregation...
July 28, 2018: BMC Neuroscience
Xiao-Ping Qi, Jian-Zhong Peng, Xiao-Wei Yang, Zhi-Lie Cao, Xiu-Hua Yu, Xu-Dong Fang, Da-Hong Zhang, Jian-Qiang Zhao
BACKGROUND: Cutaneous lichen amyloidosis (CLA) has been reported in some multiple endocrine neoplasia type 2A (MEN 2A) families affected by specific germline RET mutations C634F/G/R/W/Y or V804M, as a characteristic of the clinical manifestation in 'MEN 2A with CLA', one of four variants of MEN 2A, which was strictly located in the scapular region of the upper back. PATIENT FINDINGS: This study reports a large south-eastern Chinese pedigree with 17 individuals carrying the MEN 2A-harbouring germline C611Y (c...
July 26, 2018: Endocrine Connections
Hakan Babaoglu, Ozkan Varan, Hamit Kucuk, Nuh Atas, Hasan Satis, Reyhan Salman, Mehmet Akif Ozturk, Berna Goker, Abdurrahman Tufan, Seminur Haznedaroglu
OBJECTIVE: We aimed to present our single-center real-life experience of canakinumab use in adult patients with familial Mediterranean fever (FMF). METHODS: Data were derived from the Gazi FMF cohort, which was established in 2010. From that year, all patients with FMF were registered. The impact of FMF on their lives was tracked by either an FMF diary or mobile phone application (FMF-AIDD, free to download in App Store and Google Play). The records of patients who were treated with canakinumab were reviewed...
July 25, 2018: Journal of Clinical Rheumatology: Practical Reports on Rheumatic & Musculoskeletal Diseases
Arnt V Kristen
Transthyretin is a transport protein for thyroxine and retinol-binding protein, which is mainly produced in the liver. Hereditary transthyretin-related amyloidosis (ATTR) is caused by one of more than 120 point mutations in the transthyretin gene and inherited as an autosomal dominant disorder. The mutations cause a reduction in the stability of the tetrameric structure and dissociation into dimers and monomers as the rate-limiting step in amyloid formation is promoted. Clinical symptoms are related to the specific mutation, the age of onset, the ethnic background and environmental factors...
July 23, 2018: Der Internist
Scot Walker
Hereditary transthyretin amyloidosis is an inherited disorder that results in the gradual progressive deposit of abnormal protein called amyloid in the body's organs and tissues. There are currently no approved drugs to treat transthyretin amyloidosis, and patients may require liver transplantation for survival. There are a few drugs in development to treat hereditary transthyretin amyloidosis either by stabilizing the abnormal protein or by decreasing production of transthyretin. Both methods are being developed to slow progression of the disease...
July 2018: Hospital Pharmacy
Richard M Giadone, Jessica D Rosarda, Prithvi Reddy Akepati, Arianne C Thomas, Batbold Boldbaatar, Marianne F James, Andrew A Wilson, Vaishali Sanchorawala, Lawreen H Connors, John L Berk, R Luke Wiseman, George J Murphy
Hereditary transthyretin amyloidosis (ATTR amyloidosis) is an autosomal dominant protein-folding disorder caused by over 100 distinct mutations in the transthyretin (TTR) gene. In ATTR amyloidosis, protein secreted from the liver aggregates and forms amyloid fibrils in downstream target organs, chiefly the heart and peripheral nervous system. Few animal models of ATTR amyloidosis exist and none recapitulate the multisystem complexity and clinical variability associated with disease pathogenesis in patients...
July 21, 2018: Amyloid: the International Journal of Experimental and Clinical Investigation
Nicholas L Wright, Kathryn E Flynn, Ruta Brazauskas, Parameswaran Hari, Anita D'Souza
We conducted this retrospective study to assess patient-reported distress in light chain (AL) amyloidosis, using the Distress Thermometer (DT) survey at first evaluation at our center. Of 78 patients who completed the survey, 75 scored their distress (distress: <4 - low, 4-6 - moderate, >6 - high). Moderate and high distress were self-reported by 30% and 17% patients, respectively. More patients with distress lived alone and had lower haemoglobin than patients without. AL stage did not correlate with distress (Stage I/II median DT 4 compared to 3 in Stage III/IV, p = ...
