Search Results (689)

Background: Hereditary transthyretin amyloidosis (ATTRv) is a systemic disorder caused by homozygosity or compound heterozygosity for pathogenic mutations in the TTR gene, leading to destabilization of the transthyretin tetramer, misfolding of monomers, and subsequent amyloid fibril deposition. Among over 150 known TTR variants, p.Val142Ile is particularly associated with late-onset cardiac involvement and is the most prevalent amyloidogenic mutation in individuals of African and, to a lesser extent, European descent. This study reports the identification and familial segregation of the p.Val142Ile mutation in a large multigenerational family from Calabria (Southern Italy). Methods: Genomic DNA was extracted from peripheral blood, and Sanger sequencing of the TTR gene was performed in the proband and extended family. Results: The proband was a 75-year-old man with clinical features suggestive of cardiac amyloidosis. Genetic testing revealed homozygosity for the TTR p.Val142Ile variant. Family screening revealed multiple heterozygous carriers across three generations, most of whom were asymptomatic. Discussion: This is the first report of a native Calabrian family carrying this variant, previously unreported in this region, where p.Phe84Leu was considered the only endemic TTR mutation. Our findings expand the mutational landscape of ATTRv in Southern Italy and highlight the presence of p.Val142Ile in a previously unrecognized geographic area. These results reinforce the importance of including TTR sequencing in the work-up of unexplained cardiomyopathy, particularly in Southern Italy, where atypical variants may be emerging. Full article

Immunoglobulin light chains are essential components of intact immunoglobulins, traditionally believed to be produced exclusively by B cells. Physiologically, excess light chains not assembled into intact antibodies exist as free light chains (FLCs). Increasingly recognized as important biomarkers for diseases such as multiple myeloma, systemic amyloidosis, and light chain-related renal injuries, FLCs have also been shown in recent decades to originate from non-B cell sources, including epithelial and carcinoma cells. This review primarily focuses on novel non-B cell-derived FLCs, which challenge the conventional paradigms. It systematically compares B cell-derived and non-B cell-derived FLCs, analyzing differences in genetic features, physicochemical properties, and functional roles in both health and disease. By elucidating the distinctions and similarities in their nature as immune regulators and disease mediators, we highlight the significant clinical potential of FLCs, particularly non-B cell-derived FLCs, for novel diagnostic and therapeutic strategies. Full article

Transthyretin amyloidosis (ATTR) is a disease caused by the deposition of transthyretin-derived fibrils in the body. Despite extensive research conducted over the years, there are currently only four drugs available in clinical use to treat this condition, two of which are repurposed drugs used off-label. However, these treatments present several limitations; therefore, there is an urgent need for new therapeutic options. In this context, dietary supplements containing natural compounds capable of stabilizing the transthyretin (TTR) protein could represent a promising approach to contrast the disease progression, potentially supporting the therapeutic effects of the aforementioned drugs. In light of this, the present review highlights and analyzes the natural compounds that have most recently been reported in the literature as TTR stabilizers. In particular, the studies elucidating the potential of these compounds in the treatment of ATTR, along with the available crystallographic data explaining their binding mode to TTR, are reported. Overall, although the use of natural compounds as supplements shows promise in managing ATTR, further research is still needed to explore its feasibility and confirm its effectiveness. Hopefully, this work will help shed light on these issues and serve as a useful starting point for the development of new strategies to treat this disease. Full article

Cardiac amyloidosis (CA) results from the deposition of either immunoglobulin light chain (AL) or transthyretin (ATTR) amyloid fibrils in the myocardium, causing restrictive cardiomyopathy and, if left untreated, can lead to early death. Advancements in non-invasive diagnostic modalities have led to an increased recognition of the disease. Monoclonal gammopathy plays a pivotal role in the diagnostic algorithm for CA, particularly in differentiating AL from ATTR. This review highlights the importance of monoclonal protein detection through serum protein electrophoresis, immunofixation electrophoresis, and serum free light chain assays as initial screening tools. However, these tests alone are insufficient for a definitive diagnosis due to the complexities associated with coexisting monoclonal gammopathies and the potential for false negative and positive results. Advanced imaging modalities, such as echocardiography, cardiac magnetic resonance, and nuclear scintigraphy, along with tissue biopsy, are crucial for confirming CA and accurately determining the CA subtype. Full article

