Publications by authors named "Laura Obici"

132 Publications

Age-related amyloidosis outside the brain: A state-of-the-art review.

Ageing Res Rev 2021 Jun 8:101388. Epub 2021 Jun 8.

Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. Electronic address:

Inside and outside the brain, accumulation of amyloid fibrils plays key roles in the pathogenesis of fatal age-related diseases such as Alzheimer's and Parkinson's diseases and wild-type transthyretin amyloidosis. Although the incidence of all amyloidoses increases with age, for some types of amyloidosis aging is known as the main direct risk factor, and these types are typically diseases of elderly people. More than 10 different precursor proteins are known to cause age-associated amyloidosis; these proteins include amyloid β protein, α-synuclein, transthyretin, islet amyloid polypeptide, atrial natriuretic factor, and the newly discovered epidermal growth factor-containing fibulin-like extracellular matrix protein 1. Except for intracerebral amyloidoses, most age-related amyloidoses have been little studied. Indeed, in view of the increasing life expectancy in our societies, understanding how aging is involved in the process of amyloid fibril accumulation and the effects of amyloid deposits on the aging body is extremely important. In this review, we summarize current knowledge about the nature of amyloid precursor proteins; the prevalence, clinical manifestations, and pathogenesis of amyloidosis; and recent advances in our understanding of age-related amyloidoses outside the brain.
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http://dx.doi.org/10.1016/j.arr.2021.101388DOI Listing
June 2021

Quality of life assessment in amyloid transthyretin (ATTR) amyloidosis.

Eur J Clin Invest 2021 May 12:e13598. Epub 2021 May 12.

Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy.

Background: Amyloid transthyretin (ATTR) amyloidosis is caused by the systemic deposition of transthyretin molecules, either normal (wild-type ATTR, ATTRwt) or mutated (variant ATTR, ATTRv). ATTR amyloidosis is a disease with a severe impact on patients' quality of life (QoL). Nonetheless, limited attention has been paid to QoL so far, and no specific tools for QoL assessment in ATTR amyloidosis currently exist. QoL can be evaluated through patient-reported outcome measures (PROMs), which are completed by patients, or through scales, which are compiled by clinicians. The scales investigate QoL either directly or indirectly, i.e., by assessing the degree of functional impairment and limitations imposed by the disease.

Design: Search for the measures of QoL evaluated in phase 2 and phase 3 clinical trials on ATTR amyloidosis.

Results: Clinical trials on ATTR amyloidosis have used measures of general health status, such as the Short Form 36 Health Survey (SF-36), or tools developed in other disease settings such as the Kansas City Cardiomyopathy Questionnaire (KCCQ) or adaptations of other scales such as the modified Neuropathy Impairment Score +7 (mNIS+7).

Conclusions: Scales or PROMs for ATTR amyloidosis would be useful to better characterize newly diagnosed patients and to assess disease progression and response to treatment. The ongoing ITALY (Impact of Transthyretin Amyloidosis on Life qualitY) study aims to develop and validate 2 PROMs encompassing the whole phenotypic spectrum of ATTRwt and ATTRv amyloidosis, that might be helpful for patient management and may serve as surrogate endpoints for clinical trials.
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http://dx.doi.org/10.1111/eci.13598DOI Listing
May 2021

Expert consensus on the monitoring of transthyretin amyloid cardiomyopathy.

Eur J Heart Fail 2021 Apr 29. Epub 2021 Apr 29.

University College London Institute for Cardiovascular Science & St Bartholomew's Hospital, London, UK.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a life-threatening condition with a heterogeneous clinical presentation. The recent availability of treatment for ATTR-CM has stimulated increased awareness of the disease and patient identification. Stratification of patients with ATTR-CM is critical for optimal management and treatment; however, monitoring disease progression is challenging and currently lacks best-practice guidance. In this report, experts with experience in treating amyloidosis and ATTR-CM developed consensus recommendations for monitoring the course of patients with ATTR-CM and proposed meaningful thresholds and frequency for specific parameters. A set of 11 measurable features across three separate domains were evaluated: (i) clinical and functional endpoints, (ii) biomarkers and laboratory markers, and (iii) imaging and electrocardiographic parameters. Experts recommended that one marker from each of the three domains provides the minimum requirements for assessing disease progression. Assessment of cardiac disease status should be part of a multiparametric evaluation in which progression, stability or improvement of other involved systems in transthyretin amyloidosis should also be considered. Additional data from placebo arms of clinical trials and future studies assessing ATTR-CM will help to elucidate, refine and define these and other measurements.
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http://dx.doi.org/10.1002/ejhf.2198DOI Listing
April 2021

Psychosocial burden and professional and social support in patients with hereditary transthyretin amyloidosis (ATTRv) and their relatives in Italy.

Orphanet J Rare Dis 2021 Apr 7;16(1):163. Epub 2021 Apr 7.

Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.

Background: Hereditary transthyretin amyloidosis (hATTR), alias ATTR variant (ATTRv) is a severe and disabling disease causing sensory and motor neuropathy, autonomic dysfunction, and cardiomyopathy. The progressive decline of patient's functional autonomy negatively affects the patient's quality of life and requires increasing involvement of relatives in the patient's daily life. Family caregiving may become particularly demanding when the patient is no longer able to move independently. This study is focused on the psychosocial aspects of ATTRv from the patient and relative perspectives. In particular, it explored: the practical and psychological burdens experienced by symptomatic patients with ATTRv and their key relatives and the professional and social network support they may rely on; whether burden varied in relation to patients' and relatives' socio-demographic variables, patients' clinical variables, and perceived professional and social network support; and, any difference in burden and support between patients and their matched relatives.

Methods: The study was carried out on symptomatic patients included in the ATTRv Italian national registry and living with at least one adult relative not suffering from severe illness and being free from ATTRv symptoms. Patients and relatives' assessments were performed using validated self-reported tools.

