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One mutation, two distinct disease variants: unravelling the impact of transthyretin amyloid fibril composition
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
2017 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 281, no 4, 337-347 p.Article, review/survey (Refereed) Published
Abstract [en]

Although hereditary transthyretin (h-ATTR) amyloidosis is a monogenetic disease, a large variation in its phenotype has been observed. The common hypothesis of amyloid fibril formation involves dissociation of the transthyretin (TTR) tetramer into monomers that after misfolding reassemble into amyloid fibrils. This notion is partly challenged by the finding of two distinct types of amyloid fibrils. One of these, type A, consists of C-terminal ATTR fragments and full-length TTR, whereas the other, type B, consists only of full-length TTR. All organs of an individual patient contain ATTR deposits of either type A or type B fibrils, and the composition in each individual remains unchanged over time. The finding of two distinct types of ATTR fibrils suggests that there are at least two different pathways in operation for ATTR fibril formation. For the most common European mutation, TTR Val30Met, ATTR fibril composition is related to the outcome of liver transplantation, which is the first successful treatment for the disease, and the penetrance of the trait. In addition, the presence of C-terminal ATTR fragments has an impact on the affinity for various tracers used for noninvasive imaging of amyloid depositions such as 99 m-technetium-diphosphono-propanodicarboxylic acid scintigraphy and positron emission tomography utilizing Pittsburgh component B, and even for the gold standard diagnostic procedure, tissue biopsy stained by Congo red and examined under polarized light. The importance of amyloid fibril composition needs to be taken into consideration when designing clinical trials of treatment modalities, and also in the evaluation of diagnostic methods such as imaging techniques.

Place, publisher, year, edition, pages
2017. Vol. 281, no 4, 337-347 p.
Keyword [en]
amyloid cardiac hypertrophy, amyloid neuropathy, familial amyloidosis, pathology, therapeutics
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Clinical Laboratory Medicine
Identifiers
URN: urn:nbn:se:umu:diva-131030DOI: 10.1111/joim.12585ISI: 000397490100002PubMedID: 28093848OAI: oai:DiVA.org:umu-131030DiVA: diva2:1070918
Available from: 2017-02-02 Created: 2017-02-02 Last updated: 2017-05-29Bibliographically approved

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Suhr, Ole B.Lundgren, Erik
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