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Arquivos de Neuro-psiquiatria Apr 2024Hereditary transthyretin amyloidosis (ATTRv) is an inherited, progressive, and fatal disease still largely underdiagnosed. Mutations in the () gene cause the TTR...
BACKGROUND
Hereditary transthyretin amyloidosis (ATTRv) is an inherited, progressive, and fatal disease still largely underdiagnosed. Mutations in the () gene cause the TTR protein to destabilize, misfold, aggregate, and deposit in body tissues, which makes ATTRv a disease with heterogeneous clinical phenotype.
OBJECTIVE
To describe the long-term efficacy and safety of inotersen therapy in patients with ATTRv peripheral neuropathy (ATTRv-PN).
METHODS
Patients who completed the NEURO-TTR pivotal study and the NEURO-TTR OLE open-label extension study migrated to the present study and were followed-up for at least 18 more months to an average of 67 months and up to 76 months since day 1 of the inotersen therapy (D1-first dose of inotersen). Disease progression was evaluated by standard measures.
RESULTS
Ten ATTRv-PN patients with Val30Met mutation were included. The mean disease duration on D1 was of 3 years, and the mean age of the patients was of 46.8 years. During an additional 18-month follow up, neurological function, based on the Neuropathy Impairment Score and the Polyneuropathy Disability Score, functionality aspects (Karnofsky Performance Status), and nutritional and cardiac aspects were maintained. No new safety signs have been noted.
CONCLUSION
The treatment with inotersen was effective and well tolerated for the average of 67 months and up to 76 months. Our results are consistent with those of larger phase-III trials.
Topics: Humans; Middle Aged; Quality of Life; Brazil; Oligonucleotides; Amyloid Neuropathies, Familial; Polyneuropathies
PubMed: 38579737
DOI: 10.1055/s-0044-1781463 -
Medicina Clinica Jun 2024Transthyretin-related amyloidosis (ATTRv) is a progressive multisystem disorder, predominantly involving the peripheral nerve system (PNS) and heart. Quantification of...
INTRODUCTION
Transthyretin-related amyloidosis (ATTRv) is a progressive multisystem disorder, predominantly involving the peripheral nerve system (PNS) and heart. Quantification of small fiber damage may help guide treatment decisions, as amyloid deposits frequently affect those fibers early in disease course. Corneal confocal microscopy (CCM) is a promising method to monitor patients with ATTRv, due to similarities between corneal nerves and PNS, as the cornea is innervated by Aδ and C fibers.
METHODS
We compared CCM measures from ATTRv patients to a group of healthy individuals, matched by age and gender. We then investigated the correlations between small fiber tests (SFT): CCM, LDI-Flare and CDT, COMPASS-31 and disability scales (RODS and ONLS) in patients.
RESULTS
Of 20 patients (6 with V30M), mean age 50.3±15.3Y, 7 female (35%), six (30%) had polyneuropathy and 10 (50%) carpal tunnel syndrome. CDT was abnormal in 9 and LDI-flare in 6 patients. CCM was abnormal in 19 tested patients and significantly reduced when compared to controls (CNFL: 6.31±0.31 vs. 15.21±1.02mm/mm, p<0.001). Mean COMPASS-31-scores were 22.27±22.84; RODS and ONLS were 38.15±12.33 and 2.05±2.3, with no significant differences between sub-group scores. Disease duration was significantly correlated with ONLS (0.43, p=0.05) and RODS (0.46, p=0.03). There were no significant correlations between measures of disability and SFT.
CONCLUSIONS
In a diverse cohort of ATTRv patients, CCM was the most frequent abnormal measurement. CCM can be a useful test to triage patients in the early disease stages and with few or equivocal symptoms.
Topics: Humans; Female; Male; Amyloid Neuropathies, Familial; Middle Aged; Adult; Aged; Cornea; Microscopy, Confocal; Case-Control Studies; Carpal Tunnel Syndrome; Nerve Fibers
PubMed: 38616431
DOI: 10.1016/j.medcli.2024.02.012 -
Journal of Nuclear Cardiology :... Aug 2023Bone scintigraphy plays an important role in the diagnosis of cardiac Transthyretin-Related Amyloidosis (ATTR). The mechanism of myocardial tracer accumulation and its...
BACKGROUND
Bone scintigraphy plays an important role in the diagnosis of cardiac Transthyretin-Related Amyloidosis (ATTR). The mechanism of myocardial tracer accumulation and its dependence over time are not fully understood. Recently, a scintigraphic quantification of the cardiac amyloid deposition has been discussed. Nevertheless, little is known regarding the right time of quantitative imaging.