Results: Overall, 141 patients and 69 relatives were evaluated. Constraints of leisure activities, feelings of loss and worries for the future were the consequences of ATTRv most frequently reported by patients and relatives. Both in patients and their relatives, the burden increased with the duration of symptoms and the level of help in daily activities needed by the patient. In the 69 matched patient-relative pairs, the practical burden was significantly higher among the patients than among their relatives, while the psychological burden was similar in the two groups. Moreover, compared to their relatives, patients with ATTRv reported higher levels of professional and social network support.

Conclusions: These results show that ATTRv is a disease affecting quality of life of both patients and their families. Supporting interventions should be guaranteed to patients, to facilitate their adaptation to the disease, and to their families, to cope as best as possible with the difficulties that this pathology may involve.
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http://dx.doi.org/10.1186/s13023-021-01812-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028211PMC
April 2021

Design and Rationale of the Global Phase 3 NEURO-TTRansform Study of Antisense Oligonucleotide AKCEA-TTR-L (ION-682884-CS3) in Hereditary Transthyretin-Mediated Amyloid Polyneuropathy.

Neurol Ther 2021 Jun 26;10(1):375-389. Epub 2021 Feb 26.

Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.

Introduction: AKCEA-TTR-L is a ligand-conjugated antisense (LICA) drug in development for the treatment of hereditary transthyretin amyloidosis (hATTR), a fatal disease caused by mutations in the transthyretin (TTR) gene. AKCEA-TTR-L shares the same nucleotide sequence as inotersen, an antisense medicine approved for use in hATTR polyneuropathy (hATTR-PN). Unlike inotersen, AKCEA-TTR-L is conjugated to a triantennary N-acetylgalactosamine moiety that supports receptor-mediated uptake by hepatocytes, the primary source of circulating TTR. This advanced design increases drug potency to allow for lower and less frequent dosing. The NEURO-TTRansform study will investigate whether AKCEA-TTR-L is safe and efficacious, with the aim of improving neurologic function and quality of life in hATTR-PN patients.

Methods/design: Approximately 140 adults with stage 1 (independent ambulation) or 2 (requires ambulatory support) hATTR-PN are anticipated to enroll in this multicenter, open-label, randomized, phase 3 study. Patients will be assigned 6:1 to AKCEA-TTR-L 45 mg subcutaneously every 4 weeks or inotersen 300 mg once weekly until the prespecified week 35 interim efficacy analysis, after which patients receiving inotersen will receive AKCEA-TTR-L 45 mg subcutaneously every 4 weeks. All patients will then receive AKCEA-TTR-L through the remainder of the study treatment period. The final efficacy analysis at week 66 will compare the AKCEA-TTR-L arm with the historical placebo arm from the phase 3 trial of inotersen (NEURO-TTR). The primary outcome measures are between-group differences in the change from baseline in serum TTR, modified Neuropathy Impairment Score + 7, and Norfolk Quality of Life-Diabetic Neuropathy questionnaire.

Conclusion: NEURO-TTRansform is designed to determine whether targeted delivery of AKCEA-TTR-L to hepatocytes with lower and less frequent doses will translate into clinical and quality-of-life benefits for patients with hATTR-PN.

Trial Registration: The study is registered at ClinicalTrials.gov (NCT04136184) and EudraCT (2019-001698-10).
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http://dx.doi.org/10.1007/s40120-021-00235-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140170PMC
June 2021

Structure dynamics of ApoA-I amyloidogenic variants in small HDL increase their ability to mediate cholesterol efflux.

J Lipid Res 2020 Nov 24;62:100004. Epub 2020 Nov 24.

Department of Experimental Medical Science, Lund University, Lund, Sweden. Electronic address:

Apolipoprotein A-I (ApoA-I) of high density lipoproteins (HDLs) is essential for the transportation of cholesterol between peripheral tissues and the liver. However, specific mutations in ApoA-I of HDLs are responsible for a late-onset systemic amyloidosis, the pathological accumulation of protein fibrils in tissues and organs. Carriers of these mutations do not exhibit increased cardiovascular disease risk despite displaying reduced levels of ApoA-I/HDL cholesterol. To explain this paradox, we show that the HDL particle profiles of patients carrying either L75P or L174S ApoA-I amyloidogenic variants show a higher relative abundance of the 8.4-nm versus 9.6-nm particles and that serum from patients, as well as reconstituted 8.4- and 9.6-nm HDL particles (rHDL), possess increased capacity to catalyze cholesterol efflux from macrophages. Synchrotron radiation circular dichroism and hydrogen-deuterium exchange revealed that the variants in 8.4-nm rHDL have altered secondary structure composition and display a more flexible binding to lipids than their native counterpart. The reduced HDL cholesterol levels of patients carrying ApoA-I amyloidogenic variants are thus balanced by higher proportion of small, dense HDL particles, and better cholesterol efflux due to altered, region-specific protein structure dynamics.
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http://dx.doi.org/10.1194/jlr.RA120000920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890215PMC
November 2020

INSAID Variant Classification and Eurofever Criteria Guide Optimal Treatment Strategy in Patients with TRAPS: Data from the Eurofever Registry.

J Allergy Clin Immunol Pract 2021 02 9;9(2):783-791.e4. Epub 2020 Nov 9.

National Amyloidosis Centre, UCL Division of Medicine, Royal Free Campus, University College London, London, United Kingdom. Electronic address:

Background: TNF receptor-associated periodic syndrome (TRAPS) is a rare autoinflammatory disease caused by dominant mutation of the TNF super family receptor 1A (TNFRSF1A) gene. Data regarding long-term treatment outcomes are lacking.

Objective: To assess correlations of genotype-phenotypes in patients with TRAPS, as defined by the International Study Group for Systemic Autoinflammatory Diseases (INSAID) classification and Eurofever criteria, with treatment responses.

Methods: Data from 226 patients with variants of the TNFRSF1A gene and enrolled in the Eurofever registry were classified according to the INSAID classification in groups A (pathogenic or likely pathogenic variants), B (variants of uncertain significance or not classified variants), and C (benign or likely benign variants) and screened for Eurofever criteria.

