Clinical features of a novel TIMP-3 mutation causing Sorsby's fundus dystrophy: implications for disease mechanism

Aims-To describe the phenotype in three family members affected by a novel mutation in the gene coding for the enzyme tissue inhibitor of metalloprote inase-3 (TIMP-3). Methods-Three members of the same family were seen with a history of nyctal opia and visual loss due to maculopathy. Clinical features were consistent with Sorsby's fundus dystrophy. Exon 5 of the gene coding for TIMP-3 was am plified by the polymerase chain reaction, single strand conformation polymo rphism analysis undertaken and exon 5 amplicons were directly sequenced. Results-Onset of symptoms was in the third to fourth decade. Five of six ey es had geographic macular atrophy rather than neovascularisation as a cause for central visual loss. Peripheral retinal pigmentary disturbances were p resent. Scotopic ERGs were abnormal in all three. Mutation analysis showed a G -->T transversion in all three resulting in a premature termination cod on, E139X, deleting most of the carboxy terminal domain of TIMP-3. Conclusions-The patients described had a form of Sorsby's fundus dystrophy which fell at the severe end of the spectrum of this disease. Postulated di sease mechanisms include deposition of dimerised TIMP-3 protein.