# Sphingolipidoses and Retinal Involvement: A Comprehensive Review
## 1 Introduction  
Spingolipidoses represent a group of inherited metabolic disorders classified under lysosomal storage diseases with an incidence of approximately 1 in 10,000 individuals [1, 2]. They are characterized by a pathological accumulation of a class of lipids called sphingolipids in lysosomes, resulting from deficiencies in sphingolipid hydrolases, enzymes responsible for their degradation [1]. The specific enzyme deficiency determines the subtype of sphingolipidosis, of which more than 10 subtypes have been identified, all of which, except for Fabry disease (FD), are inherited in an autosomal recessive manner [1]. These include Niemann-Pick disease types A, B, and C (NDP), Gaucher disease (GD), GM1 gangliosidoses, GM2 gangliosidoses including Sandhoff disease (SD) and Tay-Sachs disease (TSD), Farber disease, metachromatic leukodystrophy (MLD), FD, Krabbe disease (KD), and sialidosis [2]. Due to the accumulation of lipids, cellular death and organ damage occur, causing multiple systemic symptoms [2]. Certain sphingolipidoses are characterized by enzymatic deficits that lead to the pathological accumulation of specific catabolites in targeted organs or cells. For instance, FD primarily affects the liver, while GD predominantly impacts the mononuclear phagocyte system [3]. However, a common feature of nearly all sphingolipidoses is that the primarily affected area is the nervous system [2], as certain sphingolipid subtypes, such as gangliosides,are highly expressed in this tissue. This characteristic underpins the shared clinical manifestations observed across various subgroups of sphingolipid-related disorders, including progressive neurodegenerative conditions and retinal pathologies [3]. Considering the high prevalence of retinal involvement, a meticulous fundus examination is the recommended first-line diagnostic approach for sphingolipidoses, as it can facilitate early detection [4]. Additionally, it should be included as part of the annual follow-up of patients [5]. The most common retinal finding in sphingolipidoses is the appearance of a cherry-red macula, resulting from the buildup of distinct sphingolipid precursors or metabolites within retinal cells. It is observed in GM1 and GM2 gangliosides, including TSD and SD, and in NPD type A and B [2,3]. At fundoscopic examination, the cherry-red spot appears as a typically bright red-colored region located at the center of the macula, encircled by an area of retinal opacification [6]. Retinal ganglion cells, where ganglioside accumulation occurs, are highly concentrated in the macula but are absent in its central portion, the fovea. Therefore, the fovea, lacking retinal ganglion cells with opaque sphingolipid deposits, appears bright red in contrast to the surrounding macular opacification, creating the characteristic cherry-red spot [6]. In the ophthalmological setting, this should be differentiated from sight-threatening ischemic conditions, which can present with a similar cherry-red spot in the macula [6]. A schematic representation of a cherry-red spot in the macula is shown in Figure 1.  
Color fundus photography is recommended as an essential complementary test, serving to document distinctive ophthalmoscopic features characteristic of each sphingolip  
Figure 1: Illustration of a cherry-red spot in the macula. **(a)** Fundus image indicating cherry red macular spot (central white box); **(b)** magnified image of cherry-red spot encircled by an area of retinal opacification; **(c)** spectral domain optical coherence tomography cross-sectional illustration where the arrow shows accumulation of hyperreflective material, indicating lipid deposits in the ganglion cell layer (graphics courtesy of [PERSON]). -dosis, facilitating the monitoring of disease progression, and evaluating modifications in response to systemic therapy [6].