The Gly103Arg variant in hereditary transthyretin amyloidosis

Abstract

Background: Hereditary transthyretin amyloidosis (ATTRv) is an autosomal dominant inherited systematic disease primarily affecting the peripheral and autonomic nervous system, heart, eyes and kidney. Over 140 variants have been identified worldwide, with the Gly103Arg variant reported exclusively in China. This variant is characterized by early onset eye manifestations, making accurate and timely diagnosis difficult. Therefore, we conducted a case study and literature review to investigate the clinical characteristics of the Gly103Arg variant in hereditary transthyretin amyloidosis.

Methods: We identified three patients and an asymptomatic carrier in a four-generation family by sequencing the TTR gene. The proband underwent a lumbar puncture, electromyography, abdominal fat biopsy, among other tests. Case reports of Gly103Arg variant were retrieved through a literature search for an analysis of clinical characteristics.

Results: The study included clinical data of 44 patients. Our literature review collected data on 41 patients and the present report supplied 3 patients with the Gly103Arg variant. The mean age at onset was 39.1 ± 4.27 years (range 30-47 years) with a female ratio of 52.3%. All cases were reported in China, predominantly in southern regions, especially Yunan and Guizhou Provinces. The initial manifestation was blurred vision, except for one case presenting with numbness in the upper extremities. All of them had vitreous opacity; 17 cases had peripheral neuropathy,6 cases had autonomic neuropathy, and 3 cases had cardiopathy. No disease-related deaths have been reported to date.

Conclusion: The Gly103Arg variant is unique to the Chinese population, frequently occurring in southern China. The main clinical manifestations are blurred vision, vitreous opacity, and neuropathy, with cardiopathy being rare. ATTRv should be considered if a patient diagnosed with CIDP does not respond to related therapy. Abdominal fat biopsy is a convenient and accurate diagnostic method.

Keywords: Chinese population; hereditary transthyretin amyloidosis; p.G103R variant; peripheral neuropathy; vitreous opacity.

Figure 1

(A) The pedigree of the four-generation family. I, II, III, IV represent first, second, third and fourth generation, respectively. Normal individuals are shown as clear circles (females) and squares (males), affected individuals are shown as filled symbols, asymptomatic individuals with the TTR p.G103R are shown as half-filled symbols. The individuals passed away are shown as slash. The arrow indicates the proband. The individuals who underwent genetic analyses are marked by solid triangle. (B) Sanger sequencing of exons of TTR data shows that a G to C transversion (red circle) resulted in the substitution of glycine-103 by arginine (Gly103Arg) in affected individuals of the family.

Figure 2

(A) Congo-red staining of the abdominal tissues revealed pale red unstructured materials in the superficial dermis and arteriolar wall. (B) The Congo-red positive materials were also observed with “apple-green” under polarized light. (C) Amyloidosis mass spectrometry analysis of abdominal tissues showed that TTR had the highest relative abundance. (D) Fundus examination showed vitreous opacities, cotton wool-like deposits on the retina around the optic disk.