Isolated Vitreoretinal Amyloidosis in the Absence of TransthyretinMutations

Vitreoretinal amyloidosis is believed to be associated universally withmutations in the genes encoding transthyretin and found exclusively as partof the familial amyloidotic polyneuropathy (FAP) syndrome.¹ Wedescribe herein an unusual case of biopsy-proved vitreoretinal amyloidosiswithout systemic involvement and demonstrate that vitreoretinal amyloidosiscan occur with intact wild-type transthyretin genes.

A 70-year-old woman with a history of hypercholesterolemia, chronicobstructive pulmonary disease, a distant cerebrovascular accident, and bilateralcataract extractions was first seen by us with "black snow" clouding her visionin both eyes. Review of systems was otherwise unremarkable, and her familyhistory was negative for amyloidosis. Her visual acuity was 20/50 OD and 20/60OS and worsened with pinhole examination. There was no relative afferent pupillarydefect, intraocular tensions were within normal limits, and slitlamp examinationdisclosed quiet anterior segments and clear well-centered posterior chamberintraocular lens implants bilaterally. Dilated fundus examination showed multiple,white, refractile vitreous opacities dispersed in a syneretic vitreous inboth eyes (Figure 1A). Yellow depositswere also seen deep to the retina in the periphery (Figure 1B). A therapeutic and diagnostic left vitrectomy was thenperformed.

Histopathologic analysis of the vitreous biopsy specimen showed eosinophiliclobules that stained positively with Congo red (Figure 2A) and demonstrated birefringence when examined under polarizedlight (Figure 2B). These findingswere diagnositic of amyloidosis. Oil-red-O stain was negative for lipids andvon Kossa stain was negative for calcium phosphate salts. Genomic DNA wasthen isolated from peripheral blood, and exons corresponding to the entiretransthyretin protein were amplified by the polymerase chain reaction. DirectDNA sequence analysis of the amplified fragments revealed no mutations inthe entire coding sequence, demonstrating that this patient was homozygousfor wild-type transthyretin. Moreover, single-stranded conformational polymorphismand isoelectric focusing analyses did not show any abnormal patterns for transthyretin.The patient subsequently underwent vitrectomy of the right eye. With 7 yearsof clinical follow-up at this report, she has not developed any signs or symptomsof systemic amyloidosis, although there have been increases in the vitreousdeposits in both eyes.

Amyloidosis is a heterogeneous group of disorders involving the depositionof insoluble fibrillar hyaline aggregates in peripheral tissues. Amyloidosisaffecting 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, vitreoretinalamyloidosis is thought to be found exclusively in individuals with FAP andassociated universally with mutations in the transthyretin gene. To date,more than 80 such transthyretin mutations have been described.¹ Incontrast, systemic amyloidosis can result from a number of distinct amyloiddeposits, including wild-type transthyretin³ aswell as other fibrillar proteins.⁴

To our knowledge, this is the first case report of vitreoretinal amyloidosisin the absence of transthyretin mutations. In addition, no signs of systemicamyloidosis suggestive of FAP were evident 7 years after the patient's initialpresentation, although we cannot exclude the possibility of a subclinicallevel of amyloid deposition in other tissues.^5,6 Thesefindings raise the possibility that isolated vitreoretinal amyloidosis mayrepresent a disorder separate from FAP. We conclude that vitreoretinal amyloidosisencompasses a more heterogeneous group of disorders than has been previouslydescribed.

Corresponding author and reprints: Shizuo Mukai, MD, Department ofOphthalmology, Retina Service, Massachusetts Eye and Ear Infirmary, 243 CharlesSt, Boston, MA 02114 (e-mail: shizuo_mukai@meei.harvard.edu).