Norrie disease and exudative vitreoretinopathy in families with affected female carriers

Purpose. Norrie disease (ND) is a rare X-linked recessive disorder characte rized by congenital blindness, which is often associated with sensorineural hearing loss and mental retardation. X-linked familial exudative vitreoret inopathy (FEVR) is a hereditary disorder characterized by an abnormality of the peripheral retina and is not associated with systemic diseases. X-link ed recessive disorders generally do not affect females. Here we show that f emale carriers can be associated with manifestation of an X-linked disorder . Methods. A four-generation family with an affected female, and a history of congenital blindness and hearing loss, was identified through the pro-ba nd. A second family, with a fullterm female infant, was evaluated through o phthalmic examinations and found to exhibit ocular features, such as retina l folds, retinal detachment and peripheral exudates. Peripheral blood speci mens were collected from several affected and unaffected family members. DN A was extracted and analyzed by single-strand conformation polymorphism (SS CP) following polymerase chain reaction (PCR) amplification of the exons of the Norrie disease gene. The amplified products were sequenced by the dide oxy chain termination method. Results. In an X-linked four-generation famil y, a novel missense (A11BD) mutation in the third exon of the Norrie diseas e gene, was identified. The mutation was transmitted through three generati ons and cosegregated with the disease. The affected maternal grandmother an d the unaffected mother carried the same mutation in one of their alleles. In an unrelated sporadic family, a heterozygous missense mutation (C96Y) wa s identified in the third exan of the Norrie disease gene in an affected in dividual. Analysis of exon-1 and 2 of the Norrie disease gene did not revea l any additional sequence alterations in these families. The mutations were not detected in the unaffected family members and the 116 normal unrelated controls, suggesting that they are likely to be the pathogenic mutations. Conclusions. The results further strengthen the proposal that X-linked diso rders can occur in female carriers, due likely to an unfavorable X-inactiva tion.