Results: In group A (127 of 226 patients, 56%), all fulfilled Eurofever criteria and 20 of 127 patients (16%) developed AA amyloidosis. In group B (78 of 226 patients, 35%), 40 of 78 patients (51%) did not fulfill Eurofever criteria, displaying a lower incidence of abdominal pain (P < .02) and higher efficacy rate of on-demand nonsteroidal anti-inflammatory drugs (P < .02) and colchicine (P < .001). Group C (21 of 226 patients, 9%) presented a milder disease (P < .02) and none fulfilled Eurofever criteria. Anti-IL-1 drugs were the most frequently used in patients fulfilling Eurofever criteria, with the highest efficacy rate (>85% complete response). No patients on anti-IL-1 treatments developed AA amyloidosis, and 7 women with a history of failure to conceive had successful pregnancies.

Conclusion: Anti-IL-1 drugs are the best maintenance treatment in patients with TRAPS. The diagnosis of TRAPS should be considered very carefully in patients of group B not fulfilling Eurofever criteria and group C, and colchicine may be preferable as the first maintenance treatment.
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http://dx.doi.org/10.1016/j.jaip.2020.10.053DOI Listing
February 2021

A Narrative Review of the Role of Transthyretin in Health and Disease.

Neurol Ther 2020 Dec 1;9(2):395-402. Epub 2020 Oct 1.

Amyloidosis Research and Treatment Centre, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy.

Transthyretin (TTR) is a tetrameric transport protein highly conserved through vertebrate evolution and synthesized in the liver, choroid plexus, and retinal pigment epithelium. TTR transports the thyroid hormone thyroxine and the retinol-binding protein (RBP) bound to retinol (vitamin A). Mutations in TTR are associated with inherited transthyretin amyloidosis (ATTRv), a progressive, debilitating disease that is ultimately fatal and is characterized by misfolding of TTR and aggregation as amyloid fibrils, predominantly leading to cardiomyopathy or polyneuropathy depending on the particular TTR mutation. Transthyretin amyloid cardiomyopathy can also occur as an age-related disease caused by misfolding of wild-type TTR. Apart from its transport role, little is known about possible additional physiological functions of TTR. Evidence from animal model systems in which TTR has been disrupted via gene knockout is adding to our cumulative understanding of TTR function. There is growing evidence that TTR may have a role in neuroprotection and promotion of neurite outgrowth in response to injury. Here, we review the literature describing potential roles of TTR in neurobiology and in the pathophysiology of diseases other than ATTR amyloidosis. A greater understanding of these processes may also contribute to further clarification of the pathology of ATTR and the effects of potential therapies for TTR-related conditions.
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http://dx.doi.org/10.1007/s40120-020-00217-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606379PMC
December 2020

Clinical Features at Onset and Genetic Characterization of Pediatric and Adult Patients with TNF- Receptor-Associated Periodic Syndrome (TRAPS): A Series of 80 Cases from the AIDA Network.

Mediators Inflamm 2020 7;2020:8562485. Epub 2020 Aug 7.

Clinical Pediatrics, Department of Molecular Medicine and Development, University of Siena, Siena, Italy.

This study explores demographic, clinical, and therapeutic features of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) in a cohort of 80 patients recruited from 19 Italian referral Centers. Patients' data were collected retrospectively and then analyzed according to age groups (disease onset before or after 16 years) and genotype (high penetrance (HP) and low penetrance (LP) gene variants). Pediatric- and adult-onset were reported, respectively, in 44 and 36 patients; HP and LP variants were found, respectively, in 32 and 44 cases. A positive family history for recurrent fever was reported more frequently in the pediatric group than in the adult group ( < 0.05). With reference to clinical features during attacks, pericarditis and myalgia were reported more frequently in the context of adult-onset disease than in the pediatric age (with < 0.01 and < 0.05, respectively), while abdominal pain was present in 84% of children and in 25% of adults ( < 0.01). Abdominal pain was significantly associated also to the presence of HP mutations ( < 0.01), while oral aphthosis was more frequently found in the LP variant group ( < 0.05). Systemic amyloidosis occurred in 25% of subjects carrying HP variants. As concerns laboratory features, HP mutations were significantly associated to higher ESR values ( < 0.01) and to the persistence of steadily elevated inflammatory markers during asymptomatic periods ( < 0.05). The presence of mutations involving a cysteine residue, abdominal pain, and lymphadenopathy during flares significantly correlated with the risk of developing amyloidosis and renal impairment. Conversely, the administration of colchicine negatively correlated to the development of pathologic proteinuria ( < 0.05). Both NSAIDs and colchicine were used as monotherapy more frequently in the LP group compared to the HP group ( < 0.01). Biologic agents were prescribed to 49 (61%) patients; R92Q subjects were more frequently on NSAIDs monotherapy than other patients ( < 0.01); nevertheless, they required biologic therapy in 53.1% of cases. At disease onset, the latest classification criteria for TRAPS were fulfilled by 64/80 (80%) patients (clinical plus genetic items) and 46/80 (57.5%) patients (clinical items only). No statistically significant differences were found in the sensitivity of the classification criteria according to age at onset and according to genotype ( < 0.05). This study describes one of the widest cohorts of TRAPS patients in the literature, suggesting that the clinical expression of this syndrome is more influenced by the penetrance of the mutation rather than by the age at onset itself. Given the high phenotypic heterogeneity of the disease, a definite diagnosis should rely on both accurate working clinical assessment and complementary genotype.
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http://dx.doi.org/10.1155/2020/8562485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428902PMC
August 2020

Nerve ultrasound in hereditary transthyretin amyloidosis: red flags and possible progression biomarkers.

J Neurol 2021 Jan 4;268(1):189-198. Epub 2020 Aug 4.

Department of Neurosciences, University of Padova, Via Giustiniani 5, 35128, Padova, Italy.

Background: Diagnostic delay of hereditary transthyretin amyloidosis (ATTRv, v for variant) prevents timely treatment and, therefore, concurs to the mortality of the disease. The aim of the present study was to explore with nerve ultrasound (US) possible red flags for early diagnosis in ATTRv patients with carpal tunnel syndrome (CTS) and/or polyneuropathy and in pre-symptomatic carriers.

