Abstract
Purpose: :
To describe the clinical phenotypes in a family with a mutation in the TIMP3 (tissue inhibitor of metalloproteinases–3) gene for Sorsby’s fundus dystrophy (SFD) and evaluate their treatment with high–dose oral vitamin A.
Methods: :
Twelve members from a three–generation family affected by SFD were examined and tested for a mutation in the TIMP3 gene. Evaluation included assessment of subjective visual changes, visual acuity, slit–lamp biomicroscopy, dilated fundus examination, electroretinography (ERG), dark adaptometry (DA), and two color threshold (TCT). Three of the six members from the second generation were treated with high–doses of vitamin A (50,000 IU/day for 4 weeks) orally and one of these three siblings with an additional 4 weeks of 25,000 IU/day. Vitamin A was in the water–miscible form. All three siblings were evaluated for pre– and post–treatment changes, as well as liver function tests and vitamin A blood levels.
Results: :
We examined family members from the second and third generations. Seven of the twelve (58.3%) members tested positive for the TIMP3 gene mutation. In the second generation, three of the four siblings with a positive TIMP3 mutation had severe nyctalopia, abnormal ERGs, DAs, TCTs, and fundus findings of diffuse drusen and RPE atrophy. One of the four siblings with a positive TIMP3 mutation was asymptomatic with a normal ERG, TCT, and fundus findings. Of three siblings treated with high–doses of vitamin A, one had subjective improvement of nyctalopia during the treatment with an improvement of DA rod–cone break time. However, significant pre– and post–treatment changes were not observed in the ERGs or DAs from the other two siblings. In the third generation, two of the three first cousins with a positive TIMP3 mutation had mild/moderate nyctalopia and fundus findings of isolated drusen and RPE clumping. However, all three cousins had normal ERGs, DAs, and TCTs.
Conclusions: :
Phenotypic variability exists particularly in younger patients with early stages of Sorsby’s dystrophy and the TIMP3 mutation. Such patients tend to show normal findings on tests of retinal function and either the presence or absence of fundus changes. Less phenotypic variability occurs in those with more advanced disease. In those with the most advanced disease, we did not observe an improvement in visual function after treatment with high–doses of vitamin A.
Keywords: retinal degenerations: hereditary • electroretinography: clinical • genetics