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The American Journal of Medicine Apr 2022Systemic amyloidosis is characterized by extracellular deposition of insoluble fibrillar proteins in multiple tissues, frequently at a distance from the site of... (Review)
Review
Systemic amyloidosis is characterized by extracellular deposition of insoluble fibrillar proteins in multiple tissues, frequently at a distance from the site of synthesis. The 2 most common forms, light chain (AL) and transthyretin (ATTR) amyloidosis can cause peripheral neuropathy and, rarely, myopathy. Diagnosis can be challenging, and abundant suspicion is required to identify patients. As neurological manifestations of amyloidosis may precede involvement of other organs by several years, recognizing amyloid neuropathy and myopathy are crucial, especially in this new and exciting era of effective therapies for AL and ATTR neuropathy. This review will focus on the neuromuscular manifestations of AL and ATTR amyloidosis, diagnostic approaches, and recent advances in the treatment of amyloid neuropathy.
Topics: Amyloid Neuropathies; Amyloid Neuropathies, Familial; Humans; Muscular Diseases; Prealbumin
PubMed: 35104443
DOI: 10.1016/j.amjmed.2022.01.006 -
The American Journal of Medicine Apr 2022Transthyretin amyloidosis (ATTR) is an under-recognized cause of cardiomyopathy and neuropathy. Until recently, there were limited therapeutic options for ATTR. However,... (Review)
Review
Transthyretin amyloidosis (ATTR) is an under-recognized cause of cardiomyopathy and neuropathy. Until recently, there were limited therapeutic options for ATTR. However, new therapeutics, including tafamidis, patisiran, and inotersen, increase both quality and length of life in patients with ATTR. This review details the chronological development of ATTR therapies through landmark clinical trials. In addition, we discuss emerging ATTR therapies including improvements in drug delivery methods, antibodies to break down deposited amyloid fibrils, and gene editing. ATTR is a prime example of how an understanding of the pathophysiological basis of disease can lead to effective therapies. The future of ATTR therapy is bright, with every reason to believe outcomes will continue to improve.
Topics: Amyloid Neuropathies, Familial; Cardiomyopathies; Humans; Prealbumin
PubMed: 35077703
DOI: 10.1016/j.amjmed.2022.01.002 -
Der Internist Mar 2020The diagnosis of polyneuropathy (PNP) is based on the anamnesis and description of complaints of the patient and clinical findings. The type of distribution as well as... (Review)
Review
The diagnosis of polyneuropathy (PNP) is based on the anamnesis and description of complaints of the patient and clinical findings. The type of distribution as well as known diseases and drug toxic factors can provide indications. Electromyography and electroneurography can be used to differentiate between axonal and demyelinating PNP. The laboratory examinations are initially directed towards frequent and treatable causes. These are then expanded depending on the suspected diagnosis. Analysis of cerebrospinal fluid (CSF) is facultative and should be carried out when there is a suspicion of a certain form of PNP with CSF findings indicative of the diagnosis. Nerve biopsy is indicated when the etiology of a severe or progressive PNP cannot be clarified by less invasive means and can have consequences for the treatment. A genetic investigation can be meaningful with a positive family anamnesis or with typical signs of hereditary PNP. Depending on the neuropathy and context, the diagnostic approach is structured differently. The special diagnostics for small fiber neuropathy and amyloid neuropathy as well as for diabetes and alcohol abuse are dealt with in detail in this article. Numerous cases of polyneuropathy remain unexplained and regularly have a favourable prognosis.
Topics: Amyloid Neuropathies; Biopsy; Electromyography; Humans; Neurologic Examination; Polyneuropathies; Small Fiber Neuropathy
PubMed: 32095894
DOI: 10.1007/s00108-020-00744-w -
Current Oncology Reports Jun 2023This review provides an overview of the available therapies for treating neuropathic and/or cardiac manifestations of transthyretin amyloidosis (ATTR), as well as... (Review)
Review
PURPOSE OF REVIEW
This review provides an overview of the available therapies for treating neuropathic and/or cardiac manifestations of transthyretin amyloidosis (ATTR), as well as investigational therapeutic agents in ongoing clinical trials. We discuss additional emergent approaches towards thwarting this life-threatening disease that until recently was considered virtually untreatable.
