http://informahealthcare.com/amy ISSN: 1350-6129 (print), 1744-2818 (electronic) Amyloid, 2014; 21(2): 140–142 ! 2014 Informa UK Ltd. DOI: 10.3109/13506129.2014.892871
LETTER TO THE EDITOR
Chinese familial transthyretin amyloidosis with vitreous involvement is associated with the transthyretin mutation Gly83Arg: a case report and literature review Jie Yin1*, Xinyi Xia2*, Yao Shi1, Yan Lu1, Changlin Zhao1, Zhenping Huang1, and Nong Tian1 1
Department of Ophthalmology and 2Institute of Clinical Laboratory Medicine, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, People’s Republic of China
We would like to report close on two sisters with recurrent vitreous involvement after vitrectomy and the need of subsequent surgical reintervention prompted the diagnosis of a TTR-related, familial form of vitreous amyloidosis. DNA analysis of the TTR gene showed a G!C transversion at the first nucleotide of codon 83, indicating a replacement of glycine (CGC) by arginine (GGC). A heterozygous mutation Gly83Arg was detected in two members of the family but not in unrelated controls. The diagnosis was made 5 years after the initial onset of symptoms. We offer this letter to strengthen the characterization of TTR-related vitreous amyloidosis, including family history, high vitreous recurrence after incomplete vitrectomy, and amyloid deposition to the posterior lens capsule in the anterior vitreous similar in appearance to footplate attachments. Through a literature review, we found that the TTR Gly83Arg mutant which was only reported in Chinese patients may be an important indication of solitary ocular vitreous amyloidosis without evidence of systemic involvement and was the most frequent cause of adult-onset vitreous amyloidosis in Chinese people. A 40-year-old Chinese female visited the Department of Ophthalmology, Jinling Hospital, Nanjing, China and complained of progressive deterioration of vision in her right eye. She had undergone vitrectomy in her right eye 4 years ago and in her left eye 5 years ago due to suspected vitreous hemorrhage. Her best-corrected visual acuity (BCVA) was 20/100 in the right eye and 20/40 in the left eye. The intraocular pressure was normal. Anterior segment slit-lamp examination showed linear footplate-like vitreous opacities close to the posterior lens capsule of both eyes. Fundus examination after pupillary dilatation revealed in the right eye 4+ vitreous opacities with a glass-wool appearance, and 2+ *These two authors contributed equally to this work. Address for correspondence: Nong Tian, Department of Ophthalmology, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing 210002, People’s Republic of China. Tel: +86 2580863287. Fax: +86 2580824548. E-mail: tiannong@ msn.com
Keywords Familial transthyretin amyloidosis, transthyretin, vitreous opacities History Received 18 August 2013 Revised 9 January 2014 Accepted 27 January 2014 Published online 6 March 2014
vitreous opacities in the left eye. The fundus was difficult to see due to dense vitreous opacities. The patient was otherwise healthy. She had no past medical history of peripheral neuropathy. Complete examinations including laboratory evaluations, electrocardiography and echocardiography revealed no possibility of present peripheral neuropathy. She again underwent a standard pars plana vitrectomy in the right eye. The anterior diseased vitreous was removed with great caution to avoid injury to the lens because we wanted to remain her accommodation. Post-operatively her BCVA improved to 20/40 in the right eye. Histopathological staining with Congo red of the vitreous and conjunctival specimens confirmed positive deposition of amyloid. The TTR gene of the patient was analyzed after informed consent. All four coding exons of the TTR gene and their flanking introns were amplified by polymerase chain reaction and sequenced directly. Sequencing of exon 3 revealed a single base-pair substitution, which resulted in an amino acid substitution at position 83 (TTR Gly83Arg). Complete sequencing of the TTR gene showed that no other mutations existed. The patient told us her mother and younger sister had the same symptoms. Based on this information, we guessed that a familial factor was a possibility in the early onset of amyloidosis with vitreous involvement. Therefore, we performed genetic screenings and complete physical examinations of her younger sister and two offspring. Her mother was never examined due to ambulatory disability and
