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Ocular Manifestations of Familial Transthyretin Amyloidosis
Accepted Manuscript Ocular Manifestations of Familial Transthyretin Amyloidosis Margaret M. Reynolds, Kevin K. Veverka, Morie A. Gertz, Angela Dispenzieri, Steven R. Zeldenrust, Nelson Leung, Jose S. Pulido PII:
S0002-9394(17)30378-1
DOI:
10.1016/j.ajo.2017.09.001
Reference:
AJOPHT 10249
To appear in:
American Journal of Ophthalmology
Received Date: 24 February 2017 Revised Date:
29 August 2017
Accepted Date: 1 September 2017
Please cite this article as: Reynolds MM, Veverka KK, Gertz MA, Dispenzieri A, Zeldenrust SR, Leung N, Pulido JS, Ocular Manifestations of Familial Transthyretin Amyloidosis, American Journal of Ophthalmology (2017), doi: 10.1016/j.ajo.2017.09.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Abstract
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Purpose: Among patients with familial amyloidosis, mutation in the transthyretin (TTR) protein is the most common type. Patients with TTR amyloidosis have been noted to have ocular, especially vitreous, involvement. In this report, an analysis of the types and frequency of ocular manifestations in TTR amyloidosis is presented. Design: Observational case series.
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Methods: Two hundred and sixty-three patients who presented to Mayo Clinic with TTR amyloidosis between January 1, 1970, and November 1, 2014, consented to be included in the Mayo Clinic amyloidosis database maintained by the Department of Hematology. Fifty-four patients had ocular examinations at a mean of 4.25±3.93 months after systemic symptoms.
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Results: Of 108 examined eyes in 54 patients with TTR amyloidosis, there were 26 eyes (24%) in 13 patients with ocular involvement. Patients with ocular involvement were more likely to be women than those without ocular involvement (46% vs. 15%, respectively, p=0.008) and have significantly worse visual acuity (VA) at presentation (logMAR 0.24 [Snellen equivalent 20/30] vs. logMAR 0.00 [Snellen equivalent 20/20], p=0.017). The ophthalmic findings included vitreous amyloid (26/26, 100%), neurotrophic keratitis (2/26, 8%), glaucoma (5/26, 19%), and tortuous retinal vessels (4/26, 15%). The glaucoma was classified as open-angle (2/26), exfoliative (2/26), and neovascular following central retinal vein occlusion from amyloidosis (1/26). Ten patients underwent vitrectomy for visually significant vitreous amyloidosis, which significantly improved visual acuity from a baseline of logMAR 0.70 [Snellen equivalent 20/100] to logMAR 0.05 [Snellen equivalent ~20/20], p=0.003. Three TTR mutations, Glu89Lys, Gly47Arg, homozygous Gly6Ser, not previously described, were associated with vitreous amyloid.
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Conclusion: In this large cohort of patients with TTR amyloidosis, female sex and decreased VA were associated with ocular amyloid. Three mutations which have not been previously reported to have vitreous involvement were described: Glu89Lys, Gly47Arg, and homozygous Gly6Ser.
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Key words: familial amyloidosis; transthyretin amyloidosis; vitreous amyloidosis; vitreous opacities; systemic amyloidosis
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Ocular Manifestations of Familial Transthyretin Amyloidosis 1
Margaret M. Reynolds, 2Kevin K. Veverka, 3Morie A. Gertz, 3Angela Dispenzieri, 3Steven R. Zeldenrust, 4Nelson Leung, and 1Jose S. Pulido Department of Ophthalmology, 2Mayo Medical School, 3Department of Hematology, Department of Nephrology, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905
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Corresponding Author:
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Short title: Ocular Manifestations of Familial Transthyretin Amyloidosis
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Jose S. Pulido, MD, MBA, MPH, MS Mayo Clinic Department of Ophthalmology and Department of Molecular Medicine 200 First Street, SW Rochester, MN 55905 Telephone: 507-284-3721 Fax: 507-284-4612 Email: [email protected]
For consideration of publication in the American Journal of Ophthalmology.
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Introduction
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Amyloidosis describes a diverse group of diseases, which result when a soluble protein undergoes a mutation, causing it to become misfolded and insoluble. The now-insoluble protein, termed amyloid, accumulates in the extracellular space, causing symptoms based on the site of its accumulation. Amyloidosis is subclassified according to the involved protein. Inherited forms of amyloidosis (familial amyloidosis) result from inherited protein mutations. The most common protein involved is transthyretin (TTR). Transthyretin, also called prealbumin, is composed of 127 amino acids. This protein functions to transport both thyroxine and vitamin A.1
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Over 100 TTR point mutations have been reported in the literature with differing phenotypes.2 TTR is synthesized in the choroid plexuses of the brain as well as the retinal pigment epithelial cells. Not surprisingly, ophthalmic manifestations of familial amyloidosis are reported.3 In fact, 32 of 130 (25%) reported TTR mutations have been noted to have ophthalmic involvement.4
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Few studies have looked at ocular manifestations in large cohorts of familial amyloidosis. This study reviewed the association between TTR familial amyloidosis and ocular involvement in a cohort of TTR patients seen at Mayo Clinic in Rochester, Minnesota.
Methods
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A retrospective chart review was conducted, including all patients with a diagnosis of familial amyloidosis seen at Mayo Clinic in Rochester, Minnesota, between January 1, 1970, and November 1, 2014. Approval for this retrospective cross-sectional study was obtained from the Institutional Review Board at Mayo Clinic (Rochester, Minnesota, USA). The principles of the Declaration of Helsinki were followed. All patients included in the study provided informed consent to allow use of their medical records in the amyloidosis database maintained by the Mayo Clinic Department of Hematology. Patients included in the database had biopsyconfirmed amyloidosis with Congo red staining. Mutations in TTR were identified by restriction fragment polymorphism (RFLP) between 1970 and 2001 (Mayo Medical Laboratories, Rochester, MN) or by direct Sanger sequencing after 2001 (Mayo Medical Laboratories, Rochester, MN).
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Patients were excluded if they had a syndrome consistent with primary (AL) amyloidosis, secondary (AA) amyloidosis, or familial Mediterranean fever. Patients were also excluded when specific TTR mutation information was unavailable to ensure only patients with TTR amyloidosis were included in the study. Finally, patients were excluded if they did not have an eye examination. Visual acuity, intraocular pressure, abnormalities documented within the ocular examination, and ocular diagnoses were recorded. Additionally, optical coherence tomography (OCT) of optic nerve, OCT macula, fluorescein angiography (FA), visual field, autofluorescence photographs, and fundus photographs were reviewed.
Results Inclusion criteria were met by 263 patients; 54 had eye examinations, and 26 eyes of 13 patients (24.1%) had ocular involvement. Clinical variables were compared between patients with (n=13) and without ophthalmic involvement (n=41) (Table 1). Median length of follow-up was 4.21 (range 0.052 to 15.8) years and 0.80 (range 0 to 8.81) years for patients with and
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without ocular involvement, respectively (p<0.05). Patients with ophthalmic involvement were significantly more likely to be women (46.2 vs. 14.6%, p=0.008) and non-Hispanic Caucasian 100.0% vs. 80.5% (p=0.05), respectively. Patients with ophthalmic involvement were more likely to have worse visual acuity at presentation (LogMAR 0.24±0.39 [Snellen equivalent 20/30] vs. LogMAR 0.00±0.25 [Snellen equivalent 20/20], p=0.02) than patients without ocular involvement. Of 13 patients with ophthalmic involvement, 11 were symptomatic at their first eye examination. Two patients developed ocular involvement after an initially negative eye screening. One patient with a Glu54Gly mutation developed vitreous amyloidosis 61.51 months after a negative eye screening and 61.57 months after amyloid diagnosis. A second patient with a Val30Met mutation developed vitreous amyloidosis 50.79 months after a negative eye screening and 226.78 months after amyloid diagnosis. All 13 patients had vitreous involvement (26/26 eyes); 1/1 patients with Glu89Lys mutation also had bilateral neurotrophic keratitis. Two patients, one with Glu54Gly mutation (Figure 1) and one with Asp18Glu mutation, had tortuous retinal vessels. Three patients had glaucoma, 5 of 26 eyes (19.2%). One patient had bilateral secondary open-angle glaucoma to steroids vs. amyloid (Ala36Pro), one patient had bilateral exfoliative glaucoma unknown if related to amyloid (Val30Met), and one patient with unilateral neovascular glaucoma (Tyr114Cys), which was secondary to a unilateral central retinal vein occlusion thought to be secondary to amyloidosis.
