Sjögren-Larsson syndrome (SLS) is a rare autosomal recessive neurocutaneous disorder that presents as congenital ichthyosis, spasticity, and mental retardation.1 By age 2, ophthalmic changes are generally present and progress with age. SLS is caused by a defect in lipid metabolism due to a microsomal fatty aldehyde dehydrogenase enzyme (FALDH) deficiency.2,3
Ophthalmic manifestations can involve all retinal layers, including the accumulation of undigested lipid metabolites in retinal ganglion cells, secondary to FALDH deficiency. Spectral-domain optical coherence tomography (SD-OCT) demonstrates retinal crystals in the inner and outer plexiform layers (IPL, OPL) and the nerve fiber layer (NFL), which are associated with Müller cell degeneration, and eventually, retinal pigment epithelium (RPE) compromise from lipofuscin accumulation, which leads to progressive RPE atrophy.4–7
Optical coherence tomography angiography (OCTA) is a relatively new, noninvasive imaging modality that utilizes advances in image acquisition speed and resolution to generate vascular maps in three dimensions. By obtaining images in quick succession and evaluating them for differences, the OCTA software is able to create high-resolution blood flow maps of the retina, allowing en face imaging of the retinal and choroidal vasculature.
This is the first report of OCTA findings in SLS maculopathy.
Three siblings (36, 39, and 43 years old) presented with a diagnosis of SLS confirmed by genetic testing in childhood. A detailed ophthalmologic examination included assessment of best-corrected visual acuity (BCVA), slit-lamp examination, funduscopy, and extensive fundus imaging using standard color fundus photography, fundus autofluorescence (FAF), SD-OCT (Spectralis OCT; Heidelberg Engineering, Heidelberg, Germany), and OCTA imaging (AngioPlex; Carl Zeiss Meditec, Dublin, CA).
The 36-year-old female sibling had a BCVA of 20/60 in both eyes (OU). Anterior segment exam was normal as was her peripheral retinal exam. Her optic nerves appeared healthy. On macular evaluation, intraretinal crystals, retinal pigmentary changes, and atrophy were noted OU (Figure 1A). FAF imaging revealed scattered areas of hyperautofluorescence, corresponding to areas of increased pigmentation (lipofuscin) and areas of hypoautofluorescence that signified regions with RPE atrophy (Figure 1B). SD-OCT showed crystals in the OPL, IPL, and NFL OU. Areas of ellipsoid zone (EZ) disruption and retinal pigment epithelium (RPE) disruption are noted along with subretinal deposits, presumably lipofuscin accumulation (Figure 1G). Decreased central retinal thickness (CRT) was also appreciated (Figure 1H). OCTA revealed decreased capillary density, vessel dilation, and increased flow voids in the superficial and deep capillary plexuses. (Figures 1C–1F).
(A) Fundus photo of the right eye (OD) demonstrates intraretinal crystals, retinal pigmentary changes, and atrophy. (B) Fundus autofluorescence shows scattered hyperautofluorescence consistent with pigmented regions of the macula and areas of increased lipofuscin accumulation, and patchy hypoautofluorescence indicative of retinal pigment epithelium (RPE) atrophy. (C, E) Decreased capillary density and vessel dilation are present in both the superficial (C) and deep (E) retinal capillary plexuses but are more prominent in the deep plexus on optical coherence tomography angiography (OCTA). Projection artifact is present in (E). (D) The OCTA B-scan at the level of the superficial retinal capillary plexus. (F) The OCTA B-scan at the level of the deep retinal capillary plexus. (G) Spectral-domain optical coherence tomography (SD-OCT) with crystals noted in the outer plexiform layer (yellow arrow), inner plexiform layer (red arrow), and nerve fiber layer (orange arrow) OD. Ellipsoid zone and RPE disruption with subretinal lipofuscin accumulation is present. (H) Topographical SD-OCT map showing central retinal thinning in the right macula.