July 21, 2018: Amyloid: the International Journal of Experimental and Clinical Investigation
Ian Fyfe
No abstract text is available yet for this article.
July 20, 2018: Nature Reviews. Neurology
Christina E Murray, Priya Gami-Patel, Eleni Gkanatsiou, Gunnar Brinkmalm, Erik Portelius, Oliver Wirths, Wendy Heywood, Kaj Blennow, Jorge Ghiso, Janice L Holton, Kevin Mills, Henrik Zetterberg, Tamas Revesz, Tammaryn Lashley
In the majority of affected brain regions the pathological hallmarks of Alzheimer's disease (AD) are β-amyloid (Aβ) deposits in the form of diffuse and neuritic plaques, tau pathology in the form of neurofibrillary tangles, neuropil threads and plaque-associated abnormal neurites in combination with an inflammatory response. However, the anatomical area of the presubiculum, is characterised by the presence of a single large evenly distributed 'lake-like' Aβ deposit with minimal tau deposition or accumulation of inflammatory markers...
July 20, 2018: Acta Neuropathologica Communications
Sergi Martinez-Ramirez, Sanneke van Rooden, Andreas Charidimou, Anna Maria van Opstal, Marieke Wermer, M Edip Gurol, Gisela Terwindt, Jeroen van der Grond, Steven M Greenberg, Mark van Buchem, Anand Viswanathan
BACKGROUND AND PURPOSE: Magnetic resonance imaging visible perivascular spaces in the centrum semiovale (CSO-PVS) have been associated with cerebral amyloid angiopathy (CAA).We aimed to further confirm this link by evaluating CSO-PVS volume in pathologically-demonstrated sporadic and genetically-demonstrated hereditary forms of the disease. METHODS: We studied a retrospective hospital-based cohort consisting of 63 individuals aged >55 having brain magnetic resonance imaging and pathological assessment of CAA (mean age, 73...
July 16, 2018: Stroke; a Journal of Cerebral Circulation
Christopher J Wilson, Madhurima Das, Shobini Jayaraman, Olga Gursky, John R Engen
Plasma high-density lipoproteins (HDLs) are protein-lipid nanoparticles that transport lipids and protect against atherosclerosis. Human apolipoprotein A-I (apoA-I) is the principal HDL protein whose mutations can cause either aberrant lipid metabolism or amyloid disease. Hydrogen-deuterium exchange (HDX) mass spectrometry (MS) was used to study the apoA-I conformation in model discoidal lipoproteins similar in size to large plasma HDL. We examined how point mutations associated with hereditary amyloidosis (F71Y and L170P) or atherosclerosis (L159R) influence the local apoA-I conformation in model lipoproteins...
July 31, 2018: Biochemistry
Cecilia Monteiro, Ana Martins da Silva, Natália Ferreira, Jaleh Mesgarzadeh, Marta Novais, Teresa Coelho, Jeffery W Kelly
Hereditary transthyretin (TTR) amyloidosis associated with the TTRV30M (p.TTRV50M) mutation presents predominantly as an axonal polyneuropathy, with variable involvement of other organs. Serious central nervous system (CNS) and eye manifestations, including stroke, dementia, vitreous opacities and glaucoma, have been reported in untreated V30M TTR amyloidosis patients, and in these patients after treatment with liver transplantation (LT). Distinct therapies for V30M TTR amyloidosis developed during the last decade exhibit promising results in slowing the peripheral and autonomic nervous system pathology...
July 11, 2018: Amyloid: the International Journal of Experimental and Clinical Investigation
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