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Amyloid fibril composition is related to the phenotype of hereditary transthyretin V30M amyloidosis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
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2008 (English)In: Journal of Pathology, ISSN 0022-3417, Vol. 216, no 2, 253-61 p.Article in journal (Refereed) Published
Abstract [en]

Swedish familial systemic amyloidosis with polyneuropathy (FAP) depends on a mutation leading to a methionine-for-valine substitution in transthyretin. The disease appears with different clinical manifestations, including age of onset and involvement of the heart. Liver transplantation is currently the only curative treatment, but progressive cardiomyopathy may occur post-transplant. Two amyloid deposition patterns have previously been described in the heart. In one, the amyloid consists partially of transthyretin fragments and is weakly stainable by Congo red, while in the other, only full-length molecules are found and the fibrils have a strong affinity for Congo red. The present study aimed to see whether these morphological and biochemical variations have clinical implications. Subcutaneous adipose tissue biopsies were taken from 33 patients with Val30Met FAP and examined by microscopy, electrophoresis and western blot. Clinical data included age, sex, duration of disease and echocardiographic determination of the interventricular septum (IVS) thickness. It was found that fibrils composed of only full-length transthyretin were associated with early age of onset (44.8 +/- 12.9 years), no clinical cardiac involvement and a strong affinity for Congo red. In contrast, presence of transthyretin fragments in the amyloid was associated with late age of onset (67.3 +/- 7.0 years), signs of cardiac involvement and weak Congo red staining. For each individual, the same molecular type of amyloid was found in different organs. This is the first report showing that variations in clinical appearance of familial ATTR amyloidosis are associated with specific structural differences in the amyloid fibrils, and therefore may have a molecular cause. The molecular type of amyloid can be determined from a subcutaneous fat tissue biopsy.

Place, publisher, year, edition, pages
2008. Vol. 216, no 2, 253-61 p.
Keyword [en]
amyloid, transthyretin, fibril, familial, heart, phenotype, age of onset
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-103613DOI: 10.1002/path.2411ISI: 000259510000015PubMedID: 18729067OAI: oai:DiVA.org:uu-103613DiVA: diva2:218567
Available from: 2009-05-20 Created: 2009-05-20 Last updated: 2012-01-03Bibliographically approved
In thesis
1. Two Types of Fibrils in ATTR Amyloidosis: Implications for Clinical Phenotype and Treatment Outcome
Open this publication in new window or tab >>Two Types of Fibrils in ATTR Amyloidosis: Implications for Clinical Phenotype and Treatment Outcome
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Systemic amyloidoses are a group of lethal diseases where proteins aggregate into fibrillar structures, called amyloid fibrils, that deposits throughout the body. Transthyretin (TTR) causes one type of amyloidosis, in which the aggregates mainly infiltrate nervous and cardiac tissue. Almost a hundred different mutations in the TTR gene are known to trigger the disease, but wild-type (wt) TTR is also incorporated into the fibrils, and may alone form amyloid. Patients with the TTRV30M mutation show, for unknown reasons, two clinical phenotypes. Some have an early onset of disease without cardiomyopathy while others have a late onset and cardiomyopathy. It has previously been described that amyloid fibrils formed from TTRV30M can have two different compositions; either with truncated molecules beside full-length TTR (type A) or only-full-length molecules (type B).  In this thesis, the clinical importance of the two types of amyloid fibrils was investigated.

We found that the fibril composition types are correlated to the two clinical phenotypes seen among TTRV30M patients, with type A fibrils present in late onset patients and type B fibrils in early onset patients.

The only treatment for hereditary TTR amyloidosis has been liver transplantation, whereby the liver producing the mutant TTR is replaced by an organ only producing wt protein. However, in some patients, cardiac symptoms progress post-transplantationally. We demonstrated that the propensity to incorporate wtTTR differs between fibril types and tissue types in TTRV30M patients, with cardiac amyloid of type A having the highest tendency. This offers an explanation to why particularly cardiac amyloidosis develops after transplantation, and suggests which patients that are at risk for such development.

By examining patients with other mutations than TTRV30M, we showed that, in contrast to the general belief, a fibril composition with truncated TTR is very common and might even be the general rule. This may explain why TTRV30M patients often have a better outcome after liver transplantation than patients with other mutations.

In conclusion, this thesis has contributed with one piece to the puzzle of understanding the differences in clinical phenotype and treatment response between TTR amyloidosis patients, by demonstrating corresponding differences at a molecular level.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 65 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 727
amyloid, transthyretin, familial amyloidotic polyneuropathy, TTRV30M, non-TTRV30M, wild-type, liver transplantation, cardiomyopathy, fibril composition
National Category
Biochemistry and Molecular Biology Cell and Molecular Biology Other Basic Medicine Clinical Laboratory Medicine
Research subject
Biochemistry; Biology with specialization in Molecular Biology; Experimental Pathology; Medical Biochemistry; Molecular Biology; Pathology
urn:nbn:se:uu:diva-160980 (URN)978-91-554-8234-3 (ISBN)
Public defence
2012-01-13, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjöldsv 20, Uppsala, 13:13 (Swedish)
Available from: 2011-12-20 Created: 2011-11-03 Last updated: 2012-01-03Bibliographically approved

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