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Isolated Vitreoretinal Amyloidosis in the Absence of Transthyretin Mutations
Arch Ophthalmol. 2004;122:123-125.
Vitreoretinal amyloidosis is believed to be associated universally with mutations in the genes encoding transthyretin and found exclusively as part of the familial amyloidotic polyneuropathy (FAP) syndrome.1 We describe herein an unusual case of biopsy-proved vitreoretinal amyloidosis without systemic involvement and demonstrate that vitreoretinal amyloidosis can occur with intact wild-type transthyretin genes.
Report of a Case
A 70-year-old woman with a history of hypercholesterolemia, chronic obstructive pulmonary disease, a distant cerebrovascular accident, and bilateral cataract extractions was first seen by us with "black snow" clouding her vision in both eyes. Review of systems was otherwise unremarkable, and her family history was negative for amyloidosis. Her visual acuity was 20/50 OD and 20/60 OS and worsened with pinhole examination. There was no relative afferent pupillary defect, intraocular tensions were within normal limits, and slitlamp examination disclosed quiet anterior segments and clear well-centered posterior chamber intraocular lens implants bilaterally. Dilated fundus examination showed multiple, white, refractile vitreous opacities dispersed in a syneretic vitreous in both eyes (Figure 1A). Yellow deposits were also seen deep to the retina in the periphery (Figure 1B). A therapeutic and diagnostic left vitrectomy was then performed.
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Figure 1. A, Preoperative fundus photograph demonstrating white vitreous deposits. B, Postoperative fundus photograph of the peripheral retina demonstrating yellow deposits under the retina.
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Histopathologic analysis of the vitreous biopsy specimen showed eosinophilic lobules that stained positively with Congo red (Figure 2A) and demonstrated birefringence when examined under polarized light (Figure 2B). These findings were diagnositic of amyloidosis. Oil-red-O stain was negative for lipids and von Kossa stain was negative for calcium phosphate salts. Genomic DNA was then isolated from peripheral blood, and exons corresponding to the entire transthyretin protein were amplified by the polymerase chain reaction. Direct DNA sequence analysis of the amplified fragments revealed no mutations in the entire coding sequence, demonstrating that this patient was homozygous for wild-type transthyretin. Moreover, single-stranded conformational polymorphism and isoelectric focusing analyses did not show any abnormal patterns for transthyretin. The patient subsequently underwent vitrectomy of the right eye. With 7 years of clinical follow-up at this report, she has not developed any signs or symptoms of systemic amyloidosis, although there have been increases in the vitreous deposits in both eyes.
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Figure 2. Histopathologic analysis of the vitreous biopsy specimen. A, Positive staining for eosinophilic lobules with Congo red is evident (original magnification x250). B, Birefringence is seen when the specimen is examined under polarized light (original magnification x250).
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Comment
Amyloidosis is a heterogeneous group of disorders involving the deposition of insoluble fibrillar hyaline aggregates in peripheral tissues. Amyloidosis affecting the vitreous was first reported in 1953 in individuals with FAP, an autosomal dominant disorder that includes vitreopathy, cardiomyopathy, and peripheral neuropathy.2 In fact, vitreoretinal amyloidosis is thought to be found exclusively in individuals with FAP and associated universally with mutations in the transthyretin gene. To date, more than 80 such transthyretin mutations have been described.1 In contrast, systemic amyloidosis can result from a number of distinct amyloid deposits, including wild-type transthyretin3 as well as other fibrillar proteins.4
To our knowledge, this is the first case report of vitreoretinal amyloidosis in the absence of transthyretin mutations. In addition, no signs of systemic amyloidosis suggestive of FAP were evident 7 years after the patient's initial presentation, although we cannot exclude the possibility of a subclinical level of amyloid deposition in other tissues.5-6 These findings raise the possibility that isolated vitreoretinal amyloidosis may represent a disorder separate from FAP. We conclude that vitreoretinal amyloidosis encompasses a more heterogeneous group of disorders than has been previously described.
AUTHOR INFORMATION
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Fina C. Barouch, MD
Boston, Mass
Merrill D. Benson, MD
Indianapolis, Ind
Shizuo Mukai, MD
Boston
Corresponding author and reprints: Shizuo Mukai, MD, Department of Ophthalmology, Retina Service, Massachusetts Eye and Ear Infirmary, 243 Charles St, Boston, MA 02114 (e-mail: shizuo_mukai{at}meei.harvard.edu).
REFERENCES
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1. Bhisitkul RB, Mukai S. Vitreous amyloidosis. In: Albert DM, Jakobiec FA, eds. Principles and Practice of Ophthalmology. 2nd ed. Philadelphia, Pa: WB Saunders Co; 2000:2530-2539.
2. Kantarian AD, De Jong RN. Familial primary amyloidosis with nervous system involvement. Neurology. 1953;3:399-409.
3. Westermark P, Sletten K, Johansson B, Cornwell GG III. Fibril in senile systemic amyloidosis is derived from normal transthyretin. Proc Natl Acad Sci U S A. 1990;87:2843-2845.
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4. Lachmann HJ, Booth DR, Booth SE, et al. Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. N Engl J Med. 2002;346:1786-1791.
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5. Sandgren O. Ocular amyloidosis, with special reference to the hereditary forms of vitreous involvement. Surv Ophthalmol. 1995;40:173-196.
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6. Schwartz MF, Green WR, Michels RM, Kincaid MC, Fogle J. An unusual case of ocular involvement in primary systemic nonfamilial amyloidosis. Ophthalmology. 1982;89:394-401.
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SECTION EDITOR: W. RICHARD GREEN, MD
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