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For visually significant vitreous opacities, 13 of 13 patients were offered vitrectomy. Ten patients (17 eyes) underwent vitrectomy; three patients underwent unilateral vitrectomy, seven patients underwent bilateral vitrectomy, one patient refused vitrectomy, and two patients deferred vitrectomy until their other conditions stabilized. Vitrectomy significantly improved VA (0.70 LogMAR [Snellen equivalent 20/100] to 0.047 [Snellen equivalent ~20/20], p=0.003). The average age at vitrectomy was 56.4 ±14.1 years. In addition to vitrectomy, one patient received treatment with pan-retinal photocoagulation (PRP) and intravitreal anti-VEGF with the theoretical benefit of damaging the retinal pigment epithelium where TTR is produced. This patient subsequently required a vitrectomy. Two patients (three eyes) had recurrent vitreous amyloid after vitrectomy at a median 2.79 (range 2.05 to 5.00) years after vitrectomy. No eyes required repeat vitrectomy during the dates of this study as the recurrent vitreous amyloid was not visually significant.
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Twenty-two different TTR mutations were identified among patients in the study who had eye examinations. The most common mutations were Val30Met (n=14), Thr60Ala (n=9), and Val122Ile (n=6). Of the most common TTR mutations, none of the patients with either Thr60Ala or Val112Ile had ocular manifestations. Notably, patients with Val30Met were significantly more likely to have an eye examinations than patients with Thr60Ala (p=0.02). Ophthalmic involvement was found in 5 of 14 (35.7%) Val30Met patients. Three additional mutations, which have been reported to be involved with TTR amyloidosis but have not been previously reported to have ophthalmic manifestations, were identified: homozygous Gly6Ser (1 of 1 patients), Gly47Arg (1 of 1), and Glu89Lys (1 of 1) (Table 2). Finally, familial TTR amyloidosis is a systemic disease whose phenotype varies according to TTR mutation. Systemic findings consistent with an amyloidosis phenotype (autonomic neuropathy, carpal tunnel syndrome, cardiomyopathy, chronic kidney disease thought to be secondary to amyloidosis as determined by a nephrologist, leptomeningeal disease, peripheral neuropathy, and central nervous system involvement) were obtained from patient records and recorded in Table 2. Among this cohort of patients, patients with Val30Met and
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Ser77Tyr were more likely to have peripheral neuropathy, and patients with Val122Ile and Thr60Ala were more likely to have cardiomyopathy. A full discussion on the systemic manifestations of TTR amyloidosis in the Mayo Clinic cohort was published by Swiecicki et al.5
Discussion
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This clinical investigation of the associations between TTR amyloidosis and ocular manifestations is, to our knowledge, the largest study of TTR amyloidosis and ocular involvement in the United States.5 Of 54 included patients, 24.1% had ocular involvement. The most common ocular manifestation of TTR amyloidosis was vitreous involvement. While TTR amyloidosis is thought to equally affect men and women, females were found to be more commonly affected with vitreous involvement in this study (Table 1). Non-Hispanic Caucasians were also more likely to have ophthalmic involvement. Of patients whose eyes were involved, vitrectomy offered a significant improvement in visual acuity.
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Familial TTR amyloidosis is a systemic disease. Amyloidosis occurs when a single amino acid substitution, e.g. methionine for valine at position 30 of transthyretin (Val30Met), results in a dysfunctional TTR protein. TTR is a transport protein which is synthesized mainly in the liver, but it is also synthesized in the choroid plexuses of the brain as well as the retinal pigment epithelial cells (RPE).3 The hepatic production of TTR leads to systemic manifestations of familial amyloidosis. 2,3 Systemic manifestations of patients in this study include peripheral neuropathy, autonomic neuropathy, and cardiomyopathy. (Table 2) The prevalence of these systemic manifestations varied by TTR mutation; for instance, patients with Val30Met and Ser77Tyr were more likely to have peripheral neuropathy, and patients with Val122Ile and Thr60Ala were more likely to have cardiomyopathy. A full discussion can be found in the 2015 Amyloid article written by Swiecicki et al.5 Ocular findings in patients with familial TTR amyloidosis may be secondary to either the systemic production of dysfunctional TTR or production by the RPE. Vascular abnormalities, for instance, may be secondary to systemic TTR production. Vitreous amyloid is postulated to be secondary to RPE production of TTR.
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The natural history of vitreous amyloidosis tends to involve floaters that progress, leading to visual impairment, which can be so significant that it leads to only light perception vision.6, 7 As demonstrated by this paper, fortunately, vision impairment can be reversed with vitrectomy. Some patients can have restoration of 20/20 vision.8, 9 A 1987 study of 36 vitrectomies conducted on 30 eyes of 17 patients reported significant improvement in visual acuity after pars plana vitrectomy. In fact, 48% of eyes had visual acuity of 20/40 or better.10 Among studies which have reviewed the ocular manifestations of TTR amyloidosis, a study by Ando et al. found abnormal conjunctival vessels to be the most common manifestation (75.5%), followed by pupillary abnormalities (43.2%), keratoconjunctivitis sicca (KCS) (40.5%), glaucoma (19.2%), and vitreous opacity (5.4%).11 Notably, the Ando et al. study only included patients with Val30Met mutations. Our study noted KCS in one patient, but the other findings were not reported. Under-reporting of more subtle signs is likely due to the retrospective nature of this review. While this study did not find an increased incidence of abnormal conjunctival vessels, it did find two patients to have abnormal retinal vessels, which could be due to similar pathophysiology. The specific pathophysiology causing vascular abnormalities in patients with amyloidosis has not been described. A 1994 Yoshinaga paper described a patient with white sheaths along the retinal blood vessels with obstruction of the vessels.12 It is possible that Page 4 of 9
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vascular changes are due to direct infiltration with amyloid, which has been described for oculoleptomeningeal amyloidosis.13, 14 It is also possible that these vascular changes are secondary to underlying cardiac or pulmonary conditions. Patients with TTR amyloidosis have a high rate of sleep-disordered breathing15 as well as cardiopulmonary amyloidosis.16 One of the patients with tortuous vessels is a 65-year-old man with a history of Hodgkin lymphoma with secondary bleomycin lung toxicity. The other patient is a 41-year-old woman status post liver transplant with mild cardiac amyloidosis without heart failure and was found to have obstructive sleep apnea on referral to pulmonology. It is worthwhile to pursue workup in patients with known systemic amyloidosis who have ophthalmic vascular abnormalities for sleep-disordered breathing or cardiopulmonary amyloidosis.