TTRGly83Arg with vitreous involvement in China
DOI: 10.3109/13506129.2014.892871
141
Table 1. Chinese ATTR-amyloid patients with eye complications. Ocular involvement No. 1 2 3 4 5 6 7 8
Mutation
Vitreous amyloidosis
Radiculopathy
Glaucoma
Other
Other
Nation, province or district
Age (years)*
Lys35Thr Ala36Pro Leu 55 pro Leu 55 pro Gly83Argjj Gly83Arg# Gly83Arg Tyr 114 Cys
+ + + + + + + +
+ + +
+z +**
y +y,ô,x +ô +ô
Hunan [6] China [7] Taiwan [8] Hunan [6] China [4] Guizhou [5] Yunan China [9]
40–50 30–50 20–24 29–33 40 40–47 Present case 41
*At symptom onset. yDysfunction of peripheral nerves paresthesia: sensory dissociation; allodynia; distal weakness; proximal weakness; carpal tunnel syndrome. zCorneal ulcerations. ôAutonomic dysfunction: diarrhea; constipation; orthostatic hypotension; abdominal pain; vomiting; erectile dysfunction; urine retention. xInvolvement of other organs: cardiac involvement; arrhythmia; cardiac hypertrophy; renal dysfunction; peptic ulcer; hepatic dysfunction. jjHomozygous for ATTR. #Li Zhu. **Pupil deposit.
transportation difficulties. Genetic analysis confirmed that her younger sister (38 years old) carried this mutation. She had undergone bilateral vitrectomy 3 years ago and also suffered the same bilateral deterioration of vision postoperatively. We also observed slight amyloid footplate deposits close to the posterior lens on both eyes of the younger sister. The 26-month follow-up of the elder sister after the secondary vitrectomy showed that the BCVA of her right eye remained stable and intraocular pressure was normal. No severe complications (neither retinal detachment nor glaucoma) were observed throughout the follow-up period. In this patient, the lag time between the initial onset of symptoms and confirmed diagnosis of familial transthyretin amyloidosis was at least 5 years, mainly abetted by the atypical symptoms and careless family history inquiry. Both patients suffered impaired vision after the first bilateral vitrectomy due to reopacification of the retrolental vitreous. We propose that two mechanisms were the cause of the recurrence. The first is continuous intraocular production of amyloid fibrils. TTR is synthesized mainly in the liver, but also in retinal pigment epithelial cells [1]. The fact that patients after liver transplantation were still at risk for developing ocular complications proved continuous intraocular TTR production [2]. In addition, recurrence could be induced by incomplete vitrectomy which may increase the risks of recurrent vitreous amyloidosis. As a result, the necessity for early and complete vitreous removal has been emphasized [3]. Our case is a demonstration that vitreous amyloidosis is prone to misdiagnose. Amyloidosis-related mutations in the TTR gene in Chinese people have been rarely reported. We conducted a literature search in PubMed from 1980 to May 2013 using the terms ‘‘amyloidosis’’, ‘‘transthyretin’’, ‘‘Chinese’’ and ‘‘vitreous amyloidosis’’ to gain a better understanding of the characteristics findings specific to Chinese people. Clinical data were obtained from primary reports published in English, or at least with an English abstract, and only patients undergone proper genetic testing were included. Thirteen point mutations in the TTR gene of Chinese origin had been reported.
Among these mutations, Val30Ala, Ala97Ser and Gly83Arg were the most common amyloidogenic forms. In 2008, Chen et al. [4] reported a novel point mutation associated with familial vitreous amyloidosis, the Gly83Arg mutation. This has been followed by a similar finding [5], and our present cases. We investigated the clinical characteristics of hereditary ocular amyloidosis (emphasizing vitreous involvement) specifically in TTR amyloidosis Chinese patients and found a significant difference between those with the Gly83Arg mutation and those with other mutations (Table 1). Patients presented with symptoms of vitreous amyloid, but in almost all cases there was no other evidence of systemic amyloidosis at the initial presentation. The most current list of mutations in TTR (www.amyloidosismutations.com) leads us to believe that the TTR mutation Gly83Arg has been reported only for Chinese people, and this mutation accounts for the most frequent etiology of adult-onset vitreous amyloidosis in the Chinese.