RECENT FINDINGS
Advances in noninvasive diagnostic methods for detecting ATTR have facilitated easier diagnosis and detection at an earlier stage of disease when therapeutic interventions are likely to be more effective. There are now several ATTR-directed treatments that are clinically available, as well as investigational agents that are being studied in clinical trials. Therapeutic strategies include tetramer stabilization, gene silencing, and fibril disruption. ATTR has been historically underdiagnosed. With advances in diagnostic methods and the advent of disease-modifying treatments, early diagnosis and initiation of treatment is revolutionizing management of this disease.
Topics: Humans; Amyloid Neuropathies, Familial; Cardiomyopathies
PubMed: 36943555
DOI: 10.1007/s11912-023-01397-2 -
Genes Jun 2021The term amyloidosis describes a group of rare diseases caused by protein conformation abnormalities resulting in extracellular deposition and accumulation of insoluble... (Review)
Review
The term amyloidosis describes a group of rare diseases caused by protein conformation abnormalities resulting in extracellular deposition and accumulation of insoluble fibrillar aggregates. So far, 36 amyloid precursor proteins have been identified, and each one is responsible for a specific disease entity. Transthyretin amyloidosis (ATTRv) is one of the most common forms of systemic and ocular amyloidosis, due to the deposition of transthyretin (TTR), which is a transport protein mainly synthesized in the liver but also in the retinal pigment epithelial cells. ATTRv amyloidosis may be misdiagnosed with several other conditions, resulting in a significant diagnostic delay. Gelsolin and keratoepithelin are other proteins that, when mutated, are responsible for a systemic amyloid disease with significant ocular manifestations that not infrequently appear before systemic involvement. The main signs of ocular amyloid deposition are in the cornea, irido-corneal angle and vitreous, causing complications related to vasculopathy and neuropathy at the local level. This review aims at describing the main biochemical, histopathological and clinical features of systemic amyloidosis associated with eye involvement, with particular emphasis on the inherited forms. We discuss currently available treatments, focusing on ocular involvement and specific ophthalmologic management and highlighting the importance of a prompt treatment for the potential sight-threatening complications derived from amyloid deposition in ocular tissues.
Topics: Amyloid Neuropathies, Familial; Amyloidosis, Familial; Extracellular Matrix Proteins; Eye Diseases; Gelsolin; Genetic Predisposition to Disease; Humans; Prealbumin; Retinal Pigment Epithelium; Transforming Growth Factor beta
PubMed: 34206500
DOI: 10.3390/genes12070955 -
Journal of Clinical Pharmacology Jan 2020Hereditary transthyretin-mediated (hATTR) amyloidosis is an inherited, rapidly progressive, life-threatening disease caused by deposition of abnormal transthyretin... (Randomized Controlled Trial)
Randomized Controlled Trial
Patisiran Pharmacokinetics, Pharmacodynamics, and Exposure-Response Analyses in the Phase 3 APOLLO Trial in Patients With Hereditary Transthyretin-Mediated (hATTR) Amyloidosis.