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Other studies have also found a higher prevalence of glaucoma among cohorts of these patients. A study of 49 Japanese patients with FAP found 20 eyes of 12 patients (24%) had secondary glaucoma.17 The results of our Mayo Clinic study demonstrated three patients to have glaucoma, one patient with secondary open-angle glaucoma to steroids vs. amyloid (Ala36Pro), one patient with exfoliative glaucoma unknown if related to amyloid (Val30Met), and one patient with neovascular glaucoma (Tyr114Cys) (19.2% among patients with ocular involvement, but 4.6% of all eyes). Notably, the Ando study included only patients with Val30Met TTR mutations, while the Kimura study included 41 patients with Val30Met, 6 with Tyr114Cys and 1 with Ser50Ile. Obviously, the genetic compositions of these studies are different from the present study. Also, the association between glaucoma and amyloidosis has been attributed to amyloid deposits in the anterior chamber. Amyloid deposits in the anterior chamber were demonstrated in only 1 of the 13 patients with vitreous amyloidosis in this study with a Tyr114Cys mutation.18
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The difference between the genetic composition of this Mayo Clinic study and other studies is important, as the frequency of ocular involvement has been reported to vary between TTR mutations. A study in 2003, including 37 patients with Val30Met familial amyloidosis and 6 patients with Tyr114Cys, found vitreous opacities in 9 of 37 patients (14 eyes, 24%) with Val30Met and 6 of 6 patients (12 eyes, 100%) with Tyr114Cys.8
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Because the frequencies of ocular manifestations vary, it is important to consider the incidence of ocular manifestations in TTR amyloidosis among individual mutations and among all TTR mutations. This study is unique because it described the incidence of ocular involvement among 22 different TTR mutations. Other studies have been conducted on the incidence of ocular involvement in TTR amyloidosis. Many of these studies have focused on large populations with Val30Met mutations. The frequency of different ophthalmic manifestations, even among patients with Val30Met mutations, seems to vary somewhat by region. A large study of 483 Portuguese patients with Val30Met found 43 out of 483 (8.9%) patients to have vitreous involvement.19 In Japan, differing frequencies have been reported. Among 258 patients with Val30Met, 2 had vitreous involvement (0.78%) in a study performed in Ogawa village.20 In 96 patients examined in Arao, no vitreous opacities were found.21 Finally, a 1997 study in Japan, including 37 patients who had Val30Met mutation, found the incidence of vitreous opacity to be 5.4% (2 out of 37 patients).22 In addition to Val30Met and Tyr114Cys, our Mayo Clinic study also included six additional much less common mutations, which resulted in ocular involvement. The first, Ala36Pro, was found in one patient who also had eye involvement. This rare mutation has been previously described by four papers, which have included 12 patients. All 12 patients had Page 5 of 9
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vitreous involvement.23-27 Given that 100% of patients have been found to have vitreous involvement with Ala36Pro mutation, it is likely that such patients have vitreous involvement. Next, Asp18Glu is a very rare mutation. Two cases have been reported in the literature. The first patient had no vitreous involvement.28 The second patient was reported by our institution and is included within this study.29 One case of Phe33Ile was reviewed. This patient had vitreous involvement.30
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In addition, three of the patients with vitreous involvement had TTR mutations, which have not been reported to be associated with ocular manifestations. Notably, all three mutations are very rare, with only a few case reports. Two reports of Glu89Lys were reviewed. Neither patient had ophthalmic involvement.31, 32 Another two patients were reported to have Gly47Arg; neither had ocular manifestations.33, 34 Finally, homozygous Gly6Ser was not reported to be associated with vitreous amyloidosis.35
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It is also true that some TTR mutations have never been reported to have ophthalmic manifestations. Of the nine patients with Thr60Ala, none had ophthalmic involvement. Similarly, of the six included patients with Val122Ile, none had ophthalmic findings. Review of the literature did not reveal any reports of Thr60Ala or Val122Ile TTR amyloidosis patients with ophthalmic involvement, making such associations rare, if they exist.
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This study has limitations. First, while 263 patients were found to have TTR mutations, only 54 had eye examinations. While the most common mutation among patients who have eye examinations was Val30Met, which is the most common mutation worldwide, the most common mutation in the database was Thr60Ala (80 patients), which may indicate a selection bias. Of note, Val30Met is the most common mutation worldwide, and Val122Ile is the most common mutation in the United States; therefore, it is possible that these differences demonstrate referral bias.36, 37 In addition, patients whose symptoms and history were consistent with familial amyloidosis but did not have an identified TTR mutation were excluded. Most patients who were excluded for this reason were seen before genotyping was commonly done or when mutations were identified by RFLP, a method which screened patients only for the most common mutations. As such, some of the more rare mutations could have a higher prevalence in our population than what we have reported. Exclusion of these patients could influence frequencies of ophthalmic manifestations.
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In conclusion, this clinical investigation of association with ophthalmic involvement of TTR familial amyloidosis is one of only a few reviews published on such a topic and is the largest, to our knowledge, in the United States. Women were significantly more likely to have ophthalmic involvement. Vitreous involvement was the most common type of ophthalmic involvement. Affected patients had significant ocular morbidity, with significant differences between visual acuity at presentation between those with and without ophthalmic involvement. This impaired visual acuity improved after vitrectomy. Because TTR amyloidosis has been reported to be associated with vitreous involvement and because the impaired vision improves with vitrectomy, it is reasonable to refer patients with TTR amyloidosis for ophthalmic examinations, particularly those with mutations which have been reported to be associated with ophthalmic involvement. It is equally important that, if patients with vitreous amyloid present first to an ophthalmologist, they be referred for a systemic work-up.
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Acknowledgments/Disclosure
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a. Funding/Support: Research to Prevent Blindness; Vitreoretinal Surgery Foundation; funded in part by a grant from the Deshong Family. b. Financial Disclosures: Margaret Reynolds: Vitreoretinal Surgery Foundation. Kevin K. Veverka: No financial disclosures. Morie A. Gertz: Ionis, Prothena, Celgene, Janssen, Research to Practice, Novartis, Sandoz. Angela Dispenzieri: Research dollars from Takeda, Janssen, Celgene, Alnylam, Pfizer. Steven R. Zeldenrust: No financial disclosures. Nelson Leung: No financial disclosures. Jose S Pulido: No relevant financial disclosures. Lagen Laboratories (in vitro RPE laboratory supplier). c. Other Acknowledgments: None.
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1. Sandgren O. Ocular amyloidosis, with special reference to the hereditary forms with vitreous involvement. Surv Ophthalmol 1995;40(3):173-196. 2. Benson MD, Kincaid JC. The molecular biology and clinical features of amyloid neuropathy. Muscle Nerve 2007;36(4):411-423. 3. Ong DE, Davis JT, O'Day WT, Bok D. Synthesis and secretion of retinol-binding protein and transthyretin by cultured retinal pigment epithelium. Biochemistry 1994;33(7):1835-1842. 4. Rowczenio D, Wechaleker A. Mutations in Hereditary Amyloidosis http://amyloidosismutations.com/mut-attr.php. Accessed June 9, 2016. 5. Swiecicki PL, Zhen DB, Mauermann ML, et al. Hereditary ATTR amyloidosis: a singleinstitution experience with 266 patients. Amyloid 2015;22(2):123-131. 6. Liu T, Zhang B, Jin X, et al. Ophthalmic manifestations in a Chinese family with familial amyloid polyneuropathy due to a TTR Gly83Arg mutation. Eye (Lond) 2014;28(1):26-33. 7. Long D, Zeng J, Wu LQ, Tang LS, Wang HL, Wang H. Vitreous amyloidosis in two large mainland Chinese kindreds resulting from transthyretin variant Lys35Thr and Leu55Arg. Ophthalmic Genet 2012;33(1):28-33. 8. Koga T, Ando E, Hirata A, et al. Vitreous opacities and outcome of vitreous surgery in patients with familial amyloidotic polyneuropathy. Am J Ophthalmol 2003;135(2):188-193. 9. Beirao NM, Matos E, Beirao I, Costa PP, Torres P. Recurrence of vitreous amyloidosis and need of surgical reintervention in Portuguese patients with familial amyloidosis ATTR V30M. Retina 2011;31(7):1373-1377. 10. Doft BH, Machemer R, Skinner M, et al. Pars plana vitrectomy for vitreous amyloidosis. Ophthalmology 1987;94(6):607-611. 11. Ando E, Ando Y, Okamura R, Uchino M, Ando M, Negi A. Ocular manifestations of familial amyloidotic polyneuropathy type I: long-term follow up. Br J Ophthalmol 1997;81(4):295-298. 12. Yoshinaga T, Nakazato M, Ikeda S, Ohnishi A. [Three siblings homozygous for the transthyretin-Met30 gene in familial amyloidotic polyneuropathy--evaluation of their clinical pictures with reference to those of other 10 cases reported]. Rinsho Shinkeigaku 1994;34(2):99105.
