Hyperautofluorescent Dots are Characteristic in Ceramide Kinase Like-associated Retinal Degeneration

Abstract

There is a lack of studies which seek to discern disease expression in patients with mutations that alter retinal ceramide metabolism, specifically in the ceramide kinase like (CERKL) gene. This cross-sectional case series reports a novel phenotypic manifestation of CERKL-associated retinopathy. Four unrelated patients with homozygous CERKL mutations underwent a complete ocular exam, spectral-domain optical coherence tomography, short-wavelength fundus autofluorescence (SW-AF), quantitative autofluorescence (qAF), and full-field electroretinogram (ffERG). Decreased visual acuity and early-onset maculopathy were present in all patients. All four patients had extensive hyperautofluorescent foci surrounding an area of central atrophy on SW-AF imaging, which has not been previously characterized. An abnormal spatial distribution of qAF signal was seen in one patient, and abnormally elevated qAF₈ signal in another patient. FfERG recordings showed markedly attenuated rod and cone response in all patients. We conclude that these patients exhibit several features that, collectively, may warrant screening of CERKL as a first candidate: early-onset maculopathy, severe generalized retinal dysfunction, peripheral lacunae, intraretinal pigment migration, and hyperautofluorescent foci on SW-AF.

Figure 1

Characteristic fundus in CERKL-associated retinopathy. Digital color fundus photographs in the right (A) and left (B) eyes of P1 with confirmed homozygous frameshift mutations in CERKL. An area of macular atrophy is evident, revealing underlying choroidal vessels. A pale disc and attenuated vessels are also seen bilaterally. Peripheral findings (C) include punched-out appearing, lacunar-like degeneration with intraretinal pigment migration.

Figure 2

Fundus autofluorescence imaging in CERKL-associated retinopathy. SW-AF imaging of four patients with CERKL-retinopathy shows large areas of RPE loss in the macula. P1 and P4 show the most well-delineated and largest area of maculopathy. Outside of the area of atrophy in all patients, sparse RPE loss is seen with intermixed numerous hyperautofluorescent foci, generally <120 µm in size.

Figure 3

SD-OCT imaging in CERKL-associated retinopathy. SD-OCT images are shown for patients P1 through P4. Extensive peripheral thinning and chorioretinal degeneration is seen in all patients. P1 shows the most RPE loss, with increased signal transmittance to the choroidal layers below (yellow arrow).

Figure 4

Analysis of quantitative autofluorescence (qAF) in P2 and P3. Average qAF values were calculated in 8 scaled segments within the macula. (A) Age and ethnicity-matched healthy individual. (B) P2; qAF in P2 were found to be comparable to an age-matched healthy retina but exhibited changes in the spatial distribution of AF (color map). (C) P3; qAF in P3 were significantly increased in both eyes with respect to corresponding healthy eyes. (D) Plot showing the mean and 95% confidence intervals of qAF in healthy eyes with age and the value of both eyes of P2 and P3.

Figure 5

Full-field electroretinography of four patients with homozygous mutations in CERKL. FfERG findings show a severe decrease in scotopic and photopic responses in all patients. Note that P1 and P2 underwent 30 Hz-flicker recordings with BA-contact lens electrodes and subsequent narrow band-passed filtering with computed averaging.