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This article discusses a case of ALECT2 amyloidosis, a condition characterized by the deposition of amyloidogenic protein leukocyte chemotactic factor 2 (LECT2), in a Korean-Japanese recipient after receiving a liver transplant from a Hispanic/Latino donor. The recipient developed chronic kidney disease and proteinuria 8 years after the transplant, and 18 years later, was diagnosed with renal cell carcinoma and hepatocellular carcinoma, both of which showed the presence of hepatic and renal amyloid deposits. The study suggests that LECT2, along with transthyretin, may be transmitted through organ transplantation and highlights the need for caution when transplanting organs from donors belonging to at-risk populations. [Extracted from the article]

Hereditary transthyretin (ATTRv) amyloidosis is a rare, fatal systemic disease, associated with polyneuropathy and cardiomyopathy, that is caused by mutant transthyretin (TTR). In addition to liver transplantation, several groundbreaking disease‐modifying drugs (DMDs) such as tetrameric TTR stabilizers and TTR gene‐silencing therapies have been developed for ATTRv amyloid polyneuropathy. They were based on a working hypothesis of the mechanisms of ATTRv amyloid formation. In this retrospective cohort study, we investigated survival of all 201 consecutive patients with ATTRv amyloidosis in our center. The effects of DMDs on survival improvements were significant not only in early‐onset patients but also in late‐onset patients. ANN NEUROL 2024;95:230–236 [ABSTRACT FROM AUTHOR]

Introduction/Aims: In the early stage, hereditary transthyretin (ATTRv) amyloidosis predominantly affects small nerve fibers, resulting in autonomic dysfunction and impaired sensation of pain and temperature. Evaluation of small fiber neuropathy (SFN) is therefore important for early diagnosis and treatment of ATTRv amyloidosis. Herein, we aimed to investigate the accuracy of a quick and non‐invasive commercial sudomotor function test (SFT) for the assessment of SFN in ATTRv amyloidosis. Methods: We performed the SFT in 39 Japanese adults with ATTRv amyloidosis, and we analyzed the correlations between electrochemical skin conductance (ESC) values obtained via the SFT and the parameters of other neuropathy assessment methods. Results: ESC in the feet demonstrated significant, moderate correlations with intraepidermal nerve fiber density (IENFD) results (Spearman's rank correlation coefficient [rs], 0.58; p <.002) and other neuropathy assessment methods including the sensory nerve action potential amplitude in the nerve conduction studies (rs, 0.52; p <.001), the Neuropathy Impairment Score (rs, −0.45; p <.01), the heat‐pain detection threshold (rs, −0.62; p <.0001), and the autonomic section of the Kumamoto ATTRv clinical score (rs, −0.53; p <.0001). Discussion: In this study, we found that ESC values in the feet via the SFT demonstrated significant, moderate correlations with IENFD and other SFN assessment methods in patients with ATTRv amyloidosis, suggesting that the SFT appears to be an appropriate method for assessment of SFN in this disease. [ABSTRACT FROM AUTHOR]

Amyloid signature proteins such as serum amyloid P component, apolipoprotein E (ApoE), and ApoA-IV generally co-localise with amyloid, regardless of the types of amyloid precursor protein or the organs. Most of these proteins derive from serum and have reportedly been involved in amyloid fibril formation and stabilisation, as well as in excretion and degradation of amyloid precursor proteins. However, the processes and mechanisms by which these specific proteins deposit together with amyloid fibrils have not been clarified. We analysed the binding of serum proteins to amyloid fibrils derived from amyloid β and insulin in vitro by using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Specific serum proteins including ApoA-I, ApoE, ApoA-IV, ApoC-III and vitronectin adhered to amyloid fibrils at high concentrations in vitro. In addition, the profile of these proteins commonly occurred in both amyloid β and insulin amyloid fibrils and was mostly consistent with the composition of amyloid signature proteins. We also showed that high concentrations of serum proteins can adhere to amyloid fibrils in a short time. Our in vitro results suggest that amyloid signature proteins coexist with amyloid primarily dependent on the binding of each serum protein, in the extracellular fluid, to amyloid fibrils. [ABSTRACT FROM AUTHOR]

