# Sphingolipidoses and Retinal Involvement: A Comprehensive Review
## 4 Subtypes of Sphingolipidoses
### Niemann-Pick Disease
#### 4.1.2 Retinal Manifestations  
A prevalent retinal marker across most sphingolipidoses and a distinguishing retinal feature in only NPD type A and B, is the presence of a cherry-red spot at fundus examination. Notably, this sign typically manifests only in the later stages of the disease [60]. In NPD, it is crucial to conduct an ophthalmoscopic examination, as it can reveal the cherry red spot and, also, a more specific retinal finding associated with the NPD type B, referred to as the macular halo (Figure 1). It appears as a circular yellow-white area with a possible extension up to 3.0 mm in diameter, encircling the spared fovea [3; 60; 67]. The macula halo syndrome was initially introduced by [PERSON] et al. [63] in 1983, who defined it as the presence of granular accumulations with a whitish and symmetrical appearance at the level of both maculae. They regarded the observation as a potential milder version of the cherry-red spot and a variant of NPD type B [63]. Analyzing macular halos through the use of multimodal imaging is essential for better disease characterization [67]. \begin{table}
\begin{tabular}{p{113.8 pt} p{113.8 pt} p{113.8 pt} p{113.8 pt} p{113.8 pt}} \hline
**Disease** **(Incidence)** & **Defective Enzyme** **(Mutated Gene)** & **Primary Storage** **Compound** & **Systemic Symptoms and Manifestations** & **Ocular Manifestations (Non-Retinal and Retinal Manifestations)** \\ \hline
**Niemann-Pick types A** (1:250,000) & Acid sphingomyelinase (SMPD1) [59] & Sphingomyelin [59] & **Infantile form (Type A):** hepatosplenomegaly [62], developmental delay [62], interstitial lung disease [60] & **Non retinal manifestations**: corneal clouding, pigmentation of the anterior lens capsule [3; 63] \\
**Niemann-Pick types B** (1:250,000) & Acid sphingomyelinase (SMPD1) [59] & **Sphingomyelin [59]** & **Retinal manifestations:** retinal opacification with macular cherry-red spot [44] \\
**Niemann-Pick types B** (1:250,000) & Acid sphingomyelinase (SMPD1) & Sphingomyelin [59] & **Juvenile form (Type B):** no neurological impairment, milder clinical manifestations (22),62] & **Non retinal manifestations**: ocular symptoms predominantly involve the retina [3] \\
**Niemann-Pick types B** (1:250,000) & Acid sphingomyelinase (SMPD1) & Sphingomyelin [59] & **Retinal manifestations**: interstitial lung disease (60), thrombocytopenia open epistals [60], atherogenic lipid profile (62), osteopenia [62] & **Retinal manifestations**: cherry-red maculae, much slug [4; 4], tortuosity of perimacular vessels [37], focal thickening, and high reflectivity in the GCL of the fovea [3] \\ \hline
**Niemann-Pick types C** (1:150,000) & Transporters: intracellular cholesterol transporters [59] & Unesterified cholesterol and all sphingolipids, including glycosphingolipids (GSLs) and sphingomyelin (22,65,66) & **Variable onset (Type C):** Neurological of central and peripheral nervous dysarthria, dysphagia, dystonia, convulsions, progressive dementia, vertical supernuclear gaze **Retinal manifestations**: perinacular gray discoloration [3] \\
**Niemann-Pick types A** (1:250,000) & (Genes NPC1 and NPC2)  
The use of color fundus photography is critical in NPD, as well as in other sphingolipidoses, for documenting the characteristic ophthalmoscopic features and tracking their progression over time, or potential regression in response to systemic therapy [6]. In FAF, macular halos appear as hypoautofluorescent areas [37]. SD-OCT is the primary modality for diagnosing the halo sign, proving highly effective in assessing its extent and depth [16]. The macular halo appears as a thin hyperreflective band in the inner retina corresponding to the foveal slope (foveal clivus) [63; 67]. To determine the exact level within the inner retina where these granular hyperreflective deposits are localized, several hypotheses have been proposed. Some authors suggest that lipid accumulation occurs in the GCL [3], which may account for the sparing of the fovea from the macular halo, as the fovea lacks GCL [16].