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Indian Heart Journal 2022Transthyretin cardiac amyloidosis (ATTR-CM) is a rare and under-recognized disorder characterized by the aggregation of transthyretin-derived insoluble amyloid fibrils... (Review)
Review
Transthyretin cardiac amyloidosis (ATTR-CM) is a rare and under-recognized disorder characterized by the aggregation of transthyretin-derived insoluble amyloid fibrils in the myocardium. Heterogeneity of symptoms at presentation, makes its diagnosis often delayed. An expert panel gathered on a virtual platform across India to conduct a meeting for developing a guiding tool for ATTR-CM diagnosis. The panel recommended younger age (≥40 years) for suspecting ATTR-CM and thick-walled non-dilated hypokinetic ventricle was considered as one of the important red flags. Electrocardiogram (ECG) and echocardiography (ECHO) findings were recommended as primary tests to raise the suspicion while nuclear scintigraphy and hematological tests were recommended to confirm the diagnosis and rule out amyloid light-chain (AL) amyloidosis. Cardiac magnetic resonance (CMR) and biopsy were recommended in case of ambiguity in the presence of red flags. Considering the lack of expert guidelines in the Indian scenario, a standardized diagnostic algorithm was also proposed.
Topics: Humans; Adult; Amyloid Neuropathies, Familial; Prealbumin; Consensus; India; Cardiomyopathies
PubMed: 36410415
DOI: 10.1016/j.ihj.2022.11.006 -
Annals of Neurology Aug 2015Autonomic neuropathy is a major component of familial amyloid polyneuropathy (FAP) due to mutated transthyretin, with sudomotor failure as a common manifestation. This...
OBJECTIVE
Autonomic neuropathy is a major component of familial amyloid polyneuropathy (FAP) due to mutated transthyretin, with sudomotor failure as a common manifestation. This study aimed to investigate the pathology and clinical significance of sudomotor denervation.
METHODS
Skin biopsies were performed on the distal leg of FAP patients with a follow-up duration of 3.8 ± 1.6 years. Sudomotor innervation was stained with 2 markers: protein gene product 9.5 (PGP 9.5), a general neuronal marker, and vasoactive intestinal peptide (VIP), a sudomotor nerve functional marker, followed by quantitation according to sweat gland innervation index (SGII) for PGP 9.5 (SGIIPGP 9.5) and VIP (SGIIVIP).
RESULTS
There were 28 patients (25 men) with Ala97Ser transthyretin and late onset (59.9 ± 6.0 years) disabling neuropathy. Autonomic symptoms were present in 22 patients (78.6%) at the time of skin biopsy. The SGIIPGP 9.5 and SGIIVIP of FAP patients were significantly lower than those of age- and gender-matched controls. The reduction of SGIIVIP was more severe than that of SGIIPGP 9.5 (p = 0.002). Patients with orthostatic hypotension or absent sympathetic skin response at palms were associated with lower SGIIPGP 9.5 (p = 0.019 and 0.002, respectively). SGIIPGP 9.5 was negatively correlated with the disability grade at the time of skin biopsy (p = 0.004), and was positively correlated with the interval from the time of skin biopsy to the time of wheelchair usage (p = 0.029).
INTERPRETATION
This study documented the pathological evidence of sudomotor denervation in FAP. SGIIPGP 9.5 was functionally correlated with autonomic symptoms, autonomic tests, ambulation status, and progression of disability.
Topics: Aged; Amyloid Neuropathies, Familial; Autonomic Nervous System Diseases; Biomarkers; Biopsy; Epidermis; Female; Humans; Immunohistochemistry; Leg; Male; Middle Aged; Prealbumin; Skin; Sweat Glands; Ubiquitin Thiolesterase; Vasoactive Intestinal Peptide
PubMed: 25973863
DOI: 10.1002/ana.24438 -
Liver Transplantation : Official... Mar 2015Hereditary transthyretin amyloidosis (ATTR) is a rare worldwide autosomal dominant disease caused by the systemic deposition of an amyloidogenic variant of transthyretin... (Review)
Review
Hereditary transthyretin amyloidosis (ATTR) is a rare worldwide autosomal dominant disease caused by the systemic deposition of an amyloidogenic variant of transthyretin (TTR), which is usually derived from a single amino acid substitution in the TTR gene. More than 100 mutations have been described, with V30M being the most prevalent. Each variant has a different involvement, although peripheral neuropathy and cardiomyopathy are the most common. Orthotopic liver transplantation (OLT) was implemented as the inaugural disease-modifying therapy because the liver produces the circulating unstable TTR. In this review, we focus on the results and long-term outcomes of OLT for ATTR after more than 2063 procedures and 23 years of experience. After successful OLT, neuropathy and organ impairment are not usually reversed, and in some cases, the disease progresses. The overall 5-year survival rate is approximately 100% for V30M patients and 59% for non-ATTR V30M patients. Cardiac-related death and septicemia are the main causes of mortality. Lower survival is related to malnutrition, a longer duration of disease, cardiomyopathy, and a later onset (particularly for males). Deposits, which are composed of a mixture of truncated and full-length TTR (type A) fibrils, have been associated with posttransplant myocardial dysfunction. A higher incidence of early hepatic artery thrombosis of the graft has also been documented for these patients. Liver-kidney/heart transplantation is an alternative for patients with advanced renal disease or heart failure. The sequential procedure, in which ATTR livers are reused in patients with liver disease, reveals that neuropathy in the recipient may appear as soon as 6 years after OLT, and ATTR deposits may appear even earlier. Long-term results of trials with amyloid protein stabilizers or disrupters, silencing RNA, and antisense oligonucleotides will highlight the value and limitations of liver transplantation.