Amyloidosis is a protein-misfolding disease characterised by insoluble amyloid deposits in the extracellular space of various organs and tissues, such as the brain, heart, kidneys, and ligaments. We previously reported the frequent occurrence of amyloid deposits in the ligament flavum in the presence of lumbar spinal canal stenosis (LSCS), which is a common spinal disorder in older individuals. Our earlier clinicopathological studies revealed that amyloid deposits derived from transthyretin (TTR) were involved in the pathogenesis of LSCS. ATTR amyloid was the most common form in the ligamentum flavum, but amyloid deposits that were not identified still existed in more than 50% of patients with LSCS. In this study, we found apolipoprotein AI (AApoAI) amyloid deposits in the ligamentum flavum of patients with LSCS. The deposits occurred in 12% of patients with LSCS. Biochemical studies revealed that the amyloid deposits consisted mainly of full-length ApoAI. As a notable finding, the lumbar ligamentum flavum of patients who had LSCS with double-positive amyloid deposits—positive for both ATTR and AApoAI—was significantly thicker than that of patients who had LSCS with single-positive—that is, positive for either ATTR or AApoAI—amyloid deposits. We thus suggest that lumbar AApoAI amyloid formation may enhance the pathological changes of lumbar ATTR amyloidosis in patients with LSCS. [ABSTRACT FROM AUTHOR]

Aims: Hereditary transthyretin (ATTRv) amyloidosis is the most frequent and representative form of autosomal dominant hereditary systemic amyloidosis. Disease‐modifying treatments of the disease are more effective during the early stages, and we require biomarkers to detect early pathological changes for prompt diagnosis. This study aimed to investigate whether plasma growth differentiation factor 15 (GDF‐15) levels could aid detection of early pathological changes in ATTRv amyloidosis. Methods and results: We retrospectively studied 32 patients with ATTRv amyloidosis, eight asymptomatic TTR mutation carriers, and eight healthy volunteers. We evaluated plasma GDF‐15 levels in these subjects as related to levels of brain natriuretic peptide and high‐sensitivity troponin T, echocardiographic features, 99mTc‐pyrophosphate (PYP) scans, and cardiac magnetic resonance imaging findings. Plasma GDF‐15 levels significantly increased even in asymptomatic TTR mutation carriers compared with healthy volunteers (P < 0.01). Plasma GDF‐15 levels were significantly correlated with plasma brain natriuretic peptide values (P < 0.01), serum high‐sensitivity troponin T values (P < 0.05), and interventricular septal thickness at end‐diastole (P < 0.01) in patients with ATTRv amyloidosis. Plasma GDF‐15 levels in patients with PYP‐positive ATTRv amyloidosis were significantly higher than those in patients with PYP‐negative ATTRv amyloidosis (P < 0.01). Plasma GDF‐15 levels in patients with late gadolinium enhancement‐positive ATTRv amyloidosis were significantly higher than those in patients with late gadolinium enhancement‐negative ATTRv amyloidosis (P < 0.01). Groups of patients with different TTR genotypes manifested different plasma GDF‐15 levels. Conclusions: Growth differentiation factor 15 may reflect early pathological changes of ATTRv amyloidosis. [ABSTRACT FROM AUTHOR]

Novel therapies have recently been used for different amyloidoses including hereditary transthyretin (ATTR, ATTRv) amyloidosis, wild‐type ATTR (ATTRwt) amyloidosis, immunoglobulin light chain (AL)amyloidosis, and amyloid A (AA) amyloidosis. Early, accurate diagnosis is important for improved prognosis and cure. However, early intervention with early diagnosis is often difficult, because these diseases are frequently difficult to identify given their phenotypic heterogeneity. This study aimed to analyze characteristics of patients with amyloidosis that was diagnosed at the Amyloidosis Medical Practice Center, Kumamoto University Hospital, which, as an amyloidosis center in Japan, conducts histopathological, proteomic, and genetic analyses of amyloidosis. We analyzed diagnostic results and disease manifestations of patients diagnosed during April 2012 and March 2019. This study reviewed 1937 consecutive consultations that provided clinical information. The patients' average age was 65.9 (median 69) years. Of all patients, 66.6% were male. Diagnoses included ATTRv: 13.4%, ATTRwt: 14.3%, ATTR (no genetic analysis consultation requested): 4.6%, ALλ: 19.7%, ALκ: 8.8%, AA: 3.0%, β2‐microglobulin (dialysis‐related): 0.8%, and others: 1.9%, no TTR gene mutation (no histopathological analysis consultation requested): 23.2% (including duplicate consultations). ATTRv amyloidosis cases included V30M in endemic areas: 7.4%, V30M in non‐endemic areas: 51.2%, and non‐V30M: 41.4%. Sixty‐six cases required laser microdissection and liquid chromatography‐tandem mass spectrometry. Initial manifestations included polyneuropathy: 13.2%, carpal tunnel syndrome: 5.6%, autonomic dysfunction: 2.7%, heart failure: 28.4%, cardiac hypertrophy: 2.2%, arrhythmia: 5.0%, renal impairment: 11.1%, and stroke: 1.8%. Amyloidosis types and manifestations were diverse. For early diagnosis and appropriate interventions, improved diagnostic systems are needed. [ABSTRACT FROM AUTHOR]

