Two Thai families with Norrie disease (ND): Association of two novel missense mutations with severe ND phenotype, seizures, and a manifesting carrier

We describe two Thai families with Norrie disease (ND) in three generations , including 10 affected males and one manifesting female. All affected male s in each family had severely defective eye development with complete loss of vision. in addition, three male patients tone from family 1 and two from family 2) suffered from epilepsy, and one female carrier from one family m anifested blindness with phthisis bulbi in her right eye. Mutation analysis of the ND gene (NDP) revealed two different novel missense mutations L16P and S75P) that co-segregated with ND in each family, suggesting that the ne wly appearing proline at codon 16 or codon 75 alters the conformation of th e ND protein and contributes to the severe phenotype of ND in each family, Other studies suggest that epileptic seizures or growth retardation that is associated with ND is the consequence of loss of contiguous genes, because most such patients had deletions extending beyond the Norrie locus. Our fi nding that the three affected males in the two families with the missense m utations had epilepsy does not support a contiguous gene effect, but favors the pleiotropism of NDP, at least as far as the epileptic manifestation is concerned, The unilateral blindness in the female carrier may have been du e to non-random X-inactivation. (C) 2001 Wiley-Liss, Inc.