Topics: Amyloid Neuropathies, Familial; Disease Progression; Genetic Predisposition to Disease; Humans; Liver; Liver Transplantation; Mutation; Patient Selection; Prealbumin; Risk Factors; Time Factors; Treatment Outcome
PubMed: 25482846
DOI: 10.1002/lt.24058 -
American Journal of Transplantation :... Jun 2022Hereditary transthyretin-mediated (hATTR) amyloidosis, or ATTRv amyloidosis, is a progressive disease, for which liver transplantation (LT) has been a long-standing...
Hereditary transthyretin-mediated (hATTR) amyloidosis, or ATTRv amyloidosis, is a progressive disease, for which liver transplantation (LT) has been a long-standing treatment. However, disease progression continues post-LT. This Phase 3b, open-label trial evaluated efficacy and safety of patisiran in patients with ATTRv amyloidosis with polyneuropathy progression post-LT. Primary endpoint was median transthyretin (TTR) reduction from baseline. Twenty-three patients received patisiran for 12 months alongside immunosuppression regimens. Patisiran elicited a rapid, sustained TTR reduction (median reduction [Months 6 and 12 average], 91.0%; 95% CI: 86.1%-92.3%); improved neuropathy, quality of life, and autonomic symptoms from baseline to Month 12 (mean change [SEM], Neuropathy Impairment Score, -3.7 [2.7]; Norfolk Quality of Life-Diabetic Neuropathy questionnaire, -6.5 [4.9]; least-squares mean [SEM], Composite Autonomic Symptom Score-31, -5.0 [2.6]); and stabilized disability (Rasch-built Overall Disability Scale) and nutritional status (modified body mass index). Adverse events were mild or moderate; five patients experienced ≥1 serious adverse event. Most patients had normal liver function tests. One patient experienced transplant rejection consistent with inadequate immunosuppression, remained on patisiran, and completed the study. In conclusion, patisiran reduced serum TTR, was well tolerated, and improved or stabilized key disease impairment measures in patients with ATTRv amyloidosis with polyneuropathy progression post-LT (www.clinicaltrials.gov NCT03862807).
Topics: Amyloid Neuropathies, Familial; Humans; Liver Transplantation; Polyneuropathies; Prealbumin; Quality of Life; RNA, Small Interfering
PubMed: 35213769
DOI: 10.1111/ajt.17009 -
Neurodegenerative Disease Management Feb 2019Hereditary transthyretin-mediated amyloidosis is a rapidly progressive, heterogeneous disease caused by the accumulation of misfolded transthyretin protein as amyloid... (Review)
Review
Hereditary transthyretin-mediated amyloidosis is a rapidly progressive, heterogeneous disease caused by the accumulation of misfolded transthyretin protein as amyloid fibrils at multiple sites, and is characterized by peripheral sensorimotor neuropathy, autonomic neuropathy and/or cardiomyopathy. Current treatment options have limited efficacy and often do not prevent disease progression. Patisiran is a novel RNA interference therapeutic that specifically reduces production of both wild-type and mutant transthyretin protein. In Phase II, III and long-term extension studies in patients with hereditary transthyretin-mediated amyloidosis, patisiran has consistently slowed or improved progression of neuropathy. In addition, the Phase III trial demonstrated significant improvements in quality of life measures and indicators of cardiomyopathy. Here, we highlight efficacy and safety data from the patisiran clinical trial programme.
Topics: Amyloid Neuropathies, Familial; Clinical Trials as Topic; Humans; RNA, Small Interfering; RNAi Therapeutics
PubMed: 30480471
DOI: 10.2217/nmt-2018-0033 -
European Journal of Heart Failure Sep 2022
Topics: Amyloid Neuropathies, Familial; Heart Failure; Humans
PubMed: 35912914
DOI: 10.1002/ejhf.2641 -
Orphanet Journal of Rare Diseases Jan 2018Hereditary ATTR (ATTRm) amyloidosis (also called transthyretin-type familial amyloid polyneuropathy [ATTR-FAP]) is an autosomal-dominant, adult-onset, rare systemic... (Review)
Review
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.
