Autosomal recessive Sorsby fundus dystrophy revisited: molecular evidence for dominant inheritance.

Sorsby fundus dystrophy (SFD) originally was characterized as an autosomal dominant disorder in which patients lose central vision during the 4th or 5th decade of life. Since Sorsby's initial description, interfamilial phenotypic variations have been noted and have given rise to controversy as to whether SFD constitutes more than one nosologic entity. In addition, several reports have proposed the existence of a recessively inherited form of SFD. The recent identification of the tissue inhibitor of metalloproteinases-3 (TIMP3) as the disease-causing gene in SFD has made it possible to address the questions of clinical and genetic heterogeneity. In this study, we reinvestigated a large, highly consanguineous Finnish family previously diagnosed as having early-onset autosomal recessive SFD. We identified a novel heterozygous Gly166Cys mutation in TIMP3 in all affected individuals and provide strong evidence for an autosomal dominant inheritance of the SFD phenotype in this family. Our results, in conjunction with a critical review of the reported cases, render the existence of a recessive mode of inheritance in SFD questionable. Considering all available data, we suggest that SFD is a genetically homogeneous, autosomal dominant condition.

Pseudoinflammatory fundus dystrophy: a follow-up study.

We have performed a reinvestigation of a family with a presumably autosomal recessive form of pseudoinflammatory dystrophy, which we have followed for 25 years. The symptoms in this family are subretinal haemorrhages appearing at age 13-40 years in the central fundus, resulting in glial cicatrication in the outer retinal layers, progressive myopia and profound choroidal atrophy in the advanced stages of the disease. During the follow-up study, a new affected subject was found in the younger generation, and two collateral cases, who had earlier been considered as probably affected subjects, were now considered to have other fundus affections. The new case is the daughter of an affected female. The possibilities of an autosomal dominant mode of inheritance or pseudodominance are discussed. Extended genealogical studies showed that the parents of all the affected subjects, with the exception of the new case, have their origin in an area which was isolated until recently and have several common ancestors within the last 8-10 generations. Recessive inheritance also logically explains the appearance of the disease in so few other members in the vertical line of the family. To this fundus dystrophy, the rule of Lenz seems to apply: If more or less the same phenotype can be caused by both a recessive and a dominant gene, the phenotype caused by the recessive gene is generally manifested earlier and by more severe symptoms.

Pseudoinflammatory fundus dystrophy with autosomal recessive inheritance.

A family in southwest Finland with bilateral hemorrhagic degeneration of the retina and choroid was followed up for more than 16 years. The maculas showed subretinal hemorrhages, glial cicatrization of the outer retinal layers, and profound choroidal atrophy, particularly in the advanced stages of the disease. Fluorescein angiography demonstrated leakage through the pigment layer in the retinal tissue. The age of onset varied from the second to the fourth decade. The clinical pattern was similar to Sorsby's pseudoinflammatory dominant fundus dystrophy, except that the disorder appeared earlier in this Finnish family, the members of which show secondary dyschromatopsia, many deep hyaloid bodies in the retina, disturbed dark adaptation (1 to 4 log units), subnormal light-peak/dark-trough ratios, progressive myopia, and a mode of inheritance which is probably autosomal recessive. The affected parents are consanguineous in many ways and each of their eight children is affected.