METHODS
The geometrical mean of decay corrected total counts over the heart and the heart/whole-body ratio (H/WB) were evaluated in 23 patients undergoing DPD-bone scan with planar whole-body images 1 and 3 hours post injection (p.i.). Myocardial standard uptake values (SUV)peak were assessed in another 15 patients with quantitative SPECT/CT imaging 1 hours and 3 hours p.i..
RESULTS
Total counts over the heart (1 hours p.i.: 81,676 cts, range 69,887 to 93,091 cts and 3 hours p.i.: 64,819 cts, range 52,048 to 86,123 cts, P = .0005) and H/WB ratio (1 hours p.i.:0.076 ± 0.020 and 3 hours p.i. 0.070 ± 0.022; P = .0003) were significantly increased 1 hours p.i.. Furthermore median myocardial SUVpeak (1 hours p.i.:12.2, range 9.6 to 18.9 and 3 hours p.i.: 9.6, range 8.2 to 15.0, P = 0.0012) was also significantly higher after 1 hours p.i. compared to 3 hours p.i..
CONCLUSION
Cardiac DPD activity and myocardial SUVpeak are time-dependent, which should be considered when using quantitative bone scintigraphy in ATTR patients.
Topics: Humans; Prealbumin; Tomography, X-Ray Computed; Amyloid Neuropathies, Familial; Single Photon Emission Computed Tomography Computed Tomography; Cardiomyopathies
PubMed: 36513919
DOI: 10.1007/s12350-022-03149-4 -
Europace : European Pacing,... Jun 2024Wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) is often accompanied by atrial fibrillation (AF), atrial flutter (AFL), and atrial tachycardia (AT), which are...
Clinical outcomes of catheter ablation for atrial fibrillation, atrial flutter, and atrial tachycardia in wild-type transthyretin amyloid cardiomyopathy: a proposed treatment strategy for catheter ablation in each arrhythmia.
AIMS
Wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) is often accompanied by atrial fibrillation (AF), atrial flutter (AFL), and atrial tachycardia (AT), which are difficult to control because beta-blockers and antiarrhythmic drugs can worsen heart failure (HF). This study aimed to investigate the outcomes of catheter ablation (CA) for AF/AFL/AT in patients with ATTRwt-CM and propose a treatment strategy for CA.
METHODS AND RESULTS
A cohort study was conducted on 233 patients diagnosed with ATTRwt-CM, including 54 who underwent CA for AF/AFL/AT. The background of each arrhythmia and the details of the CA and its outcomes were investigated. The recurrence-free rate of AF/AFL/AT overall in ATTRwt-CM patients with multiple CA was 70.1% at 1-year, 57.6% at 2-year, and 44.0% at 5-year follow-up, but CA significantly reduced all-cause mortality [hazard ratio (HR): 0.342, 95% confidence interval (CI): 0.133-0.876, P = 0.025], cardiovascular mortality (HR: 0.378, 95% CI: 0.146-0.981, P = 0.045), and HF hospitalization (HR: 0.488, 95% CI: 0.269-0.889, P = 0.019) compared with those without CA. There was no recurrence of the cavotricuspid isthmus (CTI)-dependent AFL, non-CTI-dependent simple AFL terminated by one linear ablation, and focal AT originating from the atrioventricular (AV) annulus or crista terminalis eventually. Twelve of 13 patients with paroxysmal AF and 27 of 29 patients with persistent AF did not have recurrence as AF. However, all three patients with non-CTI-dependent complex AFL not terminated by a single linear ablation and 10 of 13 cases with focal AT or multiple focal ATs originating beyond the AV annulus or crista terminalis recurred even after multiple CA.
CONCLUSION
The outcomes of CA for ATTRwt-CM were acceptable, except for multiple focal AT and complex AFL. Catheter ablation may be aggressively considered as a treatment strategy with the expectation of improving mortality and hospitalization for HF.
Topics: Humans; Catheter Ablation; Male; Atrial Flutter; Female; Atrial Fibrillation; Aged; Amyloid Neuropathies, Familial; Cardiomyopathies; Treatment Outcome; Middle Aged; Recurrence; Tachycardia, Supraventricular; Retrospective Studies; Prealbumin
PubMed: 38934242
DOI: 10.1093/europace/euae155 -
BMC Research Notes Oct 2023Wild-type transthyretin (ATTRwt) amyloidosis is caused by the misfolding and deposition of the transthyretin protein (TTR) in the absence of mutations in the TTR gene....
OBJECTIVE
Wild-type transthyretin (ATTRwt) amyloidosis is caused by the misfolding and deposition of the transthyretin protein (TTR) in the absence of mutations in the TTR gene. Studies regarding the variant form of ATTR amyloidosis (ATTRv) suggest that the presence of single-nucleotide polymorphisms (SNP) in genes other than the TTR, may influence the development of the disease. However, other genetic factors involved in the aetiopathogenesis of ATTRwt are currently unknown. This work investigates the presence of sequence variants in genes selected for their possible impact on ATTRwt amyloidosis. To do so, targeted sequencing of 84 protein-coding genes was performed in a cohort of 27 patients diagnosed with ATTRwt.