Methods: Patients and pre-symptomatic carriers with a TTR gene mutation were enrolled from seven Italian centers. Severity of CTS was assessed with neurophysiology and clinical evaluation. Median nerve cross-section area (CSA) was measured with US in ATTRv carriers with CTS (TTR-CTS). One thousand one hundred ninety-six idiopathic CTS were used as controls. Nerve US was also performed in several nerve trunks (median, ulnar, radial, brachial plexi, tibial, peroneal, sciatic, sural) in ATTRv patients with polyneuropathy and in pre-symptomatic carriers.

Results: Sixty-two subjects (34 men, 28 women, mean age 59.8 years ± 12) with TTR gene mutation were recruited. With regard to CTS, while in idiopathic CTS there was a direct correlation between CTS severity and median nerve CSA (r = 0.55, p < 0.01), in the subgroup of TTR-CTS subjects (16 subjects, 5 with bilateral CTS) CSA did not significantly correlate with CTS severity (r = - 0.473). ATTRv patients with polyneuropathy showed larger CSA than pre-symptomatic carriers in several nerve sites, more pronounced at brachial plexi (p < 0.001).

Conclusions: The present study identifies nerve morphological US patterns that may help in the early diagnosis (morpho-functional dissociation of median nerve in CTS) and monitoring of pre-symptomatic TTR carriers (larger nerve CSA at proximal nerve sites, especially at brachial plexi).
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http://dx.doi.org/10.1007/s00415-020-10127-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815618PMC
January 2021

ATTRv amyloidosis Italian Registry: clinical and epidemiological data.

Amyloid 2020 Dec 22;27(4):259-265. Epub 2020 Jul 22.

Fatebenefratelli Foundation-'San Giovanni Calibita' Fatebenefratelli Hospital, Clinical Pathophysiology Center, Rome, Italy.

Introduction: ATTRv amyloidosis is worldwide spread with endemic foci in Portugal and Sweden, Japan, Brazil, Maiorca, and Cyprus. A national Registry was developed to characterise the epidemiology and genotype-phenotype correlation of ATTRv amyloidosis in Italy and to allow a better planning of diagnostic and therapeutic services.

Methods: Fifteen Italian referral centres for amyloidosis spread all over the country have contributed to the Registry.

Results: Four-hundred-forty-seven subjects were enrolled, 187 asymptomatic carriers and 260 affected patients. Thirty-one different mutations were recorded. The seven most represented genetic variants were significantly different in terms of age at onset, clinical features and geographical distribution. National prevalence is 4.33/million with higher values in Southern Italy. Overall symptoms of polyneuropathy were present at disease onset in about half of the patients, symptoms of cardiomyopathy in a quarter of patients, the rest referring carpal tunnel syndrome, dysautonomia or lumbar spinal stenosis. 52.6% of patients were in FAP stage 1, 20.4% in stage 2 and 13.5% in stage 3, while 13.5% patients had no neuropathy, presenting only cardiological symptoms.

Conclusions: We presented an epidemiological study based on collaboration among referral centres for ATTRv amyloidosis spread in all the Italian territory, using web-based Registry. It provided a detailed map of the regional distribution of the disease. The increased awareness of the disease among general practitioners and medical specialists has contributed to reduce the diagnostic delay and the rate of misdiagnosis. The Registry will allow to collect also future information about clinical and instrumental follow-up.
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http://dx.doi.org/10.1080/13506129.2020.1794807DOI Listing
December 2020

Role of Colchicine Treatment in Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS): Real-Life Data from the AIDA Network.

Mediators Inflamm 2020 27;2020:1936960. Epub 2020 May 27.

Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease and Rheumatology-Ophthalmology Collaborative Uveitis Center, Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Italy.

Objective: To analyze the potential role of colchicine monotherapy in patients with tumor necrosis factor receptor associated periodic syndrome (TRAPS) in terms of control of clinical and laboratory manifestations.

Methods: Patients with TRAPS treated with colchicine monotherapy were retrospectively enrolled; demographic, clinical and therapeutic data were collected and statistically analysed after having clustered patients according to different times at disease onset, penetrance of mutations, dosage of colchicine, and different disease manifestations.

Results: 24 patients (14 males; 15 with pediatric disease onset) treated with colchicine monotherapy were enrolled. Colchicine resulted in a complete response in 3 (12.5%) cases, partial response in 14 (58.3%) patients, and lack of response in 7 (29.2%) patients. There were not significant differences in colchicine response between pediatric and adult disease onset ( = 0.42), between low- and high-penetrance mutations ( = 0.62), and according to different dosages ( = 0.66). No significant differences were identified in the frequency of specific disease manifestations between patients experiencing any response to colchicine and patients with lack of response.

Conclusions: Colchicine monotherapy is useful in a low percentage of TRAPS patients; nevertheless, it could be attempted in patients with milder phenotypes and at a lower risk of developing reactive amyloidosis.
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http://dx.doi.org/10.1155/2020/1936960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273368PMC
May 2020

Understanding the Pathophysiology of Cerebral Amyloid Angiopathy.

Int J Mol Sci 2020 May 13;21(10). Epub 2020 May 13.

Cerebrovascular Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.

Cerebral amyloid angiopathy (CAA), one of the main types of cerebral small vessel disease, is a major cause of spontaneous intracerebral haemorrhage and an important contributor to cognitive decline in elderly patients. Despite the number of experimental in vitro studies and animal models, the pathophysiology of CAA is still largely unknown. Although several pathogenic mechanisms including an unbalance between production and clearance of amyloid beta (Aβ) protein as well as 'the prion hypothesis' have been invoked as possible disease triggers, they do not explain completely the disease pathogenesis. This incomplete disease knowledge limits the implementation of treatments able to prevent or halt the clinical progression. The continuous increase of CAA patients makes imperative the development of suitable experimental in vitro or animal models to identify disease biomarkers and new pharmacological treatments that could be administered in the early disease stages to prevent irreversible changes and disease progression.
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http://dx.doi.org/10.3390/ijms21103435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279405PMC
May 2020

Description of a large cohort of Caucasian patients with V122I ATTRv amyloidosis: Neurological and cardiological features.

J Peripher Nerv Syst 2020 09 29;25(3):273-278. Epub 2020 May 29.

Unit of Neurology and Neuromuscular Diseases, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.

