Late onset cardiomyopathy as presenting sign of ATTR A45G amyloidosis caused by a novel TTR mutation (p.A65G)

Abstract Objective The clinical description of a novel TTR gene mutation characterized by a late onset amyloid cardiomyopathy. Methods and Results A 78-year-old man of Dutch origin with recent surgery for bilateral carpal tunnel syndrome (CTS) was admitted to our hospital because of heart failure with preserved ejection fraction (55%). Cardiac ultrasound showed thickened biventricular walls, and cardiac magnetic resonance imaging also showed late gadolinium enhancement. Early signs of a polyneuropathy were found by neurophysiological testing. A few months later, his 72-year-old sister was admitted to an affiliated hospital because of heart failure caused by a restrictive cardiomyopathy. In both patients, a subcutaneous abdominal fat aspirate was stained with Congo red and DNA was analyzed by direct sequencing of exons 1 to 4 of the transthyretin ( TTR ) gene. Both fat aspirates revealed transthyretin-derived (ATTR) amyloid. 99m Tc-diphosphonate scintigraphy further confirmed cardiac ATTR amyloidosis in the male patient. DNA analysis of both patients showed a novel TTR mutation c.194C > G that encodes for the gene product TTR (p.A65G) ending up as the mature protein TTR A45G. The 56-year-old daughter of the male patient had the same TTR mutation. A full diagnostic workup did not reveal any signs of amyloidosis yet. Conclusions A novel amyloidogenic TTR mutation was found in a Dutch family. The clinical presentation of ATTR A45G amyloidosis in the affected family members was heart failure due to a late-onset cardiomyopathy. The systemic nature of this disease was reflected by bilateral CTS and by early signs of a polyneuropathy in the index patient.