Dharmaraj et al. (2000) described a multigenerational kindred of Old Order River Brethren, a religious isolate descended from Swiss immigrants to America in the 1750s (Brechbill, 1972), segregating Leber congenital amaurosis. LCA in this kindred was not associated ... Dharmaraj et al. (2000) described a multigenerational kindred of Old Order River Brethren, a religious isolate descended from Swiss immigrants to America in the 1750s (Brechbill, 1972), segregating Leber congenital amaurosis. LCA in this kindred was not associated with multisystem abnormalities. Renal function remained normal. Neurologic and hepatic function were within normal limits. The patients were of normal stature and intelligence. Visual dysfunction, nystagmus, and the digitoocular phenomenon of Franceschetti-Bamatter (Franceschetti and Dieterle, 1954), namely pressing on the globes, were noticed in early infancy. A high hyperopic refractive correction was noted in all the patients. In infancy the fundi had a normal appearance, but in childhood attenuated retinal vasculature with varying degrees of pigmentary changes developed. Electroretinography showed a markedly reduced response in the affected individuals. Mohamed et al. (2003) identified 3 brothers in a consanguineous Pakistani family with Leber congenital amaurosis. Progression of macular abnormalities resulted in a colobomatous appearance in the eldest compared to only mild atrophy in the youngest. This phenotypic pattern was considered to be different from that in the Old Order River Brethren kindred reported by Dharmaraj et al. (2000).
In affected members of 3 Pakistani families segregating for LCA5, including the family reported by Mohamed et al. (2003), den Hollander et al. (2007) identified a homozygous frameshift mutation in the LCA5 gene (611408.0001). They identified 3 additional ... In affected members of 3 Pakistani families segregating for LCA5, including the family reported by Mohamed et al. (2003), den Hollander et al. (2007) identified a homozygous frameshift mutation in the LCA5 gene (611408.0001). They identified 3 additional mutations in several other affected individuals, including those in the Old Order River Brethren originally reported by Dharmaraj et al. (2000) (see 611408.0002-611408.0004). - Modifier Genes In the Old Order River Brethren pedigree originally reported by Dharmaraj et al. (2000), in which a homozygous mutation in the LCA5 gene (611408.0004) was identified in affected individuals, Zernant et al. (2005) identified an additional missense mutation (P701S) in the LCA-associated GUCY2D gene (600179) in the more severely affected of 2 sibs. When compared at the same age, the sib with 3 variant alleles presented with a more severe ocular phenotype and experienced greater difficulty with decreased visual function; retinal examination revealed higher hyperopia and more extensive peripheral pigmentary mottling. Zernant et al. (2005) suggested that the variant GUCY2D allele had a modifier effect on the phenotype.