Amyloid fibril composition is related to the phenotype of hereditary transthyretin V30M amyloidosis

Abstract

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.

Proteolytic cleavage of Ser52Pro variant transthyretin triggers its amyloid fibrillogenesis

“…The presence of cleaved fragments apparently is not influenced by the nature or the position of the amino acid substitution (8). Rather, it correlates with the abundance of the cardiac amyloid deposits (10), with increased patient age, and with late-onset disease, being most common in persons with senile systemic amyloidosis caused by wildtype, not variant, TTR. The possible pathogenic role of proteolytic cleavage is suggested further by the clinical course in persons with hereditary TTR amyloidosis who undergo liver transplantation to replace their variant TTR production with wild-type TTR.…”

A practical approach to the diagnosis of systemic amyloidoses

“…This may be due to the focal pattern of amyloid deposition in ATTR amyloidosis, 23,32 which raises the possibility of false-negative results in small samples of fat tissue. On the other hand, IEM has a less crucial role in the diagnosis of hereditary ATTR amyloidosis, because in patients with a known family history, the diagnosis could be supported by DNA analysis.…”

Biochemical markers in early diagnosis and management of systemic amyloidoses

“…TTR fragments in tissue amyloid deposits, detected by Western blot, correlate with late onset of the disease and myocardial involvement [107,108].…”