The 39-year-old male sibling presented with a BCVA of 20/80 in the right eye (OD) and 20/60 in the left eye (OS). Macular evaluation revealed intraretinal crystals and RPE changes in the fovea and parafoveal zones OU (Figure 2A). Hyperautofluorescence was noted in the fovea and in the few areas of lipofuscin accumulation OU on FAF imaging (Figure 2B). Crystals were noted in the OPL, IPL, and NFL OU, and pseudocystic atrophy was present OU. Retinal thinning, EZ disruption, and a subretinal deposit were noted on SD-OCT OS (Figure 2G). OCTA abnormalities were similar to Patient 1 with more prominent flow voids (Figures 2C–2F).
(A) Fundus photo of the left eye demonstrates intraretinal crystals, retinal pigmentary changes, and atrophy with lipofuscin accumulation noted in the superotemporal region of the macula. (B) Fundus autofluorescence with hyperautofluorescence secondary to lipofuscin accumulation. (C, E) Increased flow voids, vessel dilation, and decreased capillary density are present in the superficial (C) and deep (E) plexuses on optical coherence tomography angiography (OCTA) with projection artifact present in (E). (D) The OCTA B-scan at the level of the superficial retinal capillary plexus. (F) The OCTA B-scan at the level of the deep retinal capillary plexus. (G) Spectral-domain optical coherence tomography (SD-OCT) of the right eye shows intraretinal crystals, pseudocystic atrophy, and ellipsoid zone and retinal pigment epithelium disruption. (H) Topographical SD-OCT map showing central retinal thinning in the left macula.
The 43-year-old female sibling had a BCVA of 20/60 OD and 20/80 OS. Macular examination revealed fewer intraretinal crystals compared to her younger siblings and significant pigmentary changes and atrophy OU (Figure 3A). FAF showed foveal hyperautofluorescence surrounded by a ring of hypoautofluorescence punctuated by areas of increased lipofuscin and hyperautofluorescence (Figure 3B). Fewer crystals were present relative to her siblings on SD-OCT, but EZ and RPE disruption and subretinal deposits were more prominent (Figure 3G). OCTA imaging revealed similar changes as the other siblings with perhaps more pronounced vessel dilation in the deep capillary plexus (Figures 3C–3F).
(A) Fundus photo of the left eye with prominent pigmentary changes and retinal atrophy. (B) Fundus autofluorescence shows foveal hyperautofluorescence and a ring of hypoautofluorescence. (C, E) Increased flow voids, vessel dilation, and decreased capillary density are noted in the superficial (C) and deep (E) plexuses with more prominent vessel dilation in the deep plexus on optical coherence tomography angiography (OCTA) and projection artifact present in (E). (D) The OCTA B-scan at the level of the superficial retinal capillary plexus. (F) The OCTA B-scan at the level of the deep retinal capillary plexus. (G) Spectral-domain optical coherence tomography (SD-OCT) reveals fewer crystals relative to the patient's younger siblings. There is marked ellipsoid zone and retinal pigment epithelium disruption, and subretinal lipofuscin accumulation. (H) Topographical SD-OCT map showing central retinal thinning in the left macula.
This report of three adult siblings with SLS demonstrates the signs of late-stage SLS maculopathy, including intraretinal crystals, atrophic changes, and lipofuscin deposition. Müller cell dysfunction is thought to play a role in pathogenesis given that retinal crystals are found in the distribution of the Müller cell, Müller cell damage can contribute to a loss of macular pigment, a feature of SLS maculopathy, and Müller cell compromise could further promote accumulation of excess fatty aldehydes/alcohols in the retina that occurs as a consequence of FALDH deficiency in SLS.8,9
This report is the first to describe changes in the superficial and deep retinal capillary plexuses as a feature of SLS maculopathy. OCTA imaging of these siblings revealed decreased capillary density, vessel dilation, and increased flow voids in retinal capillary plexuses. These changes are similar to those described in patients with macular telangiectasia type 2 (MacTel 2), as are the SD-OCT findings of macular crystals and atrophic retinal changes. The pathogenesis of MacTel 2 is thought to involve Müller cell dysfunction, as well.10,11 Tamoxifen (Soltamox; Midatech Pharma, Raleigh, NC) retinopathy also demonstrates similar changes on SD-OCT,12 and flow voids in the deep capillary plexus have been documented on OCTA.13 Unlike MacTel 2 and tamoxifen retinopathy, SLS maculopathy features subretinal deposits (presumably lipofuscin accumulation) late in disease progression.
