Huizing et al. Page 8 and a genotype-phenotype correlation for most tested variants. However, reported clinical A uthor Man heterogeneity in some FSASD siblings with identical mutations also suggests a role for genetic or environmental factors in FSASD clinical variability that might have therapeutic implications [62, 63]. uscr It is unknown how accumulated intra-lysosomal free sialic acid or other stored compounds (e.g., glucuronic acid, gluconic acid) contribute to disease pathology [3–6]. Similarly, the ipt clinical effects of alternative transport functions of SLC17A5, i.e., the uptake of glutamate, aspartate or N-aspartyl-glutamate into brain synaptic vesicles [74, 75] and plasma- membrane nitrate transport in salivary gland acinar cells [76], remains enigmatic. Also, the relevance and tissue expression of the 8 recently released human SLC17A5 isoforms (Gene ID 26503) have not been explained. The effects of SLC17A5 deficiency and lysosomal free sialic acid storage on cellular sialic acid metabolism, including protein glycosylation, also A remain to be elucidated. These poorly studied features suggest that the function of SLC17A5 uthor Man may be more complex than simply mediating the efflux of sialic acid from lysosomes. SLC17A5 might play a role in determining lysosomal pH, since it is a proton-driven transporter [59, 77] and its activity is pH dependent [4, 59]. Changes in the intra-lysosomal uscr milieu due to SLC17A5 deficiency, resulting from reduced trafficking of protons or acidic ipt sugars, may affect other lysosomal functions. Most studies report normal lysosomal enzyme activities in FSASD cultured fibroblasts [53, 78–80], but some studies have reported increased levels and decreased turnover of sialoglycoproteins and gangliosides in lysosomes of FSASD cells [79, 81, 82]. The excessive accumulation of free sialic acid may lead to secondary storage of sialoglycoproteins and gangliosides, since sialic acid is a competitive inhibitor for lysosomal neuraminidases [83, 84]. The accumulation of sialo-glycoconjugates A and gangliosides in FSASD tissues may contribute to the development of clinical symptoms, uthor Man in particular in the central nervous system (CNS) [85–87], similar to other lysosomal storage diseases [88]. The sialylation status of membrane glycoconjugates, in particular brain gangliosides, in uscr FSASD remains to be determined and may contribute to the CNS symptoms and hypomyelination. Reduced ganglioside sialylation is associated with reduced myelination ipt [89], as it affects function of myelin‐associated glycoprotein (MAG), a component of the myelin sheet [90]. Hyposialylation of polysialic acid-neural cell adhesion molecule (PSA- NCAM) also affects CNS myelination [91, 92]. An Slc17a5 knock-out mouse was reported having aberrant expression of PSA-NCAM, possibly underlying the decrease of mature myelinating oligodendrocytes [87]. A CNS manifestations in FSASD were also suggested to result from a non-lysosomal brain- uthor Man specific function of SLC17A5 as a vesicular transporter for glutamate or aspartate [74, 93]. SLC17A5 carrying the p.Arg39Cys variant completely lost aspartate and glutamate transport + activity, while it retained residual H /sialic acid cotransport [74], suggesting that impaired aspartergic and glutamatergic neurotransmission in FSASD may contribute to the CNS uscr dysfunction [74, 94]. This hypothesis supports the fact that neurological symptoms ipt predominate in mild FSASD (p.Arg39Cys mutation), implying that the CNS is more Neurosci Lett. Author manuscript; available in PMC 2021 June 11.