Browsing by Subject "ATTR amyloidosis"

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    Amyloid fibril polymorphism in the heart of an ATTR amyloidosis patient with polyneuropathy attributed to the V122Δ variant
    (bioRxiv, 2024-05-10) Ahmed, Yasmin; Nguyen, Binh An; Afrin, Shumaila; Singh, Virender; Evers, Bret; Singh, Preeti; Pedretti, Rose; Wang, Lanie; Bassett, Parker; Fernandez-Ramirez, Maria del Carmen; Pekala, Maja; Kluve-Beckerman, Barbara; Saelices, Lorena; Pathology and Laboratory Medicine, School of Medicine
    ATTR amyloidosis is a phenotypically heterogeneous disease characterized by the pathological deposition of transthyretin in the form of amyloid fibrils into various organs. ATTR amyloidosis may stem from mutations in variant (ATTRv) amyloidosis, or aging in wild-type (ATTRwt) amyloidosis. ATTRwt generally manifests as a cardiomyopathy phenotype, whereas ATTRv may present as polyneuropathy, cardiomyopathy, or mixed, in combination with many other symptoms deriving from secondary organ involvement. Over 130 different mutational variants of transthyretin have been identified, many of them being linked to specific disease symptoms. Yet, the role of these mutations in the differential disease manifestation remains elusive. Using cryo-electron microscopy, here we structurally characterized fibrils from the heart of an ATTRv patient carrying the V122Δ mutation, predominantly associated with polyneuropathy. Our results show that these fibrils are polymorphic, presenting as both single and double filaments. Our study alludes to a structural connection contributing to phenotypic variation in ATTR amyloidosis, as polymorphism in ATTR fibrils may manifest in patients with predominantly polyneuropathic phenotypes.
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    ATTRv-V30M Type A amyloid fibrils from heart and nerves exhibit structural homogeneity
    (bioRxiv, 2024-05-14) Nguyen, Binh An; Afrin, Shumaila; Yakubovska, Anna; Singh, Virender; Alicea, Jaime Vaquer; Kunach, Peter; Singh, Preeti; Pekala, Maja; Ahmed, Yasmin; Fernandez-Ramirez, Maria del Carmen; Cabrera Hernandez, Luis O.; Pedretti, Rose; Bassett, Parker; Wang, Lanie; Lemoff, Andrew; Villalon, Layla; Kluve-Beckerman, Barbara; Saelices, Lorena; Pathology and Laboratory Medicine, School of Medicine
    ATTR amyloidosis is a systemic disease characterized by the deposition of amyloid fibrils made of transthyretin, a protein integral to transporting retinol and thyroid hormones. Transthyretin is primarily produced by the liver and circulates in blood as a tetramer. The retinal epithelium also secretes transthyretin, which is secreted to the vitreous humor of the eye. Because of mutations or aging, transthyretin can dissociate into amyloidogenic monomers triggering amyloid fibril formation. The deposition of transthyretin amyloid fibrils in the myocardium and peripheral nerves causes cardiomyopathies and neuropathies, respectively. Using cryo-electron microscopy, here we determined the structures of amyloid fibrils extracted from cardiac and nerve tissues of an ATTRv-V30M patient. We found that fibrils from both tissues share a consistent structural conformation, similar to the previously described structure of cardiac fibrils from an individual with the same genotype, but different from the fibril structure obtained from the vitreous humor. Our study hints to a uniform fibrillar architecture across different tissues within the same individual, only when the source of transthyretin is the liver. Moreover, this study provides the first description of ATTR fibrils from the nerves of a patient and enhances our understanding of the role of deposition site and protein production site in shaping the fibril structure in ATTRv-V30M amyloidosis.
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    Burden of hereditary transthyretin amyloidosis on quality of life
    (Wiley, 2019-08) Yarlas, Aaron; Gertz, Morie A.; Dasgupta, Noel R.; Obici, Laura; Pollock, Michael; Ackermann, Elizabeth J.; Lovley, Andrew; Kessler, Asia Sikora; Patel, Pankaj A.; White, Michelle K.; Guthrie, Spencer D.; Medicine, School of Medicine
    INTRODUCTION: Hereditary transthyretin (hATTR) amyloidosis is a progressive, degenerative disease, with peripheral neuropathy, cardiomyopathy, and other clinical manifestations. In this study we examine the impact of hATTR amyloidosis on quality of life (QOL). METHODS: Neuropathy-specific QOL, measured with the Norfolk QOL-Diabetic Neuropathy questionnaire, was compared between patients with hATTR amyloidosis and patients with type 2 diabetes, whereas generic QOL, measured with the 36-item Short Form Health Survey version 2 (SF-36v2), was compared between patients with hATTR amyloidosis, the general population, and patients with chronic diseases. RESULTS: Neuropathy-specific QOL for patients with hATTR amyloidosis was nearly equivalent to that of patients with type 2 diabetes with diabetic neuropathy accompanied by a history of ulceration, gangrene, or amputation. Generic QOL was worse than that seen in the general population, with physical functioning worse than that for patients with multiple sclerosis and congestive heart failure. DISCUSSION: Patients with hATTR amyloidosis show significant burden on QOL, particularly in physical functioning. Muscle Nerve 60: 169-175, 2019
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    Cryo-EM confirms a common fibril fold in the heart of four patients with ATTRwt amyloidosis
    (bioRxiv, 2024-03-09) Nguyen, Binh An; Singh, Virender; Afrin, Shumaila; Singh, Preeti; Pekala, Maja; Ahmed, Yasmin; Pedretti, Rose; Canepa, Jacob; Lemoff, Andrew; Kluve-Beckerman, Barbara; Wydorski, Pawel; Chhapra, Farzeen; Saelices, Lorena; Pathology and Laboratory Medicine, School of Medicine
    ATTR amyloidosis results from the conversion of transthyretin into amyloid fibrils that deposit in tissues causing organ failure and death. This conversion is facilitated by mutations in ATTRv amyloidosis, or aging in ATTRwt amyloidosis. ATTRv amyloidosis exhibits extreme phenotypic variability, whereas ATTRwt amyloidosis presentation is consistent and predictable. Previously, we found an unprecedented structural variability in cardiac amyloid fibrils from polyneuropathic ATTRv-I84S patients. In contrast, cardiac fibrils from five genotypically-different patients with cardiomyopathy or mixed phenotypes are structurally homogeneous. To understand fibril structure's impact on phenotype, it is necessary to study the fibrils from multiple patients sharing genotype and phenotype. Here we show the cryo-electron microscopy structures of fibrils extracted from four cardiomyopathic ATTRwt amyloidosis patients. Our study confirms that they share identical conformations with minimal structural variability, consistent with their homogenous clinical presentation. Our study contributes to the understanding of ATTR amyloidosis biopathology and calls for further studies.