Topics: Algorithms; Amyloid Neuropathies, Familial; Benzoxazoles; Carpal Tunnel Syndrome; Humans; Japan; Liver Transplantation; Methionine; Mutation; Valine
PubMed: 29343286
DOI: 10.1186/s13023-017-0726-x -
EBioMedicine Aug 2018
Topics: Amyloid Neuropathies, Familial; Animals; Clinical Trials, Phase III as Topic; Humans; RNA Interference; RNA, Small Interfering
PubMed: 30170686
DOI: 10.1016/j.ebiom.2018.08.025 -
European Heart Journal Jun 2023To perform evaluation of widely embraced bone scintigraphy-based non-biopsy diagnostic criteria (NBDC) for ATTR amyloid cardiomyopathy (ATTR-CM) in clinical practice,...
AIMS
To perform evaluation of widely embraced bone scintigraphy-based non-biopsy diagnostic criteria (NBDC) for ATTR amyloid cardiomyopathy (ATTR-CM) in clinical practice, and to refine serum free light chain (sFLC) ratio cut-offs that reliably exclude monoclonal gammopathy (MG) in chronic kidney disease.
METHODS AND RESULTS
A multi-national retrospective study of 3354 patients with suspected or histologically proven cardiac amyloidosis (CA) referred to specialist centres from 2015 to 2021; evaluations included radionuclide bone scintigraphy, serum and urine immunofixation, sFLC assay, eGFR measurement and echocardiography. Seventy-nine percent (1636/2080) of patients with Perugini grade 2 or 3 radionuclide scans fulfilled NBDC for ATTR-CM through absence of a serum or urine monoclonal protein on immunofixation together with a sFLC ratio falling within revised cut-offs incorporating eGFR; 403 of these patients had amyloid on biopsy, all of which were ATTR type, and their survival was comparable to non-biopsied ATTR-CM patients (p = 0.10). Grade 0 radionuclide scans were present in 1091 patients, of whom 284 (26%) had CA, confirmed as AL type (AL-CA) in 276 (97%) and as ATTR-CM in only one case with an extremely rare TTR variant. Among 183 patients with grade 1 radionuclide scans, 122 had MG of whom 106 (87%) had AL-CA; 60/61 (98%) without MG had ATTR-CM.
CONCLUSION
The NBDC for ATTR-CM are highly specific [97% (95% CI 0.91-0.99)] in clinical setting, and diagnostic performance was further refined here using new cut-offs for sFLC ratio in patients with CKD. A grade 0 radionuclide scan all but excludes ATTR-CM but occurs in most patients with AL-CA. Grade 1 scans in patients with CA and no MG are strongly suggestive of early ATTR-type, but require urgent histologic corroboration.
Topics: Humans; Amyloid Neuropathies, Familial; Retrospective Studies; Radionuclide Imaging; Amyloid; Echocardiography; Cardiomyopathies
PubMed: 36946431
DOI: 10.1093/eurheartj/ehad139 -
International Journal of Cardiology Apr 2022Bone tracers bind to amyloid-containing heart of most patients with ATTR amyloidosis. Amyloid deposits outside the heart are often scarce and bone scintigraphy is...
BACKGROUND
Bone tracers bind to amyloid-containing heart of most patients with ATTR amyloidosis. Amyloid deposits outside the heart are often scarce and bone scintigraphy is increasingly often used to diagnose cardiac involvement. However, the nature of the binding of bone tracers to the heart is not clear.
OBJECTIVE
To identify possible calcium deposits in hearts with amyloid, explaining bone tracer binding.
METHODS AND RESULTS
Formalin-fixed and paraffin embedded cardiac specimens from three patients with ATTR and one with AL amyloidosis, all with cardiac deposits, were studied. The specimens covered large parts of the heart. Sections were stained immunohistochemically for ATTR deposits and according to von Kóssa for calcifications. The study identified in all hearts, but particularly in the ATTR materials, focal, tight swarms of tiny calcifications. These were sometimes associated with amyloid but found as frequent in areas without such deposits. Autoradiography with [Tc]Tc labelled 3,3-disphos-phono-1,2-propanodicarboxylic acid (DPD) revealed labelling in von Kóssa positive areas. Electron microscopically the particles were not amorphous but had a complex structured appearance and were often surrounded by a membrane, indicating a cellular origin. Labelling with antibodies against ubiquitin and P62 pointed to result from autophagy.
CONCLUSIONS
Our study indicates that binding of skeletal probes to amyloid-containing hearts depends on an irregular presence of clouds of very tiny calcifications, which seem not to be directly associated with amyloid fibrils. Therefore, [Tc]Tc-DPD bone scans can be considered surrogate markers of ATTR amyloid but have to be used carefully to estimate amyloid amount or disease progression.
Topics: Amyloid Neuropathies, Familial; Calcinosis; Heart; Humans; Prealbumin; Tomography, X-Ray Computed
PubMed: 35077727
DOI: 10.1016/j.ijcard.2022.01.036