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Fibrinogen Aα-chain amyloidosis (AFib amyloidosis) is a hereditary form of renal amyloidosis caused by misfolding and deposition of mutant fibrinogen Aα chains. Patients typically present in middle age with proteinuria, hypertension, and progressive renal impairment. AFib amyloidosis follows an autosomal dominant inheritance pattern associated with heterozygous FGA mutations, leading to amyloid fibril formation in glomeruli and eventual kidney failure.
Genetic evidence includes five unrelated probands: three German patients heterozygous for the p.Glu526Val variant and two Chinese patients carrying FGA mutations. Three German cases showed marked proteinuria and renal amyloid deposits confirmed by Congo red staining and immunoreactivity for fibrinogen Aα (PMID:18500534). Two Chinese patients presented with proteinuria, edema, and hypertension; renal biopsies revealed extensive Congo red–positive glomerular amyloid, and proteomic analysis identified fibrinogen Aα as the predominant amyloid protein (PMID:35572989).
The recurrent missense variant c.1576G>T (p.Glu526Val) is the most common AFib-amyloidogenic FGA allele, identified across European and American populations and now in German patients (PMID:18500534). This substitution at residue 526 disrupts native Aα-chain folding, promoting amyloidogenesis.
A novel frameshift mutation, c.1639delA (p.Arg547GlyfsTer21), was discovered in one Chinese patient and predicted to generate a truncated fibrinogen Aα chain prone to misassembly and deposition (PMID:35572989).
Functional studies demonstrate robust histopathological concordance: apple-green birefringence of Congo red–positive deposits under polarized light and immunohistochemistry for fibrinogen Aα. Mass spectrometry–based proteomics confirmed fibrinogen Aα as the amyloid constituent, supporting a gain-of-toxic-function mechanism.
No conflicting reports have been described. Together, the genetic and experimental data establish a Moderate clinical validity for the FGA–AFib amyloidosis association, with characteristic phenotype-genotype correlations and consistent pathological evidence.
Key take-home: Screening for FGA variants, particularly p.Glu526Val and c.1639delA (p.Arg547GlyfsTer21), is critical for the accurate diagnosis and genetic counseling of AFib amyloidosis.
Gene–Disease AssociationModerateFive unrelated probands (three German, two Chinese) with characteristic renal amyloid deposition and two distinct pathogenic FGA variants (p.Glu526Val, c.1639delA) (PMID:18500534, PMID:35572989) Genetic EvidenceModerateFive cases with heterozygous FGA variants in an autosomal dominant pattern, including a recurrent p.Glu526Val missense and a novel frameshift c.1639delA (p.Arg547GlyfsTer21) Functional EvidenceModerateHistopathological confirmation of amyloid deposits by Congo red staining and immunohistochemistry, and mass spectrometry–based proteomics identifying fibrinogen Aα as the amyloid protein |