Hereditary transthyretin-mediated (hATTR) amyloidosis is an inherited, rapidly progressive, life-threatening disease caused by deposition of abnormal transthyretin protein. Patisiran is an RNA interference therapeutic comprising a novel, small interfering ribonucleic acid (ALN-18328) formulated in a lipid nanoparticle targeted to inhibit hepatic transthyretin protein synthesis. The lipid nanoparticle also contains 2 novel lipid excipients (DLin-MC3-DMA and PEG -C-DMG). Here we report patisiran pharmacokinetics (PK), pharmacodynamics (PD), and exposure-response analyses from the phase 3 APOLLO trial, in which patients with hATTR amyloidosis with polyneuropathy were randomized 2:1 to receive patisiran 0.3 mg/kg or placebo intravenously every 3 weeks over 18 months. In patisiran-treated patients, mean maximum reduction in serum transthyretin level from baseline was 87.8%. Patisiran PK exposure was stable following chronic dosing. There were no meaningful differences in PK exposure, serum transthyretin reduction, and efficacy (change from baseline in modified Neuropathy Impairment Score+7) across all subgroups analyzed (age, sex, race, body weight, genotype status of valine-to-methionine mutation at position 30 [V30M] and non-V30M, prior use of tetramer stabilizers, mild/moderate renal impairment, and mild hepatic impairment). transthyretin reduction and efficacy were similar across the interpatient PK exposure range for ALN-18328. There was no trend in the incidence of adverse events or serious adverse events across the interpatient PK exposure range for all 3 analytes. Incidence of antidrug antibodies was low (3.4%) and transient, with no impact on PK, PD, efficacy, or safety. The patisiran dosing regimen of 0.3 mg/kg every 3 weeks is appropriate for all patients with hATTR amyloidosis.
Topics: Administration, Intravenous; Aged; Amyloid Neuropathies, Familial; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Liposomes; Liver; Male; Middle Aged; Nanoparticles; Polyneuropathies; Prealbumin; RNA, Small Interfering; RNAi Therapeutics; Treatment Outcome
PubMed: 31322739
DOI: 10.1002/jcph.1480 -
Neurology Dec 2021Hereditary transthyretin amyloidosis (ATTRv amyloidosis) is predominantly a disease of the peripheral nerves, heart, kidney, and eye. CNS involvement has been a marginal... (Review)
Review
Hereditary transthyretin amyloidosis (ATTRv amyloidosis) is predominantly a disease of the peripheral nerves, heart, kidney, and eye. CNS involvement has been a marginal issue in research and the clinical setting until recently. Growing evidence shows that leptomeningeal amyloid accumulation is frequent and present from early stages of ATTRv amyloidosis. Several recent studies show CNS symptoms arise as a common late complication in patients with the V30M mutation after at least 14 years of symptomatic peripheral nerve disease. Conversely, in non-V30M patients, there are several descriptions, mostly case reports, of patients presenting with severe phenotypes of ocular and CNS dysfunction (oculoleptomeningeal amyloidosis), with little systemic involvement. This phenotype is found in rare families worldwide, associated with at least 14 mutations. In both patients with late and early onset CNS dysfunction, symptoms include transient focal neurologic episodes, hemorrhagic and ischemic stroke, cognitive decline, and cranial nerve dysfunction. Pathologically, there is severe amyloid deposition in the leptomeninges and cerebral amyloid angiopathy of leptomeningeal and penetrating vessels. These amyloid aggregates are formed mostly by CSF-produced transthyretin (TTR) and seem resistant to the available ATTRv therapies that increase the stability or reduce the production of plasma TTR. This indicates that CNS involvement will become a meaningful issue in patient management in upcoming years.
Topics: Amyloid; Amyloid Neuropathies, Familial; Cerebral Amyloid Angiopathy; Humans; Prealbumin
PubMed: 34663645
DOI: 10.1212/WNL.0000000000012965 -
Methodist DeBakey Cardiovascular Journal 2022Just a few years ago, cardiac amyloidosis (CA) was rarely diagnosed. With poor treatment options and delayed and infrequent diagnoses, most patients who were eventually... (Review)
Review
Just a few years ago, cardiac amyloidosis (CA) was rarely diagnosed. With poor treatment options and delayed and infrequent diagnoses, most patients who were eventually recognized to have CA were referred for hospice care. Now, the availability of sponsored genetic testing, increased use of nuclear scintigraphy, and widespread recognition have contributed to an increasing number of patients being diagnosed with transthyretin amyloid cardiomyopathy (ATTR-CM). Concomitantly, with the increased recognition of concurrent conditions (eg, carpal tunnel syndrome, lumbar stenosis, and low-flow, low-gradient aortic stenosis), specialists such as orthopedic surgeons and structural cardiologists are increasingly involved in diagnosing ATTR-CM. Although the majority of patients are still being diagnosed either too late or having their diagnosis missed altogether, we have entered an exciting new era in the treatment of cardiac amyloidosis with improved diagnostic tools, disease recognition, and different therapeutic options for both ATTR and light-chain amyloidosis (AL). As a result, survival is improving, and we are no longer faced with a dualistic choice between hospice or organ transplant. The future goal is to develop anti-fibril therapies that will be safe and effective at removing deposited amyloid fibrils and restoring organs to their pre-amyloid state. For the millions of carriers of variant ATTR, enhanced testing followed by genetic editing may allow a cure even before patients develop clinical signs of the disease.