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13. Ellie E, Camou F, Vital A, et al. Recurrent subarachnoid hemorrhage associated with a new transthyretin variant (Gly53Glu). Neurology 2001;57(1):135-137. 14. Petersen RB, Goren H, Cohen M, et al. Transthyretin amyloidosis: a new mutation associated with dementia. Ann Neurol 1997;41(3):307-313. 15. Bodez D, Guellich A, Kharoubi M, et al. Prevalence, Severity, and Prognostic Value of Sleep Apnea Syndromes in Cardiac Amyloidosis. Sleep 2016;39(7):1333-1341. 16. Ruberg FL, Berk JL. Transthyretin (TTR) cardiac amyloidosis. Circulation 2012;126(10):1286-1300. 17. Kimura A, Ando E, Fukushima M, et al. Secondary glaucoma in patients with familial amyloidotic polyneuropathy. Arch Ophthalmol 2003;121(3):351-356. 18. Meney J BE, Mincheva Z, Cauquil C, Labetoulle M, Adams D, Rousseau A. A prospective study of ocular manifestations in transthyretin-related familial amyloid polyneuropathy. Acta ophthalmologica 2014;92(s243):0. 19. Coutinho P. MdSA, Lopes Lima J., Resende Barbosa A. Forty years of experience with type I amyloid neuropathy. Review of 483 cases. . In: Glenner G. CP, de Freitas A., editor. Amyloid and Amyloidosis. Amsterdam: Execerpta Medica, 1980:88-98. 20. Kito S, Itoga E, Kamiya K, Kishida T, Yamamura Y. Studies on familial amyloid polyneuropathy in Ogawa Village, Japan. Eur Neurol 1980;19(3):141-151. 21. S. Araki TK, S. Tawara, T. Kuribayashi. Familial Amyloidotic polyneuropathy in Japanese In: G.G. Glenner PPC, A.F. Freitas, editor. Amyloid and Amyloidosis Amsterdam Excerpta Modica, 1980:67–77. 22. Tsukahara S, Matsuo T. Secondary glaucoma accompanied with primary familial amyloidosis. Ophthalmologica 1977;175(5):250-262. 23. Muller KR, Padbury R, Jeffrey GP, et al. Poor outcome after liver transplantation for transthyretin amyloid neuropathy in a family with an Ala36Pro transthyretin mutation: case report. Liver Transpl 2010;16(4):470-473. 24. Mascalchi M, Salvi F, Pirini MG, et al. Transthyretin amyloidosis and superficial siderosis of the CNS. Neurology 1999;53(7):1498-1503. 25. Zou X, Dong F, Zhang S, Tian R, Sui R. Transthyretin Ala36Pro mutation in a Chinese pedigree of familial transthyretin amyloidosis with elevated vitreous and serum vascular endothelial growth factor. Exp Eye Res 2013;110:44-49. 26. Jones LA, Skare JC, Cohen AS, Harding JA, Milunsky A, Skinner M. Familial amyloidotic polyneuropathy: a new transthyretin position 30 mutation (alanine for valine) in a family of German descent. Clin Genet 1992;41(2):70-73. 27. Jones LA, Skare JC, Harding JA, Cohen AS, Milunsky A, Skinner M. Proline at position 36: a new transthyretin mutation associated with familial amyloidotic polyneuropathy. Am J Hum Genet 1991;48(5):979-982. 28. Connors LH, Yamashita T, Yazaki M, Skinner M, Benson MD. A rare transthyretin mutation (Asp18Glu) associated with cardiomyopathy. Amyloid 2004;11(1):61-66. 29. Solano JM, Pulido JS, Salomao DR. A rare transthyretin mutation (Asp18Glu) associated with vitreous amyloid. Ophthalmic Genet 2007;28(2):73-75. 30. Nakazato M, Kangawa K, Minamino N, Tawara S, Matsuo H, Araki S. Revised analysis of amino acid replacement in a prealbumin variant (SKO-III) associated with familial amyloidotic polyneuropathy of Jewish origin. Biochem Biophys Res Commun 1984;123(3):921928.
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31. Niederhauser J, Lobrinus JA, Ochsner F, et al. Successful heart and liver transplantation in a Swiss patient with Glu89Lys transthyretin amyloidosis. Transplantation 2011;91(6):e40-42. 32. Nakamura M, Hamidi Asl K, Benson MD. A novel variant of transthyretin (Glu89Lys) associated with familial amyloidotic polyneuropathy. Amyloid 2000;7(1):46-50. 33. Fan J, Wu W, Chen W, et al. [Familial transthyretin amyloidosis with Gly47Arg mutation and cardiac involvement: a case report]. Zhonghua Xin Xue Guan Bing Za Zhi 2014;42(9):784785. 34. Murakami T, Maeda S, Yi S, et al. A novel transthyretin mutation associated with familial amyloidotic polyneuropathy. Biochem Biophys Res Commun 1992;182(2):520-526. 35. Damy T, Plante-Bordeneuve V, Dogan A. Characterization of untyped cardiac amyloidosis by mass spectrometry in a patient with Gly6Ser transthyretin polymorphism in fatal cardiogenic shock. Arch Cardiovasc Dis 2014;107(12):706-708. 36. Plante-Bordeneuve V. Update in the diagnosis and management of transthyretin familial amyloid polyneuropathy. J Neurol 2014;261(6):1227-1233. 37. Ando Y, Coelho T, Berk JL, et al. Guideline of transthyretin-related hereditary amyloidosis for clinicians. Orphanet J Rare Dis 2013;8:31.
Figure Legend
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FIGURE 1: Fundus photos of a 41-year-old woman with Glu54Gly TTR mutation before [(Top Left (Right eye) and Top Right (left eye)] and after [Bottom Left (Right eye) and Bottom Right (left eye)] bilateral vitrectomy demonstrating vitreous amyloid (Top Right and Top Left) and tortuous retinal arterioles and venules (entire figure).
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Table 1. Demographic and ophthalmic features of 54 patients with transthyretin amyloidosis (TTR)
14.63
Percent Non-Hispanic Caucasian
80.5 58.94±9.62
Median age at death (years)
67.07±11.21
0.008
100
0.05
55.16±14.95
0.430
73.72±10.13
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Median age at diagnosis (years)
46.15
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Percent Female
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No eye involvement (n=41)Eye involvement (n=13)P-value
0.579
4.73±2.94
4.30±2.33
0.889
Median age at first eye exam (years)
63.83±8.73
58.66±13.98
0.154
Median time from symptoms to exam (years)
3.78±3.23
3.33±5.02
0.738
Median time from diagnosis to eye exam (years)
1.05±2.62
0.049±5.24
0.779
0.00±0.25
0.24±0.39
0.0179
13.0±4.24
13.0±4.22
0.822
0.80±2.21
4.21±4.38
0.0452
0.09±0.22
0.17±0.64
0.0559
14.0±3.92
13.5±3.16
0.379
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Diagnosis to death (years)
Median visual acuity for visit 1 (LogMAR)
Median length of follow-up (years)
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Median intraocular pressure for visit 1 (mmHg)
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Median visual acuity for date of last follow-up (LogMAR)
Median intraocular pressure for date of last follow-up (mmHg)
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Table 2. Correlation of genetic mutation with ophthalmic and systemic findings in 54 patients with transthyretin amyloidosis (TTR) Number of Number of patients patients with eye Mutation without eye involvement involvement (n=41) (n=13) 0
Ala45Asp
2
0
Asp38Ala
1
0
Glu74Ser
1
0
Gly47Glu
2
0
Ile107Val
1
0
Ile84Thr
1
0
Leu58His
3
0
Phe33Leu
1
0
Ser77Tyr
3
Thr60Ala
9
Tyr69His
1
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6
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Peripheral neuropathy Peripheral neuropathy
0
Peripheral neuropathy, cardiomyopathy, chronic kidney disease Peripheral neuropathy, autonomic neuropathy, cardiomyopathy Leptomeningeal
0
Cardiomyopathy
0
0
Val30Met
9
5
Ala36Pro
0
1
Asp18Glu
0
1
Glu54Gly
0
1
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Peripheral neuropathy, autonomic neuropathy, cardiomyopathy Peripheral neuropathy, autonomic neuropathy, cardiomyopathy Cardiomyopathy, peripheral neuropathy Peripheral neuropathy, cardiomyopathy Peripheral neuropathy, cardiomyopathy, chronic kidney disease Peripheral neuropathy, autonomic neuropathy, Cardiomyopathy
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Ala120Ser
Val122Ile
Systemic Findings
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Ophthalmic Findings
Peripheral neuropathy, Vitreous opacities, exfoliative autonomic neuropathy, carpal glaucoma tunnel syndrome, chronic kidney disease, Peripheral neuropathy, Vitreous opacities, secondary autonomic neuropathy, glaucoma chronic kidney disease, cerebral deposition Peripheral neuropathy, Vitreous opacities, tortuous cardiomyopathy, chronic retinal vessels kidney disease requiring transplant Peripheral neuropathy, Vitreous opacities, tortuous autonomic neuropathy, retinal vessels cardiomyopathy
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Ophthalmic Findings
Glu89Lys
0
1
Vitreous opacities, neurotrophic keratitis
Gly47Arg
0
1
Vitreous opacities
Gly6Ser
0
1
Vitreous opacities
Phe33Ile
0
1
Vitreous opacities
1
Peripheral ischemic retinopathy, central retinal vein occlusion, secondary neovascular glaucoma, anterior chamber deposits, vitreous opacities, direct optic nerve infiltration
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Peripheral neuropathy, autonomic neuropathy, cardiomyopathy Peripheral neuropathy, cardiomyopathy, carpal tunnel syndrome Peripheral neuropathy, cardiomyopathy
Peripheral neuropathy, autonomic neuropathy, cardiomyopathy
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0
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Tyr114Cys
Systemic Findings
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Number of Number of patients patients with eye Mutation without eye involvement involvement (n=41) (n=13)
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S0002-9394(17)30378-1
DOI:
10.1016/j.ajo.2017.09.001
Reference:
AJOPHT 10249
To appear in:
American Journal of Ophthalmology
Received Date: 24 February 2017 Revised Date:
29 August 2017
Accepted Date: 1 September 2017
Please cite this article as: Reynolds MM, Veverka KK, Gertz MA, Dispenzieri A, Zeldenrust SR, Leung N, Pulido JS, Ocular Manifestations of Familial Transthyretin Amyloidosis, American Journal of Ophthalmology (2017), doi: 10.1016/j.ajo.2017.09.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Abstract
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Purpose: Among patients with familial amyloidosis, mutation in the transthyretin (TTR) protein is the most common type. Patients with TTR amyloidosis have been noted to have ocular, especially vitreous, involvement. In this report, an analysis of the types and frequency of ocular manifestations in TTR amyloidosis is presented. Design: Observational case series.
