Change in Variant Transthyretin Levels in Patients with Familial Amyloidotic Polyneuropathy Type I Following Liver Transplantation

First Department of Internal Medicine, Kumamoto University School of Medicine, Japan.
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 07/1995; 211(2):354-8. DOI: 10.1006/bbrc.1995.1820
Source: PubMed


Three patients with familial amyloidotic polyneuropathy (FAP) type I underwent liver transplantation from heart-beating cadaveric donors. Since 2 patients underwent blood transfusion during the operation, variant transthyretin (TTR) levels in the plasma did not decrease time dependently. However, in 1 patient without blood transfusion variant TTR levels decreased in a time dependent manner and plasma half life of variant TTR was calculated to be 2.1 days. Total protein, normal, and variant TTR levels in cerebrospinal fluid (CSF) remained unchanged after liver transplantation.

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    • "FAP was considered until recently to be an incurable disease; however, liver transplantation developed 10 years ago proves to be an effective therapeutic strategy for replacing the variant TTR gene in the liver by the WT gene-reversing systemic amyloidosis and halting progression of FAP pathology (Holmgren et al, 1993). Variant TTR in the serum disappears several days after liver transplantation; however, CSF levels of variant TTR do not significantly decrease even after long-term postsurgical observation (Adams et al, 2000; Ando et al, 1995). Hence, this approach will not correct CNS selective amyloidosis. "
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    ABSTRACT: Transthyretin (TTR) is a tetrameric protein that must misfold to form amyloid fibrils. Misfolding includes rate-limiting tetramer dissociation, followed by fast tertiary structural changes that enable aggregation. Amyloidogenesis of wild-type (WT) TTR causes a late-onset cardiac disease called senile systemic amyloidosis. The aggregation of one of > 80 TTR variants leads to familial amyloidosis encompassing a collection of disorders characterized by peripheral neuropathy and/or cardiomyopathy. Prominent central nervous system (CNS) impairment is rare in TTR amyloidosis. Herein, we identify a new A25T TTR variant in a Japanese patient who presented with CNS amyloidosis at age 42 and peripheral neuropathy at age 44. The A25T variant is the most destabilized and fastest dissociating TTR tetramer published to date, yet, surprising, disease onset is in the fifth decade. Quantification of A25T TTR in the serum of this heterozygote reveals low levels relative to WT, suggesting that protein concentration influences disease phenotype. Another recently characterized TTR CNS variant (D18G TTR) exhibits strictly analogous characteristics, suggesting that instability coupled with low serum concentrations is the signature of CNS pathology and protects against early-onset systemic amyloidosis. The low A25T serum concentration may be explained either by impaired secretion from the liver or by increased clearance, both scenarios consistent with A25T's low kinetic and thermodynamic stability. Liver transplantation is the only known treatment for familial amyloid polyneuropathy. This is a form of gene therapy that removes the variant protein from serum preventing systemic amyloidosis. Unfortunately, the choroid plexus would have to be resected to remove A25T from the CSF-the source of the CNS TTR amyloid. Herein we demonstrate that small-molecule tetramer stabilizers represent an attractive therapeutic strategy to inhibit A25T misfolding and CNS amyloidosis. Specifically, 2-[(3,5-dichlorophenyl)amino]benzoic acid is an excellent inhibitor of A25T TTR amyloidosis in vitro.
    Laboratory Investigation 03/2003; 83(3):409-17. DOI:10.1097/01.LAB.0000059937.11023.1F · 3.68 Impact Factor
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    • "Similar observations have been made in patients with AL amyloid whose amyloid regresses following successful treatment of the underlying plasma cell dyscrasia (Dubrey et al., 1996; Hawkins et al., 1993; Sezer et al., 1999; van Buren et al., 1995), with a reduction in the plasma monoclonal immunoglobulin peak. More recently, it has been demonstrated that the extent of TTR amyloid (due to a mutant form) may regress, with partial return of organ function, following transplantation using a liver from an individual who is homozygous for wild-type TTR (Ando et al., 1995; Bergethon et al., 1996; Ericzon et al., 1995; Holmgren et al., 1991, 1993). These clinical and experimental data indicate that (1) tissue amyloid deposits do turn over, and (2) since amyloid is a protein deposit proteolysis must be partly involved in the turnover process. "
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    ABSTRACT: Current assumptions and conclusions in several active areas of amyloid research are examined to see how consistent the data from chosen in vitro and in vivo model systems are with clinical and anatomic observations. These areas include the assembly of amyloid-like fibrils in vitro, the nucleation phenomenon, amyloid fibril structure in vivo and in vitro, common structural components of the amyloids, and the regression of tissue amyloid and proteolysis of amyloid proteins. Divergences and congruencies are highlighted, which in turn suggests caution in the interpretation of present data, greater collaboration and communication among investigators, and, additional areas and techniques for investigation.
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    ABSTRACT: Amyloidosen sind durch extrazelluläre, unlösliche Proteinablagerungen in Form von Fibrillen in Faltblattstruktur und mit kristallinen Eigenschaften charakterisiert. Ätiologisch werden hereditäre und die weitaus häufigeren sekundären Formen unterschieden, die z.B. durch das dialyseassoziierte β2-Mikroglobulin hervorgerufen werden. An dieser Stelle wird über die hereditären Formen der Amyloidose mit meist autosomal dominantem Vererbungsmodus referiert. Die Inzidenz der häufigsten Transthyretin-(TTR)-Mutationen variiert extrem nach geographischer Lage, sie wird für die USA mit 1:100.000 und für Nordschweden mit 1:170 geschätzt. Das Protein TTR hat Transportfunktion für Thyroxin (T4) und Retinol. Pathogenetisch verursachen TTR-Mutationen Veränderungen der Oberflächenstruktur des Moleküls, die zu Aggregationen von Molekülen und zu anschließender Ablagerung von Proteinfibrillen führen. Im Detail ist dieser Vorgang, der allerdings nicht für alle Mutationen zutreffen dürfte, noch nicht geklärt. Patienten mit hereditärer Amyloidose erkranken zwischen dem 30. und 70. Lebensjahr und versterben ca. 5–15 Jahre später. In der vorliegenden Arbeit wird über Ätiologie, Pathogenese, Diagnostik und die derzeitig einzige Therapieoption, die Lebertransplantation, referiert.
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