Evidence of autosomal dominant Leber congenital amaurosis (LCA) underlain by a CRX heterozygous null allele.

Originally described by Theodore Leber in 1869, Leber congenital amaurosis (LCA, MIM 204000) is the most early and severe form of all hereditary retinal dystrophies, responsible for congenital blindness. The diagnosis is usually made at birth or during the first months of life in an infant with total blindness or greatly impaired vision, normal fundus, and unrecordable electroretinogram (ERG). It is usually accepted that LCA accounts for 5% of all inherited retinal dystrophies. However, this frequency is an underestimate since it is now agreed that in some cases LCA could represent the extreme end of a spectrum of severity of retinal dystrophies. Hitherto, LCA was considered as an autosomal recessive, genetically heterogeneous condition. Eight LCA genes have been identified or mapped so far, namely (1) the retinal specific guanylate cyclase gene (retGC1) at the LCA1 locus (17p13.1), (2) the gene encoding the 65 kDa protein specific to the retinal pigment epithelium (RPE65) at the LCA2 locus (1p31), 8 (3) the cone-rod homeobox containing gene (CRX, 19q13.3), (4) the gene encoding the arylhydrocarbon receptor interacting protein-like 1 at the LCA4 locus (17p13.1), (5) the gene encoding the retinitis pigmentosa GTPase regulator-interacting protein 1 (RPGRIP1) at the LCA6 locus (14q11), 14 (6) the human homologue of the Drosophila melanogaster crumbs gene (CRB1, 1q31), 16 (7) LCA3 on chromosome 14q24, and (8) LCA5 on chromosome 6q. The two last loci respectively account for the disease in a consanguineous Saudi Arabian LCA family and a multigenerational kindred of Old Order River Brethren, an isolate originating from Swiss immigrants to America in the 1750s. 18 Altogether, the six identified genes account for about 48% of LCA cases in our series and are consistent with autosomal recessive inheritance. However, in 1960 and 1968 respectively, Sorsby and Williams and François described a few families with a clearly dominant mode of transmission. These observations were largely dismissed or overlooked until some de novo CRX mutations associated with LCA shed new light on these old reports. 9 22–24 In 1998, Sohocki et al reported different phenotypes associated with CRX mutations. Among these phenotypes, they described a large pedigree of autosomal dominant retinal dystrophy with intrafamilial variability ranging from typical retinitis pigmentosa to a very severe visual disturbance in some members who “share many of the characteristics of Leber congenital amaurosis (LCA)”. However, the authors were cautious in diagnosing LCA in this family because of the existence of several members with a mild phenotype and particularly a male whose visual acuity was 20/80 at the age of 27. These diagnostic reservations were also discussed by Rivolta et al in 2001. Here, we confirm autosomal dominant inheritance in an unambiguous LCA family underlain by a heterozygous null allele of CRX.