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Methods: Two hundred and sixty-three patients who presented to Mayo Clinic with TTR amyloidosis between January 1, 1970, and November 1, 2014, consented to be included in the Mayo Clinic amyloidosis database maintained by the Department of Hematology. Fifty-four patients had ocular examinations at a mean of 4.25±3.93 months after systemic symptoms.
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Results: Of 108 examined eyes in 54 patients with TTR amyloidosis, there were 26 eyes (24%) in 13 patients with ocular involvement. Patients with ocular involvement were more likely to be women than those without ocular involvement (46% vs. 15%, respectively, p=0.008) and have significantly worse visual acuity (VA) at presentation (logMAR 0.24 [Snellen equivalent 20/30] vs. logMAR 0.00 [Snellen equivalent 20/20], p=0.017). The ophthalmic findings included vitreous amyloid (26/26, 100%), neurotrophic keratitis (2/26, 8%), glaucoma (5/26, 19%), and tortuous retinal vessels (4/26, 15%). The glaucoma was classified as open-angle (2/26), exfoliative (2/26), and neovascular following central retinal vein occlusion from amyloidosis (1/26). Ten patients underwent vitrectomy for visually significant vitreous amyloidosis, which significantly improved visual acuity from a baseline of logMAR 0.70 [Snellen equivalent 20/100] to logMAR 0.05 [Snellen equivalent ~20/20], p=0.003. Three TTR mutations, Glu89Lys, Gly47Arg, homozygous Gly6Ser, not previously described, were associated with vitreous amyloid.
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Conclusion: In this large cohort of patients with TTR amyloidosis, female sex and decreased VA were associated with ocular amyloid. Three mutations which have not been previously reported to have vitreous involvement were described: Glu89Lys, Gly47Arg, and homozygous Gly6Ser.
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Key words: familial amyloidosis; transthyretin amyloidosis; vitreous amyloidosis; vitreous opacities; systemic amyloidosis
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Ocular Manifestations of Familial Transthyretin Amyloidosis 1
Margaret M. Reynolds, 2Kevin K. Veverka, 3Morie A. Gertz, 3Angela Dispenzieri, 3Steven R. Zeldenrust, 4Nelson Leung, and 1Jose S. Pulido Department of Ophthalmology, 2Mayo Medical School, 3Department of Hematology, Department of Nephrology, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905
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Corresponding Author:
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Short title: Ocular Manifestations of Familial Transthyretin Amyloidosis
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Jose S. Pulido, MD, MBA, MPH, MS Mayo Clinic Department of Ophthalmology and Department of Molecular Medicine 200 First Street, SW Rochester, MN 55905 Telephone: 507-284-3721 Fax: 507-284-4612 Email: [email protected]
For consideration of publication in the American Journal of Ophthalmology.
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Introduction
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Amyloidosis describes a diverse group of diseases, which result when a soluble protein undergoes a mutation, causing it to become misfolded and insoluble. The now-insoluble protein, termed amyloid, accumulates in the extracellular space, causing symptoms based on the site of its accumulation. Amyloidosis is subclassified according to the involved protein. Inherited forms of amyloidosis (familial amyloidosis) result from inherited protein mutations. The most common protein involved is transthyretin (TTR). Transthyretin, also called prealbumin, is composed of 127 amino acids. This protein functions to transport both thyroxine and vitamin A.1
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Over 100 TTR point mutations have been reported in the literature with differing phenotypes.2 TTR is synthesized in the choroid plexuses of the brain as well as the retinal pigment epithelial cells. Not surprisingly, ophthalmic manifestations of familial amyloidosis are reported.3 In fact, 32 of 130 (25%) reported TTR mutations have been noted to have ophthalmic involvement.4
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Few studies have looked at ocular manifestations in large cohorts of familial amyloidosis. This study reviewed the association between TTR familial amyloidosis and ocular involvement in a cohort of TTR patients seen at Mayo Clinic in Rochester, Minnesota.
Methods
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A retrospective chart review was conducted, including all patients with a diagnosis of familial amyloidosis seen at Mayo Clinic in Rochester, Minnesota, between January 1, 1970, and November 1, 2014. Approval for this retrospective cross-sectional study was obtained from the Institutional Review Board at Mayo Clinic (Rochester, Minnesota, USA). The principles of the Declaration of Helsinki were followed. All patients included in the study provided informed consent to allow use of their medical records in the amyloidosis database maintained by the Mayo Clinic Department of Hematology. Patients included in the database had biopsyconfirmed amyloidosis with Congo red staining. Mutations in TTR were identified by restriction fragment polymorphism (RFLP) between 1970 and 2001 (Mayo Medical Laboratories, Rochester, MN) or by direct Sanger sequencing after 2001 (Mayo Medical Laboratories, Rochester, MN).
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Patients were excluded if they had a syndrome consistent with primary (AL) amyloidosis, secondary (AA) amyloidosis, or familial Mediterranean fever. Patients were also excluded when specific TTR mutation information was unavailable to ensure only patients with TTR amyloidosis were included in the study. Finally, patients were excluded if they did not have an eye examination. Visual acuity, intraocular pressure, abnormalities documented within the ocular examination, and ocular diagnoses were recorded. Additionally, optical coherence tomography (OCT) of optic nerve, OCT macula, fluorescein angiography (FA), visual field, autofluorescence photographs, and fundus photographs were reviewed.
Results Inclusion criteria were met by 263 patients; 54 had eye examinations, and 26 eyes of 13 patients (24.1%) had ocular involvement. Clinical variables were compared between patients with (n=13) and without ophthalmic involvement (n=41) (Table 1). Median length of follow-up was 4.21 (range 0.052 to 15.8) years and 0.80 (range 0 to 8.81) years for patients with and
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without ocular involvement, respectively (p<0.05). Patients with ophthalmic involvement were significantly more likely to be women (46.2 vs. 14.6%, p=0.008) and non-Hispanic Caucasian 100.0% vs. 80.5% (p=0.05), respectively. Patients with ophthalmic involvement were more likely to have worse visual acuity at presentation (LogMAR 0.24±0.39 [Snellen equivalent 20/30] vs. LogMAR 0.00±0.25 [Snellen equivalent 20/20], p=0.02) than patients without ocular involvement. Of 13 patients with ophthalmic involvement, 11 were symptomatic at their first eye examination. Two patients developed ocular involvement after an initially negative eye screening. One patient with a Glu54Gly mutation developed vitreous amyloidosis 61.51 months after a negative eye screening and 61.57 months after amyloid diagnosis. A second patient with a Val30Met mutation developed vitreous amyloidosis 50.79 months after a negative eye screening and 226.78 months after amyloid diagnosis. All 13 patients had vitreous involvement (26/26 eyes); 1/1 patients with Glu89Lys mutation also had bilateral neurotrophic keratitis. Two patients, one with Glu54Gly mutation (Figure 1) and one with Asp18Glu mutation, had tortuous retinal vessels. Three patients had glaucoma, 5 of 26 eyes (19.2%). One patient had bilateral secondary open-angle glaucoma to steroids vs. amyloid (Ala36Pro), one patient had bilateral exfoliative glaucoma unknown if related to amyloid (Val30Met), and one patient with unilateral neovascular glaucoma (Tyr114Cys), which was secondary to a unilateral central retinal vein occlusion thought to be secondary to amyloidosis.
