A mouse model of free sialic acid storage disorder: Hypomyelinating leukodystrophy and Purkinje cell degeneration

Free sialic acid storage disorder (FSASD) is a rare, neurodegenerative, lysosomal storage disease caused by biallelic variants in SLC17A5, which encodes the lysosomal sialic acid exporter, sialin. While clinical severity varies, all affected individuals exhibit progressive neurological decline and characteristic lysosomal and urinary accumulation of free sialic acid. No FDA-approved therapies currently exist, and the molecular underpinnings of central nervous system (CNS) dysfunction remain poorly defined. To model the most prevalent FSASD-associated allele, we generated a Slc17a5R39C mouse model carrying the pathogenic p.Arg39Cys variant using CRISPR/Cpf1. Homozygous Slc17a5R39C/R39C mice recapitulated key features of FSASD, including biochemical accumulation of free sialic acid, ataxia, tremors, seizures, and shortened lifespan. Neuropathological analyses revealed widespread CNS hypomyelination, with relatively preserved peripheral nervous system myelination, while transcriptomic profiling showed broad suppression of myelin-associated genes and a cerebellum-specific inflammatory signature. This was accompanied by pronounced astrogliosis, progressive Purkinje cell degeneration, and elevated neurofilament proteins, including serum NfL. Altogether, the Slc17a5R39C/R39C model of FSASD provides critical insights into disease pathogenesis, highlights region-specific neurodegenerative vulnerabilities, and establishes a robust preclinical platform for mechanistic investigation and therapeutic development.