V122I is one of more than 130 mutations in transthyretin gene associated with hereditary TTR (ATTRv) amyloidosis. Main clinical expression is an infiltrative pseudohypertrophic cardiomyopathy with mild or no neurological symptoms. It is particularly common among African-Americans (prevalence: 3%-4%). We report 12 subjects from seven unrelated Caucasian families hailing from Sicily and carrying the V122I mutation. One patient was homozygous for V122I and in another family two subjects also carried the E89Q variant in compound heterozygosity. All the subjects underwent neurologic/neurophysiologic evaluation and cardiologic baseline tests; in five of them, cardiac magnetic resonance and/or (99 m) Tc-DPD scintigraphy were performed. Three of 12 subjects were asymptomatic carriers. Of the remaining nine subjects, in four of nine patients, the nerve conduction studies revealed a polyneuropathy; in one of them, this represents the only sign of disease after 5 years of follow-up. In eight of nine subjects, we found a hypertrophic restrictive cardiomyopathy and cardiac failure, associated with a carpal tunnel syndrome. Although in non-Afro-American individuals V122I prevalence is low, subjects carrying this mutation have been identified in the United Kingdom, Italy, and France. Our report describes a large cohort of V122I Caucasian patients from a non-endemic area, confirming the possible underestimation of this mutation in the non-African population. Moreover, it highlights the heterogeneity in the genotype-phenotype correlation of ATTRv mutations, suggesting that the presence of a polyneuropathy has to be identified as soon as possible, since available treatments are, in Europe, so far authorized only for ATTRv amyloid peripheral neuropathy.
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http://dx.doi.org/10.1111/jns.12385DOI Listing
September 2020

Acquired and inherited amyloidosis: Knowledge driving patients' care.

J Peripher Nerv Syst 2020 06;25(2):85-101

National Reference Center for Familial Amyloid Polyneuropathy and Other Rare Neuropathies, APHP, Université Paris Saclay, INSERM U1195, Le Kremlin Bicêtre, France.

Until recently, systemic amyloidoses were regarded as ineluctably disabling and life-threatening diseases. However, this field has witnessed major advances in the last decade, with significant improvements in therapeutic options and in the availability of accurate and non-invasive diagnostic tools. Outstanding progress includes unprecedented hematological response rates provided by risk-adapted regimens in light chain (AL) amyloidosis and the approval of innovative pharmacological agents for both hereditary and wild-type transthyretin amyloidosis (ATTR). Moreover, the incidence of secondary (AA) amyloidosis has continuously reduced, reflecting advances in therapeutics and overall management of several chronic inflammatory diseases. The identification and validation of novel therapeutic targets has grounded on a better knowledge of key molecular events underlying protein misfolding and aggregation and on the increasing availability of diagnostic, prognostic and predictive markers of organ damage and response to treatment. In this review, we focus on these recent advancements and discuss how they are translating into improved outcomes. Neurological involvement dominates the clinical picture in transthyretin and gelsolin inherited amyloidosis and has a significant impact on disease course and management in all patients. Neurologists, therefore, play a major role in improving patients' journey to diagnosis and in providing early access to treatment in order to prevent significant disability and extend survival.
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http://dx.doi.org/10.1111/jns.12381DOI Listing
June 2020

ISSAID/EMQN Best Practice Guidelines for the Genetic Diagnosis of Monogenic Autoinflammatory Diseases in the Next-Generation Sequencing Era.

Clin Chem 2020 04;66(4):525-536

Department of Medical Genetics, Rare Diseases and Personalized Medicine, Reference Center CEREMAIA, CHU Montpellier, University of Montpellier, Montpellier, France.

Background: Monogenic autoinflammatory diseases are caused by pathogenic variants in genes that regulate innate immune responses, and are characterized by sterile systemic inflammatory episodes. Since symptoms can overlap within this rapidly expanding disease category, accurate genetic diagnosis is of the utmost importance to initiate early inflammation-targeted treatment and prevent clinically significant or life-threatening complications. Initial recommendations for the genetic diagnosis of autoinflammatory diseases were limited to a gene-by-gene diagnosis strategy based on the Sanger method, and restricted to the 4 prototypic recurrent fevers (MEFV, MVK, TNFRSF1A, and NLRP3 genes). The development of best practices guidelines integrating critical recent discoveries has become essential.

Methods: The preparatory steps included 2 online surveys and pathogenicity annotation of newly recommended genes. The current guidelines were drafted by European Molecular Genetics Quality Network members, then discussed by a panel of experts of the International Society for Systemic Autoinflammatory Diseases during a consensus meeting.

Results: In these guidelines, we combine the diagnostic strength of next-generation sequencing and recommendations to 4 more recently identified genes (ADA2, NOD2, PSTPIP1, and TNFAIP3), nonclassical pathogenic genetic alterations, and atypical phenotypes. We present a referral-based decision tree for test scope and method (Sanger versus next-generation sequencing) and recommend on complementary explorations for mosaicism, copy-number variants, and gene dose. A genotype table based on the 5-category variant pathogenicity classification provides the clinical significance of prototypic genotypes per gene and disease.

Conclusions: These guidelines will orient and assist geneticists and health practitioners in providing up-to-date and appropriate diagnosis to their patients.
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http://dx.doi.org/10.1093/clinchem/hvaa024DOI Listing
April 2020

Discovering the Italian phenotype of cerebral amyloid angiopathy (CAA): the SENECA project.

Neurol Sci 2020 Aug 12;41(8):2193-2200. Epub 2020 Mar 12.