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For visually significant vitreous opacities, 13 of 13 patients were offered vitrectomy. Ten patients (17 eyes) underwent vitrectomy; three patients underwent unilateral vitrectomy, seven patients underwent bilateral vitrectomy, one patient refused vitrectomy, and two patients deferred vitrectomy until their other conditions stabilized. Vitrectomy significantly improved VA (0.70 LogMAR [Snellen equivalent 20/100] to 0.047 [Snellen equivalent ~20/20], p=0.003). The average age at vitrectomy was 56.4 ±14.1 years. In addition to vitrectomy, one patient received treatment with pan-retinal photocoagulation (PRP) and intravitreal anti-VEGF with the theoretical benefit of damaging the retinal pigment epithelium where TTR is produced. This patient subsequently required a vitrectomy. Two patients (three eyes) had recurrent vitreous amyloid after vitrectomy at a median 2.79 (range 2.05 to 5.00) years after vitrectomy. No eyes required repeat vitrectomy during the dates of this study as the recurrent vitreous amyloid was not visually significant.
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Twenty-two different TTR mutations were identified among patients in the study who had eye examinations. The most common mutations were Val30Met (n=14), Thr60Ala (n=9), and Val122Ile (n=6). Of the most common TTR mutations, none of the patients with either Thr60Ala or Val112Ile had ocular manifestations. Notably, patients with Val30Met were significantly more likely to have an eye examinations than patients with Thr60Ala (p=0.02). Ophthalmic involvement was found in 5 of 14 (35.7%) Val30Met patients. Three additional mutations, which have been reported to be involved with TTR amyloidosis but have not been previously reported to have ophthalmic manifestations, were identified: homozygous Gly6Ser (1 of 1 patients), Gly47Arg (1 of 1), and Glu89Lys (1 of 1) (Table 2). Finally, familial TTR amyloidosis is a systemic disease whose phenotype varies according to TTR mutation. Systemic findings consistent with an amyloidosis phenotype (autonomic neuropathy, carpal tunnel syndrome, cardiomyopathy, chronic kidney disease thought to be secondary to amyloidosis as determined by a nephrologist, leptomeningeal disease, peripheral neuropathy, and central nervous system involvement) were obtained from patient records and recorded in Table 2. Among this cohort of patients, patients with Val30Met and
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Ser77Tyr were more likely to have peripheral neuropathy, and patients with Val122Ile and Thr60Ala were more likely to have cardiomyopathy. A full discussion on the systemic manifestations of TTR amyloidosis in the Mayo Clinic cohort was published by Swiecicki et al.5
Discussion
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This clinical investigation of the associations between TTR amyloidosis and ocular manifestations is, to our knowledge, the largest study of TTR amyloidosis and ocular involvement in the United States.5 Of 54 included patients, 24.1% had ocular involvement. The most common ocular manifestation of TTR amyloidosis was vitreous involvement. While TTR amyloidosis is thought to equally affect men and women, females were found to be more commonly affected with vitreous involvement in this study (Table 1). Non-Hispanic Caucasians were also more likely to have ophthalmic involvement. Of patients whose eyes were involved, vitrectomy offered a significant improvement in visual acuity.
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Familial TTR amyloidosis is a systemic disease. Amyloidosis occurs when a single amino acid substitution, e.g. methionine for valine at position 30 of transthyretin (Val30Met), results in a dysfunctional TTR protein. TTR is a transport protein which is synthesized mainly in the liver, but it is also synthesized in the choroid plexuses of the brain as well as the retinal pigment epithelial cells (RPE).3 The hepatic production of TTR leads to systemic manifestations of familial amyloidosis. 2,3 Systemic manifestations of patients in this study include peripheral neuropathy, autonomic neuropathy, and cardiomyopathy. (Table 2) The prevalence of these systemic manifestations varied by TTR mutation; for instance, patients with Val30Met and Ser77Tyr were more likely to have peripheral neuropathy, and patients with Val122Ile and Thr60Ala were more likely to have cardiomyopathy. A full discussion can be found in the 2015 Amyloid article written by Swiecicki et al.5 Ocular findings in patients with familial TTR amyloidosis may be secondary to either the systemic production of dysfunctional TTR or production by the RPE. Vascular abnormalities, for instance, may be secondary to systemic TTR production. Vitreous amyloid is postulated to be secondary to RPE production of TTR.
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The natural history of vitreous amyloidosis tends to involve floaters that progress, leading to visual impairment, which can be so significant that it leads to only light perception vision.6, 7 As demonstrated by this paper, fortunately, vision impairment can be reversed with vitrectomy. Some patients can have restoration of 20/20 vision.8, 9 A 1987 study of 36 vitrectomies conducted on 30 eyes of 17 patients reported significant improvement in visual acuity after pars plana vitrectomy. In fact, 48% of eyes had visual acuity of 20/40 or better.10 Among studies which have reviewed the ocular manifestations of TTR amyloidosis, a study by Ando et al. found abnormal conjunctival vessels to be the most common manifestation (75.5%), followed by pupillary abnormalities (43.2%), keratoconjunctivitis sicca (KCS) (40.5%), glaucoma (19.2%), and vitreous opacity (5.4%).11 Notably, the Ando et al. study only included patients with Val30Met mutations. Our study noted KCS in one patient, but the other findings were not reported. Under-reporting of more subtle signs is likely due to the retrospective nature of this review. While this study did not find an increased incidence of abnormal conjunctival vessels, it did find two patients to have abnormal retinal vessels, which could be due to similar pathophysiology. The specific pathophysiology causing vascular abnormalities in patients with amyloidosis has not been described. A 1994 Yoshinaga paper described a patient with white sheaths along the retinal blood vessels with obstruction of the vessels.12 It is possible that Page 4 of 9
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vascular changes are due to direct infiltration with amyloid, which has been described for oculoleptomeningeal amyloidosis.13, 14 It is also possible that these vascular changes are secondary to underlying cardiac or pulmonary conditions. Patients with TTR amyloidosis have a high rate of sleep-disordered breathing15 as well as cardiopulmonary amyloidosis.16 One of the patients with tortuous vessels is a 65-year-old man with a history of Hodgkin lymphoma with secondary bleomycin lung toxicity. The other patient is a 41-year-old woman status post liver transplant with mild cardiac amyloidosis without heart failure and was found to have obstructive sleep apnea on referral to pulmonology. It is worthwhile to pursue workup in patients with known systemic amyloidosis who have ophthalmic vascular abnormalities for sleep-disordered breathing or cardiopulmonary amyloidosis.
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Other studies have also found a higher prevalence of glaucoma among cohorts of these patients. A study of 49 Japanese patients with FAP found 20 eyes of 12 patients (24%) had secondary glaucoma.17 The results of our Mayo Clinic study demonstrated three patients to have glaucoma, one patient with secondary open-angle glaucoma to steroids vs. amyloid (Ala36Pro), one patient with exfoliative glaucoma unknown if related to amyloid (Val30Met), and one patient with neovascular glaucoma (Tyr114Cys) (19.2% among patients with ocular involvement, but 4.6% of all eyes). Notably, the Ando study included only patients with Val30Met TTR mutations, while the Kimura study included 41 patients with Val30Met, 6 with Tyr114Cys and 1 with Ser50Ile. Obviously, the genetic compositions of these studies are different from the present study. Also, the association between glaucoma and amyloidosis has been attributed to amyloid deposits in the anterior chamber. Amyloid deposits in the anterior chamber were demonstrated in only 1 of the 13 patients with vitreous amyloidosis in this study with a Tyr114Cys mutation.18
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The difference between the genetic composition of this Mayo Clinic study and other studies is important, as the frequency of ocular involvement has been reported to vary between TTR mutations. A study in 2003, including 37 patients with Val30Met familial amyloidosis and 6 patients with Tyr114Cys, found vitreous opacities in 9 of 37 patients (14 eyes, 24%) with Val30Met and 6 of 6 patients (12 eyes, 100%) with Tyr114Cys.8
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Because the frequencies of ocular manifestations vary, it is important to consider the incidence of ocular manifestations in TTR amyloidosis among individual mutations and among all TTR mutations. This study is unique because it described the incidence of ocular involvement among 22 different TTR mutations. Other studies have been conducted on the incidence of ocular involvement in TTR amyloidosis. Many of these studies have focused on large populations with Val30Met mutations. The frequency of different ophthalmic manifestations, even among patients with Val30Met mutations, seems to vary somewhat by region. A large study of 483 Portuguese patients with Val30Met found 43 out of 483 (8.9%) patients to have vitreous involvement.19 In Japan, differing frequencies have been reported. Among 258 patients with Val30Met, 2 had vitreous involvement (0.78%) in a study performed in Ogawa village.20 In 96 patients examined in Arao, no vitreous opacities were found.21 Finally, a 1997 study in Japan, including 37 patients who had Val30Met mutation, found the incidence of vitreous opacity to be 5.4% (2 out of 37 patients).22 In addition to Val30Met and Tyr114Cys, our Mayo Clinic study also included six additional much less common mutations, which resulted in ocular involvement. The first, Ala36Pro, was found in one patient who also had eye involvement. This rare mutation has been previously described by four papers, which have included 12 patients. All 12 patients had Page 5 of 9
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vitreous involvement.23-27 Given that 100% of patients have been found to have vitreous involvement with Ala36Pro mutation, it is likely that such patients have vitreous involvement. Next, Asp18Glu is a very rare mutation. Two cases have been reported in the literature. The first patient had no vitreous involvement.28 The second patient was reported by our institution and is included within this study.29 One case of Phe33Ile was reviewed. This patient had vitreous involvement.30
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In addition, three of the patients with vitreous involvement had TTR mutations, which have not been reported to be associated with ocular manifestations. Notably, all three mutations are very rare, with only a few case reports. Two reports of Glu89Lys were reviewed. Neither patient had ophthalmic involvement.31, 32 Another two patients were reported to have Gly47Arg; neither had ocular manifestations.33, 34 Finally, homozygous Gly6Ser was not reported to be associated with vitreous amyloidosis.35
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It is also true that some TTR mutations have never been reported to have ophthalmic manifestations. Of the nine patients with Thr60Ala, none had ophthalmic involvement. Similarly, of the six included patients with Val122Ile, none had ophthalmic findings. Review of the literature did not reveal any reports of Thr60Ala or Val122Ile TTR amyloidosis patients with ophthalmic involvement, making such associations rare, if they exist.
