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Background In Argentina, there is limited data of prevalence of variant transthyretin amyloidosis (ATTRv) and phenotype‐genotype correlation. The laboratory of Hospital Italiano de Buenos Aires (HIBA) is a reference center for transthyretin (TTR) gene sequencing. The Institutional Amyloidosis Registry (RIA) enable us to characterize people with ATTRv. Our aim was to describe the prevalence of TTR mutations at a reference center in Argentina and the phenotypic presentations of patients with ATTRv included in an institutional registry. Methods Retrospective cohort study of consecutive patients with genetic variants in the TTR gene identified from 2012 to 2019 in the laboratory. We collected all phenotypic characteristics of patients who were clinically evaluated by HIBA doctors. Results Five hundred seventy‐six patients tested, 141 positive: p.Val50Met 107, p.Thr80Ala 16, p.Ala117Ser 9, p.Phe84Leu 2, p.Ile127Val 2, p.Tyr134Cys 2, p.Ala56Pro 2, p.Val142Ile 1. Only 20 patients were clinically evaluated. The mean age at diagnosis was 54 years; 70% had family history with a pedigree median of 4. Mutations were p.Thr80Ala 9, p.Val50Met 6, p.Ala56Pro 2, p.Val142Ile 1, p.Phe84Leu 1, and p.Tyr134Cys 1. Eleven patients presented polyneuropathy, 11 had gastrointestinal compromise, six patients had autonomic compromise, six presented cardiac symptoms and four patients presented ocular involvement. Conclusion We present the first prevalence report of TTR mutations in a reference center of amyloidosis in Argentina. The most frequent genetic variant was p.Val50Met. Our data show considerable phenotypic heterogeneity in the patients with ATTRv. We present the first prevalence report of TTR mutations in a reference center of amyloidosis in Argentina. The most frequent genetic variant was p.Val50Met. Considerable phenotypic heterogeneity in patients with ATTRv.

Transthyretin (TTR) amyloidogenesis involves the formation, aggregation, and deposition of amyloid fibrils from tetrameric TTR in different organs and tissues. While the result of amyloidoses is the accumulation of amyloid fibrils resulting in end-organ damage, the nature, and sequence of the molecular causes leading to amyloidosis may differ between the different variants. In addition, fibril accumulation and toxicity vary between different mutations. Structural changes in amyloidogenic TTR have been difficult to identify through X-ray crystallography; but nuclear magnetic resonance spectroscopy has revealed different chemical shifts in the backbone structure of mutated and wild-type TTR, resulting in diverse responses to the cellular conditions or proteolytic stress. Toxic mechanisms of TTR amyloidosis have different effects on different tissues. Therapeutic approaches have evolved from orthotopic liver transplants to novel disease-modifying therapies that stabilize TTR tetramers and gene-silencing agents like small interfering RNA and antisense oligonucleotide therapies. The underlying molecular mechanisms of the different TTR variants could be responsible for the tropisms to specific organs, the age at onset, treatment responses, or disparities in the prognosis.

BackgroundDuring the transition to rheumatoid arthritis (RA) many patients pass through a phase characterised by the presence of symptoms without clinically apparent synovitis. These symptoms are not well-characterised. This taskforce aimed to define the clinical characteristics of patients with arthralgia who are considered at risk for RA by experts based on their clinical experience.MethodsThe taskforce consisted of 18 rheumatologists, 1 methodologist, 2 patients, 3 health professionals and 1 research fellow. The process had three phases. In phase I, a list of parameters considered characteristic for clinically suspect arthralgia (CSA) was derived; the most important parameters were selected by a three-phased Delphi approach. In phase II, the experts evaluated 50 existing patients on paper, classified them as CSA/no-CSA and indicated their level of confidence. A provisional set of parameters was derived. This was studied for validation in phase III, where all rheumatologists collected patients with and without CSA from their outpatient clinics.ResultsThe comprehensive list consisted of 55 parameters, of which 16 were considered most important. A multivariable model based on the data from phase II identified seven relevant parameters: symptom duration <1 year, symptoms of metacarpophalangeal (MCP) joints, morning stiffness duration ≥60 min, most severe symptoms in early morning, first-degree relative with RA, difficulty with making a fist and positive squeeze test of MCP joints. In phase III, the combination of these parameters was accurate in identifying patients with arthralgia who were considered at risk of developing RA (area under the receiver operating characteristic curve 0.92, 95% CI 0.87 to 0.96). Test characteristics for different cut-off points were determined.ConclusionsA set of clinical characteristics for patients with arthralgia who are at risk of progression to RA was established.

