Sporadic transthyretin amyloidosis with a novel TTR gene mutation misdiagnosed as primary amyloidosis

Abstract

Light-chain amyloidosis [1] is a rare disease caused by a clonal plasma cell dyscrasia associated with multiorgan deposition of amyloidogenic immunoglobulin light chains. Autosomal dominant transthyretin amyloidosis (ATTR) is an even rarer disorder caused by amyloidogenic mutant alleles of TTR manifesting with progressive and fatal involvement of the peripheral nerves, ganglia, heart, kidney, and eyes. The specific therapy is orthotopic liver transplantation [2]. ATTR may be overlooked because of phenotypical variability [3], and also misdiagnosed as AL because of possible coexistence of monoclonal gammopathy and limited sensitivity/specificity of light chain immunostaining of biopsy specimens [4, 5]. We describe a patient with restrictive cardiomiopathy misdiagnosed as light chain AL amyloidosis, who was affected with ATTR associated with a novel p.Glu62Lys. The final diagnosis with immunogold electron microscopy was possible only in autoptic tissue. A 75-year-old man with type II diabetes, coronary artery disease, and no history of neurological or cardiological disorders presented with signs and symptoms of right-sided heart failure. Electrocardiogram revealed sinus rhythm, first degree A-V block, left anterior fascicular block, and Q waves at the inferior leads. At bidimensional echocardiogram, left ventricular wall thickening, mild systolic dysfunction, and restrictive diastolic pattern were found. Cardiac MRI findings were suggestive of amyloid deposition. Abdominal fat fine-needle aspiration was negative. Endomyocardial biopsy was positive at Congo Red stain and anti-k chain immunohistochemistry. Bone marrow biopsy was normal. A mild IgG/k monoclonal gammopathy was present (2.5 g/l); no Bence-Jones protein was detected, but a slightly abnormal j/k serum free light chain (sFLC) ratio was present. Cardiac troponin I (cTnI) was increased (0.21 lg/l, normal values 0–0.15) as well as NTproBNP (2,842 ng/l, nv 0-900); ALP was also elevated, suggesting a hepatic involvement. The patient was started on melphalan and dexamethasone, and the liver cholestasis enzymes normalized, but cTnI, NT-proBNP, and the j/k FLC chain ratio did not change. A shift to bortezomib-dexamethasone was not effective, and a possible hereditary amyloidosis was considered. Mutational analysis of the TTR gene demonstrated a heterozygous c.183G[A transition in exon 3 that substituted a glutammic acid with a lysine at residue 62 (p.Glu62Lys) of the mature protein; to the best of our knowledge, the nucleotide change was unreported. After re-evaluating the endocardial biopsy, immunohistochemistry demonstrated only a weak TTR positivity. Electronic supplementary material The online version of this article (doi:10.1007/s00415-012-6529-z) contains supplementary material, which is available to authorized users.