Abstract
Aims In transthyretin amyloid (ATTR) amyloidosis various principal phenotypes have been described: cardiac, neuropathic, or a mixed cardiac and neuropathic. In addition, two different types of amyloid fibrils have been identified (type A and type B). Type B fibrils have thus far only been found in predominantly early-onset V30M and in patients carrying the Y114C mutation, whereas type A is noted in all other mutations currently examined as well as in wild-type ATTR amyloidosis. The fibril type is a determinant of the ATTR V30M disease phenotype. 99mTc-DPD scintigraphy is a highly sensitive method for diagnosing heart involvement in ATTR amyloidosis. The objective of this study was to determine the relationship between ATTR fibril composition and 99mTc-DPD scintigraphy outcome in patients with biopsy-proven ATTR amyloidosis. Methods Altogether 55 patients with biopsy-proven diagnosis of ATTR amyloidosis and amyloid fibril composition determined were examined by 99mTc-DPD scintigraphy. The patients were grouped and compared according to their type of amyloid fibrils. Cardiovascular evaluation included ECG, echocardiography, and cardiac biomarkers. The medical records were scrutinized to identify subjects with hypertension or other diseases that have an impact on cardiac dimensions. Results A total of 97% with type A and none of the patients with type B fibrils displayed 99mTc-DPD uptake at scintigraphy (p < 0.001). Findings from analyses of cardiac biomarkers, ECG, and echocardiography, though significantly different, could not differentiate between type A and B fibrils in individual patients. Conclusion In ATTR amyloidosis, the outcome of 99mTc-DPD scintigraphy is strongly related to the patients’ transthyretin amyloid fibril composition.
Highlights
Transthyretin (TTR) amyloid (ATTR) amyloidosis is a systemic disease in which mutant and/or wild-type TTR assemble into amyloid
Type A amyloid fibrils are composed of full-length and truncated transthyretin, and type B of full-length transthyretin only. aPolyneuropathy disability (PND) score: 0 1⁄4 no sensory disturbances; I 1⁄4 sensory disturbances in the feet, but no impaired walking capability; II 1⁄4 walking impairment, but walking without aid; IIIA 1⁄4 walking with one stick or crutch; IIIB 1⁄4 walking with two sticks or crutches; IV 1⁄4 in wheelchair or immobilized. bPatient with post-polio syndrome that causes neurological impairment
The main finding of this investigation was the strong association between 99mTc-DPD uptake and type A amyloid fibrils, i.e. fibrils with C-terminally truncated ATTR
Summary
Transthyretin (TTR) amyloid (ATTR) amyloidosis is a systemic disease in which mutant and/or wild-type (normal) TTR assemble into amyloid. A classification of mutations and their phenotypes has been suggested to separate them into three main types: neuropathic, cardiac, and mixed neuropathic and cardiac [3] This is an arbitrary classification, and substantial phenotypic variations are noted between, and within the various TTR mutations [4]. The prevailing theory for ATTR formation is based on decreased stability of the TTR tetramer caused by ageing and/ or amyloidogenic TTR mutations, which facilitates TTR’s separation into monomers that have a tendency to misfold and reassemble into extracellular amyloid deposits [5]. An alternative pathway for ATTR fibril formation has been found for the Ser52Pro variant [6], where amyloid formation occurred after proteolysis of TTR at position 50, producing a highly amyloidogenic C-terminal fragment. Two pathways for amyloid formation may operate in ATTR amyloidosis patients, and two precursor proteins are present in their amyloid deposits
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