Light-chain (AL) amyloidosis is a rare clonal plasma cell disorder that, if left untreated, carries a high risk of organ damage and mortality. Due to the rarity of the disease and the vulnerability of affected organ systems, treatment requires significant caution and nuance. As a plasma cell dyscrasia, AL amyloidosis treatment regimens are often adapted from those used for related disorders, particularly multiple myeloma. Despite substantial progress in research and drug development, optimal treatment strategies for relapsed/refractory (RR) AL amyloidosis remain unclear, and no FDA-approved therapies currently exist for this setting. B-cell maturation antigen (BCMA) has emerged as a promising immunotherapy target, with associated drug classes including antibody–drug conjugates, bispecific antibodies, and CAR-T cell therapies. These therapies have been extensively studied in relapsed/refractory multiple myeloma (RRMM) and are now being explored in the context of RR AL amyloidosis. This review summarizes the current literature on the efficacy and tolerability of BCMA-directed therapies in AL amyloidosis, with a particular emphasis on CAR-T cell therapy and offers comparisons to outcomes observed in RRMM. Full article

Abdominal fat necrosis is a dystrophic–necrotic process that is relatively common in dairy cows. It is determined by productive strain (excess fat in the diet), negative energy balance after calving, a lack of physical activity, vitamin E and selenium deficiency, etc. Lipomatous masses are predominantly located in the omentum and mesentery in cattle, potentially causing intestinal obstruction. We report on an outbreak of abdominal fat necrosis that affected 135 of 220 cows and heifers (61.36%); this involved massive fat accumulation in the uterine and salpingian ligaments and severe reproductive disorders (reducing fertility to 20% in cows and 10% in heifers) caused by a hyperenergetic diet (supplementation with saturated fats). A transrectal ultrasound examination of the genital apparatus—both in heifers and in cows in the puerperium—revealed a diffuse pathological hyperechogenicity of the cervical folds, suggesting lipid infiltration, proliferation of the endocervical folds and hyperechogenic lipogranulomas located paracervically or in the uterine ligaments. An ultrasound examination of the ovaries showed the presence of parasalpingial lipogranulomas on the mesovarium, with a uniformly pixelated greasy appearance, that altered the topography of the salpinx, leading to the impossibility of oocyte retrieval. At the histopathological examination, in addition to the necrosis of adipocytes and the subacute–chronic inflammation of the abdominal and retroperitoneal adipose tissue, lipid infiltration of the uterine walls was also observed in the uterine ligaments and lymph nodes. Additionally, lipid infiltration was observed in the wall of the uterine artery. All muscular-type branches of the ovarian artery exhibited subendothelial (subintimal) amyloid deposits, severely reducing their lumen and leading to ischaemia. Amyloidosis was secondary to the systemic inflammatory process triggered by lipid deposition and necrosis. Fertility returned to normal 45–60 days after the exclusion of fat supplements from the diet and their replacement with a vitamin–mineral supplement rich in antioxidants. Full article

Bovine endometritis is a common postpartum disease that significantly impairs reproductive performance and reduces economic sustainability in dairy and beef cattle. It is primarily caused by gram-negative and -positive bacteria, triggering strong inflammatory responses in the endometrium. Serum amyloid A (SAA) is an acute-phase protein and precursor of amyloid A (AA) in AA amyloidosis. In cattle, multiple SAA isoforms have been identified; however, the biological functions of SAA3 remain unclear. Hence, this study investigated the role of SAA3 in bovine endometrial epithelial cells (BEnEpCs) following stimulation with gram-negative or -positive bacterial antigens. BEnEpCs were treated with lipopolysaccharide (LPS) and lipoteichoic acid (LTA) and, subsequently, the expression levels of SAA3 and SAA1 mRNA were compared by real-time PCR. To further investigate protein-level changes, immunocytochemistry (ICC) was performed to assess the expressions of SAA3 and SAA1. These analyses revealed that SAA3 mRNA expression was significantly enhanced by LPS and LTA, whereas SAA1 mRNA remained undetectable or showed only minimal responsiveness. Notably, only SAA3 protein expression increased in response to stimulation. These results indicate that SAA3 plays a crucial role in the innate immune response of BEnEpCs against gram-negative bacteria. Our in vitro findings may facilitate understanding of the innate immune activity in bovine uterus. Full article

