Huizing et al. Page 9 sensitive to SLC17A5 defects than peripheral tissues. However, a role for aspartergic A uthor Man neurotransmission is unlikely as it is not altered in Slc17a5 knock-out mice [95]. 7. FSASD Disease Models FSASD patients’ cells are the most frequently used model for the disorder. FSASD skin uscr fibroblasts and lymphoblasts/leukocytes were historically used for diagnostic purposes and ipt to elucidate parts of the disease mechanism [1, 6, 7, 18, 50, 53, 79, 81, 83]. FSASD cultured fibroblasts were also successfully used for metabolic oligosaccharide engineering (MOE) [96], resulting in a cellular functional assay using chemically modified ManNAc or Neu5Ac that can be traced to newly synthesized sialoglycoconjugates. This assay can be used to screen for therapeutic molecules that restore SLC17A5 function (Fig 1D) [97, 98]. The development of techniques for generating organoids from induced pluripotent stem cells A (iPSCs), including brain organoids [99], has created opportunities for new application of uthor Man patient specific models for FSASD with relevance to the neurodevelopmental and neurodegenerative phenotypes. Therefore, generation of human iPSCs from fibroblasts of FSASD patients should be pursued; they will be a valuable resource to model the disease and screen for therapeutics through differentiation to specialized cell types (such as neurons, uscr oligodendrocytes) or organoids (such as brain) as has been reported for some other ipt lysosomal storage disorders [100–102]. Limited studies on FSASD mouse neuronal cells have been reported so far [87, 93]; such studies would be informative and should be promoted to study FSASD disease mechanisms. The only reported FSASD model organisms are Slc17a5 knock-out mouse models [87, 103]. These mice experienced growth delays, a severely reduced lifespan, prominent lysosomal vacuolization in central and peripheral tissues, lysosomal accumulation of free sialic acid A uthor Man and glucuronic acid, and a progressive leukoencephalopathy with a postnatal progressive delay of milestone achievement (Fig 1E) [87, 103]. The leukoencephalopathy was characterized by a decreased number of myelinated axons and post-mitotic oligodendrocytes, with the latter associated with an increased percentage of apoptotic cells uscr during later stages of myelinogenesis. Such changes were believed the cause of coordination defects, seizures, and premature death, all of which are consistent with human FSASD. ipt Ultrastructural analysis showed normal migration and proliferation of oligodendrocyte precursor cells (OPCs) but a reduction in mature myelin-producing oligodendrocytes that is likely a consequence of oligodendrocyte lineage apoptosis. A delayed reduction of developmentally regulated PSA-NCAM was proposed as a mechanism for the impaired myelination and reduction in oligodendrocyte number [87]. The short lifespan of the Slc17a5 knockout mice (up to ~ 3 weeks) is restrictive for therapeutic studies, so such A uthor Man studies may benefit from generation of a knock-in FSASD mouse model, preferably mimicking one of the more common FSASD-associated SLC17A5 mutations, i.e., p.Arg39Cys or p.Lys136Glu. uscr 8. FSASD Therapeutic Approaches ipt There is no approved therapy for FSASD. The medical and psychosocial management of subjects is symptomatic and supportive [2]. The fact that the amount of stored free sialic Neurosci Lett. Author manuscript; available in PMC 2021 June 11.