SLC17A5 – Free Sialic Acid Storage Disease

Autosomal recessive free sialic acid storage disorder (Free Sialic Acid Storage Disease) is caused by biallelic pathogenic variants in SLC17A5, which encodes the lysosomal sialic acid exporter sialin. Loss of sialin function leads to lysosomal accumulation of free sialic acid, resulting in neurodegeneration, developmental delay, and intellectual disability.

Genetic evidence includes at least six affected individuals from four unrelated families with compound heterozygous or homozygous SLC17A5 variants. The Finnish founder allele c.115C>T (p.Arg39Cys) segregates with classic Salla disease (PMID:15510212). The recurrent missense variant c.406A>G (p.Lys136Glu) has been observed in severe Salla disease and intermediate FSASD (PMID:16170568). The splice donor variant c.819+1G>A causes exon 6 skipping and intermediate-severe FSASD in siblings (PMID:37713976).

The variant spectrum comprises residual-function missense alleles (c.115C>T (p.Arg39Cys), c.406A>G (p.Lys136Glu)) and null alleles such as c.533del (p.Thr178AsnfsTer?) identified in mosaic and non-mosaic contexts (PMID:39461116).

Functional characterization across multiple studies confirms sialin as the lysosomal sialic acid transporter. Plasma membrane–targeted constructs reveal that p.Arg39Cys slows but does not abolish transport (PMID:15510212), whereas severe missense and frameshift alleles completely eliminate H⁺/sialic acid co-transport and impair trafficking (PMID:15516337, PMID:16170568).

Therapeutic potential is demonstrated by adenine base editing of c.115C>T in patient fibroblasts, restoring transporter function without off-target indels (PMID:37727271). iPSC lines from mild and intermediate FSASD patients further model disease and support translational research (PMID:39461116). No evidence supports an association between SLC17A5 variants and Parkinson disease risk (PMID:40088783).

References

• EMBO Journal • 2004 • Functional characterization of wild-type and mutant human sialin. PMID:15510212
• The Journal of Biological Chemistry • 2005 • Varied mechanisms underlie the free sialic acid storage disorders. PMID:15516337
• Neurogenetics • 2005 • Homozygosity for the p.K136E mutation in the SLC17A5 gene as cause of an Italian severe Salla disease. PMID:16170568
• Pediatric Neurology • 2023 • Longitudinal Characterization of the Clinical Course of Intermediate-Severe Salla Disease. PMID:37713976
• Stem Cell Research • 2024 • Generation and characterization of two iPSC lines derived from subjects with Free Sialic Acid Storage Disorder (FSASD). PMID:39461116
• Molecular Therapy. Nucleic Acids • 2023 • Base editing corrects the common Salla disease SLC17A5 c.115C>T variant. PMID:37727271
• Parkinsonism & Related Disorders • 2025 • Comprehensive analysis of SLC17A5 variants in large European cohorts reveals no association with Parkinson's disease risk. PMID:40088783

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