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Two Types of Fibrils in ATTR Amyloidosis: Implications for Clinical Phenotype and Treatment Outcome
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 727
Keyword [en]
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
Identifiers
URN: urn:nbn:se:uu:diva-160980ISBN: 978-91-554-8234-3 (print)OAI: oai:DiVA.org:uu-160980DiVA: diva2:459640
Public defence
2012-01-13, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjöldsv 20, Uppsala, 13:13 (Swedish)
Opponent
Supervisors
Available from: 2011-12-20 Created: 2011-11-03 Last updated: 2012-01-03Bibliographically approved
List of papers
1. Amyloid fibril composition is related to the phenotype of hereditary transthyretin V30M amyloidosis
Open this publication in new window or tab >>Amyloid fibril composition is related to the phenotype of hereditary transthyretin V30M amyloidosis
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2008 (English)In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, 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.

Keyword
amyloid, transthyretin, fibril, familial, heart, phenotype, age of onset
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-103613 (URN)10.1002/path.2411 (DOI)000259510000015 ()18729067 (PubMedID)
Available from: 2009-05-20 Created: 2009-05-20 Last updated: 2017-12-13Bibliographically approved
2. Proportion between wild-type and mutant protein in truncated compared to full-length ATTR: an analysis on transplanted transthyretin T60A amyloidosis patients
Open this publication in new window or tab >>Proportion between wild-type and mutant protein in truncated compared to full-length ATTR: an analysis on transplanted transthyretin T60A amyloidosis patients
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2009 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 379, no 4, 846-850 p.Article in journal (Refereed) Published
Abstract [en]

Familial ATTR amyloidosis is caused by point mutations in the transthyretin gene. The clinical manifestations are highly varied but polyneuropathy and/or cardiomyopathy are generally the main symptoms. The amyloid fibrils can either be composed of only intact ATTR molecules or intact together with fragmented ATTR species. As plasma TTR is almost exclusively synthesized in the liver, liver transplantation is performed in order to eliminate the mutant plasma TTR. The procedure has shown best results among patients with the V30M mutation, while a rapid continued cardiac deposition of wild-type (wt) TTR has been seen for many other mutations. In this paper we investigated the proportion of wtATTR in two TTRT60A patients that underwent liver transplantation; one patient died 3 weeks after surgery, the other patient survived for 12 months. As the role of fragmented TTR species in the pathogenesis is far from understood, we investigated the proportion of wt in these species separately to the full-length molecules, which has not been done before in transplanted patients. The results show a higher proportion of wtTTR in the 12-months-surviving patient than the 3-weeks-surviving patient, but interestingly this difference in wt proportion is mainly seen among the full-length, and not the fragmented, molecules.

Keyword
Amyloid, Transthyretin, Familial amyloidotic polyneuropathy, ATTRT60A, Liver transplantation, Fibril, Cardiomyopathy, Wild-type
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-103620 (URN)10.1016/j.bbrc.2008.12.095 (DOI)000263336700009 ()19118530 (PubMedID)
Available from: 2009-05-20 Created: 2009-05-20 Last updated: 2017-12-13Bibliographically approved
3. Variation in amount of wild-type transthyretin in different fibril and tissue types in ATTR amyloidosis
Open this publication in new window or tab >>Variation in amount of wild-type transthyretin in different fibril and tissue types in ATTR amyloidosis
2011 (English)In: Journal of Molecular Medicine, ISSN 0946-2716, E-ISSN 1432-1440, Vol. 89, no 2, 171-180 p.Article in journal (Refereed) Published
Abstract [en]

Familial transthyretin (TTR) amyloidosis is caused by a mutation in the TTR gene, although wild-type (wt) TTR is also incorporated into the amyloid fibrils. Liver transplantation (LT) is the prevailing treatment of the disease and is performed in order to eliminate the mutant TTR from plasma. The outcome of the procedure is varied; especially problematic is a progressive cardiomyopathy seen in some patients, presumably caused by continued incorporation of wtTTR. What determines the discrepancy in outcome is not clear. We have previously shown that two structurally distinct amyloid fibrils (with or without fragmented ATTR) are found among ATTRV30M patients. In this study, we investigated the proportion of wtATTR in cardiac and adipose amyloid from patients having either fibril type. It was found that cardiac amyloid more easily incorporates wtTTR than adipose amyloid, offering a potential explanation for the vulnerability of cardiac tissue for continued amyloidosis after LT. In cardiac tissue, fibrils with fragmented ATTR contained a higher wt proportion than fibrils without, suggesting that continued incorporation of wtTTR after LT, perhaps, can take place more easily in these patients. In adipose tissue, a rapid increase in wt proportion after LT indicates that a rather fast turnover of the deposits must occur. A difference in wt proportion between the fibril types was seen post-LT but not pre-LT, possibly caused by differences in turnover rate. Conclusively, this study further establishes the basic dissimilarities between the two fibril types and demonstrates that their role in LT outcome needs to be further investigated.

Keyword
Amyloid, Transthyretin, Familial amyloidotic polyneuropathy, Liver transplantation, Wild-type
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-150732 (URN)10.1007/s00109-010-0695-1 (DOI)000288363300008 ()21107516 (PubMedID)
Available from: 2011-04-05 Created: 2011-04-05 Last updated: 2017-12-11Bibliographically approved
4. Amyloid fibrils with fragmented ATTR may be the rule in non-Val30Met ATTR amyloidosis
Open this publication in new window or tab >>Amyloid fibrils with fragmented ATTR may be the rule in non-Val30Met ATTR amyloidosis
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

The clinical phenotype of familial ATTR amyloidosis depends to some extent on the particular mutation, but differences exist also within mutations. We have previously described that two types of amyloid fibril compositions exist among Swedish ATTRV30M amyloidosis patients, one consisting of a mixture of intact and fragmented ATTR (type A) and one composed of only intact ATTR (type B). Patients with type A fibrils have a late age of onset and signs of cardiomyopathy, while patients with type B fibrils have an early onset and much less myocardial involvement.

The present study aimed to determine if the correlation between fibril type and clinical phenotype is true for familial amyloidosis in general. Cardiac and/or adipose tissue from 48 patients carrying 21 different non-TTRV30M mutations were examined, as well as 7 non-Swedish ATTRV30M patients. Fibril type was determined with western blotting and compared to the patients´ age of onset and degree of cardiomyopathy.

Non-Swedish V30M patients showed the same correlation as described for Swedish V30M patients, with fibrils of only full-length ATTR (type B) linked to less myocardial involvement. In contrast, all patients with non-V30M mutations had a fibril composition with ATTR fragments (type A). Some of these patients had onset of disease at young age. The vast majority had increased thickness of left cardiac ventricle, but a few individuals had values within normal limits.

This study shows that a fibril composition with fragmented ATTR is very common in ATTR amyloidosis. It also suggests that fibrils composed of only full-length ATTR is an exception, perhaps only found among young ATTRV30M amyloidosis patients.

Keyword
amyloid, transthyretin, familial amyloidotic polyneuropathy, non-TTRV30M, TTRV30M, cardiomyopathy, fibril composition
National Category
Cell and Molecular Biology Other Basic Medicine Clinical Laboratory Medicine Biochemistry and Molecular Biology
Research subject
Biochemistry; Biology with specialization in Molecular Biology; Biomedical Laboratory Science; Experimental Pathology; Medical Biochemistry; Molecular Biology; Pathology
Identifiers
urn:nbn:se:uu:diva-160979 (URN)
Available from: 2011-11-27 Created: 2011-11-03 Last updated: 2012-01-03

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