Declaration of interest The authors report no conflict of interest.
References 1. Kawaji T, Ando Y, Nakamura M, Yamamoto K, Ando E, Takano A, Inomata Y, et al. Transthyretin synthesis in rabbit ciliary pigment epithelium. Exp Eye Res 2005;81:306–12. 2. Hara R, Kawaji T, Ando E, Ohya Y, Ando Y, Tanihara H. Impact of liver transplantation on transthyretin-related ocular amyloidosis in Japanese patients. Arch Ophthalmol 2010;128:206–10. 3. Beira˜o NM, Matos E, Beira˜o I, Costa PP, Torres P. Recurrence of vitreous amyloidosis and need of surgical reintervention in Portuguese patients with familial amyloidosis ATTR V30M. Retina 2011;31:1373–7. 4. Chen L, Lu¨ L, Zhang P, Li Y, Lin J. Transthyretin Arg-83 mutation in vitreous amyloidosis. Yan Ke Xue Bao 2008;24:65–7. 5. Xie Y, Zhao Y, Zhou JJ, Wang X. Identification of a TTR gene mutation in a family with hereditary vitreous amyloidosis. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2012;29: 13–15. 6. 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;33:28–33.
142
J. Yin et al.
7. 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;110:44–9. 8. Chou CT, Lee CC, Chang DM, Buxbaum JN, Jacobson DR. Familial amyloidosis in one Chinese family: clinical,
Amyloid, 2014; 21(2): 140–142
immunological, and molecular genetic analysis. J Intern Med 1997;241:327–31. 9. Zhang Y, Deng YL, Ma JF, Zheng L, Hong Z, Wang ZQ, Sheng CY, et al. Transthyretin-related hereditary amyloidosis in a Chinese family with TTR Y114C mutation. Neurodegener Dis 2011;8: 187–93.
Copyright of Amyloid is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
LETTER TO THE EDITOR
Chinese familial transthyretin amyloidosis with vitreous involvement is associated with the transthyretin mutation Gly83Arg: a case report and literature review Jie Yin1*, Xinyi Xia2*, Yao Shi1, Yan Lu1, Changlin Zhao1, Zhenping Huang1, and Nong Tian1 1
Department of Ophthalmology and 2Institute of Clinical Laboratory Medicine, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, People’s Republic of China
We would like to report close on two sisters with recurrent vitreous involvement after vitrectomy and the need of subsequent surgical reintervention prompted the diagnosis of a TTR-related, familial form of vitreous amyloidosis. DNA analysis of the TTR gene showed a G!C transversion at the first nucleotide of codon 83, indicating a replacement of glycine (CGC) by arginine (GGC). A heterozygous mutation Gly83Arg was detected in two members of the family but not in unrelated controls. The diagnosis was made 5 years after the initial onset of symptoms. We offer this letter to strengthen the characterization of TTR-related vitreous amyloidosis, including family history, high vitreous recurrence after incomplete vitrectomy, and amyloid deposition to the posterior lens capsule in the anterior vitreous similar in appearance to footplate attachments. Through a literature review, we found that the TTR Gly83Arg mutant which was only reported in Chinese patients may be an important indication of solitary ocular vitreous amyloidosis without evidence of systemic involvement and was the most frequent cause of adult-onset vitreous amyloidosis in Chinese people. A 40-year-old Chinese female visited the Department of Ophthalmology, Jinling Hospital, Nanjing, China and complained of progressive deterioration of vision in her right eye. She had undergone vitrectomy in her right eye 4 years ago and in her left eye 5 years ago due to suspected vitreous