Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis
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The misfolded conformer of the prion protein (PrP) that aggregates into fibrils is believed to be the pathogenic agent in transmissible spongiform encephalopathies. In order to find fibril interfering compounds a screening assay in solution would be the preferred format to approximate more closely to physical conditions and enable the performance of kinetic studies. However, such an assay is hampered by the high irreproducibility because of the stochastic nature of the fibril formation process. ⋯ The assay was validated by comparison of the 50% fibril inhibition levels of peptide huPrP106-126 by six tetracyclic compounds. With this new assay, the fibrillogenic core (GAAAAGAVVG) of peptide huPrP106-126 was determined and for the first time it was possible to test the inhibition potentials of peptide analogues. Also it was found that variants of peptide huPrP106-126 with proline substitutions at positions Ala(115), Ala(120), or Val(122) inhibited the fibril formation of huPrP106-126.
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Randomized Controlled Trial Multicenter Study
Diagnostic performance of amyloid A protein quantification in fat tissue of patients with clinical AA amyloidosis.
Amyloid A protein quantification in fat tissue is a new immunochemical method for detecting AA amyloidosis, a rare but serious disease. The objective was to assess diagnostic performance in clinical AA amyloidosis. ⋯ Amyloid A protein quantification in fat tissue is a sensitive and specific method for detection of clinical AA amyloidosis. Advantages are independence from staining quality and observer experience, direct confirmation of amyloid AA type, and potential for quantitative monitoring of tissue amyloid over time.
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Transthyretin Val122Ile is one of greater than 80 mutations in transthyretin (TTR) that are associated with hereditary amyloidosis. Retrospective studies have shown a prevalence of this mutation as high as 3.9% in African-Americans. The present study was undertaken to determine in a prospective fashion the prevalence of the TTR Val122Ile allele in African-Americans in a Midwestern American city. ⋯ Zero of 490 DNA samples from newborns of Hispanic mothers and 0 of 30 from newborns with mothers classified as other (including Asian) were positive. This prospective study demonstrates that 3% of newborns of African-American women in an urban population have the TTR Val122Ile mutation which is associated with late-onset cardiomyopathy. The degree of penetrance of this mutation at the clinical level has not yet been determined.
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The risk associated with the serum amyloid A (SAA) 1 gene and developing AA-amyloidosis is still controversial. In familial Mediterranean fever or Caucasoid rheumatoid arthritis (RA), the SAA1.1 allele is a risk factor for the development of AA-amyloidosis. However, individuals with the SAA1.3 allele are susceptible to AA-amyloidosis in the Japanese RA population, but those with the SAA1.1 are not. ⋯ So far, it is unknown why the -13T SNP increases the amyloidogenicity of the patients. In the present study, a luciferase reporter gene assay showed that the transcriptional activity of the SAA1 having the -13T-containing promoter was significantly higher than activities of those with -13C-containing promoters (Fisher's protected least significance difference test). We suggest that having the -13T SNP in the SAA1 promoter correlates with the amyloidogenicity in part as a result of this increased transcriptional activity.
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Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant disorder associated with more than 80 different transthyretin (TTR) mutations. The clinical features of FAP are broad and variable, but knowledge of the pattern and natural history of disease associated with particular mutations nevertheless offers the best guidance for management of individual patients, including the role and timming of treatment by orthotopic liver transplantation. ⋯ Only four patients were deemed to be sufficiently fit to undergo orthotopic liver transplantation, and clinical deterioration was generally rapid. These observations support early intervention with orthotopic liver transplantation in patients with FAP associated with TTR Gly47Glu.