Transthyretin-related (ATTR) amyloidosis is a progressive, multisystem disease caused by the extracellular deposition of misfolded transthyretin (TTR) monomers as insoluble amyloid fibrils. Clinical manifestations vary widely and may include cardiomyopathy (ATTR-CM), polyneuropathy (ATTR-PN), or mixed phenotypes. The condition is increasingly recognized as an underdiagnosed contributor to heart failure, particularly in elderly patients. ATTR amyloidosis exists in two major forms: hereditary (ATTRv), resulting from mutations in the TTR gene, and wild-type (ATTRwt), typically affecting men over 70 years of age. Advances in disease understanding have led to a paradigm shift in management, with the introduction of targeted therapies that slow disease progression and improve prognosis. First-generation therapies such as tafamidis have demonstrated survival benefits in ATTR-CM. More recently, second-generation agents—such as the TTR stabilizer acoramidis and RNA silencers including vutrisiran and eplontersen—have shown promising efficacy in clinical trials. Additional strategies under investigation include gene editing and monoclonal antibodies targeting TTR amyloid deposits. This review outlines current diagnostic strategies and therapeutic options for ATTR amyloidosis, emphasizing the need for early detection and individualized treatment approaches. The expanding therapeutic landscape highlights the importance of accurate phenotyping and timely intervention to optimize clinical outcomes. Full article

Background/Objectives: Having serum biomarkers available for cardiac transthyretin amyloidosis (ATTR-CA) would be beneficial for diagnosis and prognosis. This study aimed to identify potential ATTR-CA biomarkers through proteomic analysis. Patients and Methods: Serum proteomic analyses were conducted on 15 ATTR-CA patients before receiving treatment, 11 ATTR-CA patients who had received tafamidis treatment for at least six months, and 13 patients with suspected cardiac amyloidosis who were later ruled out. All patients underwent blood tests, standard 12-lead electrocardiography, transthoracic echocardiography, and ^99mTc-DPD scintigraphy. Results: Proteomic analysis revealed significant differences in protein levels among the study groups. Key findings revealed increased levels of several proteins, including ceruloplasmin, apolipoprotein E, SERPINA1, and cDNA FLJ54111 (which is highly similar to serum transferrin), in ATTR-CA patients before receiving specific treatment. There was also a reduction in prothrombin, transferrin, CD14, and alpha-2-macroglobulin. In the ATTR-CA group treated with tafamidis, elevated levels of SERPINA1, paraoxonase 1, and complement C2 were observed. Notably, levels of cDNA FLJ54111 and SERPINA3 were reduced in this group. Compared to the control group, patients with ATTR-CA exhibited higher levels of ceruloplasmin, SERPINA3, and VCAM1, as well as lower levels of ApoA-I, ApoA-II, clusterin, and gelsolin. Controls exhibited elevated levels of transthyretin and prothrombin. Conclusions: This study identified candidate serum biomarkers for diagnosing ATTR-CA and monitoring the effectiveness of tafamidis treatment. Full article

Background: Transthyretin amyloidosis is a multi-system disease that may manifest as cardiomyopathy (ATTR-CM) and/or polyneuropathy. Both disease manifestations are associated with autonomic dysfunction. However, the prevalence of autonomic dysfunction in ATTR-CM remains to be evaluated. Methods: Within the scope of a prospective ATTR-CM registry, the Composite Autonomic Symptom Score-31 (COMPASS-31) questionnaire was applied to consecutive patients between November 2022 and November 2024. Baseline characteristics are described, and associations of the COMPASS-31 score with markers of disease severity were assessed. Kaplan–Meier analysis was utilized to assess the COMPASS-31 score’s association with a combined endpoint of all-cause mortality and heart failure-related hospitalizations. Results: A total of 129 ATTR-CM patients [81.7 years (IQR: 77.4–84.3), 108 male (83.7%)] were included in the final study cohort. After stratification using the COMPASS-31 median [14 points, interquartile range (IQR): 6–29], statistically significant differences with regard to New York Heart Association (NYHA) stage and the Kansas City Cardiomyopathy Questionnaire (KCCQ) were observed. Furthermore, the COMPASS-31 score was moderately correlated with the KCCQ score in Spearman correlation analysis (r = −0.55, p < 0.001). The primary endpoint occurred in 16 patients (13 HF-hospitalizations/3 deaths) after 6.3 (IQR: 2.8–17.1) months. In Kaplan–Meier analysis, a COMPASS-31 score above the median of 14 was also associated with the primary endpoint of all-cause mortality and HF-related hospitalization (log-rank p = 0.047). Conclusions: Autonomic dysfunction is highly prevalent in ATTR-CM, affecting almost two-thirds of patients. As the presence of autonomic dysfunction is likely associated with more severely impaired quality of life, routine screening for this disease manifestation of transthyretin amyloidosis may be advisable. Full article