Topics: Amyloid Neuropathies, Familial; Cardiomyopathies; Humans
PubMed: 35414857
DOI: 10.14797/mdcvj.1071 -
La Revue de Medecine Interne Oct 2020Transthyretin (TTR) cardiac amyloidosis results from the dissociation of the tetrameric, liver-synthetized transport protein, either because of a mutation (hereditary... (Review)
Review
Transthyretin (TTR) cardiac amyloidosis results from the dissociation of the tetrameric, liver-synthetized transport protein, either because of a mutation (hereditary CA), or spontaneously due to ageing (wild type CA). Monomers self-associate into amyloid fibrils within the myocardium, causing heart failure, arrhythmias and conduction defects. This overlooked disease must be recognized in case of unexplained increased thickness of the myocardium, particularly in subjects of African descent, in patients with heart failure and preserved ejection fraction, and in those with aortic stenosis. Some extra-cardiac symptoms must also be considered as red flags: carpal tunnel syndrome, lumbar canal stenosis, recent deafness, peripheral neuropathy, or dysautonomia. Medical assessment includes an electrocardiogram, biological assessment including troponin, natriuretic peptide and monoclonal protein assay, echocardiography with 2-D strain study, MRI and bone scintigraphy. Once the diagnosis established, cardiologic management must avoid beta-blockers and other rate-slowing drugs, which are deleterious in restrictive cardiomyopathy, and restrain the use of renin-angiotensin system inhibitors, of little use and often poorly tolerated. Congestion must be treated with diuretics. Anticoagulants are often necessary due to the risk of arrhythmias and stroke. Pacemaker or defibrillator implantation should be determined in patients with high risk of sudden death. Until now, etiologic treatments were liver and/or heart transplantation in some rare cases. Tafamidis, a TTR stabilizer has recently been approved, and new therapeutic approaches targeting TTR at the transcriptional level are under investigation.
Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Echocardiography; Electrocardiography; Humans
PubMed: 32826087
DOI: 10.1016/j.revmed.2020.07.002 -
Heart Failure Reviews Sep 2022Cardiac amyloidosis, once considered a rare disease, has garnered significant attention over the last few years due to three key reasons: first, increased recognition... (Review)
Review
Cardiac amyloidosis, once considered a rare disease, has garnered significant attention over the last few years due to three key reasons: first, increased recognition of this disease in conjunction with various common cardiac conditions such as heart failure with preserved ejection fraction and aortic stenosis; second, due to the advent of promising new therapies for light chain disease (AL), transthyretin (ATTR) cardiomyopathy, and amyloid neuropathy; finally, the advancements in cardiac imaging including echocardiography, magnetic resonance imaging, and nuclear cardiac scintigraphy aid in non-biopsy diagnosis of ATTR cardiac amyloidosis. The hereditary forms of ATTR have further come into importance with the availability of genetic testing and increased prevalence of certain mutations in African Americans. Recognition of non-cardiac clues to this disease has gained importance and reiterates that high clinical suspicion, detailed patient history, and examination with appropriate use of imaging are vital to confirm the diagnosis.
Topics: Amyloid Neuropathies, Familial; Amyloidosis; Aortic Valve Stenosis; Cardiomyopathies; Echocardiography; Heart Failure; Humans
PubMed: 34694575
DOI: 10.1007/s10741-021-10162-1