Most intractable tissue‐degenerative disorders share a common pathogenic condition, so‐called proteinopathy. Amyloid‐related disorders are the most common proteinopathies and are characterized by amyloid fibril deposits in the brain or other organs. Aging is generally associated with the development of these amyloid‐related disorders, but we still do not fully understand how functional proteins become pathogenic amyloid deposits during the human aging process. We identified a novel amyloidogenic protein, named epidermal growth factor‐containing fibulin‐like extracellular matrix protein 1 (EFEMP1), in massive venous amyloid deposits in specimens that we obtained from an autopsied patient who died of gastrointestinal bleeding. Our postmortem analyses of additional patients indicate that EFEMP1 amyloid deposits frequently developed in systemic venous walls of elderly people. EFEMP1 was highly expressed in veins, and aging enhanced venous EFEMP1 expression. In addition, biochemical analyses indicated that these venous amyloid deposits consisted of C‐terminal regions of EFEMP1. In vitro studies showed that C‐terminal regions formed amyloid fibrils, which inhibited venous tube formation and cell viability. EFEMP1 thus caused a novel age‐related venous amyloid‐related disorder frequently found in the elderly population. Understanding EFEMP1 amyloid formation provides new insights into amyloid‐related disorders occurring during the aging process. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Insulin-derived amyloidoma, also called an insulin ball, is a skin-related complication of insulin therapy caused by repeated insulin injections at the same site, where native folded insulin changes into amyloid fibrils and forms a mass with a granulomatous reaction. Insulin-derived amyloidoma is a clinically important condition because of its association with subcutaneous insulin resistance, but the precise effect and mechanism of the insulin absorption impairment have not been clarified. We generated insulin-derived amyloidomas in mouse skin, with the amyloidomas large enough to perform insulin tolerance tests in the mass by repeated injections of highly concentrated insulin amyloid fibrils. We demonstrated that the insulin-derived amyloidomas inhibit insulin absorption. By simultaneous administration of insulin and insulin amyloid fibrils, we showed that this effect is due to the amyloid fibril itself in the absence of a granulomatous reaction. In vitro studies revealed that insulin amyloid fibrils have extremely strong adhesion to native human insulin and various insulin analogs. Furthermore, we showed that native insulin that had adhered to insulin amyloid forms amyloid fibrils at physiological pH. These results suggest that the extreme adhesion of insulin amyloid to native insulin is the main mechanism of impaired insulin absorption and amyloidoma growth. [ABSTRACT FROM AUTHOR]

Hereditary transthyretin (ATTR) amyloidosis is a life-threatening, autosomal dominant, systemic amyloidosis caused by mutant transthyretin. In addition to ATTRV30M in endemic and non-endemic areas, more than 140 non-V30M mutations occur worldwide. The aim of this study was to analyze the clinical characteristics and genetic frequencies of hereditary ATTR amyloidosis. Diagnostic results and clinical manifestations of hereditary ATTR amyloidosis from April 1, 2012, to March 31, 2017, at Amyloidosis Medical Practice Center, Kumamoto University Hospital were analyzed. One hundred and four patients received a diagnosis of symptomatic hereditary ATTR amyloidosis. The following mutations of the TTR gene and their percentages were found: V30M in endemic areas, 10.6%; V30M in non-endemic areas, 51.0%; and non-V30M, 38.5%. The ages at onset of patients with ATTRV30M amyloidosis in non-endemic areas (66.6 ± 8.7 years) and those with non-V30M ATTR amyloidosis (55.8 ± 13.6 years) were significantly higher than those with ATTRV30M amyloidosis in endemic areas (37.0 ± 12.6 years). Of patients with ATTRV30M amyloidosis in endemic and non-endemic areas, and non-V30M ATTR amyloidosis, 63.6, 66.0, and 27.5% initially presented with polyneuropathy, respectively. Of patients with ATTRV30M amyloidosis in endemic areas, 81.8% had a family history of this disease. However, a significantly smaller percentage of patients with ATTRV30M amyloidosis (30.0%) in non-endemic areas and non-V30M ATTR amyloidosis (34.0%) had a family history. Patients with ATTRV30M amyloidosis in non-endemic areas and patients with non-V30M ATTR amyloidosis occurred more frequently than previously believed, and their clinical manifestations were diverse. [ABSTRACT FROM AUTHOR]