Characterization of the Retinal Phenotype Using Multimodal Imaging in Novel Compound Heterozygote Variants of CYP2U1

Abstract

Purpose: To report the retinal phenotype in 2 patients simulating type 2 macular telangiectasis with new variants in CYP2U1 implicated in hereditary spastic paraplegia type 56 (HSP 56).

Design: Cross sectional case series study.

Participants: Five members of a non-consanguineous family (parents and 3 male children) were investigated.

Methods: All family members underwent a full ophthalmic evaluation and multimodal retinal imaging. Two family members demonstrating retinal anomalies underwent additional OCT angiography, dual wavelength autofluorescence and fluorescence lifetime imaging ophthalmoscopy, kinetic perimetry, fundus-correlated microperimetry, electroretinography, and electro-oculography. Whole-exome sequencing was performed in all 5 family members.

Main outcome measures: To characterize the retinal phenotype in affected patients with variants in CYP2U1, using multimodal imaging: dual-wavelength autofluorescence, fluorescence lifetime, OCT angiography.

Results: The 2 siblings with compound heterozygous novel variants c.452C>T; p.(Pro151Leu), c.943C>T; p.(Gln315Ter) in CYP2U1 demonstrated parafoveal loss of retinal transparency and hyperreflectivity to blue light, redistribution of macular pigment to the parafoveal edge, photoreceptor loss, and fluorescence lifetime imaging ophthalmoscopy anomalies: a pattern compatible with that seen in macular telangiectasia type 2 (MacTel). One had manifest neurological abnormalities since early childhood; the second had no neurological abnormalities. Each parent and the third sibling were heterozygous for 1 variant and were neurologically and ophthalmically normal.

Conclusions: These CYP2U1 variants are associated with a retinal phenotype very similar to that otherwise specific for MacTel, suggestive of possible links in the etiology and pathogenesis of these diseases.

Financial disclosures: The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Keywords: CYP2U1; Hereditary Spastic Paraplegia type 56; MacTel; Maculopathy; Multimodal imaging.

Figure 1

Pedigree of the family. Filled symbols represent siblings affected by maculopathy. Dots represent CYP2U1 carrier states.

Figure 2

Multimodal retinal imaging of patient II.1. RE indicates the right eye, LE the left eye, color fundus (CF) images demonstrate a loss of retinal transparency in both eyes. Blue light reflectance (BLR) images show an increased scatter within the same area as the loss of retinal transparency. (In the RE, the bright round hyperreflectivity at the fovea and the faint round hyperreflectivity temporal inferior to the fovea are artifacts due to internal reflections within the optics of the recording device, the arcuate hyperreflectivity along the arcades in both eyes are retinal surface reflections). Infrared (IR) images with an overlay of the “en face” image of the EZ and a green line marking the position of the corresponding sample OCT B-scan traversing the foveal center. En face images of the EZ show in both eyes an attenuation of the signal within the parafovea with an outline coinciding to those seen in BLR, DWAF and FLIO images. In the RE multiple focal discontinuities (breaks) in the EZ are apparent within this area, temporally and inferiorly. In the LE the EZ breaks are located nasal to the fovea, within the papillomacular area. Within the OCT B-scan of the RE, a focal discontinuity in the photoreceptor outer segment line and the ellipsoide zone are apparent with a thinning/disorganization of the ONL as well as low reflective spaces within the inner retina. The OCT of the LE shows low reflective spaces within the inner retina and a slight attenuation of the in the photoreceptor outer segment line. The hyperreflectivity within the ONL in the nasal retinal is most likely due to an improved visibility of Henle’s layer due to a slight tilt of the scan. The OCT angiographic (OCTA) images show in the right eye a slightly enlarged, in the left eye a normal size FAZ with bordering dilated capillaries and increased intercapillary gaps. Fundus autofluorescence (AF) images show a loss of the normally present central hypo-AF peak and increased AF on the temporal side in both eyes whereas DWAF imaging demonstrates a generalized low macular pigment (MP) content within a ring of increased LP at approximately 6 degrees eccentricity. Fluorescence lifetime imaging ophthalmoscopy (color range: 200ps in red−to 500ps in blue) imaging shows a small central area with short fluorescence lifetimes surrounded by a clearly demarcated ring of prolonged lifetimes. The peripheral retina features a normal fluorescence lifetime distribution. DWAF = dual wavelength autofluorescence; EZ = ellipsoid zone; FLIO = fluorescence lifetime imaging ophthalmoscopy; LP = lipofuscin; ONL = outer nuclear layer.

