# Sphingolipidoses and Retinal Involvement: A Comprehensive Review
## 4 Subtypes of Sphingolipidoses
### Metachromatic Leukodystrophy
#### 4.6.2 Retinal Manifestations  
Due to the rarity of the disease, most of the current information is derived from ophthalmoscopic observations corroborated by corresponding histological findings. Ophthalmoscopy, often normal, remains the primary diagnostic tool. Although, a distinctive feature is the presence of a pale optic disc, indicative of optic nerve atrophy [57]. This is believed to result from retrograde degeneration of the optic nerve due to abnormal myelin metabolism [58]. Histological examination revealed neuronal storage at the level of the optic nerve, a key factor in the disease's pathogenesis [57; 67]. Additional ophthalmoscopic findings may include areas of RPE degeneration [127] and a grayish macula caused by the accumulation of lamellar lysosomes in retinal ganglion cells [57]. These ganglion cell deposits, a hallmark of the disease, have been histologically confirmed as containing metachromatic material [40]. The exclusive involvement of ganglion cells in adult MLD has not yet been fully explained. It could be because ganglion cells are more actively involved in sulfatide metabolism, thus making them more susceptible to sulfatide accumulation [40].  
In MLD, cells in the bipolar and photoreceptor layers, as well as RPE cells, are typically spared from lysosomal material accumulation [57]. However, in some cases, elevated lipofuscin levels have been observed both in the RPE and ganglion cells, suggesting that this accumulation may be driven by a mechanism akin to that observed in infantile Type II glycogenosis [40; 128]. The process of lipofuscin formation, occurring within the lysosomal compartment, may be compounded by the concurrent accumulation of sulfatides,  
\begin{table}
\begin{tabular}{p{56.9 pt} p{113.8 pt} p{113.8 pt} p{113.8 pt} p{113.8 pt}} \hline \hline
**Disease** **(Incidence)** & **Defective Enzyme (Mutated Gene)** & **Primary Storage Compound** & **Systemic Symptoms and Manifestations** & **O ocular Manifestations (Non-Retinal and Retinal Manifestations)** \\ \hline \hline \end{tabular}
\end{table}
Table 7: Summary of the characteristics of Metachromatic leukodystrophy.  
characteristic of MLD. This leads to the formation of residual bodies containing both lipofuscin and disease-specific metachromatic material [40]. This is further supported by the fact that the RPE normally contains high levels of arylsulfatase A, which likely makes it particularly vulnerable to morphofunctional alterations when these levels are deficient, as is the case in MLD [41].  
[PERSON] et al. in 2024 observed that, in a cohort of 50 patients with MLD, 1 patient exhibited visual function impairment, 11 showed a pathological light reflex, and 2 presented with nystagmus. The authors used SD-OCT to evaluate the involvement of the RNFL, hypothesizing that the thickness of the RNFL reflects the integrity of the unmyelinated axons in the anterior visual pathway, making it a potential surrogate marker for tracking disease progression; however, the RNFL was found to be normal [18]. [PERSON] et al. observed that, among a cohort of 19 MLD patients, 58% demonstrated altered VEPs, a finding corroborated by a separate previous cohort of 12 MLD patients reported by the same authors, 78% of whom exhibited similar results. This supports that VEPs should be performed as an additional diagnostic test, even in the absence of overt visual impairment or negative SD-OCT findings, as it may provide early evidence of disease progression [18].