# Sphingolipidoses and Retinal Involvement: A Comprehensive Review
## 5 Current Challenges and Future Directions  
Sphingolipidoses are rare lysosomal storage disorders characterized by intrinsic variability, primarily due to the residual enzymatic activity of the affected enzymes. This variability poses a significant challenge in the initial diagnostic phase, largely due to phenotypic overlap with other neurometabolic disorders and the occasional inconclusiveness of laboratory findings. Moreover, it may occur that, despite the presence of enzymatic deficiencies or their activators, diagnostic tests fail to detect an accumulation of the substrates that these enzymes are supposed to degrade. This may lead to a missed diagnosis, as the apparent absence of substrate accumulation could mask the underlying pathology [166]. However, an even greater challenge lies in the longitudinal assessment of disease progression and therapeutic response. Consequently, the identification of reliable biomarkers for patient stratification is crucial for optimizing clinical management. The need for early and non-invasively obtainable biomarkers stems from the presence of unmet needs, primarily due to the reliance on time-consuming and costly tests, which are not always conclusive [167]. Ocular biomarkers could constitute a valuable asset in evaluating the sphingolipidoses. The eye, owing to its accessibility and the availability of high-resolution, non-invasive imaging modalities, such as SD-OCT and OCT-A, serves as an ideal model for investigating microstructural and vascular alterations associated with sphingolipid accumulation. Previous studies have demonstrated that pathological sphingolipid deposition is associated with quantifiable changes in retinal architecture, particularly in the RNFL and the GCL [18; 27; 28; 35], as well as alterations in retinal microvascular integrity [37; 140]. Notably, lipid accumulation at intratefinal level also appears to play a pro-inflammatory role, as hypothesized in both NPD and GD. In the latter, lipid deposition can, over time, lead to anatomical and functional alterations of the retina, progressing towards fibrosis and microvascular impairment [29; 80]. In FD, the inflammatory process is so pronounced that HRFs have been observed, similar to those described in other systemic diseases such as multiple sclerosis, and have been proposed as new biomarkers of intratefinal inflammation. These alterations can cause functional damage even in a preclinical stage, as seen in NPD, GD, and FD, where mfERG results appear depressed [16; 17; 50; 162]. Analyzing sphingolipidoses at retinal level represents an essential tool for the early identification of anatomical and functional alterations, with a significant impact on clinical management. Case-control studies, particularly in more prevalent disorders such as FD and GD, have highlighted the diagnostic utility of these ocular biomarkers in differentiating affected individuals from healthy controls [12; 28; 140]. A critical future direction in the application of ocular diagnostics lies in the ability to subclassify disease phenotypes, enabling the assessment of disease activity and progression in correlation with systemic biomarkers. This necessitates the development of advanced image analysis methodologies capable of high-output, quantitative assessments of microscopic structures. A compelling example is the study conducted by [PERSON] et al. [12], in which an image-processing algorithm was employed to calculate the retinal vessel tortuosity index (RVTI) in patients with FD [12]. This parameter exhibited a strong correlation with systemic disease burden, including cardiovascular involvement and plasma lyso-Gb3 levels, suggesting its potential utility as a predictive marker for disease severity and therapeutic efficacy [12]. Similar findings were reported by [PERSON] et al., further supporting the role of retinal vascular biomarkers in disease monitoring [168].