Figure 3

MAIA microperimetry and en face OCT images of the EZ. (A, B) The MAIA microperimetry measurements of the right and left eyes of patient II. 3., (C, D) Right and left eyes of patient II. 1. The background images are Heidelberg Spectralis infrared images, with aligned overlays of the en face OCT image of the EZ. The stimulus used was Goldmann III at a 1-degree spacing within the central area. F, Preferred locus of fixation. EZ = ellipsoid zone; MAIA = macular integrity assessment system.

Figure 4

Multimodal retinal imaging of patient II.3. RE indicates the right eye, LE the left eye, color fundus (CF) images demonstrate a loss of retinal transparency in both eyes and small brown vessel-adjacent pigment foci in the left eye. Blue light reflectance (BLR) images show an increased scatter within the same area as the loss of retinal transparency. (In the RE, the small bright round hyperreflectivity and larger circular hyperreflectivity at the fovea are artifacts due to internal reflections within the optics of the recording device, the hyperreflectivity along the vessel arcades in both eyes are retinal surface reflections). Infrared (IR) images with an overlay of the “en face” image of the EZ and a green line marking the position of the corresponding sample OCT B-scan traversing the foveal center. En face images of the EZ show in both eyes a radial or petaloid arrangement of breaks in the EZ and a thinning of the ONL. Notable is the relative sparing on the temporal side, especially in the right eye. Small low reflective spaces are apparent within the inner retina. The OCT angiographic (OCTA) images show in both eyes an enlarged, deformed FAZ with bordering dilated capillaries and increased intercapillary gaps. Fundus autofluorescence (AF) images show a loss of the normally present central hypo-AF peak in both eyes. Small focal hypo-AF spots are apparent in both eyes some of these in the LE collocate with the brown focal vessel-adjacent pigment apparent in CF images. Dual wavelength autofluorescence (DWAF) imaging demonstrates a generalized low macular pigment (MP) content within a ring of increased LP at approximately 7 degrees eccentricity. Fluorescence lifetime imaging ophthalmoscopy (FLIO, color range: 200ps in red - to 500ps in blue) shows a slight central area with short fluorescence lifetimes surrounded by a clearly demarcated ring of prolonged lifetimes. This corresponds to the area of photoreceptor atrophy in the OCT image. The ring of prolonged fluorescence lifetimes features an external border with a small ring of short fluorescence lifetimes, fading out toward the retinal periphery, which features a normal fluorescence lifetime distribution. EZ = ellipsoid zone; FAZ = foveal avascular zone; LP = lipofuscin; ONL = outer nuclear layer.

Figure 5

Progression patterns of neurodegenerative and vascular changes in patient II.3. A–D, en face OCT images of the EZ, (A, C) right eye, (B, D) left eye, (E–H) OCTA images, (E, G) right eye, (F, H) left eye, top row (A, B, E, F) 3 years before baseline, bottom row (C, D, G, H) at baseline. The EZ break apparent 3 years before baseline imaging show a radial distribution with no apparent predominance of the temporal area as in typical MacTel. At baseline the focal EZ loss appears to have progressed locally by an enlargement of the previously present foci as well as by the appearance of new foci, notably superior to the fovea in the left eye. OCTA images show an enlargement of the FAZ over time, with an increase in intercapillary gaps and in the left eye a radial arrangement of vessels around a focal brown pigment apparent in the CF image and as a focal hypo-AF in the AF image. This feature is characteristic of MacTel. AF = autofluorescence; CF = color fundus; EZ = ellipsoid zone; MacTel = macular telangiectasia type 2; OCTA = OCT angiography.

Figure 6

Progression pattern of EZ loss in a typical MacTel eye. In MacTel, EZ loss starts typically temporal to the foveal center, with time increases in all directions, a second locus may appear nasal to the foveal center. Visual acuity typically remains preserved until the EZ loss involves most of the fovea. The time interval between images A to D was 1 year. EZ = ellipsoid zone; MacTel = macular telangiectasia type 2.