Hemorrhagic Stroke Research Program, J. Philip Kistler Stroke Research Center, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Cerebral amyloid angiopathy (CAA) is one of the major types of cerebral small vessel disease, and a leading cause of spontaneous intracerebral hemorrhage and cognitive decline in elderly patients. Although increasingly detected, a number of aspects including the pathophysiology, the clinical and neuroradiological phenotype, and the disease course are still under investigation. The incomplete knowledge of the disease limits the implementation of evidence-based guidelines on patient's clinical management and the development of treatments able to prevent or reduce disease progression. The SENECA (SEarchiNg biomarkErs of Cerebral Angiopathy) project is the first Italian multicenter cohort study aimed at better defining the disease natural history and identifying clinical and neuroradiological markers of disease progression. By a multidisciplinary approach and the collection of a large and well-phenotyped series and biorepository of CAA patients, the study is ultimately expected to improve the diagnosis and the knowledge of CAA pathophysiological mechanisms.
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http://dx.doi.org/10.1007/s10072-020-04306-8DOI Listing
August 2020

Quality of life outcomes in APOLLO, the phase 3 trial of the RNAi therapeutic patisiran in patients with hereditary transthyretin-mediated amyloidosis.

Amyloid 2020 Sep 4;27(3):153-162. Epub 2020 Mar 4.

Assistance Publique-Hôpitaux de Paris (APHP), French National Reference Center for Familial Amyloidotic Polyneuropathy, Centre Hospitalier Universitaire Bicêtre, Universite Paris-Sud, INSERM Unite, Paris, France.

Hereditary transthyretin-mediated (hATTR) amyloidosis is a rare, fatal, multisystem disease leading to deteriorating quality of life (QOL). The impact of patisiran on QOL in patients with hATTR amyloidosis with polyneuropathy from the phase 3 APOLLO study (NCT01960348) is evaluated. Patients received either patisiran 0.3 mg/kg ( = 148) or placebo ( = 77) intravenously once every three weeks for 18 months. Multiple measures were used to assess varying aspects of QOL. At 18 months, compared with placebo, patisiran improved Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) score; (least squares [LS] mean difference: -21.1;  = 1.10 × 10; improved across all domains), EuroQoL 5-dimensions 5-levels (LS mean difference: 0.2;  = 1.4 × 10), EuroQoL-visual analog scale (LS mean difference: 9.5; =.0004), Rasch-built Overall Disability Scale (LS mean difference: 9.0;  = 4.07 × 10) and Composite Autonomic Symptom Score-31(COMPASS-31; LS mean difference: -7.5; =.0008). Placebo-treated patients experienced rapid QOL deterioration; treatment effects for patisiran were observed as early as 9 months. At 18 months, patisiran improved Norfolk QOL-DN total score and three individual domains as well as COMPASS-31 total scores relative to baseline. Consistent benefits were also observed in the cardiac subpopulation. The benefits of patisiran across all QOL measures and the rapid deterioration observed with placebo, highlight the urgency in early treatment for patients with hATTR amyloidosis with polyneuropathy.
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http://dx.doi.org/10.1080/13506129.2020.1730790DOI Listing
September 2020

Plasma neurofilament light chain: an early biomarker for hereditary ATTR amyloid polyneuropathy.

Amyloid 2020 Jun 6;27(2):97-102. Epub 2020 Jan 6.

Molecular Neurobiology Group, Instituto de Biologia Molecular e Celular (IBMC) - Instituto de Investigação e Inovação em Saúde (i3S) da Universidade do Porto, Porto, Portugal.

Transthyretin amyloidosis due to V30M mutation (ATTR-V30M) is the most frequent hereditary ATTR amyloidosis. Besides neurophysiological measures, there are no biomarkers to detect preclinical disease or monitor disease progression. CSF or plasma neurofilament light chain (pNfL) have recently been considered sensitive biomarkers to quantitate neuro-axonal damage in several disorders of the peripheral and central nervous system. Characterise plasma NfL levels in a series of untreated ATTR-V30M patients stratified by clinical severity using a cross-sectional retrospective study design. Sixty ATTR-V30M patients and 16 controls from 2 independent cohorts were analysed for pNfL by single-molecule array assay (SIMOA) technique. Disease severity was assessed with Polyneuropathy Disability Score. pNfL is elevated in ATTR-V30M patients as a function of disease severity in both cohorts. Moreover, pNfL discriminates asymptomatic mutation carriers from early symptomatic patients (AUC = 0.97;  < .001) with high sensitivity (92.3%) and specificity (93.8%). pNfL elevation (>66.9 pg/mL) also discriminates patients with sensory neuropathy from patients with motor neuropathy (AUC = 0.91;  < .01) with a sensitivity of 61.5% and a specificity of 92.3%. pNfL is an easily accessible biomarker to establish ATTR-V30M disease conversion and to monitor disease progression. pNfL could be used as efficacy measure of disease-oriented therapies in clinical and pre-clinical trials.
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http://dx.doi.org/10.1080/13506129.2019.1708716DOI Listing
June 2020

Inotersen preserves or improves quality of life in hereditary transthyretin amyloidosis.

J Neurol 2020 Apr 18;267(4):1070-1079. Epub 2019 Dec 18.

Boston University School of Medicine, Boston, MA, USA.

Objective: To examine the impact on quality of life (QOL) of patients with hATTR amyloidosis with polyneuropathy treated with inotersen (Tegsedi™) versus placebo.

Methods: Data were from the NEURO-TTR trial (ClinicalTrials.gov Identifier: NCT01737398), a phase 3, multinational, randomized, double-blind, placebo-controlled study of inotersen in patients with hATTR amyloidosis with polyneuropathy. At baseline and week 66, QOL measures-the Norfolk-QOL-Diabetic Neuropathy (DN) questionnaire and SF-36v2 Health Survey (SF-36v2)-were assessed. Treatment differences in mean changes in QOL from baseline to week 66 were tested using mixed-effect models with repeated measures. Responder analyses compared the percentages of patients whose QOL meaningfully improved or worsened from baseline to week 66 in inotersen and placebo arms. Descriptive analysis of item responses examined treatment differences in specific activities and functions at week 66.

Results: Statistically significant mean differences between treatment arms were observed for three of five Norfolk-QOL-DN domains and five of eight SF-36v2 domains, with better outcomes for inotersen than placebo in physical functioning, activities of daily living, neuropathic symptoms, pain, role limitations due to health problems, and social functioning. A larger percentage of patients in the inotersen arm than the placebo arm showed preservation or improvement in Norfolk-QOL-DN and SF-36v2 scores from baseline to week 66. Responses at week 66 showed more substantial problems with daily activities and functioning for patients in the placebo arm than in the inotersen arm.