Hereditary transthyretin (ATTRv) amyloidosis with polyneuropathy, also known as familial amyloid polyneuropathy (FAP), represents a progressive, heterogeneous, severe, and multisystemic disease caused by pathogenic variants in the TTR gene. This autosomal-dominant neurogenetic disorder has an adult onset with variable penetrance and an inconstant phenotype, even among subjects carrying the same mutation. Historically, ATTRv amyloidosis has been viewed as a non-inflammatory disease, mainly due to the absence of any mononuclear cell infiltration in ex vivo tissues; nevertheless, a role of inflammation in its pathogenesis has been recently highlighted. The immune response may be involved in the development and progression of the disease. Fibrillary TTR species bind to the receptor for advanced glycation end products (RAGE), probably activating the nuclear factor κB (NF-κB) pathway. Moreover, peripheral blood levels of several cytokines, including interferon (IFN)-gamma, IFN-alpha, IL-6, IL-7, and IL-33, are altered in the course of the disease. This review summarizes the current evidence supporting the role of the immune response in ATTRv amyloidosis, from the pathological mechanisms to the possible therapeutic implications.

Background Hereditary gelsolin (AGel) amyloidosis is an autosomal dominantly inherited systemic amyloidosis that manifests with the characteristic triad of progressive ophthalmological, neurological and dermatological signs and symptoms. The National Finnish Gelsolin Amyloidosis Registry (FIN-GAR) was founded in 2013 to collect clinical data on patients with AGel amyloidosis, including altogether approximately one third of the Finnish patients. We aim to deepen knowledge on the disease burden and life span of the patients using data from the updated FIN-GAR registry. We sent an updated questionnaire concerning the symptoms and signs, symptomatic treatments and subjective perception on disease progression to 240 members of the Finnish Amyloidosis Association (SAMY). We analyzed the lifespan of 478 patients using the relative survival (RS) framework. Results The updated FIN-GAR registry includes 261 patients. Symptoms and signs corresponding to the classical triad of ophthalmological (dry eyes in 93%; corneal lattice amyloidosis in 89%), neurological (numbness, tingling and other paresthesias in 75%; facial paresis in 67%), and dermatological (drooping eyelids in 86%; cutis laxa in 84%) manifestations were highly prevalent. Cardiac arrhythmias were reported by 15% of the patients and 5% had a cardiac pacemaker installed. Proteinuria was reported by 13% and renal failure by 5% of the patients. A total of 65% of the patients had undergone a skin or soft tissue surgery, 26% carpal tunnel surgery and 24% at least unilateral cataract surgery. As regards life span, relative survival estimates exceeded 1 for males and females until the age group of 70–74 years, for which it was 0.96. Conclusions AGel amyloidosis causes a wide variety of ophthalmological, neurological, cutaneous, and oral symptoms that together with repeated surgeries cause a clinically significant disease burden. Severe renal and cardiac manifestations are rare as compared to other systemic amyloidoses, explaining in part the finding that AGel amyloidosis does not shorten the life span of the patients at least for the first 75 years.

Amyloidosis is a diverse group of protein conformational disorder which is caused by accumulation and deposition of insoluble protein fibrils in vital tissues or organs, instigating organ dysfunction. Renal amyloidosis is characterized by the acellular Congo red–positive pathologic deposition of amyloid fibrils within glomeruli and/or the interstitium. It is generally composed of serum amyloid A–related protein or an immunoglobulin light chain; other rare forms lysozyme, gelsolin, fibrinogen alpha chain, transthyretin, apolipoproteins AI/AII/AIV/CII/CIII; and the recently identified form ALECT2. This disease typically manifests with heavy proteinuria, nephrotic syndrome, and finally progression to end-stage renal failure. Early diagnosis of renal amyloidosis is arduous as its symptoms appear in later stages with prominent amyloid deposition. The identification of the correct type of amyloidosis is quite troublesome as it can be confused with another related form. Therefore, the exact typing of amyloid is essential for prognosis, treatment, and correct management of renal amyloidosis. The emanation of new techniques of proteomic analysis, for instance, mass spectroscopy/laser microdissection, has provided greater accuracy in amyloid typing. This in-depth review emphasizes on the clinical features, renal pathological findings, and diagnosis of the AL and non-AL forms of renal amyloidosis.

PurposeHereditary transthyretin amyloidosis (hATTR amyloidosis) is a progressive disease primarily characterized by adult-onset sensory, motor, and autonomic neuropathy. In this article, we discuss the pathophysiology and principal findings of autonomic neuropathy in hATTR amyloidosis, the most common methods of assessment and progression, and its relation as a predictive risk factor or a measure of progression in the natural history of the disease.MethodsA literature search was performed using the terms “autonomic neuropathy,” \"dysautonomia,” and “autonomic symptoms” in patients with hereditary transthyretin amyloidosis and familial amyloid polyneuropathy.ResultsVarious scales to measure autonomic function have been employed, particularly within the major clinical trials, to assess novel therapies for the disease. Most of the evaluations were taken from diabetic clinical trials. Questionnaires include the COMPASS-31 and Norfolk QOL autonomic nerve function domain, whereas clinical evaluations comprise HRDB and the orthostatic tolerance test. Several treatment options are being employed although only diflunisal and tafamidis have reported improvement in the autonomic abnormalities.ConclusionsAutonomic nerves are often affected before motor nerve impairment, and dysautonomia may support the diagnosis of hATTR amyloidosis when differentiating from other adult-onset progressive neuropathies and from other types of amyloidosis. Most of the progression of autonomic dysfunction is seen in early stages of the disease, commonly before motor impairment or affection of the overall quality of life. Unfortunately, there is no current single standardized approach to evaluate dysautonomia in hATTR amyloidosis.