RESULTS
After applying quality and frequency filtering criteria, 72 rare or novel genetic variants were found. Subsequent classification according to the ACMG-AMP criteria resulted in 17 variants classified as of uncertain significance in 14 different genes. To our knowledge, this is the first report associating novel gene variants with ATTRwt amyloidosis. In conclusion, this study provides potential insights into the aetiopathogenesis of ATTRwt amyloidosis by linking novel coding-gene variants with the occurrence of the disease.
Topics: Humans; Prealbumin; Amyloid Neuropathies, Familial; Mutation
PubMed: 37784196
DOI: 10.1186/s13104-023-06491-z -
Journal of Nuclear Cardiology :... Oct 2023
Topics: Humans; Amyloid Neuropathies, Familial; Heart; Sarcoidosis; Cardiomyopathies; Prealbumin
PubMed: 35974261
DOI: 10.1007/s12350-022-03083-5 -
Internal Medicine (Tokyo, Japan) Aug 2023We herein report a 68-year-old Japanese man with sporadic variant transthyretin (ATTRv) amyloidosis harboring the novel variant A97D (p.A117D) in TTR. He had slow...
We herein report a 68-year-old Japanese man with sporadic variant transthyretin (ATTRv) amyloidosis harboring the novel variant A97D (p.A117D) in TTR. He had slow development of asymmetric neuropathy, unintentional weight loss, mild autonomic failure and mild cardiomyopathy. TTR amyloid deposition on the gastric duodenal mucosa was detected. In silico analyses predicted that TTR A97D (p.A117D) altered the structure and function of the TTR protein. ATTRv amyloidosis is often difficult to diagnose in non-endemic regions due to its diverse phenotypes, such as atypical peripheral nerve involvement and a rare family history.
Topics: Male; Humans; Prealbumin; Amyloid Neuropathies, Familial; Mutation; Cardiomyopathies
PubMed: 36543209
DOI: 10.2169/internalmedicine.0798-22 -
Hellenic Journal of Nuclear Medicine 2023The purpose of this study was to evaluate the contribution of single photon emission computed tomography/computed tomography (SPECT/CT) standardized uptake value (SUV)...
OBJECTIVE
The purpose of this study was to evaluate the contribution of single photon emission computed tomography/computed tomography (SPECT/CT) standardized uptake value (SUV) metrics in classifying patients with suspected transthyretin cardiac amyloidosis (ATTR-CA) among the different Perugini grades.
SUBJECTS AND METHODS
One hundred four patients suspected of ATTR-CA underwent planar scintigraphy with bone seeking tracer (Tc pyrophosphate-PYP). Patients were classified according to the Perugini scale, the H/CL, H/Bone and H/Bkg ratios. A subset of 48 patients received additional SPECT/CT. Single photon emission computed tomography/CT SUV quantitative parameters, of the heart, myocardium, lungs, liver, soft tissues, bone, and SUV ratios (SUVmyo, SUVlungs, SUVliver, SUVbone and SUVsoft tissue ratios), were evaluated in order to investigate potential metrics that could more clearly differentiate Perugini grades.
RESULTS
A total of 33.7% of patients were considered grade 0, 34.6% grade 1 and 31.7% grade 2/3. A combination of H/CL >1.33 and H/Bone >0.85 showed the highest sensitivity 100%. Standardized uptake value-based metrics clearly differentiated grade 0 or 1 vs grades 2 or 3, whereas no significant difference was found between grades 0 and 1, or between grades 1 and 2. The combined cut-off values H/CL 1.33 and SUVmyo 2.88 yielded 100% sensitivity and 84.6% specificity in differentiating ATTR-CA positives vs negatives. The metric SUVmyo/SUVliver was the best metric to classify patients with grade 1 as negative (grade 0) or positive (grade 2 or 3).
CONCLUSION
Single photon emission computed tomography/CT SUV metrics could be complementary to planar scintigraphy in classifying patients among the different Perugini grades. The ratio SUVmyo/SUVliver was the only parameter with high affinity to differentiate patients with grade 1, as grade 0 or grade 2/3 for ATTR-CA.
Topics: Humans; Prealbumin; Amyloid Neuropathies, Familial; Single Photon Emission Computed Tomography Computed Tomography; Tomography, Emission-Computed, Single-Photon; Radionuclide Imaging
PubMed: 38085832
DOI: 10.1967/s002449912601 -
PloS One 2023In genetic diseases with variable age of onset, an accurate estimation of the survival function for the mutation carriers and also modifying factors effects estimations...
