High Hereditary Transthyretin-Related Amyloidosis Prevalence in Crete: Genetic Heterogeneity and Distinct Phenotypes

Abstract

Background and objectives: Our goal was to study hereditary transthyretin-related amyloidosis (hATTR) in Crete, Greece.

Methods: We aimed at ascertaining all hATTR cases in Crete, an island of 0.62 million people. For this, we evaluated patients with polyneuropathy, autonomic involvement, cardiomyopathy, and/or ophthalmopathy suggestive of hATTR, who presented to the physicians of this study or were referred to them by other physicians. Genetic analyses were performed on all patients suspected of suffering from hATTR. We included in our observational longitudinal cohort study all individuals, residents of Crete, who, during the study period (1993-2019), were found to carry a pathogenic TTR variant.

Results: Over the past 27 years, 30 individuals (15 female patients, 15 male patients), from 12 apparently unrelated families, were diagnosed with hATTR, whereas evaluation of their offspring identified 5 asymptomatic TTR pathogenic variant carriers. The most prevalent TTR variant detected was p.Val50Met, affecting 19 patients (11 female patients, 8 male patients) and causing a rather consistent phenotype characterized by predominant polyneuropathy of early adult onset (median age of symptom onset: 30 years; range: 18-37 years). Specifically, patients affected by the p.Val50Met TTR variant experienced progressive sensorimotor disturbances, involving mainly the lower extremities, associated with autonomic and/or gastrointestinal dysfunction. The second most frequent TTR variant was p.Val114Ala, found in 10 patients (4 female patients, 6 male patients) who were affected at an older age (median age of symptom onset: 70 years; range: 54-78 years). This variant caused a predominantly cardiomyopathic phenotype, manifested by congestive heart failure and associated with peripheral neuropathy, carpal tunnel syndrome, and/or autonomic involvement. In these patients, cardiac amyloid deposition was detected on 99m-technetium pyrophosphate scintigraphy and/or heart biopsy. The third TTR variant (p.Arg54Gly) was found in a 50-year-old male patient with ophthalmopathy due to vitreous opacities and positive family history for visual loss. As 22 patients were alive at the end of the study, we calculated the hATTR prevalence in Crete to be 35 cases per 1 million inhabitants.

Discussion: Our study revealed that the prevalence of hATTR in Crete is one of the world's highest. Three different pathogenic TTR variants causing distinct clinical phenotypes were identified in this relatively small population pool.

Figure 1. Origin of hATTR Patients in Crete, Greece

Origin of the families described in this work is shown with red, green, and orange signs. Red: families with the p.Val50Met TTR variant; green: families with the p.Val114Ala TTR variant; orange: family with the p.Arg54Gly TTR variant (Google. (n.d.). [Google Maps pinpoints of families with hATTR patients in Crete]. Retrieved November 25, 2020, from google.com/maps/d/viewer?mid=1DT6BRiN1yXYfrdGJYuMHm8R0RRzoM5nz&hl=en&usp=sharing). Map data ©2022 Google_.

Figure 2. Cardiac Ultrasound for Amyloid Deposition

Typical findings in transthoracic echocardiogram of a patient with the p.Val114Ala TTR variant. (A) Long axis view shows severe concentric left ventricle (LV) hypertrophy and dilated left atrium (LA). (B) Pulsed wave Doppler of mitral inflow with E:A ratio >2 suggestive of grade III diastolic dysfunction. (C) Bullseye map of longitudinal systolic strain of LV with apical sparing pattern—the cherry-on-top sign—(red denotes normal strain at the apex and pink/blue denotes abnormal strain at the mid/basal LV).

Figure 3. Radionuclide Scintigraphy With ^99mTc-PYP for Amyloid Deposition in the Heart in a Patient Harboring the p.Val114Ala TTR Variant

^99mTc-PYP planar (A), SPECT (B), and SPECT/CT 16 slices (C) myocardial imaging, taken at 1 and 3 hours after injection. (A) Planar imaging qualitative and quantitative analysis revealed a high uptake in the region of the heart and a high H/CL ratio >1.5. (B) SPECT imaging qualitative and quantitative analysis revealed a diffuse intense ^99mTc-PYP uptake in the region of the left myocardial ventricle (score 3) and a high percentage of uptake >70%. (C) SPECT/CT imaging showed a high uptake in the heart on hybrid imaging and a high standardized uptake value (suv: 3.57). These findings were diagnostic for ATTR cardiac amyloidosis. ^99mTc-PYP = 99m-technetium pyrophosphate.

Figure 4. Patient With Ocular Amyloidosis (p.Arg54Gly TTR Variant)

(A) Slitlamp photography of anterior vitreous demonstrating the characteristic glass wool appearance. (B) Fundus photography revealing hazy vitreous that obscures retinal details. (C, D) Same eye 1 year after vitrectomy. The media are clear permitting unimpeded imaging of retinal details in infrared photograph (C); however, in optical coherence tomography, residual amyloid deposits can be seen perpendicular to the retinal surface in the prefoveal area, leading to the characteristic needle-shaped appearance (D).