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This study has limitations. First, while 263 patients were found to have TTR mutations, only 54 had eye examinations. While the most common mutation among patients who have eye examinations was Val30Met, which is the most common mutation worldwide, the most common mutation in the database was Thr60Ala (80 patients), which may indicate a selection bias. Of note, Val30Met is the most common mutation worldwide, and Val122Ile is the most common mutation in the United States; therefore, it is possible that these differences demonstrate referral bias.36, 37 In addition, patients whose symptoms and history were consistent with familial amyloidosis but did not have an identified TTR mutation were excluded. Most patients who were excluded for this reason were seen before genotyping was commonly done or when mutations were identified by RFLP, a method which screened patients only for the most common mutations. As such, some of the more rare mutations could have a higher prevalence in our population than what we have reported. Exclusion of these patients could influence frequencies of ophthalmic manifestations.
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In conclusion, this clinical investigation of association with ophthalmic involvement of TTR familial amyloidosis is one of only a few reviews published on such a topic and is the largest, to our knowledge, in the United States. Women were significantly more likely to have ophthalmic involvement. Vitreous involvement was the most common type of ophthalmic involvement. Affected patients had significant ocular morbidity, with significant differences between visual acuity at presentation between those with and without ophthalmic involvement. This impaired visual acuity improved after vitrectomy. Because TTR amyloidosis has been reported to be associated with vitreous involvement and because the impaired vision improves with vitrectomy, it is reasonable to refer patients with TTR amyloidosis for ophthalmic examinations, particularly those with mutations which have been reported to be associated with ophthalmic involvement. It is equally important that, if patients with vitreous amyloid present first to an ophthalmologist, they be referred for a systemic work-up.
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Acknowledgments/Disclosure
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a. Funding/Support: Research to Prevent Blindness; Vitreoretinal Surgery Foundation; funded in part by a grant from the Deshong Family. b. Financial Disclosures: Margaret Reynolds: Vitreoretinal Surgery Foundation. Kevin K. Veverka: No financial disclosures. Morie A. Gertz: Ionis, Prothena, Celgene, Janssen, Research to Practice, Novartis, Sandoz. Angela Dispenzieri: Research dollars from Takeda, Janssen, Celgene, Alnylam, Pfizer. Steven R. Zeldenrust: No financial disclosures. Nelson Leung: No financial disclosures. Jose S Pulido: No relevant financial disclosures. Lagen Laboratories (in vitro RPE laboratory supplier). c. Other Acknowledgments: None.
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1. Sandgren O. Ocular amyloidosis, with special reference to the hereditary forms with vitreous involvement. Surv Ophthalmol 1995;40(3):173-196. 2. Benson MD, Kincaid JC. The molecular biology and clinical features of amyloid neuropathy. Muscle Nerve 2007;36(4):411-423. 3. Ong DE, Davis JT, O'Day WT, Bok D. Synthesis and secretion of retinol-binding protein and transthyretin by cultured retinal pigment epithelium. Biochemistry 1994;33(7):1835-1842. 4. Rowczenio D, Wechaleker A. Mutations in Hereditary Amyloidosis http://amyloidosismutations.com/mut-attr.php. Accessed June 9, 2016. 5. Swiecicki PL, Zhen DB, Mauermann ML, et al. Hereditary ATTR amyloidosis: a singleinstitution experience with 266 patients. Amyloid 2015;22(2):123-131. 6. Liu T, Zhang B, Jin X, et al. Ophthalmic manifestations in a Chinese family with familial amyloid polyneuropathy due to a TTR Gly83Arg mutation. Eye (Lond) 2014;28(1):26-33. 7. Long D, Zeng J, Wu LQ, Tang LS, Wang HL, Wang H. Vitreous amyloidosis in two large mainland Chinese kindreds resulting from transthyretin variant Lys35Thr and Leu55Arg. Ophthalmic Genet 2012;33(1):28-33. 8. Koga T, Ando E, Hirata A, et al. Vitreous opacities and outcome of vitreous surgery in patients with familial amyloidotic polyneuropathy. Am J Ophthalmol 2003;135(2):188-193. 9. Beirao NM, Matos E, Beirao I, Costa PP, Torres P. Recurrence of vitreous amyloidosis and need of surgical reintervention in Portuguese patients with familial amyloidosis ATTR V30M. Retina 2011;31(7):1373-1377. 10. Doft BH, Machemer R, Skinner M, et al. Pars plana vitrectomy for vitreous amyloidosis. Ophthalmology 1987;94(6):607-611. 11. Ando E, Ando Y, Okamura R, Uchino M, Ando M, Negi A. Ocular manifestations of familial amyloidotic polyneuropathy type I: long-term follow up. Br J Ophthalmol 1997;81(4):295-298. 12. Yoshinaga T, Nakazato M, Ikeda S, Ohnishi A. [Three siblings homozygous for the transthyretin-Met30 gene in familial amyloidotic polyneuropathy--evaluation of their clinical pictures with reference to those of other 10 cases reported]. Rinsho Shinkeigaku 1994;34(2):99105.
