Polymorphic corneal amyloidosis: a disorder due to a novel mutation in the transforming growth factor beta-induced (BIGH3) gene.

PURPOSE: To characterize the clinicopathologic phenotype as well as the molecular genetic basis of an autosomal dominant form of corneal amyloidosis. DESIGN: Clinicopathologic and molecular genetic study of a family with a form of corneal amyloidosis. PARTICIPANTS: Forty-nine individuals from one family were studied. METHODS: The medical records of affected family members were reviewed, and corneal tissue from those who had undergone penetrating keratoplasty (PK) was examined. Several family members were examined clinically, and corneas were photographed. Deoxyribonucleic acid from blood or buccal swabs was extracted from each consenting family member to determine the status of their transforming growth factor beta-induced (TGFBI) gene. The coding region of the TGFBI gene was analyzed for mutations in the proband\u27s DNA, and compared with the nucleotide sequences of normal individuals. This was performed by amplifying and sequencing all exons of the TGFBI gene. In all other family members, only exons 4, 8, 11, and 12 of the gene were amplified, sequenced, and analyzed for mutations. MAIN OUTCOME MEASURES: Clinicopathologic manifestations in relation to mutational status of the TGFBI gene. RESULTS: Slit-lamp biomicroscopy revealed bilateral multiple polymorphic, polygonal, refractile, chipped ice-appearing gray and white opacities. There were also occasional deep filamentous lines that did not form a distinct lattice pattern. Corneal tissue of affected individuals who underwent PK contained widespread deposits of amyloid within the corneal stroma, particularly in the deep central stroma. Twelve members of the family were found to have a heterozygous single mutation in the TGFBI gene leading to a predicted amino acid substitution of aspartic acid for alanine (A546D). Nine of these individuals had ophthalmologist-documented corneal disease. The remaining 3, who were 11, 14, and 15 years old, were asymptomatic. In addition, 4 inconsequential polymorphisms with the nucleotide changes 387 G/A (R129R), 981 G/A (V327V), 1416 T/C (L472L), and 1620 C/T (F540F) were found. CONCLUSION: A distinct, progressive form of corneal amyloidosis with an autosomal dominant mode of inheritance is characterized clinically by the presence of refractile polymorphic corneal opacities. We have designated this entity, which is caused by an A546D mutation in the TGFBI gene, polymorphic corneal amyloidosis

Idiopathic Retinal Vasculitis, Aneurysms, and Neuro-retinitis

Purpose: The authors describe the clinical feature of ten patients with a new syndrome characterized by the presence of retinal vasculitis, multiple macroaneurysms, neuro-retinitis, and peripheral capillary nonperfusion. Methods: The authors evaluated ten patients identified to have clinical features compatible with the syndrome of idiopathic retinal vasculitis, aneurysms and neuroretinitis (IRVAN). Clinical examination findings, sequential fundus photographs (when available), fluorescein angiograms, systemic investigations, response to therapy, and visual outcomes were reviewed. Results: Seven eyes of four patients sustained a marked decrease in visual acuity of 20/200 or worse. Visual loss was due to a combination of an exudative maculopathy and sequelae of retinal ischemia. Capillary nonperfusion was seen in all ten patients and was severe enough to warrant panretinal laser photocoagulation in six patients. Systemic investigations were uniformly noncontributory. Oral prednisone appears to have little beneficial effects on patients with this disorder. Conclusions: Patients with IRVAN have characteristic retinal features that readily identify this syndrome. An increased awareness of this rare syndrome may help to identify sight-threatening complications at an earlier stage. The authors caution against extensive medical investigations. Ophthalmology 1995;102:1089-109