Targeted sequencing of selected functional genes in patients with wild-type transthyretin amyloidosis.

OBJECTIVE: Wild-type transthyretin (ATTRwt) amyloidosis is caused by the misfolding and deposition of the transthyretin protein (TTR) in the absence of mutations in the TTR gene. Studies regarding the variant form of ATTR amyloidosis (ATTRv) suggest that the presence of single-nucleotide polymorphisms (SNP) in genes other than the TTR, may influence the development of the disease. However, other genetic factors involved in the aetiopathogenesis of ATTRwt are currently unknown. This work investigates the presence of sequence variants in genes selected for their possible impact on ATTRwt amyloidosis. To do so, targeted sequencing of 84 protein-coding genes was performed in a cohort of 27 patients diagnosed with ATTRwt. RESULTS: After applying quality and frequency filtering criteria, 72 rare or novel genetic variants were found. Subsequent classification according to the ACMG-AMP criteria resulted in 17 variants classified as of uncertain significance in 14 different genes. To our knowledge, this is the first report associating novel gene variants with ATTRwt amyloidosis. In conclusion, this study provides potential insights into the aetiopathogenesis of ATTRwt amyloidosis by linking novel coding-gene variants with the occurrence of the disease.

Echocardiographic markers of cardiac amyloidosis in patients with heart failure and left ventricular hypertrophy.

BACKGROUND: Cardiac amyloidosis (CA), following a non-invasive diagnosis, constitutes an increasingly prevalent heart failure (HF) etiology. This study aims to determine which echocardiography findings help to diagnose CA in patients with left ventricular hypertrophy (LVH) admitted for decompensated HF. METHODS: The present study is a retrospective observational study on a cohort of 85 LVH patients admitted for HF decompensation, in which 99mTc-DPD scanning was performed to rule out transthyretin CA. The echocardiographic findings obtained were compared between CA and non-CA groups. RESULTS: From a total number of 85 patients, 49 (57.6%) met the CA criteria and 36 (42.3%) were ruled out for the disease. Interventricular septum thickness (16 ± 3 mm vs. 14 ± 3 mm), left ventricular posterior wall thickness (14 ± 3 mm vs. 11 ± 2 mm), left ventricular mass (259 ± 76 g vs. 224 ± 53 g), left ventricular end-diastolic diameter (48 ± 7 mm vs. 53 ± 6 mm), left ventricular end-diastolic indexed volume (51 ± 18 cm3/m2 vs. 59 ± 16 cm3/m2), tricuspid annular plane systolic excursion (16 ± 5 mm vs. 20 ± 4 mm), right atrial area (27.4 ± 8.4 cm2 vs. 22.2 ± 5.7 cm2) and strain relative apical sparing (2.2 ± 0.9 vs. 1.03 ± 0.4; p = 0.04) were significantly associated with the diagnosis of CA. CONCLUSIONS: In patients with LVH admitted for HF decompensation, there are several echocardiographic features (LVH, reduced left ventricular cavity size, strain relative apical sparing, right atrial dilation, and altered right ventricular function) that are associated with the diagnosis of cardiac amyloidosis.

Coexistence of Positive 99mTc-DPD Scintigraphy and Monoclonal Gammopathy: A Frequent Challenge.

Background: Cardiac involvement is common in amyloidosis, and the vast majority of cases of amyloid cardiomyopathy are attributed to primary amyloidosis or transthyretin amyloidosis (ATTR). Although the coexistence of scintigraphy suggestive of ATTR with monoclonal gammopathy of undetermined significance is well documented, the correct diagnosis is still challenging in non-referral centers. Methods: We performed a retrospective study reviewing all amyloid cardiomyopathy cases diagnosed at our center over the last 5 years, and described our experience and diagnostic approach. Results: During the last 5 years, 74 patients with positive scintigraphy were identified. Of these patients, 41 were included in this study as they had all necessary tests for a complete diagnosis. Two of these 41 patients had variant ATTR and 29 had wild-type ATTR. Ten patients had monoclonal gammopathy (24.4%), and it was consequently impossible to obtain a specific diagnosis. During follow-up, 14 patients (34.1%), five of them from the monoclonal gammopathy group, died, reflecting the severity of disease. Conclusions: In patients with ATTR-suggestive scintigraphy, monoclonal gammopathy frequently occurs concomitantly, thus not allowing to establish a specific diagnosis. A biopsy could only be replaced by genetic testing in selected cases.

Cardiac Transthyretin Amyloidosis: A Nuclear Medicine Leading Role. Situation in a Spanish Center and "State of the Art" in Nuclear Medicine.

PURPOSE: Amyloidosis is a heterogeneous group of diseases caused by abnormal extracellular deposition of insoluble proteins and can involve myocardium. One of the causes of myocardial involvement is TTR amyloidosis. Our objective has been to evaluate the situation of cardiac amyloidosis (CA) in our center and the role of nuclear medicine, and to review the state of the art of nuclear medicine in this entity. PATIENTS AND METHODS: We have evaluated retrospectively 186 patients with clinical suspicion of CA and analyzed the clinical characteristics, free light chains and immunofixation in serum and/or urine, and the most relevant biomarkers associated with transthyretin CA (C-ATTR) of these patients and compared them with the results of the 99mTc-DPD scintigraphy. RESULTS: We have verified the growing bibliographic evidence concerning C-ATTR. A total of 51 scintigraphies (27.4%) were positive, 2 (1.1%) indeterminate and 133 (71.5%) negative according to the Perugini score. ATTR was diagnosed in 22 (11.8%; 77.3% males; mean age, 79.4 years). Of these, 12 (75% men; 82.3 years) were ATTRwt (wild-type or age-associated) patients, 2 (50% men; 52 years) experienced ATTRv (variant or hereditary), and 8 (87.5% men; 82.3 years) were not classified because of the absence genetic test. The origin of amyloidosis could not be determined in 31 (16.7%; 80.7% males; 84.5 years). In 29 of them (93.6%), it was because there was no study of free light chains or immunofixation. CONCLUSIONS: Nuclear medicine is playing an increasing role in the diagnosis and classification of CA. However, the monitoring of these is still patchy.