Amyloidosis, often referred to as “the great imitator”, is a condition characterized by the abnormal deposition of amyloid proteins in various tissues, potentially leading to organ dysfunction. When these deposits localize in the brain, they can disrupt neurological function and present with diverse clinical manifestations, making diagnosis particularly challenging. Cerebral amyloidosis is a rare entity that frequently mimics other neurological disorders, often resulting in significant delays in recognition and management. This case highlights the diagnostic challenge posed by cerebral amyloidosis and underscores its unique presentation. We present the case of a 76-year-old male with a history of rheumatoid arthritis (RA) who developed progressive right-sided weakness over several months. Three years prior, he experienced numbness on the right side of his face and upper limb. Initial imaging identified a small lesion in the left thalamic region, which was originally diagnosed as a glioma. However, due to the worsening of his clinical symptoms, further evaluation was warranted. Subsequent imaging revealed lesion growth, prompting a biopsy that ultimately confirmed the diagnosis of intracerebral amyloidoma. This case underscores the necessity of considering amyloidosis in the differential diagnosis of atypical neurological deficits, particularly in patients with systemic inflammatory conditions such as RA. The initial presentation of hemiparesis resembling a stroke, coupled with non-specific imaging findings and a prior misdiagnosis of glioma, highlights the complexity of cerebral amyloidosis. Only through brain biopsy was the definitive diagnosis established, emphasizing the need for improved diagnostic modalities to facilitate early detection. Further subtyping of amyloidosis, however, requires mass spectrometry-based proteomics or immunohistochemistry to accurately identify the specific amyloid protein involved. Clinicians should maintain a high index of suspicion for cerebral amyloidosis in patients with RA who present with progressive neurological deficits and atypical brain lesions. Early recognition and accurate diagnosis are essential to guiding appropriate management and improving patient outcomes. Full article

Hereditary transthyretin amyloidosis (ATTRv) is an autosomal dominant disorder caused by pathogenic variants in the TTR gene. The destabilized mutant form of the transport protein transthyretin (TTR) leads to the extracellular deposition of amyloid fibrils. Materials and Methods: A 65-year-old female patient with suspected clinical diagnosis of ATTR was referred for genetic testing for pathogenic variants in the TTR gene after physical, neurological and cardiac testing. Results: The patient had had cardiac dysfunction, atrial fibrillation and supraventricular tachycardia for around 10 years before the suspected and confirmed cardiac amyloidosis. The molecular genetic testing showed a heterozygous pathogenic variant in exon 3 of the TTR gene NM_000371.4(TTR): c.258A>C, p.(Glu86Asp). This variant in the TTR gene is classified as pathogenic in accordance with ACMG/AMP for the interpretation of variants. Conclusions: The presented case of a very rare pathogenic variant in the TTR gene displays the valuable role of genetic testing on the way to clarifying a diagnosis. Full article

The hypertrophic cardiomyopathy (HCM) clinical phenotype includes sarcomeric HCM, which is the most common form of inherited cardiomyopathy with a population prevalence of 1:500, and phenocopies such as cardiac amyloidosis and Anderson–Fabry disease, which are considered rare diseases. Identification of cardiac and non-cardiac red flags in the context of multi-organ syndrome, multimodality imaging, including echocardiography, cardiac magnetic resonance, and genetic testing, has a central role in the diagnostic pathway. Identifying the specific disease underlying the hypertrophic phenotype is very important since many disease-modifying therapies are currently available, and phase 3 trials for new treatments have been completed or are ongoing. In particular, many chemotherapy agents (alkylating agents, proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies targeting clonal cells) allowing one to treat AL amyloidosis, transthyretin stabilizers (tafamidis and acoramidis), and gene silencers (patisiran and vutrisiran) are available in transthyretin cardiac amyloidosis, and enzyme replacement therapies (agalsidase-alpha, agalsidase-beta, and pegunigalsidase-alpha) or oral chaperone therapy (migalastat) can be used in Anderson–Fabry disease. In addition, the introduction of cardiac myosin inhibitors (mavacamten and aficamten) has deeply modified the treatment of hypertrophic obstructive cardiomyopathy. The aim of this review is to describe the new disease-modifying treatments available in HCM and phenocopies in light of current scientific evidence. Full article

