Rare c.302C>T TTR Variant Associated with Transthyretin Amyloidosis

Abstract

Background and Objectives: Hereditary transthyretin amyloidosis (ATTRv) is a rare disease caused by pathogenic variants in the transthyretin (TTR) gene. More than 140 different disease-causing variants in TTR have been reported. Only a few individuals with a rare TTR variant, c.302C>T, p.(Ala101Val) (historically known as p.(Ala81Val)), primarily associated with cardiac ATTRv, have been described. Therefore, our aim was to analyze the clinical characteristics of individuals with the identified c.302C>T TTR variant at our center. Materials and Methods: We analyzed data from individuals with ATTRv who were diagnosed and treated at Vilnius University Hospital Santaros Klinikos. ATTRv was confirmed by negative hematological analysis for monoclonal protein, positive tissue biopsy or bone scintigraphy and a pathogenic TTR variant. Results: During 2018-2021, the TTR NM_000371.3:c.302C>T, NP_000362.1:p.(Ala101Val) variant was found in one individual in a homozygous state and in three individuals in a heterozygous state. The age of onset of symptoms ranged from 44 to 74 years. The earliest onset of symptoms was in the individual with the homozygous variant. A history of carpal tunnel syndrome was identified in two individuals. On ECG, three individuals had low QRS voltage in limb leads. All individuals had elevated NT-proBNP and hsTroponine I levels on baseline laboratory tests and concentric left ventricular hypertrophy on transthoracic echocardiography. The individual with the homozygous c.302C>T TTR variant had the most pronounced polyneuropathy with tetraparesis. Other patients with the heterozygous variant had more significant amyloid cardiomyopathy. When screening family members, the c.302C>T TTR variant was identified in two phenotypically negative relatives at the ages of 33 and 47 years. Conclusions: c.302C>T is a rare TTR variant associated with ATTRv cardiomyopathy. The homozygous state of this variant was not reported before, and is associated with earlier disease onset and neurological involvement compared to the heterozygote state.

Keywords: TTR gene; c.302C>T; cardiac amyloidosis; transthyretin.

Figure 1

Genealogies: (A) family 1, (B) family 2, (C) family 3 and (D) family 4. Arrows show probands. Asterisks show familial variant NM_000371.3:c.302C>T, NP_000362.1:p.(Ala101Val).

Figure 2

Concentric left ventricular hypertrophy in transthoracic echocardiography views: (A–D) parasternal long axis; (E–H) parasternal short axis; (A,E) proband, family 1; (B,F) proband, family 2; (C,G) proband, family 3; (D,H) proband, family 4.

Figure 3

Late gadolinium enhancement (LGE) images in cardiac magnetic resonance. (A,B) Proband, family 1: (A) midmyocardial LGE in the septum (short axis view); (B) midmyocardial LGE in inferior wall (2-chamber view). (C,D) Proband, family 2: diffuse transmural (predominantly subendocardial) LGE in LV and RV, LV and RV hypertrophy, small amount of pericardial fluid (short axis view in (C), 4-chamber view in (D)). (E,F) Proband, family 3: diffuse midmyocardial LGE in LV and RV, LV and RV hypertrophy (short axis view in (E), 4-chamber view in (F)). (G,H) Proband, family 4: diffuse subendocardial LGE in LV and RV, LV and RV hypertrophy (short axis view in (G), 4-chamber view in (H)).

Figure 4

Twelve-lead electrocardiograms: (A) proband, family 1—sinus rhythm, right bundle branch block and left anterior fascicular block; (B) proband, family 2—atrial fibrillation, left bundle branch block and low QRS voltage in the limb leads; (C) proband, family 3—atrial fibrillation and low QRS voltage in the limb leads; (D) proband, family 4—atrial fibrillation, left bundle branch block and low QRS voltage in the limb leads.

Figure 5

(A) ^99mTc-PYP bone scintigraphy and (B) histological findings of endomyocardial biopsy of family 1 proband. Hematoxylin and eosin stain. Red arrows show amorphous eosinophilic deposits in myocardium (amyloid). (C) Congo red stain. Red arrows indicate amorphous amyloid deposits (in pink).