Background Hereditary transthyretin amyloidosis (ATTRv amyloidosis) is a rare, but life-threatening protein misfolding disorder due to TTR gene mutations. Cardiomyopathy (ATTRv-CM) and polyneuropathy (ATTRv-PN) with early small nerve fibre involvement are the most common manifestations. Timely diagnosis and treatment initiation are key to limiting progression of disease. Corneal confocal microscopy (CCM) is a non-invasive method to quantify corneal small nerve fibres and immune cell infiltrates in vivo. Methods This cross-sectional study investigated the utility of CCM in 20 patients with ATTRv amyloidosis (ATTRv-CM, n = 6; ATTRv-PN, n = 14) and presymptomatic carriers (n = 5) compared to 20 age- and sex-matched healthy controls. Corneal nerve fibre density, corneal nerve fibre length, corneal nerve branch density, and cell infiltrates were assessed. Results Corneal nerve fibre density and nerve fibre length were significantly lower in patients with ATTRv amyloidosis compared to healthy controls regardless of the clinical phenotype (ATTRv-CM, ATTRv-PN) and corneal nerve fibre density was significantly lower in presymptomatic carriers. Immune cell infiltrates were only evident in patients with ATTRv amyloidosis, which correlated with reduced corneal nerve fibre density. Conclusions CCM identifies small nerve fibre damage in presymptomatic carriers and symptomatic patients with ATTRv amyloidosis and may serve as a predictive surrogate marker to identify individuals at risk of developing symptomatic amyloidosis. Furthermore, increased corneal cell infiltration suggests an immune-mediated mechanism in the pathogenesis of amyloid neuropathy.

Aims In transthyretin amyloid (ATTR) amyloidosis various principal phenotypes have been described: cardiac, neuropathic, or a mixed cardiac and neuropathic. In addition, two different types of amyloid fibrils have been identified (type A and type B). Type B fibrils have thus far only been found in predominantly early-onset V30M and in patients carrying the Y114C mutation, whereas type A is noted in all other mutations currently examined as well as in wild-type ATTR amyloidosis. The fibril type is a determinant of the ATTR V30M disease phenotype. Tc-99m-DPD scintigraphy is a highly sensitive method for diagnosing heart involvement in ATTR amyloidosis. The objective of this study was to determine the relationship between ATTR fibril composition and Tc-99m-DPD scintigraphy outcome in patients with biopsy-proven ATTR amyloidosis. Methods Altogether 55 patients with biopsy-proven diagnosis of ATTR amyloidosis and amyloid fibril composition determined were examined by Tc-99m-DPD scintigraphy. The patients were grouped and compared according to their type of amyloid fibrils. Cardiovascular evaluation included ECG, echocardiography, and cardiac biomarkers. The medical records were scrutinized to identify subjects with hypertension or other diseases that have an impact on cardiac dimensions. Results A total of 97% with type A and none of the patients with type B fibrils displayed Tc-99m-DPD uptake at scintigraphy (p < 0.001). Findings from analyses of cardiac biomarkers, ECG, and echocardiography, though significantly different, could not differentiate between type A and B fibrils in individual patients. Conclusion In ATTR amyloidosis, the outcome of Tc-99m-DPD scintigraphy is strongly related to the patients' transthyretin amyloid fibril composition.

Background Hereditary transthyretin (ATTRv) amyloidosis is a rare but life-threatening multisystemic disease. Multiple disease-modifying treatments are now available and standardised instruments for early detection and disease monitoring are essential. Still, validated and easy-to-use tools for clinical follow-up are scarce. Methods The Kumamoto scale was first described in 1997 as a method for systematically evaluating patients with ATTRv amyloidosis and has been used in clinical trials since. A panel of amyloidosis experts from Sweden, Denmark, and Norway discussed the strengths and limitations of the Kumamoto scale at the Nordic Amyloidosis Day at Arlanda in 2023, and it was decided to revise and improve the scale that has been used in routine clinical monitoring of patients in Sweden since 2020. Our aim is to introduce the revised version of the Kumamoto scale as a useful clinical monitoring tool. Results Minor adjustments were applied to make the scale more sensitive and precise. Bedside instruments for sensory examination were defined as well as the sensory and motor levels. Constipation was added as a sign of autonomic dysfunction. The subtotal and total scores remain unchanged. Conclusions We believe that the revised Kumamoto scale is a reliable and easy-to-use clinical tool for monitoring ATTRv amyloidosis.