Conclusion: Patients with hATTR amyloidosis with polyneuropathy treated with inotersen showed preserved or improved QOL at 66 weeks compared to those who received placebo.
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http://dx.doi.org/10.1007/s00415-019-09671-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109169PMC
April 2020

Amyloidosis in Heart Failure.

Curr Heart Fail Rep 2019 12;16(6):285-303

Interdisciplinary Amyloidosis Center of Northern Bavaria, University Hospital Würzburg, Würzburg, Germany.

Purpose: Amyloidosis represents an increasingly recognized but still frequently missed cause of heart failure. In the light of many effective therapies for light chain (AL) amyloidosis and promising new treatment options for transthyretin (ATTR) amyloidosis, awareness among caregivers needs to be raised to screen for amyloidosis as an important and potentially treatable differential diagnosis. This review outlines the diversity of cardiac amyloidosis, its relation to heart failure, the diagnostic algorithm, and therapeutic considerations that should be applied depending on the underlying type of amyloidosis.

Recent Findings: Non-biopsy diagnosis is feasible in ATTR amyloidosis in the absence of a monoclonal component resulting in higher detection rates of cardiac ATTR amyloidosis. Biomarker-guided staging systems have been updated to facilitate risk stratification according to currently available biomarkers independent of regional differences, but have not yet prospectively been tested. Novel therapies for hereditary and wild-type ATTR amyloidosis are increasingly available. The complex treatment options for AL amyloidosis are improving continuously, resulting in better survival and quality of life. Mortality in advanced cardiac amyloidosis remains high, underlining the importance of early diagnosis and treatment initiation. Cardiac amyloidosis is characterized by etiologic and clinical heterogeneity resulting in a frequently delayed diagnosis and an inappropriately high mortality risk. New treatment options for this hitherto partially untreatable condition have become and will become available, but raise challenges regarding their implementation. Referral to specialized centers providing access to extensive and targeted diagnostic investigations and treatment initiation may help to face these challenges.
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http://dx.doi.org/10.1007/s11897-019-00446-xDOI Listing
December 2019

Light Chains With Heavy Effects.

Am J Kidney Dis 2020 02 16;75(2):291-293. Epub 2019 Oct 16.

Amyloidosis Research and Treatment Centre, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Molecular Medicine, University of Pavia, Pavia, Italy. Electronic address:

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http://dx.doi.org/10.1053/j.ajkd.2019.08.009DOI Listing
February 2020

An evaluation of patisiran: a viable treatment option for transthyretin-related hereditary amyloidosis.

Expert Opin Pharmacother 2019 Dec 30;20(18):2223-2228. Epub 2019 Sep 30.

Amyloidosis Research and Treatment Center, Foundation IRCCS Policlinico San Matteo, Department of Molecular Medicine, University of Pavia, Pavia, Italy.

: Hereditary transthyretin-mediated amyloidosis (ATTRv; v for variant) is a rare, progressive, fatal multi-systemic disease, autosomal dominantly inherited with heterogeneous clinical phenotype caused by mutations in the gene. Mutations promoting proteolytic remodeling and tetramer dissociation result in fragmented and full-length TTR monomers that misfold, aggregate and deposit at multiple sites (mainly nerves and heart) causing peripheral neuropathy and/or cardiomyopathy.: The authors discuss patisiran, the first approved RNA interference-based therapeutic agent that suppresses the circulating levels of the amyloidogenic protein TTR both wild-type and mutant. This compound demonstrated a safe clinical profile in phase I and II studies and showed a significant clinical effect in a phase III (APOLLO) trial in ATTRv patients. An open-label-extension study is still underway but, based on the positive results, the regulatory agencies granted approval for the treatment of ATTRv with polyneuropathy in Stage I and II.: The patisiran program has demonstrated that substantial TTR concentration reduction is associated with significant and sustained improvement in polyneuropathy scores, quality-of-life profile and several outcome measures that capture the systemic burden of the disease. The drug resulted safe also in long term follow-up studies while its efficacy for ATTR with cardiomyopathy is under investigation.
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http://dx.doi.org/10.1080/14656566.2019.1671352DOI Listing
December 2019

Diagnosis and treatment of gastrointestinal dysfunction in hereditary TTR amyloidosis.

Clin Auton Res 2019 09 26;29(Suppl 1):55-63. Epub 2019 Aug 26.

Department of Medicine, Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.

Purpose: To review the management of gastrointestinal symptoms in patients with hereditary transthyretin amyloidosis, discussing diagnostic evaluations, assessment of disease progression and therapeutic strategies that could be implemented in routine practice.

Methods: Literature review. Key search terms included "gastrointestinal symptoms", "autonomic neuropathy", "hereditary transthyretin amyloidosis" and "familial amyloid polyneuropathy".

Results: Gastrointestinal disturbances are a common and serious manifestation of hereditary transthyretin amyloidosis, with significant effects on patients' quality of life and demonstrating a strong association with mortality. Gastrointestinal involvement is more often subclinical in the early stages of the disease, although in some patients gastric and/or bowel abnormalities may be the inaugural symptoms. In both cases, under-recognition, delayed investigation and suboptimal treatment frequently occur. A clear understanding of the mechanisms underlying gastrointestinal dysfunction in hereditary transthyretin amyloidosis is still lacking, but similar to diabetic enteropathy, multiple pathophysiological alterations seem to play a role.

Conclusions: Early detection and treatment of gastrointestinal disturbances is key to the successful treatment of this devastating disease. Gastroenterologists play a valuable role in both the diagnosis and the timely management of gastrointestinal symptoms in hereditary transthyretin amyloidosis and should, therefore, be part of a multidisciplinary and comprehensive approach to this disorder.
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http://dx.doi.org/10.1007/s10286-019-00628-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763516PMC
September 2019

Assessment of patients with hereditary transthyretin amyloidosis - understanding the impact of management and disease progression.

Amyloid 2019 Sep 24;26(3):103-111. Epub 2019 Jul 24.

g Department of Ophthalmology, Bicêtre Hospital Université Paris-Sud, Le Kremlin-Bicêtre, France APHP, DHU Sight Restore, French Reference centre for H-ATTR (NNERF), French Reference Network for Rare Ophthalmic Diseases (OPHTARA) , Le Kremlin-Bicêtre , France.