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13. Ellie E, Camou F, Vital A, et al. Recurrent subarachnoid hemorrhage associated with a new transthyretin variant (Gly53Glu). Neurology 2001;57(1):135-137. 14. Petersen RB, Goren H, Cohen M, et al. Transthyretin amyloidosis: a new mutation associated with dementia. Ann Neurol 1997;41(3):307-313. 15. Bodez D, Guellich A, Kharoubi M, et al. Prevalence, Severity, and Prognostic Value of Sleep Apnea Syndromes in Cardiac Amyloidosis. Sleep 2016;39(7):1333-1341. 16. Ruberg FL, Berk JL. Transthyretin (TTR) cardiac amyloidosis. Circulation 2012;126(10):1286-1300. 17. Kimura A, Ando E, Fukushima M, et al. Secondary glaucoma in patients with familial amyloidotic polyneuropathy. Arch Ophthalmol 2003;121(3):351-356. 18. Meney J BE, Mincheva Z, Cauquil C, Labetoulle M, Adams D, Rousseau A. A prospective study of ocular manifestations in transthyretin-related familial amyloid polyneuropathy. Acta ophthalmologica 2014;92(s243):0. 19. Coutinho P. MdSA, Lopes Lima J., Resende Barbosa A. Forty years of experience with type I amyloid neuropathy. Review of 483 cases. . In: Glenner G. CP, de Freitas A., editor. Amyloid and Amyloidosis. Amsterdam: Execerpta Medica, 1980:88-98. 20. Kito S, Itoga E, Kamiya K, Kishida T, Yamamura Y. Studies on familial amyloid polyneuropathy in Ogawa Village, Japan. Eur Neurol 1980;19(3):141-151. 21. S. Araki TK, S. Tawara, T. Kuribayashi. Familial Amyloidotic polyneuropathy in Japanese In: G.G. Glenner PPC, A.F. Freitas, editor. Amyloid and Amyloidosis Amsterdam Excerpta Modica, 1980:67–77. 22. Tsukahara S, Matsuo T. Secondary glaucoma accompanied with primary familial amyloidosis. Ophthalmologica 1977;175(5):250-262. 23. Muller KR, Padbury R, Jeffrey GP, et al. Poor outcome after liver transplantation for transthyretin amyloid neuropathy in a family with an Ala36Pro transthyretin mutation: case report. Liver Transpl 2010;16(4):470-473. 24. Mascalchi M, Salvi F, Pirini MG, et al. Transthyretin amyloidosis and superficial siderosis of the CNS. Neurology 1999;53(7):1498-1503. 25. Zou X, Dong F, Zhang S, Tian R, Sui R. Transthyretin Ala36Pro mutation in a Chinese pedigree of familial transthyretin amyloidosis with elevated vitreous and serum vascular endothelial growth factor. Exp Eye Res 2013;110:44-49. 26. Jones LA, Skare JC, Cohen AS, Harding JA, Milunsky A, Skinner M. Familial amyloidotic polyneuropathy: a new transthyretin position 30 mutation (alanine for valine) in a family of German descent. Clin Genet 1992;41(2):70-73. 27. Jones LA, Skare JC, Harding JA, Cohen AS, Milunsky A, Skinner M. Proline at position 36: a new transthyretin mutation associated with familial amyloidotic polyneuropathy. Am J Hum Genet 1991;48(5):979-982. 28. Connors LH, Yamashita T, Yazaki M, Skinner M, Benson MD. A rare transthyretin mutation (Asp18Glu) associated with cardiomyopathy. Amyloid 2004;11(1):61-66. 29. Solano JM, Pulido JS, Salomao DR. A rare transthyretin mutation (Asp18Glu) associated with vitreous amyloid. Ophthalmic Genet 2007;28(2):73-75. 30. Nakazato M, Kangawa K, Minamino N, Tawara S, Matsuo H, Araki S. Revised analysis of amino acid replacement in a prealbumin variant (SKO-III) associated with familial amyloidotic polyneuropathy of Jewish origin. Biochem Biophys Res Commun 1984;123(3):921928.
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31. Niederhauser J, Lobrinus JA, Ochsner F, et al. Successful heart and liver transplantation in a Swiss patient with Glu89Lys transthyretin amyloidosis. Transplantation 2011;91(6):e40-42. 32. Nakamura M, Hamidi Asl K, Benson MD. A novel variant of transthyretin (Glu89Lys) associated with familial amyloidotic polyneuropathy. Amyloid 2000;7(1):46-50. 33. Fan J, Wu W, Chen W, et al. [Familial transthyretin amyloidosis with Gly47Arg mutation and cardiac involvement: a case report]. Zhonghua Xin Xue Guan Bing Za Zhi 2014;42(9):784785. 34. Murakami T, Maeda S, Yi S, et al. A novel transthyretin mutation associated with familial amyloidotic polyneuropathy. Biochem Biophys Res Commun 1992;182(2):520-526. 35. Damy T, Plante-Bordeneuve V, Dogan A. Characterization of untyped cardiac amyloidosis by mass spectrometry in a patient with Gly6Ser transthyretin polymorphism in fatal cardiogenic shock. Arch Cardiovasc Dis 2014;107(12):706-708. 36. Plante-Bordeneuve V. Update in the diagnosis and management of transthyretin familial amyloid polyneuropathy. J Neurol 2014;261(6):1227-1233. 37. Ando Y, Coelho T, Berk JL, et al. Guideline of transthyretin-related hereditary amyloidosis for clinicians. Orphanet J Rare Dis 2013;8:31.
Figure Legend
AC C
EP
TE D
FIGURE 1: Fundus photos of a 41-year-old woman with Glu54Gly TTR mutation before [(Top Left (Right eye) and Top Right (left eye)] and after [Bottom Left (Right eye) and Bottom Right (left eye)] bilateral vitrectomy demonstrating vitreous amyloid (Top Right and Top Left) and tortuous retinal arterioles and venules (entire figure).
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Table 1. Demographic and ophthalmic features of 54 patients with transthyretin amyloidosis (TTR)
14.63
Percent Non-Hispanic Caucasian
80.5 58.94±9.62
Median age at death (years)
67.07±11.21
0.008
100
0.05
55.16±14.95
0.430
73.72±10.13
M AN U
Median age at diagnosis (years)
46.15
SC
Percent Female
RI PT
No eye involvement (n=41)Eye involvement (n=13)P-value
0.579
4.73±2.94
4.30±2.33
0.889
Median age at first eye exam (years)
63.83±8.73
58.66±13.98
0.154
Median time from symptoms to exam (years)
3.78±3.23
3.33±5.02
0.738
Median time from diagnosis to eye exam (years)
1.05±2.62
0.049±5.24
0.779
0.00±0.25
0.24±0.39
0.0179
13.0±4.24
13.0±4.22
0.822
0.80±2.21
4.21±4.38
0.0452
0.09±0.22
0.17±0.64
0.0559
14.0±3.92
13.5±3.16
0.379
TE D
Diagnosis to death (years)
Median visual acuity for visit 1 (LogMAR)
Median length of follow-up (years)
EP
Median intraocular pressure for visit 1 (mmHg)
AC C
Median visual acuity for date of last follow-up (LogMAR)
Median intraocular pressure for date of last follow-up (mmHg)
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Table 2. Correlation of genetic mutation with ophthalmic and systemic findings in 54 patients with transthyretin amyloidosis (TTR) Number of Number of patients patients with eye Mutation without eye involvement involvement (n=41) (n=13) 0
Ala45Asp
2
0
Asp38Ala
1
0
Glu74Ser
1
0
Gly47Glu
2
0
Ile107Val
1
0
Ile84Thr
1
0
Leu58His
3
0
Phe33Leu
1
0
Ser77Tyr
3
Thr60Ala
9
Tyr69His
1
TE D
6
M AN U
Peripheral neuropathy Peripheral neuropathy
0
Peripheral neuropathy, cardiomyopathy, chronic kidney disease Peripheral neuropathy, autonomic neuropathy, cardiomyopathy Leptomeningeal
0
Cardiomyopathy
0
0
Val30Met
9
5
Ala36Pro
0
1
Asp18Glu
0
1
Glu54Gly
0
1
AC C
Peripheral neuropathy, autonomic neuropathy, cardiomyopathy Peripheral neuropathy, autonomic neuropathy, cardiomyopathy Cardiomyopathy, peripheral neuropathy Peripheral neuropathy, cardiomyopathy Peripheral neuropathy, cardiomyopathy, chronic kidney disease Peripheral neuropathy, autonomic neuropathy, Cardiomyopathy
SC
1
EP
Ala120Ser
Val122Ile
Systemic Findings
RI PT
Ophthalmic Findings
Peripheral neuropathy, Vitreous opacities, exfoliative autonomic neuropathy, carpal glaucoma tunnel syndrome, chronic kidney disease, Peripheral neuropathy, Vitreous opacities, secondary autonomic neuropathy, glaucoma chronic kidney disease, cerebral deposition Peripheral neuropathy, Vitreous opacities, tortuous cardiomyopathy, chronic retinal vessels kidney disease requiring transplant Peripheral neuropathy, Vitreous opacities, tortuous autonomic neuropathy, retinal vessels cardiomyopathy
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Ophthalmic Findings
Glu89Lys
0
1
Vitreous opacities, neurotrophic keratitis
Gly47Arg
0
1
Vitreous opacities
Gly6Ser
0
1
Vitreous opacities
Phe33Ile
0
1
Vitreous opacities
1
Peripheral ischemic retinopathy, central retinal vein occlusion, secondary neovascular glaucoma, anterior chamber deposits, vitreous opacities, direct optic nerve infiltration
TE D EP AC C
Peripheral neuropathy, autonomic neuropathy, cardiomyopathy Peripheral neuropathy, cardiomyopathy, carpal tunnel syndrome Peripheral neuropathy, cardiomyopathy
Peripheral neuropathy, autonomic neuropathy, cardiomyopathy
SC
0
M AN U
Tyr114Cys
Systemic Findings
RI PT
Number of Number of patients patients with eye Mutation without eye involvement involvement (n=41) (n=13)
AC C
EP
TE D
M AN U
SC
RI PT
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EP
TE D
M AN U
SC
RI PT
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AC C
EP
TE D
M AN U
SC
RI PT
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