hemorrhage. Her best-corrected visual acuity (BCVA) was 20/100 in the right eye and 20/40 in the left eye. The intraocular pressure was normal. Anterior segment slit-lamp examination showed linear footplate-like vitreous opacities close to the posterior lens capsule of both eyes. Fundus examination after pupillary dilatation revealed in the right eye 4+ vitreous opacities with a glass-wool appearance, and 2+ *These two authors contributed equally to this work. Address for correspondence: Nong Tian, Department of Ophthalmology, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing 210002, People’s Republic of China. Tel: +86 2580863287. Fax: +86 2580824548. E-mail: tiannong@ msn.com
Keywords Familial transthyretin amyloidosis, transthyretin, vitreous opacities History Received 18 August 2013 Revised 9 January 2014 Accepted 27 January 2014 Published online 6 March 2014
vitreous opacities in the left eye. The fundus was difficult to see due to dense vitreous opacities. The patient was otherwise healthy. She had no past medical history of peripheral neuropathy. Complete examinations including laboratory evaluations, electrocardiography and echocardiography revealed no possibility of present peripheral neuropathy. She again underwent a standard pars plana vitrectomy in the right eye. The anterior diseased vitreous was removed with great caution to avoid injury to the lens because we wanted to remain her accommodation. Post-operatively her BCVA improved to 20/40 in the right eye. Histopathological staining with Congo red of the vitreous and conjunctival specimens confirmed positive deposition of amyloid. The TTR gene of the patient was analyzed after informed consent. All four coding exons of the TTR gene and their flanking introns were amplified by polymerase chain reaction and sequenced directly. Sequencing of exon 3 revealed a single base-pair substitution, which resulted in an amino acid substitution at position 83 (TTR Gly83Arg). Complete sequencing of the TTR gene showed that no other mutations existed. The patient told us her mother and younger sister had the same symptoms. Based on this information, we guessed that a familial factor was a possibility in the early onset of amyloidosis with vitreous involvement. Therefore, we performed genetic screenings and complete physical examinations of her younger sister and two offspring. Her mother was never examined due to ambulatory disability and
TTRGly83Arg with vitreous involvement in China
DOI: 10.3109/13506129.2014.892871
141
Table 1. Chinese ATTR-amyloid patients with eye complications. Ocular involvement No. 1 2 3 4 5 6 7 8
Mutation
Vitreous amyloidosis
Radiculopathy
Glaucoma
Other
Other
Nation, province or district
Age (years)*
Lys35Thr Ala36Pro Leu 55 pro Leu 55 pro Gly83Argjj Gly83Arg# Gly83Arg Tyr 114 Cys
+ + + + + + + +
+ + +
+z +**
y +y,ô,x +ô +ô
Hunan [6] China [7] Taiwan [8] Hunan [6] China [4] Guizhou [5] Yunan China [9]
40–50 30–50 20–24 29–33 40 40–47 Present case 41
*At symptom onset. yDysfunction of peripheral nerves paresthesia: sensory dissociation; allodynia; distal weakness; proximal weakness; carpal tunnel syndrome. zCorneal ulcerations. ôAutonomic dysfunction: diarrhea; constipation; orthostatic hypotension; abdominal pain; vomiting; erectile dysfunction; urine retention. xInvolvement of other organs: cardiac involvement; arrhythmia; cardiac hypertrophy; renal dysfunction; peptic ulcer; hepatic dysfunction. jjHomozygous for ATTR. #Li Zhu. **Pupil deposit.
