Vitreous amyloidosis with autonomic neuropathy of the digestive tract associated with a novel transthyretin p.Gly87Arg variant in a Bangladeshi patient: a case report

Abstract

Background: Hereditary transthyretin amyloidosis is an autosomal dominant inherited disorder, first described in families with sensorimotor and autonomic neuropathy. Since its first description, more than 120 amyloidogenic transthyretin mutations have been reported with various geographic distributions and associated with a wide range of phenotypes involving the peripheral nerve, the heart, the gastrointestinal tract, the eyes, the central nervous system, or the kidneys. In some cases of transthyretin amyloidosis, the first clinical manifestation is vitreous opacity.

Case presentation: A 46-year-old Bangladeshi woman presented with vitreous amyloidosis and progressive autonomic neuropathy of the digestive tract as initial clinical manifestations, with no clinical evidence of cardiac, renal, central nervous system, or peripheral nerve dysfunction. A novel transthyretin mutation, p.Gly87Arg, was identified in the heterozygous state in this proband of Bangladeshi origin. Histological examination of accessory salivary glands and gastric biopsies revealed Congo-red-positive deposits. Laser microdissection of salivary gland Congo-red deposits and tandem mass spectrometry-based proteomic analysis identified the mutated transthyretin peptide containing the arginine residue at position 87 of the mature protein.

Conclusions: Vitreous amyloidosis should be considered a differential diagnosis of uveitis, in particular transthyretin amyloidosis. Proteomics data from our case, consistent with the genetic findings, highly suggests that this new p.Gly87Arg variant is amyloidogenic. Here, we described the second case of transthyretin amyloidosis reported in a Bangladeshi patient.

Keywords: Amyloidosis; Bangladeshi; Transthyretin; Vitreous amyloidosis.

Fig. 1

Vitreous amyloidosis. An ocular examination revealed accumulation of extensive fibrillogranular deposits in the vitreous consistent with amyloid deposits (panels a, b, c and d), and conjunctivochalasis (panel e). Optical coherence tomography showed normal retinal appearance with a normal macular and foveal thickness (panel f). Magnetic resonance imaging of the brain revealed no leptomeningeal involvement associated with vitreous amyloidosis on T2-weighted fluid-attenuated inversion recovery sequences (panels g and h) and gadolinium-enhanced T1-weighted sequences (panels i and j). OD right eye, OS left eye

Fig. 2

Gastric scintigraphy. The test consisted of an exploration of both the solid (ovalbumin with ^99mTc-labeled colloids) and the liquid (¹¹¹In diethylene triamine pentaacetic acid diluted in water) phases of gastric emptying (left panel for liquids and right panel for solids). The parameters used for the result interpretation were the half-time emptying (T1/2) and the residual activity at 4 hours (activity/time curves for liquid and solid). In this case, there was a very slow and gradual reduction of the tracer in the stomach. The residual activity remains very high 4 hours after ingestion: 30% at 4 hours (N< 10%) for liquid, and 77% (N< 10%) for solids

Fig. 3

Analysis of amyloidosis deposits. The Congo-red stain on minor salivary gland biopsy (panel a) showed deposits localized around the acini and in the interstitium with an apple-green birefringence under polarized light (insert). Partial sequencing electropherogram showing the c.259 G>C in exon 3 of transthyretin, resulting in replacement of glycine with arginine at position 87 of the mature protein (Panel b), that is, p.Gly87Arg (Gly67Arg). Proteomic profile of the amyloid deposits using tandem mass spectrometry analysis identified transthyretin as the dominant amyloid protein (panel c). Transthyretin was associated with several proteins known to be associated with amyloid deposits such as serum amyloid P-component and apolipoprotein E. The protein sequence coverage shown in bold blue was 45%, and the mutated peptide is shown in bold red