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. Tc-diphosphonate scintigraphy further confirmed cardiac ATTR amyloidosis in the male patient. DNA analysis of both patients showed a novel TTR mutation c.194C N 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.

Three Newly Recognized Likely Pathogenic Gene Variants Associated with Hereditary Transthyretin Amyloidosis

“…A number of other variants impacting the same codon (p.A65T, p.A65G, p.A65S, and p.A65D) have been described in association with ATTRv [ 50 – 52 ], suggesting that this may be a clinically significant amino acid residue. In particular, the likely pathogenic p.A65G variant, has been reported in a Dutch family with biopsy-confirmed diagnosis of ATTRv [ 53 ], is absent from gnomAD, and exhibits a significant decrease in structural stability, albeit less severe than the decrease for p.A65V.…”

Genotype-Phenotype Associations with Restrictive Cardiomyopathy Induced by Pathogenic Genetic Mutations

“…Moreover, cardiac amyloidosis is always present at diagnosis in FAP p.T60A mutation, and is a major determinant of its poor prognosis. Other sporadic cases of RCM associated with TTR mutations such as p.A65G, p.H88R and p.S23N have recently been reported [ 46 , 47 , 48 ].…”

“…This article focuses on heritable genetic mutations and genotype-phenotype associations with familial RCM, as shown in Table 1 (Ref. [ 11 , 13 , 14 , 17 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ]). The risk stratification and clinical treatment of RCM patients could be affected and improved depending on the systematic databases of genetic alterations.…”