Vitreous amyloidosis with autonomic neuropathy of the digestive tract associated with a novel transthyretin p.Gly87Arg variant in a Bangladeshi patient: a case report
© The Author(s). 2017
Received: 7 February 2017
Accepted: 27 July 2017
Published: 13 August 2017
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.
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.
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.
KeywordsAmyloidosis Bangladeshi Transthyretin Vitreous amyloidosis
Hereditary transthyretin amyloidosis (ATTR amyloidosis), Online Mendelian Inheritance in Man (OMIM) 105210, is an autosomal dominant inherited disorder, first described in families from Northern Portugal with sensorimotor and autonomic neuropathy, and associated with the Val30Met (p.Val50Met) transthyretin (TTR) mutation . Since its first description in the Portuguese population, more than 120 amyloidogenic TTR 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 TTR amyloidosis, the first clinical manifestation is vitreous opacity, often associated with leptomeningeal amyloidosis. We describe a case of a Bangladeshi patient presenting with ATTR amyloidosis with vitreous amyloid deposition and autonomic neuropathy of the digestive tract as initial clinical manifestations, and associated with a novel amyloidogenic TTR mutation, Gly67Arg (p.Gly87Arg).
In the present report, we describe a novel amyloidogenic TTR mutation, p.Gly87Arg, associated with vitreous amyloidosis and autonomic neuropathy of the digestive tract in a Bangladeshi patient. ATTR amyloidosis was diagnosed based on the clinical findings, heterozygosity for the new TTR mutation, amyloid deposition in salivary glands and gastric tissue, and confirmation of the presence of the p.Gly87Arg variant within the deposits by tandem mass spectrometry-based proteomic analysis. Vitreous amyloidosis has been reported to be a differential diagnosis of uveitis, in particular TTR amyloidosis [4, 5]. It is the second description of ATTR in a Bangladeshi patient, with the first case being reported in a family with polyneuropathy associated with the Ile73Val TTR variant, without vitreous amyloidosis . The p.Gly87Arg mutation is a new amyloidogenic TTR variant associated with vitreous deposition. Circulating TTR is mainly derived from the liver, but TTR is also synthesized by the retinal pigment epithelium of the eye  and choroid plexus of the brain , which can lead to vitreal and leptomeningeal amyloid deposition. Vitreous amyloid deposition, presumed to result from local synthesis of TTR in the eye, was reported with various TTR mutations and variably associated with leptomeningeal amyloid deposition . It has been shown that in the case of Val30Gly, Tyr114Cys, Val30Met, and Ile84Ser TTR variants associated with vitreous amyloidosis, the TTR amyloid deposition consisted almost entirely of the variant protein with only a mild percentage of the wild-type TTR . Here, we found that the amyloid fibrils were mainly composed of the p.Gly87Arg variant, albeit proteomic analysis was performed on salivary tissue and not directly from vitreous deposits.
In the eye, vitreous amyloidosis has been reported as a differential diagnosis of uveitis, in particular TTR amyloidosis. We report a case of vitreous opacity and severe autonomic neuropathy of the digestive tract associated with a novel TTR amyloidogenic variant, p.Gly87Arg. This is the second reported case of ATTR amyloidosis in a Bangladeshi patient, further supporting that ATTR is a worldwide genetic disorder.
We acknowledge Dr Stephane Sebahoun for interpretation of gastric scintigraphy, and Céline Leroux for TTR sequencing.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
BT, MC, and SV conceived of the study and drafted the manuscript. MC carried out histology and mass spectrometry. CB and SV carried out the molecular genetic studies. AQ, JBD, DM, and AB carried out the ophthalmologic follow-up of the patient. JL edited the manuscript. BT, CLJ, and LM participated in the follow-up of the patient. CC, CL, and DA carried out the neurological follow-up of the patient. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Ethics approval and consent were obtained from local Institutional Review Board, Cochin Hospital.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
The authors declare that they have no competing interests.
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- Planté-Bordeneuve V, Said G. Familial amyloid polyneuropathy. Lancet Neurol. 2011;10:1086–97.View ArticlePubMedGoogle Scholar
- Sekijima Y. Transthyretin (ATTR) amyloidosis: clinical spectrum, molecular pathogenesis and disease-modifying treatments. J Neurol Neurosurg Psychiatry. 2015;86:1036–43.View ArticlePubMedGoogle Scholar
- Lauria G, Bakkers M, Schmitz C, Lombardi R, Penza P, Devigili G, et al. Intraepidermal nerve fiber density at the distal leg: a worldwide normative reference study. J Peripher Nerv Syst JPNS. 2010;15:202–7.View ArticlePubMedGoogle Scholar
- Coupland SE. The pathologist’s perspective on vitreous opacities. Eye Lond Engl. 2008;22:1318–29.Google Scholar
- Seca M, Ferreira N, Coelho T. Vitreous Amyloidosis as the Presenting Symptom of Familial Amyloid Polyneuropathy TTR Val30Met in a Portuguese Patient. Case Rep Ophthalmol. 2014;5:92–7.View ArticlePubMedPubMed CentralGoogle Scholar
- Booth DR, Gillmore JD, Persey MR, Booth SE, Cafferty KD, Tennent GA, et al. Transthyretin Ile73Val is associated with familial amyloidotic polyneuropathy in a Bangladeshi family. Mutations in brief no. 158. Online. Hum Mutat. 1998;12:135.View ArticlePubMedGoogle Scholar
- Getz RK, Kennedy BG, Mangini NJ. Transthyretin localization in cultured and native human retinal pigment epithelium. Exp Eye Res. 1999;68:629–36.View ArticlePubMedGoogle Scholar
- Schreiber G. The evolution of transthyretin synthesis in the choroid plexus. Clin Chem Lab Med. 2002;40:1200–10.View ArticlePubMedGoogle Scholar
- Liu T, Zhang B, Jin X, Wang W, Lee J, Li J, et al. Ophthalmic manifestations in a Chinese family with familial amyloid polyneuropathy due to a TTR Gly83Arg mutation. Eye Lond Engl. 2014;28:26–33.Google Scholar
- Liepnieks JJ, Wilson DL, Benson MD. Biochemical characterization of vitreous and cardiac amyloid in Ile84Ser transthyretin amyloidosis. Amyloid Int J Exp Clin Investig Off J Int Soc Amyloidosis. 2006;13:170–7.View ArticleGoogle Scholar