transportation difficulties. Genetic analysis confirmed that her younger sister (38 years old) carried this mutation. She had undergone bilateral vitrectomy 3 years ago and also suffered the same bilateral deterioration of vision postoperatively. We also observed slight amyloid footplate deposits close to the posterior lens on both eyes of the younger sister. The 26-month follow-up of the elder sister after the secondary vitrectomy showed that the BCVA of her right eye remained stable and intraocular pressure was normal. No severe complications (neither retinal detachment nor glaucoma) were observed throughout the follow-up period. In this patient, the lag time between the initial onset of symptoms and confirmed diagnosis of familial transthyretin amyloidosis was at least 5 years, mainly abetted by the atypical symptoms and careless family history inquiry. Both patients suffered impaired vision after the first bilateral vitrectomy due to reopacification of the retrolental vitreous. We propose that two mechanisms were the cause of the recurrence. The first is continuous intraocular production of amyloid fibrils. TTR is synthesized mainly in the liver, but also in retinal pigment epithelial cells [1]. The fact that patients after liver transplantation were still at risk for developing ocular complications proved continuous intraocular TTR production [2]. In addition, recurrence could be induced by incomplete vitrectomy which may increase the risks of recurrent vitreous amyloidosis. As a result, the necessity for early and complete vitreous removal has been emphasized [3]. Our case is a demonstration that vitreous amyloidosis is prone to misdiagnose. Amyloidosis-related mutations in the TTR gene in Chinese people have been rarely reported. We conducted a literature search in PubMed from 1980 to May 2013 using the terms ‘‘amyloidosis’’, ‘‘transthyretin’’, ‘‘Chinese’’ and ‘‘vitreous amyloidosis’’ to gain a better understanding of the characteristics findings specific to Chinese people. Clinical data were obtained from primary reports published in English, or at least with an English abstract, and only patients undergone proper genetic testing were included. Thirteen point mutations in the TTR gene of Chinese origin had been reported.
Among these mutations, Val30Ala, Ala97Ser and Gly83Arg were the most common amyloidogenic forms. In 2008, Chen et al. [4] reported a novel point mutation associated with familial vitreous amyloidosis, the Gly83Arg mutation. This has been followed by a similar finding [5], and our present cases. We investigated the clinical characteristics of hereditary ocular amyloidosis (emphasizing vitreous involvement) specifically in TTR amyloidosis Chinese patients and found a significant difference between those with the Gly83Arg mutation and those with other mutations (Table 1). Patients presented with symptoms of vitreous amyloid, but in almost all cases there was no other evidence of systemic amyloidosis at the initial presentation. The most current list of mutations in TTR (www.amyloidosismutations.com) leads us to believe that the TTR mutation Gly83Arg has been reported only for Chinese people, and this mutation accounts for the most frequent etiology of adult-onset vitreous amyloidosis in the Chinese.
Declaration of interest The authors report no conflict of interest.
References 1. Kawaji T, Ando Y, Nakamura M, Yamamoto K, Ando E, Takano A, Inomata Y, et al. Transthyretin synthesis in rabbit ciliary pigment epithelium. Exp Eye Res 2005;81:306–12. 2. Hara R, Kawaji T, Ando E, Ohya Y, Ando Y, Tanihara H. Impact of liver transplantation on transthyretin-related ocular amyloidosis in Japanese patients. Arch Ophthalmol 2010;128:206–10. 3. Beira˜o NM, Matos E, Beira˜o I, Costa PP, Torres P. Recurrence of vitreous amyloidosis and need of surgical reintervention in Portuguese patients with familial amyloidosis ATTR V30M. Retina 2011;31:1373–7. 4. Chen L, Lu¨ L, Zhang P, Li Y, Lin J. Transthyretin Arg-83 mutation in vitreous amyloidosis. Yan Ke Xue Bao 2008;24:65–7. 5. Xie Y, Zhao Y, Zhou JJ, Wang X. Identification of a TTR gene mutation in a family with hereditary vitreous amyloidosis. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2012;29: 13–15. 6. 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;33:28–33.
142
J. Yin et al.
7. 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;110:44–9. 8. Chou CT, Lee CC, Chang DM, Buxbaum JN, Jacobson DR. Familial amyloidosis in one Chinese family: clinical,
Amyloid, 2014; 21(2): 140–142
immunological, and molecular genetic analysis. J Intern Med 1997;241:327–31. 9. Zhang Y, Deng YL, Ma JF, Zheng L, Hong Z, Wang ZQ, Sheng CY, et al. Transthyretin-related hereditary amyloidosis in a Chinese family with TTR Y114C mutation. Neurodegener Dis 2011;8: 187–93.
Copyright of Amyloid is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
