Retinal pigment epithelium (RPE) thinning and photoreceptor loss correlate with thickness of sub-RPE deposits of lipid, esterified- and non-esterified cholesterol
Late-onset retinal degeneration (LORD) is an autosomal dominant disorder characterized by onset in the fifth to sixth decade with night blindness and punctate yellow-white deposits in the retinal fundus, progressing to severe central and peripheral degeneration, with choroidal ... Late-onset retinal degeneration (LORD) is an autosomal dominant disorder characterized by onset in the fifth to sixth decade with night blindness and punctate yellow-white deposits in the retinal fundus, progressing to severe central and peripheral degeneration, with choroidal neovascularization and chorioretinal atrophy (Hayward et al., 2003).
Peripheral photoreceptor degenerations, such as retinitis pigmentosa (RP; 268000), cause symptoms early in the course of disease due to loss of rod function. Examination reveals defective vision in the mid-zone of the visual field and morphologic changes in ... Peripheral photoreceptor degenerations, such as retinitis pigmentosa (RP; 268000), cause symptoms early in the course of disease due to loss of rod function. Examination reveals defective vision in the mid-zone of the visual field and morphologic changes in the postequatorial retina. Cone degeneration follows rod degeneration with subsequent loss of central vision. Among the different types of RP, onset of nyctalopia due to loss of rod function varies from early childhood to early adulthood. Kuntz et al. (1996) described an autosomal dominant late-onset retinal degeneration characterized by nyctalopia in the sixth decade followed by severe visual loss by the eighth decade. Early clinical features included punctate yellow-white lesions, sometimes beginning unilaterally, accompanied by abnormal dark adaptation and abnormal electroretinography. Histopathology of an eye of an 80-year-old affected family donor showed a thick layer of extracellular deposits between the retinal pigment epithelium (RPE) and Bruch membrane underlying marked areas of photoreceptor loss, except in the inferior periphery. Milam et al. (2000) studied another family with late-onset retinal degeneration, including the eyes of an 82-year-old donor, 5 of his descendants, and his affected sister. The pattern of the sub-RPE deposits (lipid, esterified, and nonesterified cholesterol) in the eyes of the donor differed from that of the donor eye studied by Kuntz et al. (1996). In the next generation, however, dark adaptation abnormalities mirrored the regional distribution (midperipheral) of the deposits in the eye studied by Kuntz et al. (1996). Milam et al. (2000) found that the fine structure and staining characteristics of the sub-RPE deposits in late-onset retinal degeneration resemble those in age-related macular degeneration (153800) and Sorsby fundus dystrophy (136900). They noted that 2 other autosomal dominant diseases characterized by focal yellow-white deposits (drusen) beneath the RPE, malattia leventinese (126600) and Doyne honeycomb retinal dystrophy (126600), are caused by mutations in a connective tissue gene, epidermal growth factor-containing fibrillin-like extracellular matrix-1 (601548). The authors therefore suggested that autosomal dominant late-onset retinal degeneration may involve mutations in a gene for an extracellular matrix protein. Hayward et al. (2003) noted that the thick extracellular sub-RPE deposit associated with LORD extends from the central retina to the ora serrata. It contains protein and lipid and consists of an inner collagenous/mucopolysaccharide layer, an outer lipid layer, and a layer of neovascularization between the elastin layer of the Bruch membrane and the RPE. In later stages there is widespread loss of RPE and photoreceptors, with choroidal neovascularization and disciform macular scarring.
Hayward et al. (2003) demonstrated a proposed founder mutation in the CTRP5 gene (608752.0001), which encodes a novel short-chain collagen, as the cause of late-onset retinal degeneration (LORD) in 7 of 14 affected families. The mutation, which changed ... Hayward et al. (2003) demonstrated a proposed founder mutation in the CTRP5 gene (608752.0001), which encodes a novel short-chain collagen, as the cause of late-onset retinal degeneration (LORD) in 7 of 14 affected families. The mutation, which changed a highly conserved serine to arginine (S163R), occurred in the globular C1q domain of CTRP5 and resulted in abnormally high molecular weight aggregate formation, which may alter its higher order structure and interactions. The authors presented a novel disease mechanism involving abnormal adhesion between the RPE and Bruch membrane. - Exclusion Studies In patients with autosomal dominant late-onset retinal degeneration, Kuntz et al. (1996) detected no mutations in the coding sequence of the rhodopsin (180380), peripherin/RDS (PRPH2; 179605), or TIMP3 (188826) genes. Rhodopsin and TIMP3 were further excluded by linkage analysis.