To the best of our knowledge, this is the first documentation of OCTA findings in SLS maculopathy. The crystalline retinopathy and retinal capillary network abnormalities are similar to macular telangiectasia type 2 and tamoxifen retinopathy which could reflect a common etiology, likely Müller cell dysfunction.
- Sjogren T, Larsson T. Oligophrenia in combination with congenital ichthyosis and spastic disorder; a clinical and genetic study. Acta Psychiatr Neurol Scand Suppl. 1957;113:1–112.
- Willemsen MAAP, Johannes RMC, Rotteveel JJ, et al. Juvenile macular dystrophy associated with deficient activity of fatty aldehyde dehydrogenase in Sjögren-Larsson syndrome. Am J Ophthalmol. 2000;130(6):782–789. doi:10.1016/S0002-9394(00)00576-6 [CrossRef]
- De Laurenzi V, Rogers GR, Hamrock DJ, et al. Sjögren-Larsson syndrome is caused by mutations in the fatty aldehyde dehydrogenase gene. Nat Genet. 1996;12(1):52–57. doi:10.1038/ng0196-52 [CrossRef]
- Newman E, Reichenbach A. The Müller cell: A functional element of the retina. Trends Neurosci. 1996;19(8):307–312. doi:10.1016/0166-2236(96)10040-0 [CrossRef]
- Nilsson SE, Jagell S. Lipofuscin and melanin content of the retinal pigment epithelium in a case of Sjögren-Larsson syndrome. Br J Ophthalmol. 1987;71(3):224–226. doi:10.1136/bjo.71.3.224 [CrossRef]
- Van der Veen RL, Fuijkschot J, Willemsen MA, et al. Patients with Sjögren-Larsson syndrome lack macular pigment. Ophthalmology. 2010;117(5):966–971. doi:10.1016/j.ophtha.2009.10.019 [CrossRef]
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- Reichenbach A, Bringmann A. New functions of Müller cells. Glia. 2013;61(5):651–678. doi:10.1002/glia.22477 [CrossRef]
- Fuijkschot J, Cruysberg JR, Willemsen MA, et al. Subclinical changes in the juvenile crystalline macular dystrophy in Sjögren-Larsson syndrome detected by optical coherence tomography. Ophthalmology. 2008;115(5):870–875. doi:10.1016/j.ophtha.2007.05.063 [CrossRef]
- Roisman L, Rosenfeld PJ. Optical coherence tomography angiography of macular telangiectasia type 2. Dev Ophthalmol. 2016;56:146–158. doi:10.1159/000442807 [CrossRef]
- Runkle AP, Kaiser PK, Srivastava SK, et al. OCT angiography and ellipsoid zone mapping of macular telangiectasia type 2 from the AVATAR study. Invest Ophthalmol Vis Sci. 2017;58(9):3683–3689. doi:10.1167/iovs.16-20976 [CrossRef]
- Doshi RR, Fortun JA, Kim BT, et al. Pseudocystic foveal cavitation in tamoxifen retinopathy. Am J Ophthalmol. 2014;157(6):1291–1298. doi:10.1016/j.ajo.2014.02.046 [CrossRef]
- Todorich B, Yonekawa Y, Thanos A, et al. OCT angiography findings in tamoxifen maculopathy. Ophthalmology Retina. 2017;1(5):450–452. doi:10.1016/j.oret.2017.01.001 [CrossRef]