In genetic diseases with variable age of onset, an accurate estimation of the survival function for the mutation carriers and also modifying factors effects estimations are important for the management of asymptomatic gene carriers across life. Among the modifying factors, the gender of the parent transmitting the mutation (i.e. the parent-of-origin effect) has been shown to have a significant effect on survival curve estimation on transthyretin familial amyloid polyneuropathy (ATTRv) families. However, as most genotypes are unknown, the parent-of-origin must be calculated through a probability estimated from the pedigree. We propose in this article to extend the method providing mutation carrier survival estimates in order to estimate the parent-of-origin effect. The method is both validated on simulated data and applied to familly samples with ATTRv.
Topics: Humans; Age of Onset; Amyloid Neuropathies, Familial; Genotype; Heterozygote; Prealbumin; Mutation
PubMed: 37561731
DOI: 10.1371/journal.pone.0288958 -
ESC Heart Failure Apr 2024The early diagnosis of cardiac amyloidosis (CA) is paramount, since there are effective therapies that improve patient survival. The diagnostic accuracy of classical...
AIMS
The early diagnosis of cardiac amyloidosis (CA) is paramount, since there are effective therapies that improve patient survival. The diagnostic accuracy of classical electrocardiographic (ECG) signs, such as low voltage, pseudoinfarct pattern, and conduction disturbances in the diagnosis of CA, is inferior to that of the echocardiographic myocardial deformation criteria; therefore, our aim was to find more accurate novel ECG criteria for this purpose.
METHODS
We tested the diagnostic value of five novel ECG criteria, two of them devised by us, in 34 patients with confirmed CA (20 transthyretin amyloidosis and 14 AL amyloidosis) and 45 control patients with left ventricular hypertrophy on echocardiography due to hypertension, valvular aortic stenosis and hypertrophic cardiomyopathy. The following novel ECG criteria, that suggested CA, were tested: QRS amplitude in lead I < 0.55 mV (I < 0.55); QRS amplitude in lead aVR < 0.5 mV (aVR < 0.5); average QRS amplitude of leads I + aVR < 0.575 mV [(I + aVR) < 0.575]; average QRS amplitude of leads I + aVR/average QRS amplitude of leads V < 0.375 [(I + aVR)/(V) < 0.375]; average QRS amplitude of leads I + aVR/longest intrinsicoid deflection in leads I,aVL,V < 0.0115 [(I + aVR)/I,aVL,VID < 0.0115].
RESULTS
The I < 0.55, aVR < 0.5, (I + aVR) < 0.575, (I + aVR)/(V) < 0.375, (I + aVR)/I,aVL,VID < 0.0115 test accuracy (TA) were 81%, 84.8%, 82.3%, 84.8%, and 83.3%, respectively; the sensitivity (SE): 76.5%, 82.4%, 85.3%, 82.4%, and 76.9%; specificity (SP): 84.4%, 86.7%, 80%, 86.7%, and 87.5%; positive predictive values (PPV): 78.8%, 82.4%, 76.3%, 82.4%, and 80%; negative predictive values (NPV): 82.6%, 86.7%, 87.8%, 86.7%, and 85.4%; area under curve (AUC) values: 0.8922, 0.8794, 09016, 0.8824, and 0.8462 were respectively. These parameters of the novel ECG criteria were at least as good as those reported by other authors in the literature of the qualitative (TA: 67%, SE: 80%, SP: 34%, PPV: 75%, NPV: 42%, AUC: 0.57) and quantitative apical sparing (TA: 64-80%, SE: 66-81.3%, SP: 55-78.3%, PPV: 33-83.9%, NPV: 41-75%, AUC: 0.62-0.68) and left ventricular ejection fraction/global longitudinal strain >4.1 (TA: 77%, SE: 93%, SP: 38%, PPV: 79%, NPV: 69%, AUC: 0.65) echocardiographic criteria. Among the classical criteria, the low voltage in limb leads criterion was present most frequently (in 73.5%) in patients with CA, with slightly worse diagnostic value than the novel ECG criteria (TA: 78.5%, SE: 73.5%, SP: 82.2%, PPV: 75.8%, NPV: 80.4%).
CONCLUSIONS
The novel ECG criteria [mostly the aVR < 0.5, (I + aVR)/(V) < 0.375] seem at least as reliable in the diagnosis of CA as the best echocardiographic myocardial deformation criteria and might be used either together with the echocardiographic criteria or as stand-alone criteria to diagnose CA in the future.
Topics: Humans; Stroke Volume; Ventricular Function, Left; Electrocardiography; Echocardiography; Amyloid Neuropathies, Familial
PubMed: 38243379
DOI: 10.1002/ehf2.14655