Background: Granulomatous and amyloidogenic cardiomyopathies are infiltrative conditions that can be fatal if left untreated. Among these, cardiac amyloidosis and cardiac sarcoidosis are significant but often underdiagnosed causes of heart failure, each serving as cardiac manifestations of broader systemic diseases. Advancements in imaging techniques and the emergence of novel therapies—particularly for cardiac amyloidosis—have brought these conditions into sharper focus for both clinicians and researchers. Methods: We conducted a comprehensive review of the literature by searching databases including PubMed and Scopus for studies published since 1990 regarding clinical features, diagnostic techniques, and treatment strategies for cardiac amyloidosis and cardiac sarcoidosis. Studies were selected based on relevance to imaging methods, including echocardiography, cardiac magnetic resonance imaging (CMR), positron emission tomography (PET), and technetium-labeled nuclear scintigraphy, as well as treatment modalities for both conditions. Results: Imaging techniques, particularly CMR, technetium-labeled nuclear scan, and PET, were found to be crucial for the early identification and differentiation of cardiac amyloidosis and cardiac sarcoidosis. Distinct late gadolinium enhancement patterns were observed in CMR along with morphological differences, aiding in diagnosis. Technetium-labeled nuclear scintigraphy can definitively distinguish between subtypes of cardiac amyloidosis in the absence of paraproteinemia. Early diagnosis has been shown to significantly improve patient outcomes. Early treatment can reduce morbidity in both cardiomyopathies. Conclusions: Multimodality imaging can help in the early detection of cardiac amyloidosis and cardiac sarcoidosis. Treatment strategies differ substantially: cardiac amyloidosis is primarily managed with disease-modifying therapies for the transthyretin subtype and chemotherapy/stem cell transplant for the AL subtype, while cardiac sarcoidosis is treated with corticosteroids and immunosuppressive drugs to reduce inflammation. Early and accurate diagnosis through advanced imaging techniques is critical to improving outcomes for patients with these conditions. Full article

Background/Objectives: To reduce the early mortality of light-chain amyloidosis (AL), earlier diagnosis is needed. To pursue this goal, we conducted a multicenter study screening for AL λ-type (NCT04615572) in subjects > 60 years of age with λ smoldering myeloma (SMM) or monoclonal gammopathy of undetermined significance (MGUS), a light-chain differential (dFLC, λ minus κ) > 23 mg/L, and no prior amyloid diagnosis. Methods: Variables included AL-related IGVL gene usage and clonal plasma cell cytogenetic abnormalities, such as t(11;14) or gain 1q, which are present in 75% of AL cases. Here, 9 out of 33 λ IGVL genes, accounting for 90% of AL λ cases, were considered to be AL-related. Bone marrow was obtained, plasma cell cytogenetics and next generation sequencing for IGVL genes were performed, and subjects with AL-related IGVL genes were screened for AL using tissue studies. Results: From 2021 to 2023, we enrolled 30 subjects (19 M/11 F) with a median age of 68.5 years old (IQR 64.3–73), 17 SMM and 13 MGUS, with a median of 6% marrow plasma cells (range, 3.5–40). Here, 11 SMM and 4 MGUS cases had t(11;14) or gain 1q; 10/17 SMM and 12/13 MGUS had AL-related genes, and AL was ultimately confirmed by tissue biopsy in 3 with SMM. SMM, AL-related IGVL genes, and t(11;14) or gain 1q were found in 6 SMM subjects, including the 3 with AL (3/6 vs. 0/16; p < 0.05, Fisher’s exact, two-tailed). Conclusions: These results justify a larger study screening for AL in SMM to develop a likelihood algorithm for AL using dFLC, IGVL gene usage, and the presence of t(11;14) or gain 1q. Full article