Fleck-like lesions in <i>CEP290-associated</i> leber congenital amaurosis: a case series

To provide a detailed ophthalmic phenotype of a small cohort of patients with Leber Congenital Amaurosis (LCA) caused by mutations in CEP290 (CEP290-LCA) with a focus on elucidating the origin of yellow-white lesions observed in 30% of patients with this condition. This is a retrospective review of records of five patients with CEP290-LCA. Patients had comprehensive ophthalmic evaluations. Visual function was assessed with full-field electroretinograms (ffERGs) and full-field sensitivity testing (FST). Multimodal imaging was performed with spectral domain optical coherence tomography (SD-OCT), fundus autofluorescence (FAF) with short- (SW) and near-infrared (NIR) excitation wavelengths. All patients showed relative structural preservation of the foveal and near midperipheral retina separated by a pericentral area of photoreceptor loss. Yellow-white, fleck-like lesions in an annular distribution around the near midperiphery co-localized with hyperreflective lesions on SD-OCT. The lesions located between the inner segment ellipsoid signal and the apical retinal pigment epithelium (RPE). The inner retina was normal. Longitudinal observations in one of the patients indicates the abnormalities may represent an intermediate stage in the degenerative process between the near normal appearing retina previously documented in young CEP290-LCA patients and the pigmentary retinopathy observed along the same region in older individuals. We speculate that fleck-like lesions in CEP290-LCA correspond to malformed, rudimentary or degenerated, including shed, photoreceptor outer segments. The topography and possible origin of the abnormalities may inform the planning of evolving genetic therapies for this disease.</p

Mutations identified in the Belgian cohort.

<p>Mutations identified in the Belgian cohort.</p

Composite fundus photographs of 12 patients with mutations in <i>RHO</i>, <i>RP1</i>, <i>SNRNP200</i>, <i>PPRF8</i>, <i>PRPF31</i>, <i>TOPORS</i> and <i>NR2E3</i> leading to adRP.

<p>Overall, the phenotypes shown represent a range of adRP phenotypes varying from milder, classic, to end-stage RP. (A) Age 55 years (FAM_009), <i>RHO</i> mutation, c.1028G>A p.(Ser343Asn) (novel). A classic RP phenotype, including good macular preservation, attenuated retinal vasculature, outer retinal atrophy and predominantly spicular intraretinal pigment migration in the midperiphery. (B) Age 54 years (FAM_010), <i>RHO</i> mutation, c.1028G>A p.(Ser343Asn) (novel). Milder phenotype compared to A. Diffuse outer retinal atrophy in the periphery with good macular preservation. Notice the absence of intraretinal pigment migration. (C) Age 55 years (FAM_002), <i>RHO</i> mutation, c.265G>C p.(Gly89Arg) (novel). End-stage RP with macular atrophy, attenuated retinal vasculature and diffuse intraretinal pigment migration in the midperiphery. (D) Age 53 years (FAM_043), recurrent <i>NR2E3</i> mutation, c.166G>A p.(Gly56Arg). Outer retinal atrophy with mild intraretinal pigment migration in the periphery and perifoveal outer retinal atrophy. (E) Age 51 years (FAM_017), <i>RP1</i> mutation, c.2245_2248delinsTGAG p.(Leu749*) (novel). A classic RP phenotype, similar to the description of panel A. (F) Age 72 years (FAM_016), <i>RP1</i> mutation, c.2200del p.(Ser734Valfs*4) (novel). End-stage RP with complete outer retinal atrophy and intraretinal pigment migration including periphery and macula. (G) Age 72 years (FAM_019), <i>RP1</i> mutation, c.2597del p.(Leu866*) (novel). Typical yellowish hue due to outer retinal atrophy with intraretinal pigment migration in the periphery and macular preservation. (H) Age 30 years (FAM_022), <i>SNRNP200</i> mutation, c.1981G>T p.(Val661Leu) (novel). Outer retinal atrophy with spicular intraretinal pigment migration, most pronounced in the retinal midperiphery. (I) Age 38 years (FAM_025), <i>PRPF8</i> mutation, c.6840C>A p.(Asn2280Lys) (novel). Outer retinal atrophy with intraretinal pigment migration of the spicular type in the midperiphery and a good macular preservation. (J) Age 50 years (FAM_028), <i>PRPF8</i> mutation, c.6964G>T p.(Glu2322*) (novel). Mild outer retinal atrophy in the periphery with macular preservation, normal retinal vasculature and a normal optic disc. (K) 53 years (FAM_035), <i>PRPF31</i> mutation, c.541G>T p.(Glu181*). Outer retinal atrophy with macular preservation. (L) 51 years (FAM_048), <i>TOPORS</i> mutation, c.2556_2557del p.(Glu852Aspfs*20) (novel). Pigment epithelium alterations with white dots in the retinal periphery. Notice absence of intraretinal pigment migration and presence of perifoveal atrophy.</p

Schematic representation of novel mutations and prevalence of causal mutations in adRP genes.

<p>(A-D): Schematic representation of the novel mutations identified in this study. (A) <i>RP1</i> gene. The five mutations are located within the mutational hotspot (nucleotides 1490–3216), indicated with a black horizontal line. E = exon. Grey rectangles are coding regions and orange rectangles are 5’ untranslated region (5’ UTR) and 3’ UTR. (B) RP1 protein. Both truncating mutations identified in this study belong to Class II mutations (amino acids 500–1053), indicated with a black line. The <i>Drosophila melanogaster</i> (BIF) domain (amino acids 486–635) is depicted as a blue rectangle. aa = amino acid. (C) SNRNP200 protein. The two novel mutations identified in this study are both located within the first DExD/H box helicase-like domain (amino acids 477–690). Both the first and the second (amino acids 1324–1528) DExD/H box helicase domains are represented as blue rectangles. Both Sec63-like domains (amino acids 981–1286 and 1812–2124) are indicated as golden rectangles. aa = amino acids. (D) PRPF8 protein. The novel mutation identified here is located within the highly conserved region C-terminal to the Jab1/MPN domain (amino acids 2099–2233), depicted as a blue rectangle. aa = amino acid. (E) Prevalence of causative mutations in adRP genes in a Belgian adRP cohort. The ‘unknown’ part may include new disease genes and mutation mechanisms as well as known disease genes not screened in the course of this study.</p