Timely diagnosis of hereditary variant transthyretin (ATTRv) amyloidosis is critical for appropriate treatment and optimal outcomes. Significant differences are seen between patients receiving treatment and those who are not, though disease progression may continue despite treatment in some patients. Healthcare professionals caring for patients with ATTRv amyloidosis therefore need reliable ongoing assessments to understand the continuing course of disease and make appropriate treatment choices on an individual basis. Various signs and symptoms experienced by patients may be evaluated as indicators of disease progression, though there is currently no validated score that can be used for such ongoing assessment. Recognizing this situation, a group of clinicians highly experienced in ATTR amyloidosis developed an approach to understand and define disease progression in diagnosed and treated patients with ATTRv amyloidosis. The suggested approach is based on the recognition of distinct phenotypes which may usefully inform the particular tools, tests and investigations that are most likely to be appropriate for individual patients. It is aimed at implementing appropriate and ongoing assessment of patients being treated for ATTRv amyloidosis, such that the effectiveness of management can be usefully assessed throughout the course of disease and management can be tailored according to the patient's requirements.
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http://dx.doi.org/10.1080/13506129.2019.1627312DOI Listing
September 2019

Next generation sequencing panel in undifferentiated autoinflammatory diseases identifies patients with colchicine-responder recurrent fevers.

Rheumatology (Oxford) 2020 02;59(2):344-360

Autoinflammatory Diseases and Immunodeficiencies Centre, Pediatric Rheumatology Clinic, IRCCS Giannina Gaslini Institute, University of Genoa.

Objectives: The number of innate immune system disorders classified as systemic autoinflammatory diseases (SAID) has increased in recent years. More than 70% of patients with clinical manifestations of SAID did not receive a molecular diagnosis, thus being classed as so-called undifferentiated or undefined SAID (uSAID). The aim of the present study was to evaluate a next-generation sequencing (NGS)-based clinically oriented protocol in patients with uSAID.

Methods: We designed a NGS panel that included 41 genes clustered in seven subpanels. Patients with uSAID were classified into different groups according to their clinical features and sequenced for the coding portions of the 41 genes.

Results: Fifty patients were enrolled in the study. Thirty-four patients (72%) displayed recurrent fevers not consistent with a PFAPA phenotype. Sixteen patients displayed a chronic inflammatory disease course. A total of 100 gene variants were found (mean 2 per patient; range 0-6), a quarter of which affected suspected genes. Mutations with a definitive diagnostic impact were detected in two patients. Patients with genetically negative recurrent fevers displayed a prevalent gastrointestinal, skin and articular involvement. Patients responded to steroids on demands (94%) and colchicine, with a response rate of 78%.

Conclusion: Even with a low molecular diagnostic rate, a NGS-based approach is able to provide a final diagnosis in a proportion of uSAID patients with evident cost-effectiveness. It also allows the identification of a subgroup of genetically negative patients with recurrent fever responding to steroid on demand and colchicine.
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http://dx.doi.org/10.1093/rheumatology/kez270DOI Listing
February 2020

Screening for Transthyretin Amyloid Cardiomyopathy in Everyday Practice.

JACC Heart Fail 2019 08 10;7(8):709-716. Epub 2019 Jul 10.

Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro Majadahonda, CIBERCV, Madrid, Spain; University Francisco de Vitoria (UFV), Pozuelo de Alarcon, Madrid, Spain. Electronic address:

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a life-threatening, progressive, infiltrative disease caused by the deposition of transthyretin amyloid fibrils in the heart, and can often be overlooked as a common cause of heart failure. Delayed diagnosis due to lack of disease awareness and misdiagnosis results in a poorer prognosis. Early accurate diagnosis is therefore key to improving patient outcomes, particularly in the context of both the recent approval of tafamidis in some countries (including the United States) for the treatment of ATTR-CM, and of other promising therapies under development. With the availability of scintigraphy as an inexpensive, noninvasive diagnostic tool, the rationale to screen for ATTR-CM in high-risk populations of patients is increasingly warranted. Here the authors propose a framework of clinical scenarios in which screening for ATTR-CM is recommended, as well as diagnostic "red flags" that can assist in its diagnosis among the wider population of patients with heart failure.
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http://dx.doi.org/10.1016/j.jchf.2019.04.010DOI Listing
August 2019

Inotersen for the treatment of adults with polyneuropathy caused by hereditary transthyretin-mediated amyloidosis.

Expert Rev Clin Pharmacol 2019 Aug 3;12(8):701-711. Epub 2019 Jul 3.

i Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico S. Matteo , Pavia , Italy.

: Hereditary transthyretin-mediated amyloidosis (ATTRv; v for variant) is an underdiagnosed, progressive, and fatal multisystemic disease with a heterogenous clinical phenotype that is caused by gene mutations that destabilize the TTR protein, resulting in its misfolding, aggregation, and deposition in tissues throughout the body. : Inotersen, an antisense oligonucleotide inhibitor, was recently approved in the United States and Europe for the treatment of the polyneuropathy of ATTRv based on the positive results obtained in the pivotal phase 3 trial, NEURO-TTR. This review will discuss the mechanism of action of inotersen and its pharmacology, clinical efficacy, and safety and tolerability. A PubMed search using the terms 'inotersen,' 'AG10,' 'antisense oligonucleotide,' 'hereditary transthyretin amyloidosis,' 'familial amyloid polyneuropathy,' and 'familial amyloid cardiomyopathy' was performed, and the results were screened for the most relevant English language publications. The bibliographies of all retrieved articles were manually searched to identify additional studies of relevance. : Inotersen targets the disease-forming protein, TTR, and has been shown to improve quality of life and neuropathy progression in patients with stage 1 or 2 ATTRv with polyneuropathy. Inotersen is well tolerated, with a manageable safety profile through regular monitoring for the development of glomerulonephritis or thrombocytopenia.
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http://dx.doi.org/10.1080/17512433.2019.1635008DOI Listing
August 2019