Change in Variant Transthyretin Levels in Patients with Familial Amyloidotic Polyneuropathy Type I Following Liver Transplantation
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.
Available from: Yoshiki Sekijima
- "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.
Available from: Robert Kisilevsky
- "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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