Transthyretin valine-94-alanine, a novel variant associated with late-onset systemic amyloidosis with cardiac involvement

A 63-year-old Caucasian male, diagnosed with dilated cardiomyopathy in 1993, remained clinically stable for several years. In 2003, a marked increase of N-terminal pro-natriuretic peptide serum level (611 ng/ml to 4926 ng/ml) was observed; left ventricular (LV) septum thickness was 10 mm. In addition, sensorimotor polyneuropathy and autonomic dysfunction occurred. Further progression of heart failure occurred despite unchanged systolic LV function. Endomyocardial biopsy in 2006 revealed transthyretin amyloidosis by Congo red and immunohistochemical staining, as well as Val94Ala substitution by transthyretin gene analysis. Cardiac amyloid deposition was quantified by technetium-99m-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) scintigraphy. Mutational search of the relatives (n = 1) was unremarkable. The transthyretin Val94Ala mutation is characterized by sensorimotor polyneuropathy, autonomic dysfunction, and gastrointestinal and cardiac involvement with amyloid. This mutation is an addition to the growing spectrum of transthyretin mutations with late onset of clinical symptoms, but noteworthy because of progressive, finally disabling disease course. Final clinical assessment of severity of cardiac involvement in the present patient is rendered complex by possible concomitant or preceding idiopathic dilated cardiomyopathy.